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ISSN 0929-6743
Differential Diagnosis in Neurology
By
Robert Jay Schwartzman Drexel University College of Medicine, Philadelphia, PA, USA
Amsterdam • Berlin • Oxford • Tokyo • Washington, DC
© 2006 The author. All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without prior written permission from the publisher. ISBN 1-58603-624-6 Library of Congress Control Number: 2006927014 Publisher IOS Press Nieuwe Hemweg 6B 1013 BG Amsterdam Netherlands fax: +31 20 687 0019 e-mail:
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[email protected] LEGAL NOTICE The publisher is not responsible for the use which might be made of the following information. PRINTED IN THE NETHERLANDS
DEDICATION to my wife, Denise
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Preface Differential Diagnosis in Neurology grew out of my taking daily morning report with neurology residents and examining patients in front of colleagues over the last 30 years. Dr. Eugene Stead, who was Chairman of Medicine for many years at Duke, taught me the importance of the fine points of the history and the significant details of the examination that separate one disease from another. Dr. G. Milton Shy was a master diagnostician melded each disease with its scientific basis and proposed diagnostic possibilities. It was a great privilege rounding with both and I hope a trace of their medical knowledge and scholarship comes through in these pages. The essence of “differential diagnosis” is “splitting” rather than “lumping”. It requires bringing knowledge to the table and then adding experience. The book is meant to be a skeleton that will give the clinician a general background with regard to the disease at hand. Molecular genetics, physiology and biochemistry will uncover mechanisms and associations that will further expand differential diagnosis of all neurological disease. There is no bibliography as it would be grossly out-of-date within one year. The reader is expected to utilize digital libraries to augment the basic information with the latest mechanism and treatment. It is hoped that the clinician will use the volume as a workbook in which new entities are added or older classifications revised. A possible strength of the volume is that one person wrote it and therefore it is somewhat uniform. Its glaring weakness is that one person can not know the depth of information needed to be comprehensive for each entity described.
Acknowledgment
I gratefully acknowledge my present and former colleagues, fellows, residents and students who have enriched my career in medicine. I thank my administrative assistants, Janet McCracken and Barbara Romm for helping me in all aspects of the project. I am delighted that I actually finished the project Yale Altman suggested many years ago and Anne Marie de Rover saw through to completion. I am especially pleased to acknowledge the support of Amy and Mark Tilly who made the volume possible.
vii
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Contents Preface
vii
SECTION I. VASCULAR DISEASE Chapter Chapter Chapter Chapter Chapter Chapter Chapter
1. 2. 3. 4. 5. 6. 7.
Ischemic Stroke Venous Strokes Medical Causes of Stroke Cerebral Emboli Hypoxic-Ischemic Encephalopathy Chronic Small Vessel Disease Hemorrhagic Vascular Disease
3 51 54 96 108 113 115
SECTION II. EPILEPSY Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter Chapter
1. 2. 3. 4. 5. 6. 7. 8. 9.
Introduction Generalized Seizures Progressive Myoclonic Epilepsy Partial Seizures Status Epilepticus Pseudoseizure Genetic Aspects of Seizures Unusual Seizures and Concomitant Medical Conditions Differential Diagnosis of Seizure Disorder vs Syncope
149 150 156 158 170 172 173 179 182
SECTION III. ANTERIOR HORN CELL DISEASE THAT AFFECTS ADULT PATIENTS Chapter Chapter Chapter Chapter Chapter
1. 2. 3. 4. 5.
Spinal Muscular Atrophies Linked to Chromosome 5q11.12–13.3 Immune Mediated and Genetic Lower Motor Neuron Syndrome Motor Neuron Disease Associated with Physical Agents Rare Causes of Motor Neuron Disease Amyotrophic Lateral Sclerosis
189 192 195 195 196
SECTION IV. SPINAL CORD DISEASE Chapter 1. Chapter 2. Chapter 3. Chapter 4. Chapter 5. Chapter 6. Chapter 7. Chapter 8. Chapter 9. Chapter 10.
Introduction Congenital Defects of the Spinal Cord Vertebral Column Bony Trauma Vascular Anatomy of the Spinal Cord Spastic Paraparesis Enzyme and Metabolic Disorders Affecting the Spinal Cord Autoimmune Causes of Spinal Cord Dysfunction Infections Affecting the Spinal Cord Tumors of the Spinal Cord Vascular Disease of the Spinal Cord
203 207 211 215 222 228 230 233 240 253
SECTION V. CRANIAL NERVES Chapter 1. Cranial Nerve I Chapter 2. Cranial Nerve II
263 264 ix
Contents
x
Chapter 3. Chapter 4. Chapter 5. Chapter 6. Chapter 7. Chapter 8. Chapter 9. Chapter 10. Chapter 11. Chapter 12. Chapter 13.
Cranial Nerve III Cranial Nerve IV Cranial Nerve V Cranial Nerve VI Cranial Nerve VII Cranial Nerve VIII Cranial Nerve IX Cranial Nerve X Cranial Nerve XI Cranial Nerve XII Multiple Cranial Neuropathy
284 289 290 293 294 299 308 310 313 314 316
SECTION VI. RADICULOPATHY Chapter Chapter Chapter Chapter Chapter Chapter Chapter
1. 2. 3. 4. 5. 6. 7.
Introduction Disc Disease Cervical Root Disease Thoracic Root Disease Lumbosacral Root Disease L1–L5; S1–S5 Epidural and Vertebral Metastasis Differential Diagnosis of Radiculopathy
319 320 325 329 332 334 338
SECTION VII. BRACHIAL PLEXUS Chapter Chapter Chapter Chapter Chapter Chapter
1. 2. 3. 4. 5. 6.
Introduction Differential Diagnosis by Plexus Component Traumatic Brachial Plexus Injury Differential Diagnosis of Thoracic Outlet Syndromes Neoplasms Affecting the Brachial Plexus Unusual Causes of Brachial Plexus Pathology
345 346 347 351 354 356
SECTION VIII. CERVICAL PLEXUS Chapter 1. Introduction Chapter 2. Clinical Presentations of C1–C4 Lesions Chapter 3. Pharyngeal Plexus
361 361 362
SECTION IX. LUMBOSACRAL PLEXUS LESIONS Chapter Chapter Chapter Chapter Chapter Chapter
1. 2. 3. 4. 5. 6.
Introduction Trauma of the Lumbosacral Plexus Tumors of the Lumbosacral Plexus Medical Causes of Lumbosacral Plexopathy Retroperitoneal Hemorrhage Immune Mediated/Toxic and Anesthetic Causes of Lumbosacral Plexopathy
365 366 367 368 370 371
SECTION X. DIFFERENTIAL DIAGNOSIS OF PERIPHERAL NEUROPATHY Chapter Chapter Chapter Chapter
1. 2. 3. 4.
Introduction Acute Predominately Small Fiber Sensory and Autonomic Neuropathy Dorsal Root Ganglion Disorders Differential Diagnosis of Symmetric Sensory Polyneuropathies
375 376 381 383
Contents
Chapter 5. Chapter 6. Chapter 7. Chapter 8. Chapter 9. Chapter 10. Chapter 11. Chapter 12. Chapter 13. Chapter 14. Chapter 15. Chapter 16. Chapter 17. Chapter 18. Chapter 19. Chapter 20.
Inherited Peripheral Neuropathies The Neuropathies of Disordered Lipid Metabolism Neuropathies of Disorders of Defective DNA Repair The Neuropathy of Heavy Metals and Industrial Agents Nutrition Associated Neuropathies Immune Mediated Neuropathies Vasculitic Peripheral Neuropathy and Neuropathies Associated with Connective Tissue Disorders Neuropathies Associated with Infection Diabetic Neuropathy Neuropathies Associated with Tumors Neuropathies Associated with Medical Illness Tumors of Peripheral Nerves Traumatic and Compressive Neuropathy Nonvasculitic Ischemic Nerve Injury Differential Diagnosis of Neuropathy by Pathology, Evolution Overtime and Precipitating Cause Differential Diagnosis of Neuropathy by Predominant Symptom, Hereditary or Feature
xi
386 396 399 400 416 418 425 434 440 443 448 453 456 476 479 482
SECTION XI. NEUROMUSCULAR JUNCTION DISORDERS Chapter Chapter Chapter Chapter Chapter Chapter
1. 2. 3. 4. 5. 6.
Introduction Myasthenia Gravis (Acquired and Congenital) Lambert Eaton Syndrome (LEMS) Drugs/Toxins that Alter Neuromuscular Transmission Botulism Tetanus
493 493 497 497 501 502
SECTION XII. MUSCLE DISEASE Chapter 1. Chapter 2. Chapter 3. Chapter 4. Chapter 5. Chapter 6. Chapter 7. Chapter 8. Chapter 9. Chapter 10. Chapter 11. Chapter 12. Chapter 13.
Inherited Myopathies Congenital Myopathies Myotonic Disorders of Muscle Periodic Paralysis Disorders with Continuous Motor Unit Activity (CMUA) Ryanodine-Receptor/Calcium Channel Disease Inflammatory Myopathy Metabolic Muscle Disease Mitochondrial Myopathies Malignant Hyperthermia Rhabdomyolysis and Myoglobinuria Myopathy Caused by Nutritional Deficiency Endocrine Myopathy
507 521 531 535 538 539 541 554 563 578 580 587 595
SECTION XIII. CEREBELLAR DISEASE Cerebellar Disease The Afferent and Efferent Cerebellar Pathways of Clinical Relevance Specific Anatomically Based Cerebellar Syndromes The Autosomal Recessive Ataxias Friedreich’s Ataxia Ataxia Telangiectasis (A-T) Rare AR Cerebellar Ataxias Autosomal Dominant Ataxias Episodic Ataxia (EA1)
605 605 606 607 607 608 609 611 613
Contents
xii
Rare Dominant Ataxias Unusual Genetic Ataxia Mitochondrial Ataxias Metabolic Ataxias Differential Diagnosis of Cerebellar Diseases An Overview of Non-Vascular Cerebellar Disease Infections Differential Diagnosis of Episodic Ataxia
614 615 615 617 618 619 622 623
SECTION XIV. BASAL GANGLIA AND MOVEMENT DISORDERS Chapter Chapter Chapter Chapter Chapter Chapter Chapter
1. 2. 3. 4. 5. 6. 7.
Bradykinetic Disorders Hyperkinetic Disorders Dystonia Myoclonus Tic Disorders Miscellaneous Movement Disorders Differential Diagnosis of Hyperkinetic Movement Disorders
628 637 649 652 656 657 658
SECTION XV. THE CEREBRAL CORTEX / BEHAVIORAL NEUROLOGY Chapter Chapter Chapter Chapter Chapter Chapter Chapter
1. 2. 3. 4. 5. 6. 7.
The Left Frontal Lobe The Parietal Lobe The Temporal Lobe The Occipital Lobe Arousal Memory and Amnesia Aphasia and Apraxia
663 665 666 667 669 671 674
SECTION XVI. DEMENTIA Chapter 1. Chapter 2. Chapter 3. Chapter 4. Chapter 5. Chapter 6. Chapter 7. Chapter 8. Chapter 9. Chapter 10. Chapter 11. Chapter 12.
Introduction Alzheimer’s Disease and Dementia with Lewy Bodies Fronto Temporal Dementias (FTDs) Prion Disease Hereditary Dementias Secondary Dementias Adult Lysosomal Disorders with Dementia Peroxisome Single Enzyme Defects of Adolescence and Adulthood Toxic Disorders with Dementia Neoplasms Causing Dementia Head Trauma as a Cause of Dementia Vasculitic and Microangiopathic Forms of Dementia
683 684 688 695 698 702 707 716 718 720 722 722
Section I VASCULAR DISEASE
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Chapter 1. Ischemic Stroke
Chapter 1 Ischemic Stroke General Features of the Differential Diagnosis of Ischemic Stroke, Embolus, and Intracranial Hemorrhage
Cerebral thrombosis occurs most frequently in the early morning hours during sleep. Patients frequently awaken and fall as they are unaware of their deficits. Transient ischemic episodes occur prior to thrombotic stroke in approximately 30% of patients and TIA’s precede 50% of strokes in the posterior circulation. They are almost always atherosclerotic in origin. TIA’s are usually emboli that arise either from the heart or intraarterial vessels (carotid, arch of the aorta or vertebral arteries to distal smaller branches). They occasionally occur from distal field ischemia due to compromised vessels and decreased cerebral perfusion or vasospasm (migraine). They may cause symptoms at each level of the brain as they progress through the circulation. They often occur in showers so that a number of vessels may be occluded simultaneously. The symptoms of intra arterial vessel to vessel emboli are usually 170 mHg) should be treated. An 11 mmHg decrease of systolic blood pressure (The systolic hypertension in the elderly study) and a 3.6 mmHg reduction of diastolic blood pressure produced a 36% reduction in stroke risk.
7
Postmenopausal hormonal replacement Two recent studies have demonstrated protective effects of hormonal replacement. Patient estrogen compounds had a relative risk of stroke of 0.72 while combination estrogen progesterone compounds had a relative risk score of 0.61. Less potent estrogen compounds were ineffective in stroke prevention. Strokes associated with hyperhomocystinemia Hyperhomocystinemia is a risk factor for premature atherosclerotic peripheral vascular disease, myocardial infarction and stroke. Prevalence of HHC has been noted in approximately 20–42% of stroke cohorts. Physical activity Physical exercise correlates with a progressive decrease in stroke rate. There is no evidence that weight reduction without exercise is beneficial for decreasing the risk of stroke.
Hyperlipidemia Elevated total cholesterol and low-density lipoproteins are independent risk factors for stroke.
Cholesterol reduction with statin drugs, risk of stroke and total mortality A total of 16 trials were evaluated that investigated approximately 29,000 subjects who were followed for >3 years. In those taking statin drugs (3-hydroxy-3-methylglutaryl coenzyme) reductase inhibitors (HMG-COA) had an average reduction in total and low density lipoprotein cholesterol of 22% and 30% respectively. Those taking statin drugs had a robust decrease of stroke of 29% and of mortality from stroke of 22%. Lipoprotein (a) is a low density lipoprotein (LDL) covalently linked by a di-sulfide-bridge to a large glycoprotein called apo(a). Sequencing of apo(a) suggests a high degree of homology with plasminogen. Lp(a) competes with plasminogen for the plasminogen binding site and reduces its cellular binding which may reduce endothelial cell fibrinolysis and thus produce a procoagulant state. Lp(a) accumulates on the endothelium of atherosclerotic coronary arteries but not on normal blood vessels. Lp(a) may be increased in a significant number of patients with acute stroke but has no association with cardiovascular risk factors stroke severity, or ischemic events during follow up.
Oral contraceptives Studies conducted with high estrogen formulations in the past demonstrated an increased risk of stroke empirically in women older than 35. Lower estrogen formulations in women younger than 35 who do not smoke have the same risk as the general population. The Nurses Health Study revealed that the relative risk of stroke was 1.2 with estrogen formulations, which was directly related to dose. Patients utilizing 50 μg of estrogen had a relative risk of 2.9, while in those utilizing 30–40 μg the relative risk was 1.8. The relative risk of progesterone preparations was 0.9. The problem with the study was that it was done in older women and few patients utilized oral contraceptives.
Silent cerebral infarction associated with coronary artery disease Silent cerebral infarction is a predictor of symptomatic cerebrovascular disease. Silent cerebral infarction by definition is an infarct demonstrated by CT or MRI without a history of stroke. In the Framingham study, latent, primarily lacunar infarcts were detected in 10% of patients. Silent cerebral infarction occurs in about 80% of patients with significant coronary artery disease. Myocardial infarction and angina pectoris are both associated with a high incidence of lacunar infarction. Patients who present with their first stroke (symptomatic) may have had a preceding silent infarct 25% of the time.
Diabetes mellitus The risk of stroke is increased 2.5 to 3.5 times in diabetics compared to controls. Long standing prospective trials with both insulin and hypoglycemic agents to reduce the risk of stroke are not convincing. Smoking Cigarette smoking increases the risk of stroke two times from accelerated atherosclerosis as well as effects on α1 antitrypsin and platelet inhibitory factor. The increased risk is dose dependent. Cessation of smoking reduces the risk of stroke rapidly at any age, whereas it takes 1 year to effect a 50% reduction of coronary artery events and 10 years to decrease the risk of lung cancer compared to controls.
SECTION I. Vascular Disease
8
These infarcts are usually small, deep and in the basal ganglia. They are usually less than 1 cm. The occipital lobes may be disproportionately involved. Demographic variables that may be important for silent cerebral infarct (SCI) are age, male gender and African-American ethnicity. Left atrial enlargement may also be a risk factor for SCI.
4. Diffuse vasculopathy 5. Irregular heart rhythm a. Atrial fibrillation b. Sick sinus syndrome 6. Left ventricular hypertrophy
Characteristics of Silent Cerebral Infarction at First Stroke Presentation
Modifiable Risk Factors
1. 2. 3. 4. 5. 6.
Advanced age Small 76 years of age – 5.4% year c. Inpatients – 5–9% incidence of stroke d. Outpatient – 1.9–4.8% incidence of stroke Atrial Fibrillation Alone (Framingham Study Group)
Patients with coronary artery disease, congestive heart failure, and rheumatic heart disease were excluded. Ninety percent of patients were greater than 60 years of age. Patients were included who had nonspecific EKG changes. Patients with AF alone had a four times higher risk of stroke (24%). Mayo Clinic Study Group – 15 year prospective study. This study had the same exclusion factors as the Framingham study but added hypertension and nonspecific EKG changes. The cumulative incidence of stroke was 1.5%. The Olmsted County Minnesota Study – This study had the same entrance and restrictions criteria as the Mayo Clinic Study and found a 17% incidence of stroke.
Chapter 1. Ischemic Stroke Acute Myocardial Infarction (6 studies)
The risk of stroke with anterior wall MI is 6% (4–12%). Inferior wall MI carries a risk of 10%. Most cardiac embolic events occur within 1–2 weeks after the infarction. Left Ventricular Thrombus After Myocardial Infarction
Forty percent of patients that suffered a stroke after MI had a left ventricular thrombus (LVT), which is usually absent the first 24 hours after a myocardial infarction. Most thrombi develop between 1–14 days after infarction. Transthoracic echocardiography cannot detect thrombi less than 5 mm. Nonischemic Cardiomyopathy
The incidence of stroke is 4%/year in three studies of cardiomyopathy (0–12%). Echocardiographic detection of LVT ranged from 0–37% in five studies. The risk of emboli is linear with the severity of the cardiomyopathy. It is difficult to determine the true rate of embolic ischemic stroke from these studies because many different causes of myopathy were included. Mitral Valve Prolapse (MVP)
The prevalence of MVP is approximately 5% in the general population. The most common cause of MVP is a variant of mitral leaflet excursion rather than myomatous degeneration of valve leaflet chordae or the annulus. Five studies revealed an incidence of 4% of stroke with MVP in young adults (2– 6%). There are two distinct populations of patients with MVP. It is most common in young women. The complications are most prevalent in older patients and men. Complication prone MVP is most likely with older age, male sex, redundant and thickened leaflets, associated mitral regurgitation, tricuspid valve prolapse and mitral annulus abnormality. Infective Endocarditis
The prevalence of stroke in infective endocarditis is 15–20%. The majority of strokes occur within 48 hours of diagnosis or at presentation. The risk of stroke after antibiotic treatment is 5%. Staphylococcus aureus, and mechanical valve SBE are positive predictors for stroke whereas valve site is not. Mycotic aneurysms amenable to surgery are seen in 2% of patients. Large and enlarging mycotic aneurysms can be healed by antibiotic therapy. The risk of late rupture of mycotic aneurysms is low. They are invariably found on peripheral vessels rather than at the Circle of Willis. Intracranial hemorrhage carries a high mortality. Left Ventricular Aneurysm (LVA) and Left Ventricular Thrombi (LVT) Remote from the Site of MI
LVT usually are noted within two weeks of an acute MI and spontaneously resolve or may persist indefinitely. LVT that
9
overlie wall motion abnormalities may have a delay of many months before they are detected after the acute MI. Left ventricular aneurysm (LVA) after acute MI has a low incidence of associated LVT as determined by cardiac catheterization. Emboli occurred in 3% of patients that were anticoagulated with LVT and 13% of those not anticoagulated. Nonbacterial Thrombotic Endocarditis (NBTE)
NBTE is frequently unrecognized although it accounts for 27% of ischemic strokes in cancer patients and had a prevalence of 1–5% in one autopsy series. It is associated with the prothrombotic state seen with cancer and has its highest occurrence during chemotherapy.
Special Risk Factors for Ischemic Stroke
Asymptomatic Large Vessel Atherosclerosis
There is a clear-cut benefit for secondary prevention of stroke if the carotid artery is narrowed >70% (NASCET and ECST European Carotid Surgery Trial). The benefit of surgery for 30–69% stenosis of symptomatic arteries is being evaluated. Asymptomatic stenosis surgery in the best surgical centers carries a 1.5–2.7% risk of stroke. Risk of Stroke with Intra-aortic Atherosclerotic Debris
Atherosclerotic disease of the thoracic aorta is common in elderly patients with coronary artery disease. Emboli arise from thrombi, fibrinous material, and cholesterol crystals that dislodge from complex ulcerated plaques. Transesophageal echocardiography with the high frequency (5MHZ) transducer can resolve intraaortic atherosclerotic debris from a simple atherosclerotic plaque. Autopsy studies have demonstrated a prevalence of 38% of complex atherosclerotic aortic plaques greater than 8 nm in patients with clinical coronary artery disease. Pedunculated and highly mobile plaques have a higher embolic potential than layered and immobile atherosclerotic debris. Risk of Catheter Related Emboli in Patients with Atherosclerotic Debris in the Thoracic Aorta
Cardiac catheterization or intra-aortic balloon placement in patients with transesophageal echocardiographic evidence of atherosclerotic debris carries a significant risk of embolization (10% and 5% respectively). The strongest predictors of atherosclerotic aortic debris are advanced age and peripheral vascular disease. The classifications of degrees of aortic atherosclerosis are: (1) grade 1 – normal aorta; (2) grade 2 – simple atherosclerotic plaque (intimal calcification); (3) grade 3 – plaque protruding 5 mm into the aortic lumen which is layered; (5) grade 5a – 5 mm plaque that is mobile.
10
SECTION I. Vascular Disease
Embolic events occurred following femoral catheterization (17%) while none occur following brachial catheterization. Embolic events from insertion of intra-aortic balloons occur in 40–50% of patients with atherosclerotic aortic debris and are primarily peripheral. The generally accepted incidence of stroke or peripheral embolization from cardiac catheterization is approximately 0.07%. Patients at particularly high risk of catheter related emboli are older than 65 years and have had a prior history of stroke. The incidence of catheter related stroke is 30% in those patients with mobile aortic debris and approximately 6% in those with layered aortic debris. Stroke Risk with CABG (Coronary Artery Bypass Graft) Surgery
There is approximately a 20% mortality from stroke in the setting of a CABG 6.1% of patients undergoing this procedure suffer a serious adverse cerebral outcome. The high risk features for a type I outcome (fatal cerebral injury and nonfatal strokes) are: advanced age, proximal aortic atherosclerosis, pulmonary disease, neurologic disease and hypertension. The most significant of these risk factors is atherosclerotic emboli released into the circulation by surgical manipulation of the aorta. This condition is found in approximately 20% of patients older than 70 and in approximately 12% of all patients undergoing the procedure. A history of prior TIA or stroke is also a significant risk factor. Increased risk of stroke is also seen with DM, unstable angina, prothrombic state, left ventricular thrombus and use of an intra-aortic balloon pump. The Risk of Stroke Associated with Cardiac Surgery
In general, patients undergoing coronary artery bypass, valvular surgery or both have a risk of stroke between 2–6%. Patients who suffer stroke are older and have a high rate of prior TIA, congestive heart failure and peripheral vascular disease. Surgical aspects that predispose to stroke are a pump time of greater than 120 minutes. Most strokes occur (approximately 60%) by postoperative day 2, but a significant number of delayed strokes occur (post operative day 3 to 9). Hemispheric syndromes are seen in approximately 2/3 of patients, brainstem and cerebellar infarction in 10–15% and lacunar syndromes in a similar number. Delayed strokes may occur due to a disrupted embolic source (plaque in the arch of the aorta) or an ongoing hypercoagulable state. Many studies have noted other variables associated with an increased risk of stroke with heart surgery. These include: carotid artery stenosis greater than 50%; repeat heart surgery, valve surgery, prior stroke, and perioperative hypotension. Late stroke risk factors are possibly: (1) anemia; (2) embolism (calcified atheromatous platelet fibrin complicated plaques); (3) decreased platelet number and function are decreased following surgery which increases the risk of bleeding; (4) reactive thrombocytosis.
Risk of Stroke in Cardiac Surgical Patients with a History of Stroke
Patients with deficits from previous strokes have a higher chance of experiencing a new stroke and of suffering reappearance or worsening of old deficits. These patients have a higher mortality rate, take longer to awaken from anesthesia, and to extubate. They are more likely to sustain a depressed level of consciousness and confusion after operation and are more likely to aspirate and require reintubation. Patient age rather than the interval between stroke and surgery is most significant. In general, a recent stroke is associated with reappearance or worsening of the prior deficit and a remote stroke predisposes to a new focal postoperative deficit. Retrospective studies suggest a stroke rate of approximately 13% inpatients with a prior stroke while a large prospective study demonstrated a rate of 43%. The stroke rate of patients with no prior history of stroke undergoing cardiac surgery varies between 1.5% to 5%.
Special Cases of Stroke Risk in Carotid Endarterectomy
Preoperative Risk Factors for Endarterectomy for Asymptomatic Carotid Artery Stenosis
The benefit of carotid endarterectomy (CEA) for significant asymptomatic carotid stenosis (>70%) is dependent on surgical risk (50% carotid stenosis in 3.4% to 22% of patients. The incidence of >80% stenosis is approximately 6–12%. Stroke complicates 1% to 4% of all coronary artery bypass procedures. It is higher in patients with extracranial carotid disease. Coronary Bypass Related Stroke Causes
1. 2. 3. 4. 5. 6.
Emboli from the carotid and aortic arch Endocardium (emboli) Pump oxygenator (emboli) Hypoperfusion (occlusive arterial lesions or hypotension) Air embolization Extracranial hemorrhage Carotid lesions of at least 60% will occur in 3% to 15% of patients undergoing a CABG. Selection criteria for the combined CABG-CEA patients versus CEA alone are accounted for by differences in perioperative morbidity and mortality. Ultrasound Lesion Morphology in Retinal Ischemia
Carotid arterial disease is a significant factor in causing retinal ischemic symptoms. The retinal ischemic symptoms are related to the morphology of the plaque lesion as well as the degree of carotid stenosis. Approximately 10% of patients who present with retinal ischemic symptoms first will develop
12
SECTION I. Vascular Disease
a stroke. Complex heterogeneous plaques have an uneven distribution of low level and high level ultrasound echoes within the lesion and have an irregular or pitted surface and have been associated with both cerebral and retinal ischemia. In patients who presented with retinal ischemia there is a low incidence of continuing retinal emboli but a 26% rate of cerebrovascular or cardiovascular events. Complex heterogeneous plaque morphology is a significant risk factor for cardiovascular events. The Risk of Stroke in Patients with First Ever Retinal Transient Ischemic Attacks and High-Grade of Carotid Stenosis
The risk of ipsilateral stroke at 2 years following first ever retinal TIA is approximately 15% whereas it is approximately 40% if the first event was a hemispheric TIA. Most of the 2 year risk for both groups occurred in the first 2 months after the initial event. Patients with hemispheric TIAs as their first ever event were approximately 3 times more likely to suffer an ipsilateral stroke at 2 years than those patients who suffered retinal TIA as their first ever event regardless of stenosis severity within the 70–79% range. Patients with amaurosis fugax from all sources have a yearly stroke rate of 2–4%.
Natural History of Stenosis from Intracranial Atherosclerosis
Atherosclerosis of the intracranial vessels occurs in the setting of widespread vascular disease but may develop selectively in Blacks and Asians. Risk factors for intracranial atherosclerosis are race, hypertension, diabetes, smoking, and hyperlipidemia. These patients have an increased risk of heart disease, stroke and death. In patients who have failed medical therapy (anticoagulation), angioplasty of intracranial vessels carries a risk of stroke of 20–33%, which is secondary to occlusion of small perforating vessels, selection bias, vessel dissection and thromboembolism. In general, intracranial petrous to supraclinoid carotid lesions were stable while ACA, MCA, PCA and distal vertebral and basilar artery vessels progressively stenosed. In general 40% of stenoses were stable, 20% regressed and 40% progressed. Pathological specimens demonstrate that narrowing is caused by atherosclerosis and at times concomitant thrombosis. Emboli may also cause vessel narrowing and then complete resolution due to clot lysis. Absence of carotid bifurcation disease is associated with lesion progression while duration of tobacco use, hypertension and diabetes were associated with ICA atherosclerosis. Intracranial atherosclerotic lesions like coronary artery atherosclerotic disease are dynamic and both progress and regress over time.
Special Risk Factors for Ischemic Stroke (Summary)
1. Asymptomatic stenosis of >70% 2. Intra-aortic atherosclerotic debris 3. Catheter related emboli with thoracic aorta debris or other material 4. Stroke risk of CABG 5. Stroke risk with cardiac surgery 6. Risk of stroke in cardiac surgery patients with a history of stroke 7. Preoperative risks factors for asymptomatic CEA 8. Preoperative risks predict severity of CEA related stroke 9. Carotid recurrent stenosis and risk of stoke 10. Risk of stroke in carotid near occlusion 11. Carotid siphon stenosis and risk of stroke 12. CEA and CABG stroke risk 13. Lesion morphology as risk of retinal stroke 14. Stroke risk in first ever retinal TIA vs hemispheric TIA 15. Natural history of intracranial stenosis
Ischemic Vascular Disease
The hallmarks of ischemic cerebrovascular disease are the suddenness of the ictal event, the preceding risk factors, the patterns of the deficits and the course of recovery. Transient ischemic attacks precede 70% of ischemic events in the anterior circulation and 50% of those that occur in the posterior circulation. They may be divided into short 1 hour ischemic deficits although most last between thirty seconds and 2 minutes. Transient ischemic attacks are overwhelmingly caused by intraarterial artery to artery emboli, primarily thrombus material or detritus from atherosclerotic plaques, or clots from the atrial appendices, the walls of dyskinetic heart segments or from heart valves. There are a great number of causes of emboli originating from the heart due to intrinsic heart disease, tumor of the valves and systemic disease. Larger TIAs in general are caused by cardiac clots or large vessel emboli whereas those that last Wernicke’s (DH) 8. Hemineglect contralateral side (NDH) 9. Pronated arm, externally rotated leg (contralaterally) 10. Depressed reflexes (contralaterally) acutely 11. Babinski’s sign (contralaterally)
Features of Intracranial Internal Carotid Occlusive Disease
Atherosclerosis of the Carotid Siphon
Calcification of the siphon is common and is coexistent with extracranial disease. There is a high death rate from coronary artery disease and disease in this location is more common in Afro-American than Caucasians. There are frequent concordant lesions in the origins of the internal carotid and vertebral arteries. Tandem ICA and siphon disease is common. There is a higher ratio of stroke to TIA in carotid siphon disease than cervical carotid disease. The major clinical differential points of siphon versus internal carotid diseases are: 1. Few episodes of amaurosis fugax 2. No ocular retinal pathology 3. Retrograde extension of the siphon clot may cause delayed optic ischemia 4. Leg is more affected than the arm 5. Associated scattered ACA and MCA infarcts are noted. These may involve the foot and face, sparing the arm 6. Slowly progressive symptoms 7. Worse prognosis than ICA origin disease 8. There are no collaterals through the external carotid artery Occlusion of the Top of the Carotid (T Portion)
A block at the top of the carotid causes infarction of both the anterior cerebral and the internal carotid artery. It is most common with sickle cell disease and with circulating anticoagulants.
The Anterior Choroidal Artery (ACHA) Syndrome
The anterior choroidal artery is the second branch of the internal carotid artery. It partially supplies the caudal 2/3 of the posterior limb of the internal capsule, the posterior optic tract, the uncus of the temporal lobe, medial GP1 , cerebral peduncle, lateral geniculate body and portions of the thalamus. AchA does not supply the corona radiata or the ventricular wall. Its most consistent branches are to the optic tract, cerebral peduncle and choroid plexus. There are variable anastomosis with branches of the MCA, PCA and posterior communicating artery. This artery supplies territories in both anterior and posterior circulations. A. Most Consistent Clinical Presentation 1. Hemiparesis, hemisensory loss, hemianopsia a. Pure motor hemiplegia (face, arm and leg affected) b. Bilateral AchA infarcts: 1) pseudo bulbar palsy; 2) mutism; 3) quadriparesis c. Hemisensory symptoms: incomplete or temporary and comprise all modalities B. Unusual Sensory Manifestations 1. Hemisensory deficit with spared proprioception 2. Painful thalamic-type syndrome
Chapter 1. Ischemic Stroke
C.
D.
E.
F.
G.
H.
a. Formication (crawling paraesthesias) b. Feeling of limb swelling c. Pain in the arms and legs 3. Hemiataxia with the sensory symptoms 4. Temporary sensory loss Clinical Features of the Motor Deficit 1. Face, arm and leg affected 2. Ataxic hemiparesis (thalamic) 3. Hypesthetic ataxic hemiparesis Visual Field Deficits and Eye Movement Abnormalities 1. Congruent homonymous visual field deficit sparing the central sector a. Lateral geniculate body infarcted b. Known as a quadruple sectoranopic defect 2. Homonymous congruent superior quadrantanopia a. With or without macular sparing 3. Congruent homonymous hemianopia 4. Ipsilateral conjugate eye deviation Higher Cortical Deficits with AchA Infarction (Unusual) 1. Nondominant hemisphere a. Visual neglect b. Constructional apraxia c. Short term visual memory loss d. Anosognosia e. Motor impersistence 2. Dominant hemisphere infarction a. Decreased fluency b. Semantic paraphasia c. Perseveration d. Deficits in language processing e. Poor understanding of word associations f. Poor comprehension g. Short term verbal memory loss AchA Infarction of Lateral Thalamus and Posterior Limb of the Internal Capsule 1. Dysarthria 2. Language processing defects 3. Short term verbal memory loss Bilateral AchA Infarction 1. Urinary incontinence without dementia 2. Dysarthria 3. Dysphagia 4. Dysphonia 5. Palatal paralysis – (may occur with unilateral stroke) 6. Pseudobulbar affect 7. Depression 8. Blunted affect 9. Mutism 10. Lethargy Anatomic Variants of AchA 1. Anastomosis with: a. MCA b. Posterior communicating artery 2. Paraventricular areas
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a. Watershed between the deep MCA perforators and lateral lenticulostriate arteries b. Watershed between the posterior choroidal arteries (near the superior portion of the internal capsule) 3. May supply the temporo-occipital lobe (PCA territory) I. Pathogenesis of AchA Occlusion 1. Surgical manipulation a. Aneurysm (spasm) b. Seizure surgery 2. Hyperviscosity states 3. Decreased perfusion 4. Embolism a. Cardiac b. Often with concomitant MCA embolism 5. Thrombosis a. Intracranial atherosclerosis
Anterior Cerebral Artery
The anterior cerebral artery arises from the internal carotid artery at the level of the anterior clinoid process to supply the medial surfaces of the frontal and parietal lobes as well as the anterior 4/5 of the corpus callosum, the ventrobasilar frontal cortex (substantia innominata, septal nuclei, and nuclei of the diagonal band) and the anterior thalamus. The A1 segment from the carotid joins the anterior communicating artery AcoA in the interhemispheric fissure. There are approximately 8 perforating branches from the A1 segment. Proximal A1 branches perfuse the genu, contiguous areas of the posterior limb of the internal capsule, the anterior hypothalamus, anteroventral putamen and pallidum. Distal A1 segment branches perfuse the optic nerve, chiasm and tract. The perforating branches of the AcoA perfuse the most anterior aspects of the hypothalamus, the basal forebrain, and the medial anterior commissure, fornix and lamina terminalis, corpus callosum and anterior cingulum. A2 branches, part of the ascending segment, perfuse the gyrus rectus, the inferior frontal cortex, the anterior thalamus and the rostrum of the corpus callosum. The recurrent artery of Heubner takes origin near the AcoA and travels backward along the A1 segment to penetrate the brain at the lateral anterior perforating substance, Sylvian fissure or orbitofrontal cortex to supply the head of the caudate and anterior limb of the internal capsule. The distal A2–A5 segments comprise the pericallosal and callosomarginal arteries. If the callosomarginal artery is absent, all cortical branches originate from the pericallosal artery (18–60%) of patients. The ascending orbitofrontal and the frontopolar arteries arise from the A2 segment and supply the inferior, medial and lateral surfaces of the frontal pole. The superior frontal gyrus is supplied rostrocaudally by A2–A4 segments of the pericallosal artery. The paracentral artery, the superior parietal artery may arise from either the callosal marginal or the A4–A5 segment of the pericallosal
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SECTION I. Vascular Disease
artery to supply the superior precuneus while the posterior inferior cuneus is supplied by A5 branches of the inferior parietal artery from the pericallosal artery. There are a great number of normal variations of the anterior cerebral artery and anterior portion of the Circle of Willis. The usual etiology of ACA-territory infarction is a cardioembolic stroke particularly if there is increased blood flow through the artery due to a contralateral ICA occlusion or a congenital defect of the anterior Circle of Willis. In situ thrombosis of the artery is more common in Asian patients. Extension of thrombus from the ipsilateral carotid is the usual atherosclerotic mechanism. Occlusion by transtentorial herniation, vasospasm from ruptured ACOA aneurysm or embolisms from these aneurysms are particular causes of infarction peculiar to this artery. Bilateral occlusion is rare but has been reported. Approximately 25% of these patients have had an azygous or unilateral supply of both ACAs from one carotid artery, the others having suffered probable emboli from atrial fibrillation or recent myocardial infarction. Bilateral infarction of the ACA causes akinetic mutism with poor recovery. The artery may be infarcted by the angitis of collagen vascular disease, prothrombotic states, lacunar infarction, rare emboli (fat, air, and atrial myxoma), dissection or fibromuscular dysphasia.
Anterior Cerebral Artery (ACA) Stroke: Clinical Signs and Symptoms
The clinical signs and symptoms of ACA are distinct. The artery is involved primarily following vasospasm secondary to anterior communicating aneurysm rupture, damage from neurosurgical procedures, propagation from ICA occlusion and artery-to-artery embolism from more proximal atherosclerotic occlusive disease. Cortical branch occlusion causes severe weakness of the distal foot and leg, the proximal arm with sparing of the face and tongue. The patient can frequently perform fractional movement of the hand and thumb. Muscle tone is flaccid early and then becomes spastic. The paracentral lobule, upper motor cortex and subcortical fibers from these areas that project into the corona radiata are affected. A few patients may only suffer a crural monoplegia (contralateral weakness of the leg). The pattern of weakness may vary considerably with some patients suffering arm and leg weakness to the same degree, others with hemiparesis and brachial predominance. Distal occlusion of the ACA may also cause pure motor hemiparesis and homolateral ataxia and crural paresis.
Patterns of ACA Weakness
1. Paresis of foot and leg > arm; face and tongue spared 2. Crural monoplegia (contralateral paralysis of leg and foot) 3. Contralateral arm and leg involved equally
4. Contralateral hemiparesis with brachial facial predominance 5. Homolateral ataxia with crural paresis 6. Pure motor hemiparesis Infarction of the recurrent artery of Heubner from the A1 segments affects the head of the caudate, the putamen and the anterior limb of the internal capsule. This lesion may cause faciobrachial predominance in the observed hemiparesis. The proximal perforators from A1 may also supply the genu and anterior internal capsule. Right-sided > left-sided medial frontal infarction that includes the SMA may cause contralateral motor neglect. Sensory deficits are most severe in the foot and leg contralaterally. They are most often in discriminative touch but may be severe to all modalities.
Psychomotor Dysfunction
The anterior cerebral artery supplies regions of the limbic system and basal ganglia essential for integration of emotional aspects of movement and frontal lobe function. Transient loss of consciousness may occur with ACA infarction. Bilateral damage to the anterior cingulate gyrus or head of the caudate nucleus may cause akinetic mutism. These patients do not initiate speech or movement and have no emotional expression. They do not respond to sensory stimuli but may follow the examiner with their eyes. Transient abulia may be seen with a unilateral lesion of the caudate head and cingulate gyrus and is characterized by decreased spontaneous speech and delayed response to questions, minimal spontaneous activity and impersistence. These patients may speak almost normally on the telephone. Infarction of projections from the caudate nucleus to the orbital and dorsolateral prefrontal cortex causes agitation hyperactivity and delirium. If they occur on the dominant side and disrupt connections into the thalamus, aphasia may be noted. Medial frontal lobe infarction causes euphoria, lability of affect and pathological jocularity. Antegrade amnesia may occur from damage to the paramedian basal forebrain during aneurysm surgery that damages perforators from the ACOA. If concomitant mesial frontal damage occurs confabulation may occur with the amnesia.
Aphasia and Language Disorders
Damage to the left supplementary motor area (SMA) may cause decreased spontaneous speech, normal articulation, repetition and comprehension. Transcortical motor or mixed transcortical aphasia have been documented with SMA lesions. Mirror writing can develop with right SMA lesions. Acquired stuttering may occur with anterior callosal or bifrontal lesions. Occlusion of either the right or left anterior cerebral artery may cause muteness.
Chapter 1. Ischemic Stroke Anterior Cerebral Artery Speech Disorders
1. 2. 3. 4. 5. 6. 7. 8.
Muteness Transcortical motor aphasia Transcortical sensory aphasia Acquired stuttering Whispered speech Reduced spontaneous speech Normal comprehension Normal articulation
Urinary and Fecal Incontinence
Unilateral or bilateral ACA infarction may cause urinary and fecal incontinence by damaging the midportion of the superolateral and medial superior frontal gyrus and the anterior cingulate gyrus. Damage to the paracentral lobule may induce precipitate micturition that cause patients to urinate uninhibitedly when their bladder is partially full.
The Grasp Reaction of ACA Infarction
The grasp reflex is caused by a contralateral basal ganglia or frontal lesion. This response is flexion and adduction of the hand when an object is gently moved from the palmar hypothenar eminence through the palmar index finger and thumb. This is an involuntary response. The instinctive grasp reaction is elicited by a stationary touch in the same areas of the hand and consists of: (1) several grasping movements directed toward the object; (2) a true grasp is one grasp in response to an object; (3) the traction response follows stretching of the patient’s flexed fingers that he cannot release; (4) a magnetic response in which the patient shadows the movements of the examiner’s hand. A contralateral lesion of the mesial superior frontal and cingulate gyrus or rarely the basal ganglia cause a grasp reflex.
Callosal Disconnection Syndromes Following ACA Infarction
In right-handed patients, a left handed ideomotor apraxia may occur following ACA infarction. The patient is unable to perform a simple command with the left hand such as a military salute. This is due to disconnection of Wernicke’s area and the premotor cortex from the premotor and primary motor cortex of the right hemisphere. It may also occur after infarction of the left premotor area (8), the anterior corpus callosum or the right premotor cortex. The patient may have impaired ability to imitate the examiner’s movements with the left hand. Left-hand agraphia may be seen with ACA infarction. Patients are unable to write readable letters, utilize correct words and often demonstrate substitutions or perseverations both to
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dictation and with spontaneous writing. No linguistic mistakes are made with the right hand. They are able to write or copy correctly but cannot type or use block letters. In general, ideomotor apraxia and agraphia occur concomitantly with callosal lesions but may be dissociated. The callosal fibers for praxis cross the midline in the rostral portion of the posterior body of the corpus callosum. Unilateral tactile anomia occurs in the left hand. The patient can manipulate the objects correctly with either hand. He has an associated unilateral left agraphia that is caused by a lesion of the posterior part of the body of the corpus callosum. Right handed constructional dysfunction and crossed pseudoneglect to both visual and tactile line dissection tasks have been noted with callosal posterior body infarction. A crossed visuomotor ataxia results from damage to the dorsal aspect of the posterior callosum. A crossed avoiding reaction (patient unable to move the left hand when an object is placed in the right hemispace) has been seen with a lesion of the genu and body of the corpus callosum. The alien hand syndrome denotes a patient who has a feeling that the left hand does not belong to them and notes that one hand works at cross purposes with the other. In general, these patients have suffered a mesial frontal lobe and corpus callosum lesion. The patient cannot voluntarily suppress motor perseveration in which the patient compulsively repeats stereotyped movements. These movements are usually associated with a grasp reflex and instinctive grasp reaction. Compulsive manipulation of tools placed in front of the patient is a release of praxis from damage of the left mesial frontal lobe, cingulate gyrus and genu of the corpus callosum. The syndrome occurs with a concomitant grasp reflex and instinctive grasp reaction but no disconnection syndrome. The utilization behavior of Lhermitte differs from compulsive manipulation of tools because it is bilateral and lacks the compulsive quality noted in the compulsive manipulation of tools. Diagnostic dyspraxia is a dissociative movement in which the left hand undoes the actions of the right. Usually the left hand works at cross-purposes to the right. Damage to the body of the corpus callosum is required for this behavior. Damage to the contralateral mesial frontal lobe and genu of the corpus callosum may cause purposeless movements of the contralateral hand such as an updrift, tucking the hand in the axilla or grasping the throat.
Alien Hand Phenomena and Variants
1. 2. 3. 4. 5. 6.
Le signe de la main étagère “strange hand” Intermanual conflict Motor perseveration Compulsive manipulation of tools Diagnostic dyspraxia Updrift, hand in the axilla, grasping the throat
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SECTION I. Vascular Disease
Callosal Disconnection Syndromes
Bifurcation Pattern (Superior/Inferior Division)
1. Ideomotor apraxia – left hand 2. Agraphia – left hand 3. Tactile anomia – left hand
1. Superior division (pial branches): a. Ascending orbitofrontal branch b. Prefrontal branches c. Precentral branches d. Central or central sulcal branches e. 2–3 anterior parietal branches f. 1–3 angular branches 2. Inferior division (pial branches): a. Ascending temporopolar branch b. Anterior temporal branch c. Middle temporal branch d. Posterior temporal branch
Pathologic Grasp Phenomena
1. Grasp reflexes 2. Instinctive grasp reaction: a. True grasp c. Traction response b. Instinctive groping d. Magnetic response
The Middle Cerebral Artery
The middle cerebral artery is most commonly affected in ischemic cerebral vascular disease. African-American or Asian patients have a higher incidence of infarction of this artery than white patients. The TIAs of the MCA disease are less frequent than those stemming from carotid disease and occur over a shorter time period. White patients present with TIAs of the MCA more frequently than with stroke; cigarette smoking is a strong risk factor for all groups that suffer MCA infarction. Major differential points of MCA occlusive disease from that of the ICA are: (1) deficits on awakening; (2) fluctuation or progression of symptoms over the following 1–7 days; (3) probable low flow mechanism. Carotid disease is more suggestive of an embolic mechanism. There are no ocular symptoms with MCA disease. Approximately 2/3 of all first brain infarcts are in the MCA territory. Approximately 1/3 affect the deep MCA territory and 10% occlude both deep and superficial territories. Approximately 50% of MCA infarction are restricted to the superficial pial arteries.
Anatomy of the MCA and Its Patterns
1. Pial branches supply: a. Almost the entire convex surface of the brain b. Lateral frontal, parietal and temporal lobes c. Insula, claustrum and extreme capsule 2. MCA emerges from the ICA for 1.8–2.6 cm as a single trunk a. Proximal M1/M2 segments give rise to medial and lateral lenticulostriate arteries 3. The stem divides into three patterns: a. Bifurcation pattern 1) Superior and inferior division – 79% b. Trifurcation pattern: 1) Superior, middle, inferior division – 12% c. Four or more trunks – 10%
Trifurcation Pattern
1. Superior division: a. Ascending orbitofrontal branch b. Prefrontal branches c. Precentral branches 2. Middle division: a. Central/central sulcal branches b. Variable origin of: 1) Precentral/anterior and posterior parietal branches 2) Angular/temporo-occipital branches 3. Inferior division (pial branches): a. Ascending temporopolar b. Anterior temporal branches c. Middle temporal branches d. Posterior temporal branches e. Variable origin of (posterior parietal/angular/temporooccipital arteries): 1) In both bifurcation and trifurcation patterns superficial branches may come from the stem of the MCA prior to its division: a) Ascending temporopolar branches b) Anterior and middle temporal branches
Anomalies of the Middle Cerebral Artery
1. Rare: occur in 3% of individuals 2. Duplication of the MCA: a. A second vessel arises from the ICA which supplies the anterior and middle temporal territories 3. Variable patterns of ACA and PCA pial terminal anastomosis at hemispheric border zones 4. If the main MCA trunk is short the lenticulostriate arteries may arise from the superior division
Chapter 1. Ischemic Stroke General Features of Superficial Middle Cerebral Artery Territory Infarction
Patients frequently develop distal MCA trunk occlusions that spare the deep penetrators from the M1 and M2 segments of the proximal MCA. The pathogenesis is most often thrombosis in situ rather than embolic. Complete infarction of the superficial MCA territory of the dominant hemisphere causes head and eye deviation to the side of the lesion, lethargy, global aphasia (often early mutism) and perseveration. The hemiparesis and hemisensory loss is brachiocephalic predominant with an invariant contralateral homonymous hemianopia. Nondominant hemisphere infarction in addition to similar motor and eye signs demonstrate contralateral neglect, constructional apraxia, alloesthesia, anosognosia and multiple nondominant (ND) parietal lobe symptomatologies. Superior division dominant (D) hemisphere infarction causes brachiofacial predominant motor and sensory symptoms, no visual field deficits, but gaze preference or eye deviation (Brodmann’s 8 and 10) to the affected side. Broca’s aphasia, ipsilateral ideomotor or limb kinetic apraxia and oral buccal lingual apraxia may be seen. Nondominant infarcts have similar motor and sensory deficits with hemi spatial neglect and emotional aprosody. Inferior division territory infarction causes minimal weakness but usually an up drift can be appreciated acutely. Astereognosis, difficulty with dynamic and static parietal copy, point localization is noted after the ictus. The most common visual field deficit is a contralateral superior quadrantanopsia if Meyer’s loop is involved, although a contralateral noncongruent homonymous hemianopsia may also be seen (optic tract). Dominant hemisphere lesions cause a Wernicke’s aphasia with an occasional patient demonstrating acute agitation. Characteristics of nondominant lesions are a contralateral predominant sensory hemineglect, anosognosia, constructional apraxia and an agitated confusional state.
Superior Division of the Middle Cerebral Artery (Pial Branches)
Ascending Orbital Frontal Artery
This artery perfuses the orbital portion of the middle and inferior frontal gyrus and the inferior pars orbitalis. Its infarction (emboli or arteritis) causes behavioral disinhibition and a contralateral grasp sign. Prefrontal Arteries
The territory perfused by these arteries is the middle frontal gyrus, pars triangularis, anterior pars opercularis and superior pars orbitalis. The clinical symptomatology includes apathy, abulia, poor ability to change motor sets, perseveration (DH), impersistence (NDH), poor judgment and abstraction, imitation and utilization behavior, and poor retrieval of short
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term semantic material. A transcortical motor aphasia may be noted with (DH) lesions and motor neglect with nondominant hemisphere infarction. Precentral Arteries
This group of arteries supplies the posterior middle frontal gyrus, the posterior pars opercularis and the anterior and midportion of the precentral gyrus. The clinical features of infarction of this branch or branches are proximal upper extremity weakness or distal brachiofacial weakness. Dominant hemisphere lesions may have a concomitant transcortical motor aphasia. Due to infarction of area 8, patients may have bilateral upper extremity ideomotor apraxia. If the infarction involves the posterior left middle frontal gyrus (Exner’s area) they may have agraphia out of proportion to hand weakness. Central Sulcal Artery
The central artery group supplies the posterior bank of the precentral gyrus and the anterior half of the post central gyrus. A pathognomic clinical sign of infarction of this territory is monoparesis of the upper extremity (pseudoradial palsy) although brachiofacial weakness is the most common pattern. Infarction of the motor knuckle anteriorly causes selective weakness of muscles innervated by C5 and C6. Posterior infarction causes C8–T1 innervated muscle weakness. Sensory loss is noted in the same distribution. Rarely a pure motor stroke affecting arm, face, and leg occurs. Infarction of the parietal operculum may cause a cheiro-oral sensory loss (corner of the mouth and hand). Dominant hemisphere infarctions cause Broca’s aphasia or dysarthria and dysprosody. Nondominant hemisphere infarction usually causes less severe dysarthria. Anterior Parietal Artery
This artery or group of arteries supplies the post central gyrus, parasagittal portion of the central sulcus, and the anterior inferior portions of both the inferior and superior parietal lobules. Anterior parietal branch occlusions may cause a contralateral updrift of the arm with abnormal proprioceptive finger movements (mini myoclonus). Loss of touch, pain and position sense is common in the arm and face distribution. Vibration is usually spared. The distal upper extremity may be most severely affected. Incoordination of the affected hand may be noted. Dominant hemisphere infarction may cause conduction aphasia while nondominant lesions are associated with visual-spatial deficit. Posterior Parietal Artery
Infarction of this territory involves the posterior portions of the superior and inferior parietal lobules and the supramarginal gyrus. Discriminative sensations such as two point localization, stereognosis and graphesthesia are predominantly
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SECTION I. Vascular Disease
involved. Patients may demonstrate an inferior quadrantanopsia or noncongruent homonymous hemianopsia. Dominant hemisphere lesions may cause anomic aphasia (SMG), agraphia, and alexia (areas 39, 40, 41). Ideational and bilateral representational ideomotor apraxia as well as a posterior alien hand syndrome may occur. Left right confusion, finger agnosia, dyscalculia, inability to cross the midline and dysgraphia (Von Gerstmann syndrome) may be seen singularly or concurrently. Nondominant hemisphere infarction causes contralateral sensory spatial neglect, constructional apraxia and visuospatial deficits. Differential Diagnosis of Parietal Sensory Loss
In general, parietal sensory symptoms from infarction have a regional pattern. Dramatic involvement of 1/2 of the body is characteristic of thalamic disease. Other thalamic signs are the upper extremity is more severely affected and often the trunk is spared. The deficit may be limited to the finger tips (ventral posterior inferior nucleus) and primarily involves the discriminative aspects of sensation. Vibration loss is a thalamic or dorsal column nuclear deficit. Motor dysfunction with these sensory symptoms occurs in a large majority of patients. This motor deficit first described by Foerster as an afferent paresis or tactile paresis (loathness to move). Partial pseudosegmental, pseudoradicular, cheiro-oral (posterior parietal operculum) pseudospinal patterns may be seen with parietal lesions. The usual pseudoradicular pattern is C6 or C8–T1. A pseudothalamic pattern (SI area) consists of deficits of elementary modalities of sensation with faciobrachial predominance (syndrome of Roussy and Foix). Spinothalamic type of sensory loss (Brodmann’s area 43, part of SMG and the posterior insula) may be seen. Patients may demonstrate asymbolia for pain, if SII is infarcted (adjacent to the lower extent of SI). Portions of the cortical sensory syndrome with loss of discriminative touch, position sense, astereognosis, ability to copy posture, sensory hemineglect (NDH) with preserved vibration sense may be seen with both anterior and posterior parietal branch infarctions. Corona radiata and occasionally SI infarction may cause a feeling of heaviness in the contralateral extremities and are associated with difficulty initiating and sustaining movement (disconnection of deep SI, 3b and area 4) in the depths of the central fissure. Angular Artery Branch
This artery supplies the posterior portion of the superior temporal gyrus, parts of the supramarginal and angular gyri and the superior lateral occipital gyri. The major features of infarction of this branch are the angular gyrus syndrome (Von Gerstmann). Frequently associated is anomic or transcortical aphasia, alexia without agraphia, an inability to cross the midline and constructional apraxia. Nondominant lesions are associated with: (1) contralateral spatial neglect; (2) visuospatial and constructional deficit; (3) loss of opticokinetic nystagmus (eyes remain toward the ipsilateral side); (4) hemianopia or inferior quadrantanopsia; (5) anosognosia (denial
of illness); (6) asomatognosia (denial of a limb); and (7) alloesthesia (perception of sensation on the normal side when the affected side is stimulated are seen). If there is a short mainstem MCA, the lenticulostriate arteries may originate from the superior trunk. Infarction in this circumstance would involve the basal ganglia and the internal capsule. Inferior Division of Middle Cerebral Artery
The general characteristics of an inferior division MCA infarction are: (1) Wernicke’s aphasia (DH); (2) contralateral superior quadrantic VF deficit; (3) poor drawing and copying (NDH); (4) agitation (NDH). Ascending Temporopolar/Anterior Temporal/Middle Temporal Branch Occlusion
The anterior temporal artery supplies the anterior portion of the superior, middle, and inferior temporal gyri. The temporopolar artery complex supplies the anterior pole of the superior middle and inferior temporal gyri. The middle temporal group of arteries supplies the superior gyrus below the pars triangularis and pars opercularis as well as the middle portion of the middle temporal gyrus and posterior portion of the inferior temporal gyrus. The clinical features of infarction of the anterior temporal branches are a contralateral homonymous superior quadrantanopsia. If on the dominant side, the visual field deficit may be associated with an anomic aphasia with categorypredominant naming deficits. Nondominant infarction may cause hemispatial neglect and an acute confusional syndrome. Temporo-Occipital/Posterior Temporal Branch Occlusion
These arteries supply the posterior half of the superior temporal gyrus and the posterior portions of the middle and inferior temporal gyri and the inferior portion of the lateral occipital gyri. These occlusions cause a contralateral superior quadrantanopsia or hemianopsia. Dominant hemisphere infarction of the posterior superior temporal gyrus causes Wernicke’s aphasia. This infarction is frequently embolic and if pure (no other neurologic symptoms) is often caused by atrial fibrillation or another cardiac source. Nondominant hemisphere infarction produces an acute confusional state, contralateral hemispatial neglect and constructional apraxia.
Other Common MCA Occlusions of the Superficial Territory
Insular Branch Occlusion
The insula is supplied by the MCA trunk or proximal portions of its division and is rarely infarcted in isolation. Bilateral infarctions from seriatim strokes cause the Foix–Marie– Chavany syndrome which consists of severe apraxia for all of
Chapter 1. Ischemic Stroke
the muscles of branchial origin. Patients have difficulty swallowing, moving the face and tongue, buccal movements and initiating and articulating speech. This is a cause of aphemia which is a dramatic dysarthria that renders speech unintelligible. It may occasionally occur from unilateral insular branch occlusion. Long Penetrating Medullary Artery Occlusion
Infarction of a group of long-penetrating arteries cause large infarcts in the centrum semiovale. Their origin is in the MCA pial branches and they usually cause a contralateral motor and sensory deficit as well as a noncongruent hemianopsia. If in the dominant hemisphere, patients are dysphasic while NDH lesions are associated with hemineglect and visuospatial deficits. Infarcts of less than 1.5 cm in diameter cause pure motor or sensory strokes, ataxic hemiparesis without cognitive impairment or isolated involvement of face, arm or leg (fibers are widely separated). This fractionation is less common than with deep subcortical infarcts. Severe ipsilateral carotid disease produces the lesions by distal field ischemia or embolic disease.
Deep Territory MCA Infarction
The deep territory is composed of penetrating branches from the M1 and M2 proximal segments of the MCA which are known as the lenticulostriate arteries. If these arteries are infarcted, the process is usually embolic and occlusion of many perforators occurs simultaneously. This type of infarction is a striatocapsular infarction rather than a lacunar infarction in which only 1 lenticulostriate perforator is occluded. In general, striatocapsular infarction involves the head of the caudate, the putamen, and the lateral internal and external capsule and may extend into the corona radiata. The insular cortex and the thalamus is spared. Striatocapsular infarcts may involve the territory of Heubner’s artery (recurrent branch from A1) or the anterior choroidal artery. In general, the area infarcted is in the range of 2–7 cm, is wedge or comma shaped, and is not ovoid as are the smaller lacunar infarctions. Cortical symptoms are rare and if present resolve quickly. The cortex is not infarcted due to leptomeningeal anastomoses. In situ thrombosis or cranial arteritis involving a segment of M1 that occludes multiple perforators is rare. Acutely, patients present with predominantly motor or sensory motor hemiparesis with or without dysarthria. Hemiparesis results from damage to the posterior limb (mid 1/3) of the internal capsule (motor cortex corticospinal fibers) or if only the frontal part of the internal capsule is involved (the lateral premotor cortex corticospinal fibers or those from the SMA cortex in the genu) are involved. The differential diagnosis of striatocapsular infarcts are: (1) lacunar syndromes; (2) pure sensory stroke; (3) strokes in
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the basis pontis; (4) ICH of the striatum. If the leptomeningeal anastomosis fails patients may suffer cortical deficits which add to the underlying deficit and rule out lacunar stroke. In striatocapsular stroke, cortical deficits such as aphasia or neglect resolve in the face of persistent motor or sensory deficits. In a moderate or large territorial or MCA branch occlusion the cortical deficits are more severe and long lasting. Extended striatocapsular stroke is most often associated with Wernicke’s aphasia (involvement of insular or superior temporal gyrus). Rarely focal dystonia, contralateral choreoathetosis, or hemiballismus has been noted. Bilateral striatocapsular infarction may cause tetraplegia and akinetic mutism.
Striatocapsular Stroke
1. 2. 3. 4. 5.
Predominant motor or sensorimotor hemiparesis Minimal cortical signs and symptoms that resolve 2 to 7 cm in size Wedge or comma shaped Involves caudate, putamen, anterior or posterior limb of the internal capsule 6. Rare contralateral movement disorder 7. Rare tetraplegia with akinetic mutism (if bilateral) Distal field infarction (or low flow state in the periventricular white matter) between the penetrating cortical branches and the ascending lenticulostriate branches that does not infarct the basal ganglia or internal capsule may mimic some of these findings. If the head of the caudate nucleus, the putamen and the anterior portion of the internal capsule are infarcted the pattern represents that of occlusion of the recurrent artery of Heubner whose origin is the A1 segment of the ACA aberrant (medial lenticulostriate artery). The resultant hemiparesis has brachiocephalic predominance with tongue involvement. A similar infarction can occur from occlusion of the perforating branches of the most proximal portion of the A1 segment of the ACA artery. If the caudate head and the anterior limb of the internal capsule are involved, the eyes may be deviated ipsilaterally and the face and arm are more severely affected than the leg. Caudate infarction interrupts fibers that project to the frontal and dorsolateral prefrontal cortex and may be associated with an acute confusional, agitated or an abulic state. If the infarction extends anteriorly and destroys fibers that project to the medial dorsal and anteroventral thalamic nuclei, patients may have an expressive aphasia. Rarely with infarctions in this area patients demonstrate a hemisensory defect that affects the face and hand more severely than the leg. Dysarthria is more severe with left sided than right sided capsular lesions (corticobulbar projections to cranial nerves VII, X and XII). A noncongruent homonymous hemianopsias results from optic tract infarction. This may also be accompanied by a Behr’s pupil (larger, poorly reactive pupil on the ipsilateral side).
24
SECTION I. Vascular Disease
The lateral lenticulostriate group of perforators takes origin from the M2 proximal middle cerebral artery segment and supplies the putamen, claustrum, external and extreme capsule and the insular cortex. Putaminal infarction causes brachiocephalic predominant weakness with increased tone and hyperreflexia but no sensory loss. Rarely putaminal infarction causes contralateral dystonia, choreoathetosis, and abnormal contralateral hand posture. Bilateral insular cortex infarction (insular branches of the MCA) produces the Foix–Chavany– Marie syndrome which causes apraxia of all branchial derived musculature and disrupts speech and swallowing. The dysarthria may be so severe that speech is unintelligible (usually requires bilateral infarction).
b. Posterior 1/3: 1) Pure sensory 2) Arm, face, and leg involved c. Arterial supply (lenciculostriate) 6. Rare behavioral signs and symptoms of striatocapsular stroke are: a. Fluctuating alertness b. Inattention c. Memory loss d. Apathy e. Frontal lobe deficits 7. These deficits are caused by infarction of: a. Inferior and anterior thalamic peduncles b. Anterior limb of internal capsule
The Capsular Warning Syndrome
The Differential Diagnosis of Striatocapsular Infarctions
These are TIA’s restricted to the face, arm and leg and are not often seen with severe carotid stenosis accompanied by a low flow state. The major clinical features are: 1. Simultaneous sensorimotor involvement of face, arm and leg 2. No neglect, dysphasia or dyspraxia 3. Three or more clinical events within 24 hours 4. Onset over seconds 5. Pure motor hemiparesis is most common 6. Sensory symptoms clear prior to motor signs 7. Capsular infarction follows in approximately 40% of patients As noted above, the capsule may be predominately involved in specific areas.
1. 2. 3. 4.
Capsular Genu Syndrome
1. Contralateral facial, lingual and brachial weakness 2. With or without ipsilateral horizontal conjugate eye deviation 3. Rare thalamic aphasia
Midpoint Infarction of the Upper Capsule with Lower Corona Radiata Extension (Anterior 1/3 of the Posterior Limb)
Clinical Signs and Symptoms
1. 2. 3. 4.
Dysarthria Contralateral clumsy hand Faciolingual weakness Blood supply is from the lenticulostriate arteries that concomitantly supply the upper ventricular wall (anastomosis with ependymal vessels) 5. Posterior 1/3 limb of internal capsule infarction: a. Middle third 1) Face < arm < leg weakness 2) Purely motor
Lacunar infarcts (1–2 perforating vessels) Pure sensory stroke (thalamic infarction) Infarction of the basis points (penetrating basilar branches) Small striatal or intracranial hemorrhage If leptomeningeal anastomoses fail, or there is a concomitant shower of emboli, patients may suffer cortical deficits. As noted earlier, lack of cortical dysfunction is characteristic of lacunar stroke.
Clinical Differential Diagnosis of Capsular Infarction
1. The first of frequent hemiplegic events is more likely capsular than pontine. 2. Premonitory events are characteristics of anterior choroidal artery ischemia. 3. Capsular ischemia: patients are aware of its onset; it resolves over seconds to minutes. 4. Incipient occlusion of the ICA often is accompanied by repetitive events with cortical dysfunction. 5. Hemodynamic events are posturally influenced and are shorter than embolic events. 6. Artery-to-artery embolic events are more widely separated in time.
Rare Patterns of Stroke in the MCA Territory
Central sulcal branch artery infarction may cause a right pseudothalamic sensory loss (primary sensory modality involvement), ideational apraxia and conduction aphasia. Wernicke’s aphasia and hemianopsia often follows embolic occlusion of the temporooccipital branch of the inferior MCA division particularly in the setting of atrial fibrillation. Precentral branch occlusion may cause transcortical motor aphasia, proximal weakness of the arm and ideomotor apraxia. The anatomical variants of the middle cerebral artery, specifically the origin of the angular artery may determine
Chapter 1. Ischemic Stroke
unusual stroke symptoms following infarction in the MCA territory. Stenosis of the M1 segment of the MCA in conjunction with hypertension may cause periventricular longitudinal infarction. Double infarcts are those that involve two components of one arterial territory. Aphasia without hemiparesis occurs when Broca’s and Wernicke’s area are infarcted leaving the motor strip intact. Hemiplegia with visual field deficits occur when the superior division (central sulcal branches) are occluded concomitantly with temporo/occipital branches (inferior division) thus sparing the primary sensory cortex. Conduction aphasia with hemiparesis has been noted with motor cortex and supramarginal gyrus lesions. Fragmentation of emboli at the MCA bifurcation or seriatim strokes are the most likely mechanisms.
Complete MCA Infarction (Superficial and Deep Territory)
Panhemispheric MCA occlusion is often embolic particularly if sudden. If it occurs with a slower or stuttering onset it is most likely due to carotid occlusion. These patients have cerebral swelling usually within 12 hours of infarction that impairs consciousness. Their head and eyes are deviated ipsilaterally, they demonstrate periodic or Cheyne–Stokes respiration, a flaccid contralateral hemiparesis and hemisensory deficit, homonymous hemianopsia and global aphasia (DH), or severe contralateral sensory neglect (NDH). The eyes are usually congruently deviated slightly below the horizontal due to pressure on the center for upgaze (the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF)that is ventral to the superior colliculus. In stem MCA infarction, edema is most severe at 3 days. Prior to herniation, patients may demonstrate an ipsilateral sluggish and oval pupil (pressure on the III nerve) as well as ipsilateral or bilateral ptosis (frontal eye field compromise).
Clinical Summary of Complete Superficial Territory Infarction
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Hemiparesis faciobrachial > leg Hemineglect for space and motor activity (NDH) Anosognosia (NDH) Asomatognosia (NDH) Spatial disorientation (internal/external/geographical) NDH Disorientation NDH > DH hemisphere Depressed reflexes contralaterally (acutely); rarely increased (cortical disinhibition) Babinski’s sign contralaterally (ipsi or bilaterally if there is increased ICP) Angular gyrus syndrome (DH) Supra marginal gyrus syndrome (DH) Wernicke’s aphasia (DH)
12. 13. 14. 15. 16. 17. 18. 19.
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Broca’s aphasia (DH) Conduction aphasia (motor DH) Conduction aphasia (sensory DH) Alexia without agraphia (DH) Ideomotor/limb-kinetic apraxia D > NDH Ideational apraxia (DH) Alien hand syndrome (DH > NDH) Sympathetic apraxia or callosal apraxia (DH)
Superior Division MCA Occlusion (Bifurcation Pattern)
1. Broca’s aphasia (DH) 2. Exner’s area (severe inability to write) DH; Brodmann’s area 45 3. Parietal hand (updraft; loathness to move) 4. Dysarthria 5. Motor conduction aphasia (DH) 6. Limb kinetic/ideomotor apraxia (DH) 7. Alien hand syndrome (area6/DH) 8. Brachiofacial pattern of weakness > leg weakness 9. Depressed reflexes contralaterally 10. Head and eye deviation (ipsilaterally) 11. Babinski’s sign contralaterally 12. Frontal behavioral syndrome 13. Apathy and abulia 14. Brachiofacial crural weakness (rare) 15. Phonemic paraphasia 16. Rare cheiro oral sensory loss Inferior Division MCA Occlusion (Bifurcation Pattern)
1. 2. 3. 4. 5. 6.
Wernicke’s aphasia (DH) Sensory conduction aphasia (DH) Supramarginal gyrus syndrome (DH) Angular gyrus syndrome (DH) Hemineglect for space (NDH) Depressed opticokinetic nystagmus (ipsilateral hemisphere) 7. Depressed optic scanning (contralateral space) 8. Constructional apraxia (NDH) Prosopagnosia (NDH) 1. Loss of higher cortical sensory function (contralateral) 2. Ideational apraxia 3. Posterior type alien hand Summary of MCA Infarctions
a. 2/3 of first brain infarcts involve the MCA b. 1/3 of MCA infarction involves the deep MCA territory c. 1/10 of MCA infarction involves both superficial and deep territory d. 50% are branch occlusions
26
SECTION I. Vascular Disease
Sentinel Differential Diagnostic Feature of Large Vessel Stroke of the Anterior Circulation
The hallmark of carotid disease is retinal involvement either embolic from burst plaques or artery to artery. Hollenhorst plaque material at a bifurcation of a retinal artery is pathognomonic. Horner’s syndrome associated with a brachycephalic predominant lesion points to the internal carotid artery. Due to the circle of Willis collaterals may save a great deal of the hemisphere. Carotid siphon disease has no ocular pathology, but the anterior cerebral artery may be involved concomitantly with the middle cerebral artery. Emboli from the siphon may occlude the anterior cerebral artery and the inferior branch of the dominant middle cerebral artery sparing the major portions of the motor sensory cortex. This causes a Wernicke’s aphasia with shoulder and leg weakness. The anterior choroidal artery supplies aspects of both anterior and posterior circulations. The hallmark of its infarction is a quadruple sectoranopic defect that spares the central sector. The defect arises from infarction of the lateral geniculate body. Infarction of the uncus and components of its thalamic supply cause a deficit in short term memory and language processing. Hyperesthetic hemiparesis (thalamic) and hyperesthetic ataxic hemiparesis are patterns of infarction. The usual pattern of anterior cerebral artery infarction is severe weakness and sensory loss of the foot, minimal involvement of the shoulder and face with excellent preservation of hand movement. The patient may be able to wiggle the thumb, but not the arm if the Az section is involved. If the recurrent artery of Heubner is infarcted and the patient demonstrates facio brachial predominant weakness. Involvement of the supplementary motor area (distal ACA) causes transcortical motor aphasia, mirror writing acquired stuttering and muteness. Muteness is often seen as well with sudden occlusion of the stem of the MCA. Medial frontal lobe infarction often causes euphoria, lability and iocularity. Anterior callosal involvement causes sympathetic apraxia (inability to follow commands with the left hand) and the anterior alien hand syndrome (inter manual conflict). The major differential distinction of middle cerebral artery disease is that from internal carotid artery occlusion. TIAs in the middle cerebral artery distribution occur on awakening, are less frequent than carotid TIAs and once initiated occur over a shorter time period. They frequently fluctuate or progress over 1–7 days. The mechanism often is distal field ischemia so symptoms often vary with posture. There are no monocular symptoms. Characteristic of superficial territory involvement is hemiparesis and hemisensory deficit with brachycephalic predominance. The frontal eye fields are frequently involved (FEF) with no corresponding visual field deficit. Severe motor neglect and parietal visuospatial deficits are noted if the non-dominant parietal lobe is involved. The angular artery syndrome of Van Gerstmann localizes the lesion to posterior parietal territory if the DH is involved. The pre and frontal superficial branches of the superior division
supply Broca’s area (44). The DLPC (dorsolateral pre frontal cortex) is also frequently involved and causes memory retrieval difficulties. Characteristic of inferior division infarction of the superficial territory is Wernicke’s aphasia (pathognomonic of embolus if isolated and concomitant with atrial fibrillation) and agitation. Deep territory middle cerebral artery territory infarction is characterized by internal capsule and basal ganglia infarction. The important differential point from superficial territory and carotid infarction is involvement of the leg, absence of eye deviation and the transient nature of any cortical deficits. This infarction causes a striatocapsular stroke with persistent motor sensory signs. The medial and lateral lenticulostriate group of arteries from the M1 and M2 segments of the MCA of the lateral group is involved. The putamen may be affected causing motor weakness, increased tone and reflexes without sensory loss. The capsular warning and genu syndromes may be seen prior to stroke.
Differential Diagnosis of Posterior Circulation Stroke
General Features
The posterior circulation can be considered the arch of the aorta, the innominate and subclavian arteries and vertebral, basilar posterior cerebral and their derivative arteries. The arch of the aorta is a rich source of embolic material to the posterior circulation. Its prominence in this regard has recently been accentuated by transesophageal echo cardiography. A mobile grade V plaque is extremely dangerous as a source of embolus. Approximately 30% of emboli to the posterior circulations arise from this source. Emboli to both anterior and posterior circulations arise from the heart or the arch of the aorta in the great majority of cases. The embryologic connections from the carotid to the basilar artery are rare source of emboli. These include the persistent trigeminal artery, the otic, hypoglossal and pro-at canthal arteries. The most significant of these arteries is the persistent trigeminal which connects this top of the basilar to the carotid artery just below the siphon. The vertebrobasilar system can be divided into diagnostic thirds. Each major artery has sentinel features that can guide diagnosis. Characteristic of a subclavian stenosis proximal to the origin of the vertebral artery is the subclavian steal syndrome. The patient uses the affected arm (left greater than right) which further lowers pressure in the arm (lower than that in the vertebrobasilar system) and blood flows to the arm from the vertebral supply. Most patients have a clear difference in blood pressure between the two arms and a significant decrease of pulse volume and clear lag of the pulse in the affected side. The syndrome usually causes more claudication in the arm than brainstem symptoms. It is rarely significant clinically. A rare syndrome of ischemia of the brachial plexus and posterior circulation can occur from ischemia of the vertebral and axillary artery (feeds the plexus) that occurs simul-
Chapter 1. Ischemic Stroke
taneously. Patients may complain of arm pain in the lateral or medial cord distribution, hand weakness concomitantly with lower brainstem, and cranial nerve symptoms. Atheromatous occlusion with or without emboli may cause simultaneous carotid and vertebral artery symptoms on the right side. In general, the left carotid takes origin from the aorta and this will not occur on this side. The common congential anomaly of the posterior cerebral artery taking origin from the carotid may cause complete hemispheric infarction if that carotid is occluded. The patency of the posterior communicating arteries may determine upper basilar perfusion if there is occlusion of the mid basilar or vertebral arteries. Proximal vertebral artery disease is most common at the origin from the subclavian artery which is accessible to stenting and angioplasty. The most prominent clinical symptoms are dizziness, diplopia (VIth nerve), dysphagia, oscillopsia, bilateral leg weakness and sensory loss on the trunk. Isolated dizziness especially points to the labyrinth rather than the brainstem. The origin of the posterior inferior cerebellar artery is from the vertebral. It is most commonly involved due to occlusion of the parent artery. The sentinel features of its involvement are dysphagia, nausea and vomiting (out of proportion to dizziness), hoarseness, lateral pulsion to the side of the lesion). These patients have a great deal of difficulty walking which is out of proportion to their ipsilateral ataxia. Seventh nerve weakness (ipsilateral) may occur due to recurrent medullary fibers. Ipsilateral facial pain “salt and pepper” in Vth nerve distribution is characteristic. Medial medullary infarction is suggested by contralateral flaccid paralysis of arm and leg (infarction above C2) or ipsilateral flaccid hemiparesis if ischemia involves the cervical medullary junction. Spasticity evolves within days to weeks and causes flexion of the upper extremity and extension of the lower extremities. The motor deficit is more severe distally in the upper extremity which is also typical for pontine infarction. Infarction of the pyramidal decussation may cause a crural paresis. The sensory loss is lemniscal, the face may be involved alone and rarely there is dissociation of position severe and vibratory loss. Upbeat nystagmus implies pontomedullary junction infarction. Respiratory dysfunction (Ondine’s curse), mild ptosis with hypohidrosis and XIIth nerve involvement may occur. Bilateral medial medullary infarction is manifest by flaccid quadriplegia, paralysis of the tongue, loss of lemniscal sensation, and cardiorespiratory failure. Combined medial and lateral medullary infarction is suggest by ipsilateral involvement of IX, X, XI, XII a Horner’s syndrome, contralateral lemniscal and spinothalamic sensory loss and hemiparesis. Ipsilateral ataxia is apparent if the patient is hemiparetic. The most common infarction of the pons is ventral and occurs due to occlusion of the anteromedial or anterolateral branches from the basilar artery. These infarctions are suggested by the constellation of facio-branchial crural
27
hemiparesis, brachiocrural ataxia (homo-lateral to the motor deficit), ataxic hemiparesis and the dysarthria clumsy hand syndrome. Ataxic hemiparesis and dysarthria clumsy hand occur more often in the middle and upper pons or at the ventrotegmental junction. Pontine hemiparesis is greater in the distal upper extremity than the lower extremity. Pontine tegmental involvement is suggested by cranial nerve involvement (V, VIth) a depressed level of consciousness and an intranuclear ophthalmoplegia or 1½ syndrome. Tegmental pontine syndrome from occlusion of short circumferential vessels is headed by mild motor deficit, cranial nerve involvement V–VII, and lemniscal (medial) or spinothalamic sensory loss. The major circumferential artery of the lower pons is the anterior inferior cerebellar artery. Infarction of this artery characteristically causes sudden ipsilateral hearing loss, ipsilateral ataxia arm greater than leg (the reverse of PICA), dizziness, ipsilateral VIIth nerve palsy (small artery to the facial nerve peripherally in the CPA angle) and contra lateral loss of pain and temperature of the limbs and trunk. Mid basilar branch disease is suggested by the motor deficits with a fluctuating and progressive course, the ocular signs of horizontal gaze dysfunction, ataxic hemiparesis (level of the MCP) the clumsy hand dysarthria syndrome and classic lacunar syndromes. Basilar artery thrombosis may have dizziness as the most frequent early symptom, a herald hemiparesis, alternating levels of consciousness to stupor or coma. Dysarthria, pseudobulbar symptoms, tongue paralysis are common. Pin point pupils and ocular bobbing are diagnostic. The locked in syndrome with maintained consciousness is pathognomonic of ventral pontine infarction. The top of the basilar (distal 1/3) is commonly involved from embolic disease. The superior cerebellar artery and specific components of the posterior cerebral artery are involved and determine the specific symptoms and signs of the infarction. The superior cerebellar artery brainstem territory is most often infracted in conjunction with the posterior cerebral artery. Severe dysarthria with various degrees of appendicular ataxia are characteristic. The associated components of the posterior cerebral artery often suggest the diagnosis. The posterior cerebral artery supplies the medial temporal lobe, the midbrain (paramedian branches), the medial and lateral motor sensory thalamus, medial parietal lobe and the occipital cortex. Hippocampal formation ischemia from proximal PCA branch occlusion causes transient global amnesia. A similar amnestic syndrome, much longer lasting may also occur from dorsal medial thalamic ischemia from occlusion of the paramedian top of the basilar branch occlusion. Midbrain involvement from paramedian ischemia causes clonic syndromes involving the third nerve. Crossed hemiparesis is webers syndrome, crossed movement disorder is Benedict’s, and Claude’s is cerebellar ataxia. Disorders of vertical gaze such as 1½ syndrome, dissociation of vertical and horizontal
28
SECTION I. Vascular Disease
opticokinetic nystagmus and pupillary abnormalities are characteristic. A peduncular hemiparesis from cerebral peduncle infarction may simulate MCA infarction. The IIIrd nerve is not involved and the face may be spared. Rarely a nuclear IIIrd nerve syndrome is noted with bilateral ptosis, pupillary dilatation and failure of upgaze. Nystagmus retractorius may occur from vascular lesions of the periaquaductal ava but is more characteristic of dorsal midbrain pressure. Posterior cerebral artery thalamic involvement is characterized by stricking sensory involvement. The patient is aware of a midline split of sensory deficit. The leg may be involved first (VPL). The finger tip involvement of one hand is diagnostic of thalamic VPI nuclear involvement. Bilateral involvement of intraoral sensation is characteristic of VPM ischemia. Thalamic sensory loss includes vibration. This modality is never lost with a cortical lesion, but may be seen with dorsal column nuclear lesions. Thalamic motor involvement may be suspected from a characteristic thumb in the palm drift. Proprioceptive deficits combine with weakness. Ataxia of stance is characteristic of thalamic lesions that affect zones of proprioceptive and cerebellar input that converges in VL. Rarely dystonic postures are seen after UA/VL thalamic motor lesions. Occipital lobe posterior cerebral artery involvement should always be suspected in the face of a dense congruent VF deficit of which the patient is aware. If there is visual neglect the patient has parietal lobe involvement. Deficits in optic scanning and visio-coordinative hand function and fixation gaze comprise Balint’s syndrome that overlaps parietal and occipital posterior cerebral artery territories. Anton’s syndrome of cortical blindness is manifest by visual confabulation euphoria and normal pupillary function. Specific field deficits such as a checkerboard field, quadrantic altitudinal deficits, macular sparing and temporal crescent of spared vision all point to PCA occipital lobe branch occlusions. Lateral posterior choroidal artery infarction is suggested clinically by a homonymous quadrantanopsia. If the lateral geniculate body is involved, patients demonstrate a homonymous horizontal sectoranopia. There may be a concomitant transcortical aphasia and hemisensory deficit. This infarction is suggested by pulvinar involvement on MRI or CT. Medial posterior choroidal artery infarction is less common than lateral PchA infarction and is suggested by nystagmus retractorius and a central Horner’s syndrome. A mild hemiparesis and lemniscal sensory deficit may occur. CT or MRI of medial pulvinar involvement suggest this atrial territory. The following is a detailed differential analysis of posterior circulation vascular infarctions.
a. Arise from the proximal subclavian arteries b. Subclavian steal syndrome: 1) Obstruction of proximal subclavian artery (prior to the origin of the vertebral artery): a) Low pressure system within the ipsilateral vertebral artery b) Blood supply of the ipsilateral arm is deficient. During exercise these blood vessels dilate which further lowers vascular resistance in the exercised arm c) Higher pressure system: (1) Contralateral vertebral artery (2) Blood flows retrogradely down the ipsilateral VA into the arm (brainstem becomes ischemic) 2. Clinical symptoms: a. Most patients are asymptomatic in the face of arterial demonstration of a steal b. Complaints relate primarily to arm ischemia: 1) Fatigue, achiness with exercise, autonomic dysregulation (coolness) c. Neurologic symptoms are more common with concomitant carotid disease d. 75% of patients are asymptomatic (demonstrated in Takayasu’s disease) e. Rare neurologic symptoms (usually brief) occur: 1) Arm is used repetitively and often overhead 2) Blurred vision 3) Oscillopsia 4) Diplopia 5) Vertigo/spinning 6) Incoordination and imbalance 3. Clinical signs: a. Delayed antecubital and wrist pulse on the stenotic ride b. Smaller pulse volume c. Supraclavicular bruit (rare) d. Inflation of blood pressure cuff on the ipsilateral side: 1) If the bruit is generated from ECVA the bruit increases as more blood flows through the stenosis (less reversal) 2) If the bruit is generated from the subclavian stenosis the bruit decreases (increased pressure of ipsilateral system because there is no arm “run-off”) e. Clinical sequelae: 1) Stroke is rare with subclavian steal 2) Clots can form in a subclavian occlusion a) Embolization to vertebral artery territory 3) Raynaud’s phenomenon and autonomic dysregulation of the affected extremity may occur
Posterior Circulation
Occlusion or Severe Stenosis of the Subclavian and Innominate Arteries
1. Extracranial vertebral arteries (ECVA):
Innominate Stenosis on the Right Side
1. Decrease of carotid flow 2. Exacerbated by cigarette smoking
Chapter 1. Ischemic Stroke
3. 4. 5. 6.
Women > men Associated with other large vessel occlusive disease Right subclavian steal < frequent than left Clot may spread from the innominate into the carotid arteries a. Recurrent arm and brain ischemia b. Floating thrombi within the innominate artery 4. Differential Diagnosis of Subclavian Artery Disease a. Takayasu’s disease b. Severe atherosclerosis c. Aortic arch syndrome d. Syphilis (chronic aortitis) e. Cervical rib f. Giant cell arteritis g. Athletics that utilize a constant throwing motion In Takayasu’s disease, there is major inflammation and occlusion of the aortic arch vessels. Intermittent claudication of the arm is the most common symptom. Loss of vision with head position (precarious arterial supply to optic nerve head from posterior ciliary artery and central retinal artery compromise). Trophic loss of integument of the face and cataracts are common. Most patients with Takayasu’s disease are asymptomatic in the face of an arteriographic steal. Giant cell arteritis may compromise the great vessels at the arch with occlusion and stroke of the carotid artery. A cervical rib most frequently compresses the lower trunk of the brachial plexus with atrophy and weakness of the intrinsic hand muscles.
Vertebrobasilar Infarction
General Features of Lateral Medullary Territory Infarction
A. Proximal Vertebral Artery Disease 1. General Characteristics: a. Most frequent location of extra axial vertebral artery disease (ECVA) is at the origin from the subclavian artery (accessible to stenting and angioplasty) b. ICA and ECVA stenosis frequently are affected concomitantly c. Occurs in Caucasians > Asian and African Americans 2. Clinical Features a. Most common symptom is dizziness 1) Extremely rare for this symptom to be solitary 2) TIAs are not precipitated by arm movement as is the case with subclavian-steal syndrome (on rare occasions) b. Diplopia c. Dysphagia d. Oscillopsia (environment moving) e. Hemiparesis f. Bilateral leg weakness g. Sensory loss on the trunk
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3. Hypoplastic congenital vertebral and basilar arteries coexist: a. Patient suffers posterior circulation ischemia b. L-vertebral artery 80% of the time dominant over right c. Complete atresia of a vertebral artery is rare B. Lateral Medullary Territory (Posterior Inferior Cerebellar Artery) 1. Direct penetrators from the distal vertebral supply the lateral medulla and cerebellum 2. Posterior inferior cerebellar artery (PICA) supplies the lateral medulla and inferior cerebellum including the floccular nodular lobe 3. Posterior inferior cerebellar artery (PICA) frequently overlaps AICA territory or forms an AICA/PICA artery that supplies both territories 4. Variable: PICA/AICA supply to the lateral medulla or portions of the pons 5. Lateral medullary syndrome: most often occurs from occlusion of the distal perforators of the vertebral artery (VA) 6. If coexisting, AICA involved: middle cerebellar peduncle involved (core territory) 7. If coexisting, PCIA involved: lower cerebellum infarcted 8. Dorsal medulla supplied by branches of PICA (two posterior medullary arteries) C. Clinical Signs and Symptoms of Lateral Medullary Infarction 1. General: a. 40% are sudden (ictal) b. 60% a gradual or stepwise pattern over 24–48 hours c. 25% of patients have had a preceding TIA in the same arterial territory 2. Cranial Nerve Abnormalities: a. Dysphagia (rostral nucleus ambiguous) b. Hoarseness (caudal N. ambiguous) c. Crowing cough (N. ambiguous) d. Nausea and vomiting: 1) Vestibular nuclei 2) N. tractus solitarius (NTS) 3) Vomiting out of proportion to dizziness e. Ipsilateral Horner’s Syndrome 1) Descending central sympathetic fibers f. Hiccoughing (singultus; NTS) g. Ipsilateral VII nerve dysfunction 1) Occurs in 33–50% of patients. This is due to two groups of recurrent VII nerve fibers 2) In the upper medulla an origin that recurs through the lateral medulla 3) Fibers that leave the pyramidal tract (at the decussation in the medial medulla and course rostrally to the contralateral tegmentum h. Lateral medullary infarction lateral recurrent fibers of VII are infarcted
30
SECTION I. Vascular Disease
i. dysarthria caused by faciopalatal-glossal dysfunction and cerebellopetal pathways 3. Visual Signs and Symptoms a. Blurred vision b. Oscillopsia (with acute infarction) 1) Environment appears to move with patient’s nystagmus (usually horizontal) c. Vertical, horizontal or oblique diplopia 1) Disruption of the ocular tilt reaction (OTR) d. Incyclotropia 1) Cyclorotation abnormalities (clockwise or counterclockwise eye rotation) 2) Disruption of the vestibulo-ocular response (VOR) e. Horizontal and rotary nystagmus is most prominent to the ipsilateral side f. Skew deviation-ipsilateral eye down (otic-oculomotor pathways) g. Hypermetric saccades to the ipsilateral side (flocculo-nodular lobe of the cerebellum); hypoactive saccades to the contralateral side h. Deviation of the subjective visual vertical (SVV) to the ipsilateral side (internal concept of the body’s vertical position) 4. Motor Signs a. Ipsilateral hemiparesis (Opal ski’s Syndrome) 1) If the pyramidal fibers below the decussation at C2 are involved b. Contralateral hemiplegia occurs with the combined lateral and medial medullary syndrome; no weakness with pure PICA infarction c. Most often there is ataxia without weakness 5. Sensory Signs and Symptoms a. Ipsilateral facial pain and sensory loss 1) Touch, temperature, pain, cold decreased (ipsilateral V) 2) Loss of ipsilateral corneal reflex (V) 3) “Salt and pepper” facial paresthesia and pain b. Far lateral medullary infarction of the spinothalamic tract (STT) 1) Crossed hemisensory loss to pinprick and temperature on the contralateral body below the clavicle c. More medial infarction of the lateral medullary STT 1) Contralateral loss of pinprick and temperature of the face, trunk, and upper limb (the ipsilateral STT from the arm, trunk and leg) and the crossed ventrotegmental ascending fibers that cross medially in the medulla that subserve the contralateral face d. Medial medullary infarction 1) Bilateral facial hypalgesia with variable contralateral sensory loss (dog’s nose pattern) 2) “Onion skin” facial sensory loss
a) Nose involved b) Preauricular area spared c) Maybe seen as well with V nerve entry zone lesions 6. Headache a. Occipital b. Unilateral c. Non-throbbing d. Vth nerve origin of trigeminal pain afferents to the dura, proximal blood vessels and sinuses (somatic visceral convergence) 7. Brainstem Dysfunction a. Autonomic dysregulation 1) Cardiac arrhythmia 2) Blood pressure variability a) Lateral medullary vasomotor center b) Most often postural hypotension b. Respiration 1) Sleep apnea 2) Failure of automatic breathing Ondine’s curse a) Disruption of oscillations of lateral and medial respiratory neurons b) Afferent disruption of IX and X pulmonary afferents (Herring-Breuer reflex) may be carried centrally in STT 8. Cerebellar Syndrome a. Gait and ipsilateral limb ataxia b. Axial lateropulsion (if restiform body involved from concomitant medial branch infarction); patient is pushed to the side of the lesion
Unilateral Medial Medullary Infarction (Dejerine’s Syndrome)
Less than 1% of posterior circulation strokes Branch occlusion from the VA A. Motor Signs and Symptoms 1. Flaccid hemiparesis a. Contralateral if above C2 b. Ipsilateral if the infarction spreads to the cervical medullary junction 2. Spasticity within days to weeks a. Flexion of upper extremities b. Extension of the lower extremities 3. Rarely weakness can be minimal or absent 4. Rarely upper limb monoparesis a. Fibers after decussation may be lateral 5. Motor deficit is more severe distally in the upper extremity (also typical for pontine infarction) 6. Patterns of weakness at the level of the pyramidal decussation a. Leg fibers may cross anteriorly and then remain lateral to arm fibers
Chapter 1. Ischemic Stroke
b. Some studies – arm fibers decussate anteriorly to leg fibers c. Crural paresis: 1) Proximal portion of the limbs affected with finger and toe movements preserved 2) Hemiplegia cruciatas a) Arm involved ipsilaterally with contralateral leg weakness d. Pontine recurrent pathway may be infarcted with facial weakness B. Sensory Signs and Symptoms 1. Contralateral lemniscal type sensory loss of the hemibody with or without the face 2. More marked distally 3. May involve the face only 4. Pseudospinal dropped sensory level on the trunk 5. Dissociation between vibration and position loss a. Vibration may be involved with more lateral extension 6. Pain sensation a. Occasionally decreased with preserved temperature, sensation, and mild hypesthesia C. Cognitive Dysfunction 1. Medial reticular formation involvement: a. Apathy b. Somnolence c. Hallucinations d. Delirium 2. Pathologic laughing and crying with infarction of: a. Internal capsule b. Pons c. Pyramidal tract (usually bilateral) d. Bilateral temporal lobe (usually trauma) e. Medial frontal lobe (laughing) D. Ophthalmologic Signs 1. Upbeat nystagmus: a. Dorsolateral medulla or pontomedullary junction infarction that spares the medial medulla b. Ipsilateral MLF or perihypoglossal nuclei are involved in upgaze c. Horizontal nystagmus (ipsilateral) or multiple directional nystagmus related to vestibular nuclear involvement or their connections to the cerebellum in the lateral medulla d. Rare – ocular bobbing (usually a pontine lesion) E. Lateral Pulsion 1. Contralateral lateral pulsion a. Dorsolateral medulla and cerebellum are not involved b. Patient feels as if he is pushed to the side c. Lesion at the level of the restiform body F. Respiratory Dysfunction 1. Ataxic breathing 2. Decrease of voluntary control of breathing secondary to corticospinal destruction and lack of intercostal muscle control
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3. Loss of automatic breathing (Ondine’s curse) G. Autonomic Dysregulation 1. Mild ptosis with hypohidrosis a. Severe miosis (0.5 mm pupil) with pontine infarction b. Dissociation of ptosis and pupillary sympathetic fibers is due to a somatotopic arrangement of sympathetic fibers around the N. ambiguus 2. Bladder retention or inhibited contractions only occur with bilateral MMI H. Cranial Nerve XII 1. Isolated contralateral XII nerve 2. More common with hemorrhage than infarction I. Isolated Drop Attacks 1. May progress to stroke over several days 2. Ischemia of: a. Medullary or pontine corticospinal fibers b. Medial reticular formation involvement (loss of tone)
Differential Diagnosis of Vascular Etiologies of Unilateral Medial Medullary Infarction
a. b. c. d. e.
Branch occlusion from VA (upper medulla) Dolichoectasia of vertebrobasilar system Embolus Syphilis Branch occlusion from the anterior spinal artery (lower medulla) secondary to atheroma f. of the VA or anterior spinal artery
Underlying Associated Conditions
a. b. c. d. e.
Diabetes mellitus Birth control pills Dissection of VA in 3/4 of patients Thrombosis of VA in 3/4 of patients Embolus in 1/4
Bilateral MMI Infarction
A. Clinical Features: 1. Quadriplegia (flaccid) 2. Associated loss of lemniscal sensation 3. Paralysis of the tongue 4. May have step wise progression 5. Bladder retention or uninhibited contractions 6. Death by cardiorespiratory failure B. Differential diagnosis: 1. Anomalous anterior spinal from one vertebral artery 2. Occlusion of the ASA after it forms a single vessel
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SECTION I. Vascular Disease
Medial and Lateral Syndrome (Babinski–Nageotte)
1. Clinical features of combined LMI and MMI: a. IX, X, XI, XII ipsilaterally b. Horner’s ipsilaterally c. V ipsilateral (most often STT modalities) d. Ocular findings (LMI and MMI) e. Contralateral hemiparesis; may be ipsilateral (depending on infarction below decubation be C2) f. Lemniscal and STT sensory loss (contralateral) g. Ipsilateral ataxia
Pontine Infarction
1. General Features a. Isolated pontine infarction occurs in 15% of acute vertebrobasilar strokes b. The territory supplied by intrinsic pontine vessels is constant c. In 1/3 of patients TIAs precede stroke onset: 1) Spontaneous laughing and crying spells – “Fourier prodromique” 2) Herald hemiparesis 3) Pseudoseizure – tonic limb spasms with consequent paresis
d. Dysarthria clumsy hand (DCH) syndrome e. AH and DCH occur in the middle upper pons; in the ventrolateral pons, or at the ventrotegmental junction f. Dysarthria (posterior 1/3 of ventral pons; medial)
Patterns of Weakness in Pontine Hemiparesis
a. Greater in the distal upper extremity than lower extremity b. Less commonly the leg has distal weakness greater than the arm c. Crural or brachiocrural paresis with preservation of finger and toe movement d. Arm fibers – disrupted by more dorsal lateral lesions e. Leg fibers – disrupted by more lateral lesions f. Facial palsy associated with palato-glossal weakness – involvement of pontomedullary bundle g. Dysarthria more common in left pontine infarction h. Isolated dysarthria and facial weakness are rare i. Correlation of severity of motor deficits and contralateral ataxia j. Ataxia – involvement of corticopontocerebellar fibers (Türck’s tract); make up the MCP
Ventral Pontine Infarcts and Tegmental Involvement Ventral Infarction of the Pons
a. Most common type; approximately 55% of pontine infarcts b. Occlusion of anteromedial or anterolateral arteries (from the basilar artery) c. Localized to the middle or lower pons d. May involve the medial tegmentum e. Rarely reaches the floor of the IVth ventricle
Ventromedial Pontine Syndrome
a. Large infarcts: anteromedial or anteromedial and anterolateral territories b. Facio-brachial crural hemiparesis with dysarthria c. Homolateral (to the motor deficit) brachiocrural ataxia; occasionally contralateral curral ataxia d. Dysarthria with medial infarction at the level of the MCP
Ventrolateral Pontine Syndrome
a. Smaller infarction in anterolateral territory b. Pure motor hemiparesis (PMH); leg representation is dorsolateral c. Ataxic hemiparesis (AH)
1. 3/4 of patients – associated medial tegmental dysfunction, usually mild and transient a. Lemniscal sensory deficit b. Vth nerve weakness c. Decreased level of consciousness d. Fascicular VIth nerve palsy e. Intranuclear ophthalmoplegia f. One and a half syndrome (abduction alone of the contralateral eye) 2. Collateral vascularization of short and long circumferential vessels is the explanation for transient nature of tegmental signs 3. isolated dorsal pontine syndrome is rare, suggests nonischemic etiology
Tegmental Pontine Syndrome
1. Represent approximately 30% of pontine infarctions 2. Small lacunar infarcts 3. Mediolateral tegmental area of the middle upper pons; occlusion of short circumferential vessels 4. Mild motor deficit 5. Eye movement disturbance 6. Lemniscal or spinothalamic sensory loss 7. Cranial nerve palsy V to VII
Chapter 1. Ischemic Stroke Ventrotegmental Pontine Syndrome
Bilateral Ventrotegmental Infarcts
1. Combination of lateral and medial tegmental signs 2. Intranuclear ophthalmoplegia with severe motor deficit
1. 2. 3. 4. 5. 6. 7.
Lateral Pontine Syndrome (Long Circumferential Cerebellar Arteries)
1. AICA or superior cerebellar artery infarction 2. Lateral pontine syndrome of Marie-Foix is rare a. Homolateral cranial nerve palsies are rarely seen
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Least common of isolated pontine infarcts (11%) Associated with extension or multiple brainstem infarction Acute pseudobulbar palsy Bilateral motor deficits with tegmental signs Para and tetraplegia Ataxic tetraparesis Locked in syndrome: a. Awake b. Unable to move c. Upgaze and eye closure maintained
Pontine Pure Motor Hemiparesis (PMH)
Clinical features of pontine hemiparesis: 1. Dysarthria, vertigo, gait abnormality 2. Lacunar process (spares the basal surface); if the basal surface is involved this suggests a branch artery occlusion 3. Approximately 60% have transient symptoms 4. Midpontine – primarily upper limb involvement 5. Mild dysarthria-corticobulbar fibers are affected 6. Contralateral cerebellar ataxia (25% of patients)
Basilar Branch Disease
a. Nonlacunar (maximal diameter > 1.5 cm) b. Unilateral ventral infarct extending to pontine surface c. Bilateral infarcts: atheroma of the basilar artery wall occludes one or more perforators d. Motor deficits with fluctuating and progressive course e. Small artery disease: tegmental or small ventral infarcts do not extend to the surface of the pons; 1) Classic lacunar syndrome
Pontine Ischemic Rarefaction (MRI Evaluation)
1. 2. 3. 4. 5.
Hypertensive vascular changes Increased perivascular changes Perivascular demyelination Gait instability MRI increased T2 pontine signal
Pontine Signs
1. 2. 3. 4.
Horner’s syndrome (lateral involvement) Hypogeusia (ipsilateral taste loss) Hemiataxia (MCP) Oculopalatal pharyngeal myoclonus a. Mollaret’s triangle b. Disruption of fibers between the inferior olive, dentate nucleus and the VL nucleus of the thalamus 5. Contralateral STT sensory loss
Isolated Tegmental Pontine Infarcts
1. Supranuclear eye movement disturbance 2. Sensory deficit: one limb; cheiro-oral pattern a. Abducens palsy (isolated) b. Facial palsy (isolated)
Clinical Signs and Symptoms of Basilar Artery TIA Prior to Infarction
1. Increasing TIA frequency 2. Diplopia, vertigo, blurred vision, ataxia, gait disturbances, hemiparesis 3. Confusion and somnolence; to stupor and coma 4. Motor abnormalities, pupillary abnormalities, hyperreflexia, bilateral Babinski signs
Clinical Signs and Symptoms of Basilar Artery Thrombosis
1. 2. 3. 4. 5.
Herald hemiparesis Dizziness most frequent early symptom Dull, non-throbbing headache (basiocciput) Alternating levels of consciousness (confusion to stupor) Dysarthria, pseudobulbar symptoms, paralysis of the tongue, emotional lability 6. VI and VII cranial nerve palsies with contralateral hemiplegia and paraesthesias 7. Bilateral pontine infarction symptomatology 8. Ocular bobbing, ocular dipping, arm), head tilt (ipsilateral) c. Paraverbal involvement: dysarthria; left sided paravermal zone of rostral cerebellum causes consistent dysarthria
Clinical Signs and Symptoms
1. Prodromal vertigo (minutes); dizziness, dysarthria a. Ipsilateral peripheral VIInd nerve (small artery to facial nerve in CPA angle) b. Hearing loss (sudden) ipsilaterally c. Ipsilateral Vth nerve involvement d. Horner’s syndrome (ipsilaterally) e. Ipsilateral appendicular dysmetria (arm > leg) f. Contralateral loss of pain and temperature of the limbs and trunk g. Delayed facial paralysis Unusual Signs
a. Ipsilateral conjugate or lateral gaze palsy (floccular involvement) b. Dysphagia (superior part of the lateral medulla) c. Ipsilateral motor weakness (involvement of the corticospinal tract in the pons or mesencephalon contralaterally) d. Periodic alternating nystagmus
Differential Diagnosis of Causes of SCA Infarction
Coma
1. Cardiac embolic source 2. Artery-to-artery embolus a. Vertebral artery b. Aortic arch 3. Vertebral dissection 4. In young patients a. SCA dissection b. Fibromuscular dysplasia (FMD) c. Patent foramen ovale (PFO)
Anterior Inferior Cerebellar Artery Infarction
1. Origin: first 1/3 of the basilar artery 2. Brainstem signs at presentation 3. Involved territory: lateral caudal pons; middle cerebellar peduncle (always involved) 4. Supplies the inner ear: internal auditory artery from which derive the anterior vestibular artery; common cochlear artery 5. 70% involve the anterior inferior flocculus 6. AICA and PICA may arise from a common trunk from the vertebral or basilar artery 7. Anastomosis between the AICA and PICA – constant when both arteries have equal dominance 8. AICA dominance on one side; then consequent ipsilateral vertebral PICA hypoplasia 9. Infarction of the inferolateral pons; may extend up to the middle third of the lateral pons or down to the superior part of the lateral medulla 10. AICA infarction: may be associated with PICA and SCA infarction with consequent ventromedial pontine infarction
a. Tetraplegia (massive ventromedial infarction of the basis pontis) b. Cerebellar infarction PICA/AICA/SCA distribution c. Isolated vertigo mimicking labyrinthitis; infarction of the internal auditory artery or its superior vestibular division d. Isolated cerebellar signs Differential Diagnosis of SCA and AICA Infarction
1. Atherosclerotic lower basilar artery occlusion 2. Occlusion of the vertebral artery above PICA 3. Vascular anomalies of the vertebrobasilar system: a. Persistent trigeminal artery with embolus from carotid system b. Dolichoectasia of the basilar artery c. Hypoplastic vertebral artery 4. Pure AICA: a basilar branch occlusion; plaque in the basilar extends to occlude its origin; micro atheromata block the origin of the artery 5. Migraine (Bickerstaff variant) 6. Extracranial and intracranial vertebrobasilar dissection: a. Intradural dissection: 1) Subadventitial hematoma of the basilar artery causes: a) Subarachnoid hemorrhage b) Brainstem stroke c) Pseudoaneurysm d) May occur silently b. Extracranial dissection 1) Hematoma within the media or intima 2) Emboli at the site rather than a blood flow limiting process cause symptoms
Chapter 1. Ischemic Stroke
7. Post operative cerebellar and brainstem stroke: Signs and symptoms: a. Altered consciousness; stupor, restless agitation b. Vestibulocerebellar syndrome Differential diagnosis: a. Neck positioning during or after surgery b. Thrombus that embolized from compressed arteries 8. Hypercoagulability after surgery a. Increased thrombin activity b. Increased fibrinogen c. Increased factor VIII d. Decreased fibrinolytic activity e. altered platelet function
Posterior Cerebral Artery (PCA) Infarction
Vascular Territory Supplied by the PCA
General 1. Major blood supply of: midbrain, thalamus, occipital lobes, part of the posterior inferior parietal lobe 2. The arterial segment prior to the posterior communicating artery fusion with the basilar artery is the P1 segment a. 10% of PCAs take origin from the carotid artery (fetal origin). If this occurs, there is a concomitant hypoplastic P1 from the basilar artery 3. 29% of patients have large or (24%) unusually small PCA arteries Vascular Supply 1. Vascular supply of the P1 segment (peduncular or pre communal segment; between the tip of the basilar artery and the posterior communicating artery) is: a. Medial midbrain; posteromedial thalamus b. Origin of the paramedian mesencephalic arteries (take off is the top of the basilar) 2. Tuberothalamic (polar arteries) a. Origin is the posterior communicating artery b. Anterior and anterolateral thalamus c. Tuber thalamic artery may be absent. Its territory is then supplied by the thalamic subthalamic artery (thalamoperforating arteries) 3. P2 segment is the origin of the peduncular perforating (PPA); thalamogeniculate arteries (TGA) a. Thalamoperforate artery supplies: 1) Lateral midbrain 2) VA and VL of the motor thalamus 3) Part of the internal capsule 4) VPL, VPM of the thalamus b. Thalamogeniculate artery supplies the ventrolateral thalamus: arteries arise form the ambient portion of the PCA c. Anterior temporal artery arises form the ambient portion of the PCA and supplies the medial temporal lobe
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d. Posterior temporal artery (origin between the tentorium and the medial temporal lobe) e. Parietooccipital artery: originates form the ambient segment; supplies the occipital and medial inferior parietal lobe); this branch is the origin of the posterior pericallosal artery f. Calcarine artery 1) Usually arises as a single branch of the PCA 2) In 16% of patients the calcarine artery arises from the parietooccipital artery
Clinical Symptoms and Signs of Unilateral PCA Ischemia and Infarction
1. PCA stenosis: a. TIA’s precede infarction b. Usually atherosclerotic narrowing 2. General Features of PCA Infarction: a. Ambient section is affected most frequently which causes a hemispheric branch occlusion b. P1 segment – 13% of PCA occlusions c. PCA with thalamic involvement – 37% of infarctions d. Occipital, parietal and posterior temporal branch arteries are frequently involved concomitantly e. Anatomic areas involved: medial midbrain, posteromedial thalamus, lateral thalamus, and posterior hemisphere f. Penetrating arteries from the top of the basilar artery may arise from one PCA (artery of Percheron) and therefore the thalamic infarction may be bilateral and paramedian: 1) Infarctions are usually embolic from the heart, proximal aorta and the proximal vertebral arteries (to the top of the basilar artery) 2) Patients that have suffered rostral paramedian tegmental mesencephalic and posteromedial thalamic infarcts are comatose, hyper somnolent and may demonstrate vertical gaze palsies and an amnestic state The distinguishing features of proximal PCA infarction (P1 precommissural branch) are: a. Hemiplegia, infarction of the cerebral peduncle (medial 3/5); may spare the face b. Paramedian mesencephalic and PPA arteries are involved c. Partial or complete III nerve palsy d. Nuclear III rd nerve signs include: 1) Bilateral ptosis (central caudal nucleus) 2) Failure of upgaze bilaterally (superior rectus is bilaterally innervated) 3) Dilated pupils 4) Rare a. Midline infarctions: patients are lethargic and abulic
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SECTION I. Vascular Disease
Ambient Segment (P2) Infarction (Thalami Perforating Artery)
Occlusion is proximal to the origin of the thalamogeniculate artery: 1. Vascular supple to the motor thalamus a. Ventroanterior, ventrolateral nuclei b. VOA, VIM, VOP (stereotactic nomenclature, part of VL) 1) VIM is the target for stereotactic surgery to relieve tremor) 2. Motor symptoms: a. Contralateral 4–6 HZ tremor b. Usually sudden onset of choreoathetosis: 1) Frequent arterial involvement of diabetic patients c. Rare contralateral dystonia d. Thalamic hand e. More medial lesions in this territory cause thalamic ataxia 1) Interrupt cerebellar projections (dentatorubral loop) 2) “ataxia of stance”
Thalamogeniculate Artery Infarction (TGA)
a. Infarction of the lateral thalamus and posterior temporal lobe is known as the syndrome of Foix–Hillman a. Pathogenesis: trunk PCA occlusion (multiple penetrating branches involved) or single atheromatous branch occlusion
Symptoms of Ventrolateral Thalamic Infarction (thalamogeniculate artery, TGA)
1. Sensory symptoms a. Leg may be involved most severely; pattern of face, arm and leg b. Conscious perception that the symptoms bisect the body (face, trunk, penis) c. Intraoral involvement (may be bilateral) d. Quality of sensation: tingling, pricking, crawling, burning (active dysesthesias and paraesthesias) e. Loss of pinprick, touch, or thermal sensation. May lose vibration sensibility which is rarely lost with cortical infarction. The other location for vibratory loss is the dorsal column nuclei. f. If medial, ventrolateral or thalamoparietal projections are involved: a. Proprioceptive, thermal sensory loss, decreased pain g. Tips of the fingers of the contralateral hand (VPI nucleus) 2. Slight hemiparesis 3. Clumsiness and ataxia (dentate thalamic projections) 4. Choreiform and ataxic limb movements (contralateral)
5. Thalamic hand posture 6. Clinical symptomatology of thalamic pain: a. Delayed onset (months after VPM/VPL infraction) b. Hyperpathic c. Mechanical and thermal hyperalgesia and allodynia of the affected area d. Spontaneous e. If provoked-not stimulus bound 7. Associated infarcts in the temporal and occipital lobes if midbrain and thalamus are involved
PCA – Hemispheral Infarction
1. Visual field loss: a. Most common defect – contralateral homonymous dense VF loss b. Infarction may occur in: lateral geniculate body, optic radiations, or the striate cortex c. 50% of patients are aware of the deficit d. If unaware of the deficit there is parietal lobe involvement 2. Acute or with resolution of VF defect: a. Photopsias, colors, and hallucinations in the affected field 3. Usual VF deficits: congruent contralateral hemianopia, inferior or superior quadrantanopsia a. Macular sparing often noted (middle cerebral artery supply) b. Involvement or sparing of the contralateral visual temporal crescent (anterior most portion of the calcarine fissure subserves the most peripheral temporal field) c. Homonymous central scotomata (occipital pole infarct) d. “Checker board” deficit (one inferior quadrant with contralateral superior quadrant) 4. Complex visual phenomena Visual Perseveration a. Object seen in sighted field-then noted in the defective hemifield although gaze fixation maintained b. Object in sighted field appears in the defective hemifield after gaze is shifted to defective field c. Palinopsia (perseveration of an object) d. Motion detection in blind field but no ability to discriminate (Riddoch’s object phenomena) e. Defects in distance, depth and localization in the defective hemifield 5. Sensory symptoms of PCA hemispheric infarction a. Paraesthesia, numbness or loss of pain; thermal or positional sense loss
Higher Cortical Deficits from Hemispheric Infarction
1. Dominant Hemisphere: parieto-occipital and or temporal branch occlusion:
Chapter 1. Ischemic Stroke
2.
3.
4.
5.
a. Alexia without agraphia patients; write, speak, and spell normally. They cannot read words or name colors (damage must include left occipital cortex and splenium of the corpus callosum). Can read letters and numbers. Cannot access Wernicke’s area b. Alexia with agraphia 1) Angular gyrus or white matter of the inferior parietal lobule involved 2) Abnormalities of reading, writing, and spelling Inferior parietal lobule infarction a. Decreased ability to read letters and paragraphs b. Decreased spelling and writing c. Components of Gerstmann syndrome are noted: dyscalculia, finger agnosia, right left confusion, and dysgraphia and conduction aphasia. The latter may be accompanied by paraphasia Paralexia a. DH: reading errors to the right side of words b. NDH: reading errors at beginning of words Visual agnosia a. Dominant hemisphere b. Concomitantly with alexia and agraphia and decreased color naming Amnesia a. Involvement of left hippocampus and adjacent white matter
ND Hemisphere – PCA Infarction
a. Neglect of contralateral visual field b. Constructional apraxia (parietal and temporal lesions) c. Right posterior parietal lesion-disorientation for geographical space d. Reduplicative paramnesia (two versions of a geographic location)
Mechanisms of Unilateral PCA Infarction
1. Embolism: cardiac, proximal vertebral artery, arch of aorta, fetal origin of PCA 2. Emboli arise from the end of atheromatous plaques of recently occluded proximal vertebral artery 3. African Americans and Asians patients: infarction is more frequent in context of stenosis with in situ thrombosis 4. Migraine 5. Coagulopathy 6. Transtentorial herniation – temporal and calcarine branches compressed against the tentorium
Bilateral PCA Infarction
1. Infarcts often restricted to bilateral inferior or superior calcarine branches
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Clinical Syndromes
A. Cortical blindness (Anton’s syndrome) 1. Bilateral infarction of the striate cortex a. Anton’s syndrome 1) Denial of blindness 2) Maneuver around objects (visual crescent remains, bilateral hemianopsias or scotomata) 3) Visual confabulation 4) Normal pupillary reaction to light 5) Euphoria B. Balint’s Syndrome (Superior Parietal and Occipital Lobe) 1. Simultagnosia (patients see objects piecemeal); cannot describe the entire object) 2. Optic ataxia (lack of coordination of hand eye movements; usually under reaching the object) 3. Apraxia of gaze (inability to look at an object on command) 4. Difficulty in breaking fixation of gaze 5. Poor visual scanning of areas of interest 6. May be limited to one visual field C. Amnesia 1. Bilateral infarction of the temporal lobe 2. Amnesia occurs concomitantly with visual sensory loss and acute depression of level of consciousness D. Emboli and infarction (below calcarine fissure) 1. Upper quadrant altitudinal defect 2. Abnormal color perception 3. Difficulty in recognizing faces (prosopagnosia) 4. Inability to re visualize the form of an object; able to re visualize direction and place relationships of objects 5. Agitated delirium (involvement of the lingual and fusiform gyri, inferior temporal lobe) 6. Central achromatopsia (may perform adequately on Ishihara plates) unable to match hues or colors 7. Agitated delirium (left posterior inferior temporal lobe) 8. Emboli to tip of the basilar artery have predilection for inferior calcarine branches Bilateral Superior Bank Infarction a. Severe hypotension (MCA/PCA border zone) is the usual mechanism b. Less common than lower bank infarcts c. Disorientation to place, difficulty in revisualization of locations (where people and places are topographically) E. Pathogenesis of Bilateral PCA Infarction 1. Seriatim infarction; stenosis of arteries from atherosclerosis 2. Simultaneous; embolus to top of the basilar artery or from thrombus in the basilar artery 3. Capillary-leak syndrome (primarily white matter) of the occipital lobe a. Hypertensive encephalopathy
SECTION I. Vascular Disease
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b. c. d. e.
Cyclosporine and FK 506 (tacrolimus) Uremia Eclampsia Dissection of distal basilar artery
a. Homonymous horizontal sectoranopia 2. AchA a. AchA-middle horizontal sector is spared
Ocular Motility Deficits with PchA Infarction Infarction of the Lateral Posterior Choroidal Artery (L PchA)
PchA territory involved: 1. Lateral geniculate body (LGD) 2. Pulvinar and posterior thalamus 3. Hippocampus and parahippocampal gyrus Clinical syndromes of lateral PchA infarction 1. Homonymous quadrantanopsia 2. With or without hemisensory loss 3. Homonymous horizontal sectoranopia (lateral LGD) 4. Memory loss 5. Delayed movement disorder 6. Transcortical aphasia Specific visual field deficits 1. Wedge or tubular homonymous sectoranopia with delayed sectorial optic atrophy 2. Lower or upper quadrantanopsia more common but less specific with LGD infarction 3. Wedge or tubular sectoranopia also possible with AchA, MCA, PCA infarction 4. Visual field deficits with concomitant anatomical lesions of the LGD Correlative anatomy of the lateral geniculate body 1. Anterolateral LGD subserve lower quadrants 2. Anteromedial LGD subserve medial quadrants 3. Posterior LGD subserve the macula 4. Central LGD: supplied by lateral posterior choroidal artery a. VF defect: homonymous horizontal sectoranopia b. Supplied by PchA 5. AchA also supplies the LGD Visual field deficits 1. Quadruple sectoranopia is characteristic 2. Complete homonymous hemianopia 3. Superior quadrantanopsia-may have macular sparing 4. Homonymous hemianopia a. Sparing of the horizontal sector b. Inferior lateral LGD infarction 5. Homonymous superior-quadrantanopsia a. Lateral geniculate infarction b. Infarction of: 1) Optic tract 2) Origin of the geniculocalcarine tract
Differential Point Between AchA vs PchA Infarction by VF
1. PchA
1. Impairment of ipsilateral pursuit 2. Poor contralateral saccades
Sensory Symptoms with PchA Infarction
1. Involvement of thalamic radiations of the internal capsule or damage to ventroposterior nucleus (caudal part)
Motor Symptoms of PchA Infarction
1. Damage to corticospinal or corticobulbar fibers in the internal capsule (PchA) 2. AchA more severe hemiparesis than PchA
Aphasia and Higher Cortical Deficits (PchA)
1. Transcortical motor aphasia – pulvinar damage 2. Transient visual and verbal memory disturbance 3. Disorientation for time without confusion or confabulation a. May also be seen following thalamic stereotactic surgery 4. Abulia 5. NDH lesion: a. Visual spatial processing deficit with dorsal lesions
Thalamic Stroke with PchA Infarction
1. Neuropsychologic deficits 2. Pulvinar infarction on CT/MRI 3. Paramedian infarction; tuber thalamic artery involvement (concomitant)
Visual Hallucinations (PchA)
1. Paramedian thalamic infarction
Medial Posterior Choroidal Artery (M PchA)
General Features: 1. Territory supplied: medial pulvinar; dorsomedial thalamus; anterior thalamic nuclei 2. Less common than lateral PchA infarcts
Chapter 1. Ischemic Stroke Clinical Signs and Symptoms
Ocular Signs (Midbrain)
1. 2. 3. 4.
Nystagmus retractorius Up gaze or horizontal gaze paralysis Meiosis Central Horner’s syndrome
Sensory Loss (MpchA)
a. Lemniscal or spinothalamic Motor Symptoms
a. Mild hemiparesis Pathogenesis (MpchA)
1. HCVD and DM 2. Cardiac embolism, large artery disease, migrainous stroke, catheter induced thrombosis
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patients tend to infarct the border zones of the posterior circulation. Specific syndromes have been described for many of these infarctions. The “man in the barrel” suggests an anterior cerebral/middle or cerebral artery border zone infarction. The shoulder on upper arm components of the homunculus are involved. These patients have preserved intrinsic hand muscle function. Posterior MCA/PCA infarction may cause Balint’s syndrome of infarction of the superior parietal lobule. These patients have a simultagnosia, poor optic scanning, failure to break fixation and optic ataxia. Ascending lenticulostriate and penetrating medullary vessels from pial conducting vessels cause the periventricular vascular stripe. Leg fibers may be preferentially affected. Isolation of the speech area suggests serve cortical hypoxia, carbon monoxide poisoning or hypotension. Ischemia of the optic nerve head from poor perfusion of the central retinal artery and posterior ciliary artery with giant cell arteritis and prolonged hypotension. Border zone infarcts of the brainstem do not demonstrate clear patterns of anatomical localization as those of the anterior circulation. The following discussion is of the differential diagnosis and characterization of border zone infarcts.
Differential Diagnosis of M PchA vs Pch A vs Ach A
1. M PchA: a. sensory loss is noted acutely with later onset of pain and abnormal movements 2. Movement disorder: a. Choreoathetotic myoclonic syndrome b. Pseudobulbar tremor c. Dystonic posture of the fingers d. Dystonic thalamic hand worsened by voluntary activity e. Akathisia 3. L PchA infarct a. Sectoranopia VF deficit 4. AchA infarct: a. Quadruple sectoranopia VF deficit b. Greater hemiparesis than L PchA stroke
Border Zone Infarction
Border zone infarctions occur between two or three arterial territories during prolonged periods of hypotension or cardiac arrest. The infraction may occur between pial conducting vessels or internally between ascending vessels that are feeding deep nuclear structures and descending penetrating vessels. They tend to be symmetric and occur in characteristic areas. There are internal laminar infarctions between the capillaries that are the functional metabolic columns of the brain. An O2 molecule diffuses approximately 10μ from the hemoglobin of its 7μ RBC. These 10μ constitute the functional intercapillary metabolic zones of the brain. Patients less than 40 years of age have infarctions in the anterior circulation while older
Border Zone Infarcts
1. Infarctions at the junction between two or three arterial territories a. watershed infarcts 1) Between two arterial territories with a reciprocal arteriolar collateral network: a) In the hemisphere between two pial networks 2) End artery border zone infarcts a) Terminoterminal infarcts
Differential Diagnosis
1. Stenosis or occlusion of extracranial arteries Initiating factors: bradycardia, high hematocrit, systemic hypotension, drop in cerebral perfusion pressure 2. Systemic hypotension due to: a. Cardiac surgery b. Bilateral symmetrical distributions c. More common in posterior watershed zones (MCA/ PCA) 3. Systemic disease a. Artery-to-artery cholesterol microemboli b. Sickle cell anemia c. Polycythemia vera 4. Clinical features of border zone infarcts a. Rare headache b. Syncope at onset c. Dizziness in brainstem zones
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SECTION I. Vascular Disease
Anterior Border-Zone Infarction (MCA Territory)
Posterior Border-Zone Infarction (MCA/PCA Territory)
1. Clinical patterns a. Motor weakness of the contralateral leg > arm with spared face; shoulder weakness 2. DH infarcts: a. Transcortical motor aphasia b. No initial mutism (more for stem or SMA occlusion) 3. NDH: mood disturbance usually mild or absent 4. Proximal arm weakness with preserved distal movement and strength if limited to the cortex “Man in the Barrel” if bilateral: a. Severe shoulder proximal weakness b. Preserved strength and fine movement of the hand c. Preserved movement of the thumb; extremely rare in core MCA territory. Thumb may be spared in posterior motor knuckle syndrome d. Similar pattern may occur with multiple emboli from MI stenosis
1. Lateral homonymous hemianopsia or lower quadrantanopsia 2. Transcortical sensory or Wernicke’s aphasia 3. No pure alexia 4. NDH: hemineglect and anosognosia 5. Brachiofacial hemiparesis or no motor deficit 6. Hemihypesthesia and cortical sensory loss
Internal Watershed
1. Homolateral carotid stenosis with M1 in situ stenosis: a. Ischemia of periventricular white matter b. Sensorimotor stroke c. Occurs in a setting of severe systemic hypotension 2. Patients with ICA occlusion have no border zone infarction in this distribution if there is collateral flow through the posterior communicating artery
Deep Cerebral Infarcts Extending to the Subinsular Region
1. Extend between the lateral ventricle and subinsular region 2. Paraventricular region extends for 7.5 cm 3. Subinsular extent of 1/3 of the anterior posterior extent of the insula 4. Clinical features a. Hemiparesis b. Aphasia (transcortical conduction type) c. Dysphasia d. Dysarthria 5. Clinical features overlap with paraventricular infarcts 6. Deep cerebral infarcts (DCI) > paraventricular infarcts a. Risk factors: 1) Cigarette smoking 2) HCVD 3) Large artery occlusion (ICA; MCA) 7. Larger size of DCI a. Poorer collateral blood supply
Capsular-Thalamic Border Zone Infarction
1. Deep border zone between the carotid and vertebrobasilar circulation 2. Ischemic area is between the internal capsule and lateral thalamus a. Also territory between the ascending lenticulostriate arteries from the MI segment of the MCA and the descending pial MCA arteries (medullary arteries) 3. Clinical signs and symptoms a. Brachiofacial paresis b. Corresponding sensory loss (cortical type) c. DH: subcortical aphasia 4. Vascular stripe on MRI a. T2 weighted signals periventricularly
Bilateral Hemispheric Border Zone Infarction
1. 2. 3. 4.
Transient loss of consciousness (global hypoperfusion) Bilateral motor and sensory loss No dysconjugate eye movements (I & O or 1½ syndrome) Bilateral cortical anterior border zone: “man in the barrel” syndrome (proximal arm muscles weakness) 5. Deep subcortical white matter: paraparesis or plegia (spinal stroke pattern); motor cortical fibers to lower extremities (infarction of the centrum semiovale) 6. Bilateral posterior border zone infarction a. Balint’s syndrome (optic ataxia) b. Anton’s syndrome (cortical blindness) c. Visual disorientation and hallucinations
Border-Zone Cerebellar Infarction
A. General Features: 1. Less than 2 cm in diameter 2. Between SCA and PICA boundary zones 3. Between left and right SCAs on the cortex 4. Between SCA and PICA branches in the deep cerebellar white matter B. Involved Territories 1. Cortical border zone infarcts a. Perpendicular to the cortex
Chapter 1. Ischemic Stroke
b. At boundary zones between 1) SCA and PICA territories 2) AICA-PICA 3) Medial PICA–lateral PICA 4) Medial PICA-SCA 5) Medial SCA–lateral SCA c. Between the medial rostral territories of the right and left SCA territories 2. Deep watershed territory: a. Caudal cerebellum b. Deep boundary zones of AICA–lateral PICA, medial PICA–lateral SCA and medial SCA territories c. Appear as round holes above the dentate nucleus; d. Rare cortical dorsal border zone infarcts between PICA and SCA territories C. Clinical Features 1. Similar to territorial infarcts 2. Rarely: transient loss of consciousness; pitching sensation; dysequilibrium 3. May represent low flow state of the posterior circulation D. Differential Diagnosis of Pathogenesis (BZI) 1. Focal hypoperfusion from severe occlusive disease of the vertebral or basilar artery secondary to atherosclerosis 2. Rarely generalized hypotension
Border-Zone Brainstem Infarction
1. Hypotensive setting 2. Symmetrical necrosis of the tegmentum a. Between pontine penetrating vessels and short and long circumflex arteries 3. Clinical picture a. Cranial nerve/brainstem dysfunction b. Coma
Granular Cortical Atrophy
1. Multiple small foci of cortical infarction in all borderzones
Lacunar Stroke
Lacunes are small ovoid lesions 1–2 mm in size noted in deep nuclear grey matter of the basal ganglia and thalamus as well as the internal capsules, centrum semiovale and pons. They are found in the setting of poorly controlled diabetes and hypertension. They are caused by fibrinoid necrosis of the endothelium and adventia of the single perforating arterioles. The infarct is limited to the territory of deep perforators and is caused by in situ infarction. The process may also be caused
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by atheromatous occlusion of the mouth of these blood vessels. If a series or group of perforators are involved simultaneously emboli are suspected as causal (thus most often occurs in the lenticulostriate territory). Discrete clinical syndrome are noted with infarctions of these perforators which outline their territory and allow anatomic localization. Involvement of arm, face, and leg suggests lacunar infarction of the middle 1/3 of the posterior limb of the intend capsule. Genu involvement is suggested by more face than arm involvement and severe dysarthria. The posterior 1/3 of the capsule may be selectively involved with hemisensory numbness. Occasionally, a single extremity may become weak from involvement of the medullary strica arteries is then perfuse the centrum semiovale. The motor and sensory fibers are separated in the fiber deep into the brain. The dysarthria clumsy hand syndrome occurs from posterior ventral 1/3 pontine infarction in which the corticobulbar fibers, speech and arm fibers are closely opposed. Ataxic hemiparesis suggests pontine lacunar involvement at the midpontine level. Lacunar infarctions rarely ever are associated with headache VF cut or aphasia. Pine motor, pure sensory and mixed deficits are common. There is no cortical sensory, behavior manifestations which differentiates this from pial artery stroke. Puremotor hemiparesis with III nerve pattern (Weber, Benedict; Claude’s and Nothnagel’s) places the lesion in the midbrain. Rarely hemiballisms occurs from lacunar infarction of the subthalamic nucleus due to paramedian thalamic involvement. Lacunes of basilar artery territories are suggested by dizziness, diplopia, and intranuclear ophthalmoplegic without weakness.
Lacunar Disease
1. General Features: a. Involvement of the territory of one single perforating arteriole b. ACA > PCA 2) 2–5 cm long 3) Selective territories 4) No collaterals 5) Subserves the centrum semiovale 6) Do not anastomose with the deep perforators (lenticulostriate arteries) e. Cortical arteries with subcortical territories that supply: 1) U fibers 2) Extreme capsule 3) External capsule 4) Claustrum f. Most commonly found: 1) Centrum semiovale 2) Basal ganglia 3) Thalamus 4) Midbrain 5) Pons 6) Medulla Infarction in these territories are often not lacunar (i.e., from one perforator) but may be secondary to distal field ischemia (carotid stenosis) or cardiac thromboembolism.
Epidemiology of Lacunar Stroke
1. Lacunes – 20–30% of ischemic strokes 2. Blacks and Hispanics 2x incidence of whites 3. No increase in HCVD, DM, cigarette smoking, hypercholesterolemia or TIA compared to other ischemic strokes 4. Some series a 40–50% incidence of ischemic heart disease 5. If a specific lacunar syndrome is present: there is an 87% chance the patient has suffered a lacunar stroke 6. Predictive value for lacunar stroke a. Pure sensory stroke 100% b. Highly correlated 1) Ataxia, hemiparesis 2) Sensorimotor stroke 7. Ataxic hemiparesis can occur from: corona radiata, pons, basal ganglia or thalamus infarction a. Pontine site is the most frequent
8. 25% of lacunes are due to a non-lacunar mechanism a. Atherosclerosis b. Cardiac source of emboli 1) 10–15 perforators are affected simultaneously 2) Larger size
Clinical Presentation of Lacunar Infarction
General Features: 1. Occur more commonly during sleep 2. Arm, face, leg may be affected separately (corona radiata and pons most common areas of infarction) 3. Pure motor, pure sensory or mixed clinical patterns 4. Rare aphasia (a differential point against lacunar stroke) 5. No headache 6. No visual field deficit 7. May have stuttering course over 2–3 days 8. No cortical sensory or behavioral manifestations (strong differential point for lacunar stroke) 9. Cause of multi-infarct dementia (état spongiosis)
Clinical Patterns of Lacunar Stroke
1. Pure sensory stroke (PSS) (primarily thalamus) 2. Pure motor hemiparesis a. Corona radiata b. Middle internal capsule c. Cerebral peduncle (medial 3/5) d. Ventral pons e. Medullary pyramidal 1) At decussation with cruciate pattern (ipsilateral arm; contralateral leg) 3. Ataxic hemiparesis (AH) (pontine grey – MCP and descending CST) 4. Dysarthria clumsy hand syndrome (pons) 5. Pure motor hemiparesis sparing the face (farther posterior in the middle 1/3 of the posterior limb of the internal capsule) 6. Mesencephalic; decreased upgaze (Nothnagel’s syndrome) 7. Thalamic dementia (DM, AV nuclei) 8. PMH with horizontal gaze palsy – lower 1/3 of pons, PPRF (para pontine reticular formation) 9. PMH with III nerve (Weber’s syndrome) 10. PMH with III nerve and ataxia – Claude’s syndrome (midbrain) 11. PMH with III and movement disorder (Benedict’s) (midbrain) 12. PMH with VI nerve palsy (Ramon’s syndrome); pons 13. PMH with confusion (brainstem RF; thalamus AV/DM) 14. Sensorimotor stroke (thalami-capsular) 15. Hemiballism – (STN; paramedian mesencephalic vessels)
Chapter 1. Ischemic Stroke
16. Lacune of basilar territory (dizzy, diplopia, gaze dysfunction) 17. Lateral medullary partial infarction (penetrators from the vertebral artery) 18. Lateral pontomedullary territory (partial AICA) 19. Loss of memory (DM nuclei of thalamus); paramedian perforator 20. Locked in syndrome (infarction of ventral pons; bilateral cerebral peduncles) 21. Unusual lacunar syndromes a. Weakness in one leg with falling (corona radiata; ventral portion of ventral pons) b. Pure dysarthria – posterior 1/3 of ventral pons c. Acute dystonia (thalamoperforate to basal ganglia)
Differential Diagnosis by Arterial Territory and Anatomical Structure of Pontine Stroke with Lacunar Infarction
1. Paramedian arteries a. Medial basis pontis b. Ventral tegmentum 1) Corticospinal tract 2) VIth cranial nerve fibers as they exit 3) Facial nerve fibers as they exit 4) Rare PPRF (para pontine reticular formation by extension) 2. Short circumferential arteries a. Lateral 3/5 of the pons involved 3. Long circumferential arteries a. Lateral tegmentum b. Tectum 1) Cerebellar projections 2) Vth and VIIIth cranial nerves 3) Part of sensory lemniscus infarcted 4. Large bilateral pontine infarcts a. Basilar artery lesions 1) PPRF, 1½ syndrome 2) Ocular bobbing and dipping 3) 75% of patients d. May occur in carotid MCA territory if V1 involved. Occurs 2 weeks after onset of skin lesions or may be delayed 4. SLE a. Vasculitis (inflammation of blood vessels) less common than vasculopathy (abnormalities of blood vessel intima and media) b. Embolic infarcts most common cause of infarction: 1) Libman Sachs endocarditis 2) Chronic valvulitis 3) Mural thrombus c. Antiphospholipid antibodies d. Lupus anticoagulant e. Seizures f. Psychosis g. Recurrent and multiple small strokes 5. Differential diagnosis of noninflammatory angiopathies with multiple strokes: a. Eales Disease (arterioles and venules involved) b. Sneddon’s syndrome (livedo reticularis) c. Moyamoya syndrome (carotid occlusion at siphon with collaterals) d. MELAS (mt DNA) mitochondrial encephalopathy with lactic acidosis and stroke e. Cerebral amyloid angiopathy (associated dementia) f. Intravascular lymphoma (angiotrophic endovascular lymphomatosis); dural involvement g. Arterial dissection of intracranial and cervical arteries (diseases of collagen) D. Hematological Disorders 1. Thrombotic thrombocytopenic purpura (TTP) a. Multiple occlusions of small vessels
SECTION I. Vascular Disease
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2.
3.
4.
5.
b. Large artery occlusion c. Hallucinations d. Renal failure e. Focal cortical deficits f. Seizures Polycythemia vera a. Posterior > anterior circulation stroke b. Megakaryocyte proliferation greater than one million has a high incidence of stroke c. Hemoglobins of 18–22 g/dl d. Rheological abnormalities (dysfunction of laminar flow) Sickle Cell Disease (HbSS) a. Stroke occurs in 3–17% of patients b. Ischemic stroke 15% c. Large and small vessels involved d. Strokes association with thrombosis than IgM c) Stroke risk with secondary APA’s in SLE is increased with: (1) Oral contraceptives (2) Smoking (3) Hypertension 4) Stroke types a) Branch occlusion most common b) Multiple infarcts c) Centrum semiovale strokes d) Cardioembolic from Libman–Sachs endocarditis 5) Vasculitis in SLE a. Ischemic and hemorrhagic stroke b) Intracranial hemorrhage (1) Parenchymal (2) SAH (3) Most associated with vasculitis c) Most likely cause of stroke if: (1) Active systemic disease (2) Normal TEE 6) Associated collagen vascular disease 7) Hyperviscosity syndromes a) Bing–Neel syndrome (poor cerebral perfusion from high viscosity) b) Bleeding gums c) Myeloproliferative and dysglobulinemia states (IgM particularly severe) d) Multiple occlusions of small blood vessels e) Petechial hemorrhage f) Waldenström’s macroglobulinemia (1) Petechia below the knee (2) Acrocyanosis E. Hypoperfusion 1. Severe hypotension (cerebral perfusion pressure of less than 70 mm systolic) 2. Prolonged hypoxemia 3. Cardiac circulatory failure (no reflow phenomena of specific microcirculations) 4. Symmetrical and asymmetrical watershed infarcts 5. Infarcts in deep and superficial MCA territories 6. Cerebellar watershed infarcts 7. Multiple clinical syndromes depending on involved circulations F. Venous infarction 1. Hemorrhagic 2. Specific circumstance: pregnancy, prothrombotic state, cancer, Behçet’s disease 3. Grey matter (basal/thalamus); subcortical white matter Differential Diagnosis of Stroke in Young Patients
Approximately forty percent of cerebral thrombosis in young patients will be caused by HCVD 23%, diabetes mellitus
Chapter 1. Ischemic Stroke
11%, and migraine in 6%. Dissection certainly must be considered in patient with neck or face pain. Carotid dissection will often be announced by oculosympathetic paresis. Posterior neck pain, occasionally accompanied by lateral eye brow pain occurs with vertebral obstruction and dissection. Migraine headaches are characteristic of mitochondrial disease, collagen vascular disease and CADASIL. Sporadic hemiplegic migraine has a greater chance of permanent stroke than familial migraine. Migraine with multiple visual auras is suggestive of anticardiolipin antibody syndrome. Prothrombotic states should always be sought in the context of a family history of thrombophlebitis or venous clotting in the upper extremity or chest wall. Vasospastic occlusion as well as hemorrhage from underlying vascular malformation or aneurysms are characteristics of strokes from cocaine or other sympathomimetic drugs. Oral contraceptives, hypertension and diabetes cause strokes of PICA and the thalamoperforate and thalamogeniculate arteries. Cigarette smoking in this context exacerbates this risk in young patients. Sickle cell disease, leukemia and lymphoma cause approximately 5–10% of thrombotic strokes in young patients. Sickle cell disease is particularly dangerous during pregnancy. Stroke is frequent during chemotherapy for leukemia and lymphoma possibly due to the release of thromboplastin from lysed neoplastic cells. Cardiac causes of stroke in young patients are similar to those in adults except that congenital anomalies, infective endocarditis (drug use), mitral valve prolapse and PFO are more common.
Stroke in Young Patients
1. Approximately 3% of cerebral infarctions occur in patients AVM d. Intracranial hemorrhage
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1) Leukemia 2) Thrombotic thrombocytopenia 3) Aplastic anemia e. Infarction – 18% f. Embolism – 56% cardiac (33% from cardiovascular surgery) g. Thrombosis 1) Carotid 30% 2) Vertebrobasilar 7% 5. Early onset atherosclerosis with or without HCVD associated with: a. Evidence of: coronary artery disease, peripheral vascular disease or arterial occlusive disease 6. Oral contraceptive risk (general) a. 1/10,000 women b. Death from stroke
Migraine
1. 5% of stroke in young women 2. No relation to specific attack 3. Vasospasms, vessel occlusion, platelet hyper agreeability (subset of migrainous)
Pregnancy
1. Pregnancy and the puerperium a. 3% of cerebral thrombosis in young women b. 4% within 30 days
Differential Diagnosis of Stroke from Cross Section of Community or Referral Hospitals
1. Stroke in patients (15 to 44); heterogeneous population a. 50% probable cause b. 20% possible cause c. 30% (cryptogenic); arch of aorta source, PFO and atrial septal aneurysm discovery are decreasing this percentage 2. First Stroke a. 50% women b. 60% black patients (38% of population studies); 35% Caucasian patients (60% of population studied) 3. Patients with recurrent stroke: a. 60%women b. 70% black patients c. 16% arm) 3) Bilateral signs and symptoms 4) May have transient signs and symptoms b. Pseudotumor cerebri if SSS is involved alone: 1) Severe headache 2) Papilledema 3) VIth nerve palsy 4) Decreased level of consciousness 5) Edema and hemorrhage of the medial dorsal cerebral hemisphere 3. Temporal lobe involvement a. Posterior aphasia b. Superior quadrantanopia c. Agitation 4. Cerebellar involvement a. Gait ataxia b. Ipsilateral rotary nystagmus 5. Spread of thrombus: a. Into jugular vein (if an axillary or jugular line is infected the spread is to the lateral sinus) b. Adjacent dural sinuses c. Rare concomitant pulmonary emboli 6. Imaging studies: a. Lytic lesions, opacification of mastoid air cells, eburnation and bone sclerosis b. Secondary cholesteatoma
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Cavernous Sinus Thrombosis
1. Etiology a. Infection of veins draining the medial face, orbit, nose and nasal sinuses b. Infectious etiologies 1) Staphylococcus aureus 4) Gram negative bacteria 2) Pneumococci 5) Mucormycosis (3) Streptococci 6) Aspergillus c. Noninfectious etiologies 1) Surgery of sinuses/facial structures 2) Prothrombotic states 3) Thrombosis of dural A-V fistula 2. Clinical Features: a. Fever; often with stiff neck b. Headache (particularly periorbital) c. Facial pain d. Conjunctival edema and erythema e. Orbital and retinal congestion f. Dysfunction of: 1) III, IV, V nerves 2) V1 and occasionally V2 3) Complete ophthalmoplegia 4) Occlusion of ophthalmic artery (blindness) 5) Bilateral eye findings 6) Involvement of ICA with hemiparesis (rare) 7) Cavernous sinus thrombosis with spread to superior petrosal sinus a) Vth nerve is involved g. Noninfectious etiologies 1) Indolent course 2) Proptosis 3) Conjunctival edema 4) No or minimal occulomotor involvement 3. Cavernous sinus anatomy a. Anterior and posterior intercavernous sinus (connects the two sides) b. Inferior petrosal sinus drains into the sigmoid sinus c. Superior petrosal sinus drains into the transverse or sigmoid sinus
Internal Cerebral Veins; Vein of Galen and Straight Sinus
1. Deep system drains: a. Thalamus d. Geniculate bodies b. Basal ganglia e. Cerebellum c. Midbrain 2. Etiology: a. Dehydration d. Ulcerative colitis b. Sickle cell disease e. Oral contraceptives c. Infection 3. Internal cerebral vein and vein of Galen occlusion: a. Clinical features 1) Patients present stuporous or in coma
SECTION I. Vascular Disease
54
2) Severe headache may precede decreased level of consciousness 3) Hemiparesis b. Thalamic and basal ganglemic hemorrhage 1) Coma 2) Decerebrate posture 3) Vertical gaze palsy 4) Apathy and abulia in some patients as a presenting sign
Jugular Vein Thrombosis
1. Clinical features: a. Headache c. Vomiting b. Fever d. Involvement of IX, X, XI cranial nerves
Cortical Cerebral Venous Thrombosis
1. Clinical features: a. Seizures at presentation b. Focal neurological signs 1) Aphasia 2) Hemiparesis c. Headache d. Less commonly a decreased level of consciousness 2. MRI evaluation: a. Brain edema with hemorrhage b. Pial surface of the hemisphere is involved
Cerebellar Venous Occlusion
1. Clinical features: a. Severe headache b. Incoordination c. Cranial nerve palsies d. Pseudotumoral course with brainstem compression 2. Clinical Features of Venous Sinus Compression from Tumor Metastasis Usual Tumors: a. Ewing’s sarcoma (occipital region of skull) b. Plasmacytoma c. Metastatic lung cancer d. Neuroblastoma e. Choriocarcinoma f. Metastatic breast carcinoma Differential rests between mass beneath the inner table of skull versus tumor invasion of the dura and sinus. Isolated dural sinus thrombosis may be benign. 3. Diagnostic Features of Venous Occlusive Disease: a. Specific circumstances as noted b. Headaches is often the presenting symptom c. Seizure and lethargy more common than in arterial disease
d. Increased intracranial pressure in the absence of focal deficits e. Slower and more indolent progression than arterial disease 4. Imaging evaluation: a. CT: 1) Evidence of sinus and middle ear disease 2) Cord sign a) Cerebral vein imaged as high density linear, thin tubular structure 3) Delta sign at the confluens of sinuses a) Hyperdense triangular mass within the sinus on contrast CT; which does not enhance 4) Bilateral thalamic and basal ganglia hemorrhage 5) Small compressed ventricles 6) Lesions out of a typical arterial distribution b. Contrast enhanced CT: 1) Dilated cortical and medullary veins 2) Gyral enhancement c. Deep Venous Occlusion demonstration by CT 1) Bilateral hypodensity of thalamus and basal ganglia 2) Edema and compression of the IIIrd ventricle 3) Retention of contrast in thalamostriate veins, basilar vein of Rosenthal, non- opacification of vein of Galen d. MRI/MRV: 1) May directly image the occluded venous sinus 2) Demonstrates collaterals e. Arteriography 1) Delineates all venous and arterial structures a) Now necessary as angioplasty and intravenous thrombotics may be options b) Better visualization of congenital variants 2) Multifocal and bilateral 3) Seizures and increased intracranial pressure 4) Cortical surface causes focal leg seizure (superior sagittal sinus) or arm (cortical vein)
Chapter 3 Medical Causes of Stroke
The medical cause of stroke occur in younger patients associated with cardiac disease, autoimmune vasculitis, infection, mitochondrial deficits or clotting factor dysfunction. Dissection from trauma or in association with collage vascular disease and migraine is also common. Specific symptoms such as cerebral autosomal dominant arteriopathy with subcortical infarction and stroke (CADASIL), hereditary endoheliopathy, neuropathy, renal disease and stroke as well as mitochondrial disease and named syndromes such as Susac, Eales, Sneddon’s, Cogan’s and Grönblad–Strandberg Disease, all test the
Chapter 3. Medical Causes of Stroke
diagnostic acumen of the examiner. Clotting disorders of deficiency, inhibition of activated coagulation factors or hereditary fibrinolytic defects are AD, AR or acquired. The examiner needs to elicit the sentinel characteristic of each entity to diagnose the category of medical illness and then the specific disease. Genetic cause of embolic stroke are: 1. AD, MVP 2. Tuberous sclerosis 3. Familial atrial myxoma (AD; AR); 4. Hereditary cardiac conduction defects (long QT) 5. Hereditary cardiomyopathies 6. Mitochondrial disease Mitral valve prolapse has a prevalence rate of 5–21% in the population. It occurs occasionally in an AD form and rarely causes a cerebral embolus. Auscultation reveals a mid systolic click-systolic murmur and 2D-ECHO cardiography determines greater than 2 mm or more abnormal movement of the anterior or posterior leaflets. Tuberous sclerosis patients are easily diagnosed by their characteristic skin manifestations, seizures and mental retardation. Rhabdomyosarcoma may be the cause of cerebral emboli. Heredity is AD. Hereditary long QT defects most frequently presents with syncope especially provoked by drugs that decrease cardiac conduction or with rare sudden death during strenuous athletics. Hereditary cardiomyopathies with a dilated myocardium occur in mitochondrial disease, limb-girdle muscular dystrophy, congenital myopathies, DMD, BMD, and myotonia type; all of these entities have characteristic physical findings such as proximal weakness, calf hypertrophy contracture of elbows, arms and ankles (Emery–Dreifuss muscular dystrophy); rigid spine syndrome. Mitochondrial disease should be suspected in short patients with undue fatigue with exercise, sensorineural hearing loss, diabetes and dilated cardiomyopathy. Atrial myxomas with emboli may present with fevers of unknown origin, petechiae across the chest wall, pial vessel emboli and peripheral cerebral aneurysm that bleed (myxomatous material grows through the walls of the affected arteries). Genetic cause of thrombotic stroke are: 1. Homocystinuria (marfanoid habitus) and dislocated arm 2. Dyslipoproteinemias such as Tangier disease with orange tonsils, alpha hypolipoproteinemia and intermittent neuropathy 3. Hemoglobinopathies particularly SS disease have relevant telangiectasis and arachnodactyl; while neurofibromatosis type I with characteristic coast of Maine spots and abnormalities of renal vasculature Clotting disorders secondary to polycythemia vera occur primarily in the posterior greater than anterior circulation and tend to thrombose large cerebral vessels. Retinal venous occlusion in coagulopathies from clotting factor deficiency are
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characteristically seen in young patients whose parents have had a fetal wastage, protein losing enteropathy, nephrotic syndrome or migraine with aura. Protein S deficiency and stroke occurs in middle aged women. Protein C deficiency often occurs concomitantly with the Factor V Leiden mutation. Antithrombin III deficiency should be suspected in the setting of severe resistance to heparin anticoagulation. Anticardiolipin antigen and lupus anticoagulant often are associated with migraine with visual aura. Cerebral sinus thrombosis is common in all defects of inhibitors of clotting. Platelet abnormalities and stroke should be suspected in a setting of petechiae particularly of the lower extremities. The primary anti-phospholipid antibody syndrome is associated with spontaneous abortion and fetal wastage. Valve cusps are affected and the syndrome may be associated with cerebral emboli. The lupus anticoagulant is an antibody to phospholipids (on platelets) which blocks the formation of the prothrombin activator and is associated with clotting and not hemorrhage. There is usually evidence of systemic venous clotting. In general platelet counts greater than one million/mm3 are associated with hypercoagulability. Functional platelet abnormalities rather than absolute number may be the important parameter. This may occur in a small group of migraine patients and in essential thrombocythemia. Heparin induced thrombocytopenia and thrombosis occurs as a transitory and asymptomatic reduction in platelet count or as an immunopathologic condition. The later (Type II) usually occurs after the 5th day of treatment and causes both arterial and venous thrombosis. Gangrene of a limb, thrombosis and stroke is the usual triad. White clots are noted in blood vessels. Disseminated intravascular coagulation occurs in a setting of gram negative sepsis, cancer and obstetrical emergency. It is announced by oozing from all venipuncture sites and acrocyanosis. Arterial and venous clotting as well as hemorrhage dominate the clinical profile. The following discussion highlights the major characteristics and differential features of the genetic causes of embolic and thrombotic stroke, coagulopathies and rheological abnormalities that are seen in clinical practices.
Genetic Causes of Embolic Stroke
1. Mitral valve prolapse (MVP) – AD 2. Tuberous sclerosis – AD 3. Familial atrial myxoma (AD, AR) 4. Hereditary cardiac conduction defects (long QT) AD 5. Hereditary cardiomyopathy AD, AR, X-linked 6. Mitochondrial disease (maternal inheritance) A. MVP 1. Associated with:
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SECTION I. Vascular Disease
a. Osteogenesis imperfecta e. Becker MD b. Ehlers Danlos syndrome f. Van Willebrand’s c. Marfan’s Syndrome disease d. Duchenne MD g. Fragile X syndrome B. Tuberous Sclerosis 1. Cardiac rhabdomyomas that cause emboli 2. 80% are new mutations 3. Abnormalities of cerebral arteries and aorta also occur C. Atrial Myxoma 1. AD/AR forms; most atrial myxomas are sporadic 2. 20% of familial atrial myxoma are associated with an AD heredity 3. Associated with: a. Myxoid fibroadenoma b. Lentiginous blue nevi c. Large cell calcifying Sertoli cell tumors d. Primary adrenocortical nodular dysplasia e. Pituitary growth hormone tumors
Cardiac Dysrhythmia with Emboli
A. Idiopathic Hypertrophic Subaortic Stenosis (IHSS) 1. Syncope after exercise a. Muscle constricts subaortic outlet; epinephrine dilates blood vessels in muscle. Severe hypotension results after strenuous exercise 2. Atrial fibrillation late in the course of the illness a. Emboli during the arrhythmia 3. Female > male at risk for stroke 4. Hypertension a cause of stroke 5. Other stroke mechanisms: a. Associated mitral annulus calcification b. AV conduction defect B. mt DNA Cardiomyopathy 1. Kearns–Sayre syndrome a. Heart/block (bundle branch block; AV node block) b. Ophthalmoplegia c. Hearing loss (VIIIth nerve) d. Diabetes mellitus e. Dilated cardiomyopathy with emboli (poor flow; clot formation) f. Decreased ventricular ejection fraction g. Endocardial thickening h. Intellectual decline i. Cerebellar ataxia j. Stroke like episodes after seizure C. Dilated cardiomyopathy (DCM) 1. DCM with and without conduction-system disease 2. Familial DCM with CSD (conduction syndrome) chromosome 1 p1-q21 3. X-linked dystrophinopathy (Becker’s; Duchenne) 4. Female carrier of BMD and DMD 5. Sporadic and AR limb-girdle muscular dystrophy 6. Emery Dreyfus Muscular Dystrophy
7. 8. 9. 10. 11. 12.
Adhalinopathies Barth Syndrome Rigid Spine Syndrome Welander’s distal myopathy Distal vacuolar myopathy Systemic carnitine deficiency
Genetic Causes of Thrombotic Stroke
A. Homocystinuria (AR) 1. Homocysteine to cystathionine; deficient enzyme is cystathionine beta synthase (most common defect) 2. Homocystinuria a. Severe atherosclerotic changes b. Increased levels of homocysteine injuries endothelium 3. Clinical Features: a. Marfanoid habitus b. Osteoporosis c. Mental retardation d. Premature atherosclerosis e. Venous and arterial occlusions f. High myopia g. Dislocated lens 4. Heterozygosity a. Incidence 1 : 200 persons b. Increased stroke risk c. Oral methionine load causes increased homocysteine level in the serum B. Dyslipoproteinemias 1. Familial hypoalphalipoproteinemia (Tangier Disease) a. Tangier Disease: 1. AR 2. Low HDL 3. Increased triglycerides 4. Orange tonsils 5. Intermittent neuropathy 6. Premature atherosclerosis with stroke 7. Increased carotid artery intima-media thickness in subjects with primary hypoalphalipoproteinemia 8. ABCA1 Gene Mutation a. Cell membrane protein is deficient
Hemoglobinopathies
A. General Vascular Features 1. Small and large vessel thrombosis 2. Sickling in the vaso-vasorum (blood supply of the vessel wall) 3. SAH 4. ICH 5. Embolic disease
Chapter 3. Medical Causes of Stroke Hemoglobinopathies
SS Disease 1. General Characteristics a. Scleral telangiectasia b. Arachnodactyly c. Auto splenectomy d. Pneumococcal peritonitis e. Meningitis f. Bone marrow infarction g. Severe joint and abdominal pain A. Occlusive disease: 1. Large intracranial arteries 2. Small penetrating vessels 3. Dilated and ectatic arteries 4. Moya-Moya collateral pattern 5. SAH B. MRI/CT Evaluation 1. Subcortical infarction 2. Cortical infarction 3. Border-zone infarction C. Pathology 1. Thickened arterial walls from intimal and subintimal proliferation 2. Rare thrombosis of veins and cerebral sinuses D. Sickled Cells 1. Adhere to the endothelium 2. Activate inflammatory cells and clotting factors that form the nidus for thrombosis 3. Small vessel sludging 4. Deficiency of nitric oxide decreases compensatory vasodilatation E. TCD 1. Velocities above 200 cm/second may occur in large vessels SSA Disease 1. Stroke propensity SC Disease 1. “Sea fan” macular sign (abnormal collection of blood vessels) 2. Propensity of strokes during pregnancy 3. Aseptic necrosis of the hip
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b. Moya-Moya like syndrome occurs with carotid occlusion c. Hypertensive vascular disease secondary to renal artery stenosis 1. Rarely secondary to associated pheochromocytoma
Polycythemia Vera
A. General Characteristics 1. AD form 2. Variants: a. High oxygen affinity variant b. Mutant hemoglobin c. Mutant receptor for erythropoietin d. Increased erythropoietins (E) e. Abnormal metabolism of 2,3-diphosphoglyceride B. Neurologic Features 1. Thrombotic events occur in 20–50% of patients 2. Thrombosis of large cerebral vessels a. Posterior greater than anterior circulation thrombotic stroke b. Scattered lesion pattern: 1. Suggestive of embolic microcirculation strokes c. Retinal venous occlusions d. Risk factors for thrombosis: (1) Age (2) Use of phlebotomies (3) Rate of phlebotomies (4) Prior history of thrombosis (5) Platelet counts not definitively linked to increased risk of thrombosis (6) Risk of stroke occurs with > 1.5 million platelets/mm3 e. Thrombotic events: 1) Most frequently occur 2 years preceding diagnosis 2) Thrombosis 3.4% per year 3) Overall mortality of 2.9/100 patients/year 4) patients receiving chemotherapy have higher mortality
Coagulopathies Neurofibromatosis I
A. General Characteristics 1. Associated with abnormalities of the renal and cerebral circulation B. Abnormalities of the Intracranial Vasculature 1. Beading of blood vessels 2. Aneurysms and arterial stenosis a. Intracerebral carotid artery 1. at the level of the ophthalmic artery
A. General Categories: 1. Decreased inhibitors of activated coagulation factors 2. Hereditary fibrinolytic deficits 3. Clotting factor deficiencies B. Autosomal Dominant Defects 1. Heparin co-factor II 2. Protein C deficiency 3. Decreased release of plasminogen activator 4. Homozygote XII deficits (thrombotic tendency)
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SECTION I. Vascular Disease
5. Prothrombin gene defect C. AR Defects: 1. Prekallikrein deficiency (Fletcher factor) D. Propensity for Thrombosis 1. Antithrombin III defects 2. Protein S deficiency 3. Plasminogen defects 4. Factor V Leiden defect E. Acquired Causes of Hypercoagulability 1. Diabetes mellitus 2. Hyperlipidemic states 3. DIC (consumption with fibrinolysis) 4. Platelet disorders 5. Vasculitis 6. Malignancy (thromboplastin-like substances released into circulation) 7. Hyperagreeable (sticky) platelets 8. Endothelial damage 9. Cardiopulmonary bypass: a. Increased fibrinolytic activity b. Decreased coagulant activity c. Increased plasminogen activator inhibitor level d. Platelets >1,000,000 – 7× risk of bleeding 10. Antiphospholipid antibody 11. Anticardiolipin antibody 12. Lupus anticoagulant 13. Heparin induced thrombosis 14. Rheological Abnormalities a. Hyperviscosity b. Deficits in laminar and pulsatile flow
Hereditary Cause of Hemorrhagic Stroke
1. X-linked VIII and IX deficiency 2. AR-afibrinogenemia 3. Factor VII, X, XI, XIII deficiency A. Clinical Features: 1. Rare bleeding in factor XI deficiency 2. VIII deficiency less than 10% of normal values are necessary to bleed 3. Latent period of deficits prior to stroke
Coagulopathies: General Categories
A. Comprehensive Procoagulant Screen 1. Common gene mutations a. Factor V (R1691A) mutation b. Prothrombin (G20210A) mutation c. MTHFR (C677T); methyl tetrahydrofolate reductase mutation 2. Rare Genetic Deficiencies a. Protein C c. Antithrombin III b. Protein S d. Plasminogen
3. Putative candidates for genetic thrombophilia a. Elevated lipoprotein b. Homocysteine Probable genetic risk factors 1. Increased: a. Fibrinogen c. Factor VIII b. Factor IX d. Decreased factor XII
Platelet Dysfunction
A. General Features 1. Increased platelet counts – above 1 million a. Associated with hypercoagulability 2. Increased coagulability may occur with increased adhesion and aggregation a. Functional platelet abnormality > than absolute number may be the important parameter 1) Sticky platelets B. Essential Thrombocythemia 1. Associated with stroke and digital artery infarction 2. Transient ischemic attacks 3. Major ICH
Leukemia
A. General Characteristics 1. Rheological abnormalities occur with WBC > 250,000/mm3 a. Capillary sludge 1) Infarction 2) Small brain hemorrhages 2. SAH a. Vaginal bleed prior to cerebral bleed at approximately 30,000 platelets Decreased Natural Inhibitors of Coagulation (a) Antithrombin III (b) Low levels of heparin releasable tissue factor inhibitor in young patients with thrombosis 1) Coincidence of defect with thrombosis is putative (c) Pre-Kallikrein deficiency 1) Severely prolonged activated partial thromboplastin time (a PTT) 2) Due to Factor XII activation 3) No increased bleeding risk 4) Bleeding risks occur in association with hereditary defects of: a) VIII, IX, XI
Most Common Deficiencies of Inhibitors of Clotting
1. Antithrombin III 3. Protein S 2. Protein C 4. Factor V Leiden Antithrombin III Deficiency:
Chapter 3. Medical Causes of Stroke
1. General Characteristics a. Usually AD inheritance b. Defect may be qualitative as well as quantitative c. Reduced synthesis in the liver d. May be lost in the nephrotic syndrome or by protein losing enteropathy Clinical Features: 1. Strong family history of venous thrombosis 2. Approximately 50% of patients with deficiency suffer: a. Venous thrombosis b. Pulmonary embolism c. Rarely myocardial infarction d. Rarely peripheral arterial disease e. Occasional stroke f. Other thrombolic risk factors potentiated in this setting
Protein C
1. General characteristics: a. AD b. Most common functional defect occurs with concomitant Factor V Leiden mutation: 1) Causes resistance to activated protein C which prevents degradation of factor V c. Hereditary protein C deficiency: 1) Lowered plasma levels in the patient and one first degree relative 2) Protein C to S ratio is a better determinant of protein C gene mutation or carrier status d. Clinical Features 1) Cerebral venous thrombosis 2) Occasional arterial thrombosis 3) Rare cerebral emboli from the heart
Protein S
1. General Characteristics a. Increases affinity of protein C for phospholipid b. Protein C inhibits procoagulant activity of Factor V and VIII c. 65% of plasma protein S is bound to c4b-binding protein which increases during infection d. Levels of protein S are low with: 1) Nephrotic syndrome 2) Protein losing enteropathy 3) Failure of synthesis with liver disease 4) Antibodies to protein S occur with post varicella purpura fulminans 5) Lower levels in women than men e. A particularly important risk factor for stroke in middle aged women 2. Clinical Features a. Dural venous thrombosis
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b. Arterial stroke c. Stroke in young patients with the concomitant risk factor of smoking
Factor V Leiden
1. Most common cause of decreased protein C function 2. Mutation of the gene that codes coagulation factor V (factor V G1691A) 3. Factor V Leiden prevalence in population: a) heterozygotes 7.7% b) hemo zygotes 0.2% 4. Risk for ischemic stroke a) heterozygotes + hemo zygotes – 0.92% b) control population – 0.68% 5. Clinically correlated with: a) thromboembolism in pregnancy b) venous thromboembolism of lower extremity c) cerebral venous and dural sinus thrombosis
Prothrombin Gene Defect
1. Second most common gene mutation causing prothrombotic state a) AR (G20210A mutation) b) Substitution, deletion or insertion of single nucleotides in the prothrombin gene 2. Two phenotypes: a) hypoprothrombinemia 1) low levels of coagulant activity 2) antigen type 1 b) dysprothrombinemia 1) low coagulant activity 2) borderline or normal antigen levels A. Clinical Manifestation 1. Cerebral venous thrombosis 2. Recurrent peripheral venous thromboembolism 3. Rare arterial clotting B. Factor VIII Alteration 1. Deficiency causes bleeding into: a) joints c) abdomen b) skin d) cranium 1) SDH 2) ICH 2. Increased Factor VIII in patients associated with: a) Thrombophlebitis b) Spontaneous abortion c) Increased incidence of stroke d) May be associated with: 1) Infections (preceding occlusive disease) 2) Crone’s disease and ulcerative colitis
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SECTION I. Vascular Disease
Chrone’s Disease and Ulcerative Colitis
Circulating Lupus Anticoagulant
General Characteristics 1. Associated with: a) Increased factor VIII b) Elevated factor V c) Reduced levels of antithrombin III d) Platelet dysfunction 2. Clinical associations: a) Venous dural sinus occlusion b) Ischemic arterial stroke c) Thrombophlebitis d) Putative mechanism for increased coagulability: 1) concomitant endothelial and valve injury e) patients with high IgG antibody titers in the presence of APLA syndrome 1) higher probability of stroke
General Characteristics: 1) High levels with the appropriate clinical symptomatology constitutes the antiphospholipid antibody syndrome 2) Lupus anticoagulant: a) Is an antibody to phospholipids b) Blocks the formation of the prothrombin activator (1) Causes a prolonged activated partial thromboplastin time (APPT) that is not corrected by added plasmin c) Most patients with the antibody do not have SLE d) Associated with increased clotting and not bleeding e) Anti IgA, IgG or IgM anticardiolipin (antiphospholipid antibodies) are found without concomitant autoimmune disease-the process is a primary APLA syndrome. 3) Clinical manifestations: a. evidence of systemic venous clotting b. large and small artery occlusions c. mitral and aortic valve lesions
Primary Antiphospholipid Antibody Syndrome
1. General Characteristics a. IgG, IgA, IgM are formed against phospholipids. Those on platelets include: 1) Phosphatidylethanolamine 2) Phosphatidylserine b. No identified autoimmune disease is present 2. Clinical features: a. Thrombophlebitis b. Small and large vessel arterial stroke c. Spontaneous abortions and fetal wastage d. Thrombotic endocarditis 1) Organized thrombus with marked fibrosis of the valves a) Valve cusps are involved b) Lesions embolize
Neurologic Manifestations
1. 2. 3. 4. 5. 6. 7. 8. 9.
Amaurosis fugax Chorea Migraine Transverse myelitis Stroke may be the initial presentation Intracranial occlusive disease Venous and dural thrombosis Atypical extracranial occlusions Binswanger’s leukoencephalopathy
APLA Syndrome Associations
Heparin Induced Thrombocytopenia and Thrombosis
1. SLE found in 1/3 of patients 2. SLE like syndrome in 5% of patients 3. Most patients have a higher frequency of: a. Myocardial infarction b. Arterial thrombosis of the lower extremities c. After age 50 males > females
A. General Characteristics Two types of heparin-induced thrombocytopenia (HIT) 1. Type I a. Transitory and asymptomatic reduction in platelet count b. Rarely < 100,000 platelets c. Resolves spontaneously d. Does not require cessation of the drug e. Putative mechanism: heparin induced platelet clumping f. Rare clinical manifestations 2. Type II a. Immunologic pathophysiology b. Occurs after the 5th day c. men 2. 50% of patients it is secondary (occurring with other processes) a. Most often associated with rheumatoid arthritis 3. characterized by: a. Keratoconjunctivitis sicca b. Xerostomia c. Associated with other connective tissue diseases 4. Lymphoid invasion of exocrine tissues of the body: a. Otitis (eustachian tube dysfunction) b. Recurrent bronchial infection c. Dryness of genital mucosa d. Atrophic gastritis e. Atrophy of the oral mucosa 5. Raynaud’s phenomena 6. 50% of patients have arthralgias 7. Renal interstitium involved 8. Muscle, skin, nerve, vasculitis a. Usually involved with RA (rheumatoid arthritis) 9. Neurological manifestations 10. peripheral nervous system: a. Large fiber sensory loss b. Dorsal column involvement c. Autonomic impairment 1) Adies pupil (tonic pupil) 2) Anhidrosis 3) Orthostatic hypotension d. Vth nerve involvement 1) Gasserian ganglionitis e. Central nervous system involvement: 1) Myelitis 4) Meningoencephalitis 2) Seizure 5) Focal brain infiltrates 3) Dementia 6) f. Stroke: 1) Pial vessels 3) Hemiparesis, aphasia, ataxia 2) Large vessels 4) Cognitive and behavioral deficits g. Associated with primary progressive multiple sclerosis h. CSF: 1) Lymphocytic pleocytosis < 30 cells mm3 2) Mildly elevated protein 60–80 mg% i. MRI evaluation 1) Lesions resemble those of MS 2) Dorsal column spinal cord lesions 3) Discrete cortical lesions that resemble infarcts
Rheumatoid Arthritis
General features: 1. Crippling arthritis associated with: a. Ocular manifestations (keratoconjuctivitis) b. Cardiac involvement
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c. Vasculitis of the bowel 2. Possibly affects 1% of the population 3. Associated neurological manifestations: a. Myopathy (proximal) b. Neuropathy (severe atrophy of intrinsic hand muscles) c. Atlantoaxial subluxation (C2–C3; spinal cord compression) d. Rheumatoid pachymeningitis e. Rheumatoid dural nodules (seizures) f. Encephalopathy g. Generalized sensorimotor neuropathy h. Rare mononeuritis multiplex i. C2 pannus with spinal cord compression j. CTS 4. Cerebral rheumatoid vasculitis occurs: a. Concomitantly with aggressive systemic rheumatoid vasculitis b. Rarely in isolation c. Ischemic stroke associated with: 1) Localized vasculitis (rare) 2) Rheumatoid pachymeningitis 3) Cardiac emboli 4) Multifocal small infarcts d. Cerebral hyperviscosity syndrome due to: 1) High titers of circulating rheumatoid factor 2) Increased levels of fibrinogen, and fibrinogen depredation products
Scleroderma
A. General Features: 1. Microvascular pathology and diffuse tissue fibrosis that affects: a. Skin d. Heart b. Gastrointestinal tract e. Kidneys c. Lungs 2. Neurological Manifestation Peripheral nervous systems: a. Myopathy in 17% of patients b. Cranial nerve involvement 1) Vth nerve most often involved 2) Possibly at the ganglion level c. Sensorimotor neuropathy d. Mononeuritis multiplex e. Carpal tunnel syndrome f. Cranial neuropathies (Vth nerve) g. Autonomic neuropathy h. Myelopathy (rare) 3. CNS Features: stroke a. Disseminated cerebral arteritis b. Hemorrhage from renal hypertension c. SAH (rare) d. Cardiac emboli (rare)
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SECTION I. Vascular Disease
Churg–Strauss Syndrome
A. General Characteristics 1. Asthma 2. Eosinophilia 3. Previous allergic disorder 4. Lung involvement 5. Pituitary infarction 6. >60% of patients have CNS involvement 7. May be relapsing B. Primary Vascular Involvement 1. venules 3. arterioles 2. capillaries 4. small vessel necrotizing vasculitis C. Neurological Manifestations 1. Encephalopathy 2. Peripheral neuropathy a. Distal motor sensorimotor 3. Rare small vessel stroke 4. Pachymeningitis
Henoch–Schönlein
1. General characteristics: a. Predominant IgA meningeal deposits (1) Small vessel necrotizing arteritis b. Clinical associations: (1) Purpura (2) Abdominal pain (3) Arthritis (4) Renal involvement (5) Carcinoma of respiratory and GI tract (6) Adult involvement (a) Preceded by mucosal infection of the upper respiratory tract 2. Neurological complications a. Occasional small vessel stroke (1) Primarily in children (2) ICH (children) (a) Factor XIII deficiency b. Allergic reactions to drugs are a precipitant
3. 4. 5. 6.
Eosinophilic fasciitis (rarely associated) Jaw claudication (rare) Rarely associated with temporal arteritis Stroke a. Cerebral arteritis b. Pial vessel infarcts 7. Laboratory evaluation a. Sed rate a good measure of disease activity b. pANCA elevated c. Overlap with other serum markers of hypersensitivity disease
Hypersensitivity Vasculitis 1. General characteristics: a. Rash b. Palpable purpuric skin lesions c. Legs more commonly affected than arms d. Extremities may be symmetrically swollen and erythematous 2. Etiology a. Specific allergens c. Post infectious b. Penicillin and sulfa drugs 3. Henoch–Schönlein: General manifestations: a. Joint pain may be prominent 4. Mixed cryoglobulinemia a. Acrocyanosis b. Cold induced acroparesthesias c. Sensorimotor neuropathy d. Increased IgM
Peripheral Nervous System Manifestation
1. Sensorimotor neuropathy 2. Plexopathy 3. More common than CNS manifestations
Stroke 1. Diffuse petechiae in centrum semiovale a. Secondary to low platelets
Wegener’s Granulomatosis
A. General characteristics 1. Necrotizing vasculitis of: a. Sinuses c. Upper respiratory tract b. Lungs d. Kidneys 2. Neurological manifestation a. Optic nerve ischemia b. Orbital involvement c. Extraocular muscle palsies d. Retinal involvement e. Posterior ischemic optic neuropathy
Mixed Collagen Vascular Disease
1. General characteristics a. Features of: 1) SLE 2) Scleroderma 3) Polymyositis b. Concomitant high titers of antibody to: 1) RNase-sensitive ribonucleic complex a) small RNPC (ribonucleic protein)
Chapter 3. Medical Causes of Stroke
2. Neurological manifestations: a. Headache g. Aseptic meningitis b. Seizure h. Monocular blindness c. Psychosis i. Vth nerve involvement d. Encephalopathy j. Sensorimotor neuropathy e. Transverse myelitis k. Entrapment neuropathy f. Ataxia 3. Stroke a. Rare b. Secondary to cerebral vasculitis 4. Neurologic features are dependent on the dominant clinical syndrome, i.e., SLE vs scleroderma vs polymyositis
Thrombotic Thrombocytopenic Purpura (Moschowitz Syndrome)
1. General characteristics a. Female 2 : 1 > male b. Fever (interleukin I) c. Renal failure d. Thrombocytopenia e. Microangiopathic hemolytic anemia 2. Associated with: a. Pregnancy b. Bone marrow transplantation c. HIV d. SLE e. Ticlopidine f. Sjögren’s Syndrome g. Rheumatoid arthritis h. Influenza vaccination i. D-penicillamine j. Cyclosporine k. Citomycin 3. Neurological manifestations a. Diffuse encephalopathy 1) Visual hallucinations 3) Seizures 2) Headache 4) Visual loss b. Transient focal deficits c. Aphasia d. Papilledema e. Relapsing course f. Posterior leukoencephalopathy 4. Pathology a. Arteriolar and capillary involvement b. Platelet rich thrombi c. Multifocal microinfarctions 5. Pathogenesis a. Non-familial form 1) Inhibitor of Von Willebrand factor cleaving protease b. Familial form (constitutive deficiency of the protease) c. Large multimeres of Von Willebrand Factor adhere to and aggregate platelets
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Reiter’s Disease
1. General characteristics: a. May follow G.I. illness b. Severe heel pain 2. Neurologic complications: a. Optic neuritis b. Encephalitis c. Ascending motor paralysis (GBS like syndrome) d. Seizures e. Brainstem dysfunction f. Acute transverse myelitis g. Neuralgic amyotrophy h. Superficial pial stroke
Relapsing Polychondritis
1. General characteristics a. Episodic inflammation of cartilage throughout the body 2. Clinical characteristics a. Pain and tenderness of cartilaginous portions of the ear in 85% of patients b. 40% suffer inner ear disease with: 1) Hearing loss 3) Vertigo 2) Tinnitus 4) Rarely deafness c. Ocular involvement: 1) Conjunctivitis, episcleritis, scleritis 2) Iritis and iridocyclitis 3) Keratoconjunctivitis sicca 4) Choroiditis 5) Orbital pseudotumor (proptosis) 6) Optic neuritis 7) Retinal vasculitis d. Nasal cartilage inflammation 1) 70% of patients 2) Saddle nose deformity e. Aortic insufficiency f. Laryngotracheal involvement in 50% g. 10% of patients develop PAN 3. Associated Diseases: a. Rheumatoid Arthritis b. Systemic lupus erythematosus c. Reiter’s syndrome d. Ankylosing spondylitis e. Ulcerative colitis f. Hashimoto’s thyroiditis g. 25% have myelodysplastic syndrome 4. Neurologic Signs and Symptoms: a. Occur in 3% of patients b. Extraocular muscle palsy c. Optic neuritis d. Bilateral VIIth nerve 1) Associated with inner ear disease e. Mononeuritis multiplex 1) Associated with PAN
SECTION I. Vascular Disease
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f. CNS manifestations: 1) Meningoencephalitis 2) Headache 3) Altered consciousness 4) Papilledema 5) Meningeal signs 6) Seizure 7) Ischemic stroke
Ulcerative Colitis and Regional Enteritis
A. General characteristics 1. Dominant bowel symptoms 2. Large joint arthritis 3. Keratoconus B. Neurological Manifestations 1. Cerebral venous and sinus thrombosis 2. Large vessel strokes 3. Loss of protein C and S (protein losing enteropathy)
Celiac Disease
1. General characteristics: a. Severe diarrhea c. Antibodies to gliadin b. Gluten sensitivity 2. Neurologic manifestations: a. Proximal myopathy b. Sensorimotor peripheral neuropathy c. Spinal cord dysfunction d. Cerebellar degeneration with ataxia 3. Stroke a. Large conducting and pial vessel stroke
Giant Cell Arteritis
1. General characteristics a. Incidence of 17.4/100,000 people b. Superficial temporal and occipital arteries are most frequently involved c. Internal carotid, extracranial vertebral arteries, coronary, femoral and rarely intracranial arteries may be affected d. Extracranial vessels most commonly involved in giant cell arteritis are: 1) Aortic arch (dissection) 2) Rupture of an aortic aneurysm 3) Annuloaortic ectasia 2. Presents as a systemic illness: a. Low grade fever b. Iching of proximal muscles c. Weight loss d. Onset of headache
1) Painful burning scalp 2) Not pulsatile e. Jaw claudication f. Perforated nasal septum g. Ischemic tongue lesions (similar appearance to carcinoma) h. Painful cord like superficial temporal arteries (only 30– 40% positive by biopsy) 1) ESR is increased in greater than 90% of patients’; biopsy negative in at least 50% of patients i. Sites of arterial involvement causing stroke: 1) Distal extracranial ICA at the carotid siphon 3. Rare sites of involvement: a. Pial and brainstem arteries 4. Extracranial giant cell arteritis: a. Occurs in 10–15% of patients with polymyalgia rheumatica 5. Relapses may occur after successful treatments
Neurological Manifestations
1. Blindness from: a. Occlusion of the posterior ciliary arteries (derived from the internal carotid) or their collaterals (from the external carotid) b. Central retinal artery occlusion c. Ischemic optic neuropathy from infarction at the optic disc d. Visual loss occurs suddenly 1) may occur in the second eye within minutes or at approximately 2 months 2) men > women with severe ocular problems 3) visual loss is permanent due to infarction of the optic nerve head and retina 2. Visual field deficits a. Altitudinal rather than central 3. Anterior optic nerve involvement: a. Mild papilledema b. Infrequent disk hemorrhage c. Resolves over 10 days 4. Retrobulbar ischemic optic neuropathy: a. Gradual optic pallor and atrophy 5. Diplopia: a. 2–14% of patients b. Vasculitis of extraocular muscles with total ophthalmoplegia (rare) 6. Cranial nerve palsies: a. Rare that VIII th nerve is involved b. Infarction of the internal auditory artery (origin is AICA) 7. Tongue: a. Hemianesthesia of the tongue b. Lingual paralysis c. Ischemic tongue lesion 1) Similar to squamous cell carcinoma in appearance
Chapter 3. Medical Causes of Stroke
8. Facial pain: a. Arteritis of the facial branch of the external carotid artery 9. Myelopathy: a. Vasculitis of the vertebral and anterior spinal artery with cervical cord infarction 10. Peripheral neuropathy: a. Distal symmetrical sensorimotor neuropathy b. Mononeuritis multiplex c. One month after onset 11. Myopathy: a. Steroid related proximal myopathy
Cerebrovascular Disease
1. TIA of anterior and posterior arterial systems 2. Encephalopathy a. Arteritis of pial and superficial arteries 3. Multiinfarct dementia 4. Infarction of major branches of both anterior and posterior circulations 5. arotid bruits noted in 10–20% of patients: a. Bilateral bruits: 1) 60% of these patients have associated involvement of the aortic arch 6. Vertebrobasilar arterial involvement may present with: a. Acute confusional state b. Coma
Laboratory Evaluation
(1) Elevated sedimentation rate (2) Mild normocytic anemia (3) Mild peripheral leukocytosis
Isolated Angitis of the CNS
A. General features: 1. This is putatively and immune mediated arteritis of strictly cerebral blood vessel 2. Other names for the process: a. Isolated granulomatous angiitis b. Giant cell granulomatous angiitis of the CNS 3. Mean age of onset 49; any age can be affected 4. Male predominance 2 : 1 5. Vasculitis isolated to the CNS: a. Exclusion of systemic inflammation, infection or other causes of CNS vasculitis; rarely associated with angioid angiopathy 6. Segmental necrotizing granulomatous vasculitis that involves: a. Cortical arteries b. Spinal arteries
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c. Leptomeningeal arteries d. Usual vessel size involved is 200–500 μm (microns) 1) Any size vein or artery may be involved 2) Precapillary arterioles < 200 μm are involved e. Intima and adventitia of arteries are infiltrated with: 1) Lymphocytes, giant cells, and granulomas 2) Granulomas may invade the cortex f. Veins may be affected in 50% of patients B. Neurologic Manifestations 1. Earliest symptoms: a. Headache b. Phonophobia c. Photophobia d. Unusual stroke-like presentation e. Diffuse encephalopathy (usual presentation) f. Gradual onset 2. Later signs and symptoms: a. Altered mental status b. Dementia c. Myelopathy d. Hemiparesis e. Diffuse encephalopathy f. Rare territorial stroke g. Pathology of intracranial vessels 1) Thrombosis 2) Small aneurysms develop on arteries h. Myelopathy may precede encephalopathy i. Seizures occur j. Usual progression 1) Step-like deterioration of a progressive encephalopathy k. Rare SAH C. Imaging Evaluation 1. MRI a. Positive 68% of the cases b. Infarcts demonstrated (ischemic) c. Rarely hemorrhagic infarction d. Small hematoma (rare) e. Rare intracerebral aneurysm 2. Arteriogram a. Positive in approximately 50% of patients; involved vessels 100 mg/dl
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SECTION I. Vascular Disease
Nongranulomatous Angiitis of the CNS
A. General characteristics: 1. Segmental necrotizing angiitis without granulomata 2. Male: female 1.8 to 1 3. Multiple small but occasionally large foci of infarction throughout the CNS 4. Mean age at onset 49 B. Neurological Manifestations: 1. Acute presentation a. Stupor or coma within days to weeks 2. Classic presentation: a. Fever and weight loss uncommon b. Mental status change c. Headache d. Hemiparesis e. Impairment of consciousness f. Focal, multifocal or diffuse encephalopathy 3. Rare vascular presentation: a. TIA c. SAH b. large vessel stroke d. Multiinfarct stroke 4. Rare neurologic presentation a. Increased ICP b. Chronic meningitis or arachnoiditis c. Cerebral hemorrhage d. Radiculopathy C. Evolution of the Disease 1. Stepwise occurrence of focal neurologic deficits D. Laboratory Evaluation 1. Mild elevation of ESR in 2/3 of patients 2. CSF mononuclear pleocytosis (mean of 70 monocytes/ mm3 ) E. Imaging Evaluation: 1. MRI: a. White and grey matter involvement b. Occasional hemorrhage c. Bilateral subcortical lesions d. Enhanced meninges 2. Arteriography a. Abnormal in approximately 60% 1) Segmental narrowing and sausage shaped dilatation (beading) 2) Rarely: avascular mass or intracerebral aneurysm 3) Affected vessels < 500 μm 3. Leptomeningeal biopsy more often positive than brain biopsy
Benign Angiitis of the CNS
A. General Characteristics 1. Affects young women 2. Setting of intermittent hypertension B. Neurologic Manifestations
1. Transient reversible neurologic deficits 2. Multi-segmental arterial narrowing 3. Self limited course C. Course, setting and favorable prognosis differentiate this entity from isolated angiitis of the CNS
Post Partum Cerebral Angiopathy
General Characteristics: 1. May occur up to two days after delivery 2. Associated with a. Bromocriptine c. Ergotamines b. Sympathomimetic drugs 3. May be recurrent Neurological Manifestations 1. Transient bilateral parieto-occipital high signal intensity lesions on MRI (T2) 2. Frontal intracranial hemorrhage 3. Primary angiitis of the central nervous system associated with cerebral amyloid angiopathy General Characteristics 1. Mean age of onset: a. PACNS with amyloid angiopathy (65 years) b. PACNS (44.8 years) c. Cerebral angioid angiopathy (CAA) (76 years) Neurological Manifestations 1. Multifocal neurological signs and symptoms 2. Headache 3. Hallucinations 4. Subacute cognitive deficits CSF 1. Eosinophilic pleocytosis 2. Xanthochromia >40% of patients The following are different conditions that mimic vasculitis of an immune basis and vasculitis differentiated by pathologic process, association with neoplastic disease, site of involvement, topography, vessel size and segmental narrowing on arteriogram.
Differential Diagnosis of Conditions Mimicking Vasculitis
1. Dissecting aneurysm 2. Antiphospholipid syndrome 3. Drugs a) Methamphetamine d) Ephedrine b) Sympathomimetic drugs e) Propyl ethanolamine c) Ginseng f) Cocaine 4. Cholesterol emboli 5. Intravascular lymphomatosis 6. Coll.’s syndrome
Chapter 3. Medical Causes of Stroke Differential Diagnosis of Arteritis Associated with Autoimmune Diseases
1. SLE 2. PAN 3. Sarcoid 4. Sjögren’s 5. Rheumatoid arthritis 6. Scleroderma 7. Churg–Strauss 8. Wegener’s granulomatosis 9. Hypersensitivity arteritis 10. Mixed collagen vascular disease
11. Giant cell arteritis 12. Reiter’s Syndrome 13. Relapsing polychondritis 14. Ulcerative colitis 15. Regional enteritis 16. Celiac Disease 17. Serum sickness 18. Henoch–Schönlein purpura 19. Cryoglobulinemia
Differential Diagnosis of Systemic Necrotizing Arteritis
1. 2. 3. 4.
Wegener’s granulomatosis Lymphomatoid granulomatosis Sarcoid Hairy cell leukemia
Differential Diagnosis of Arteritis with Neoplasia
1. 2. 3. 4. 5.
Hodgkin’s disease Non-Hodgkin’s lymphoma Neoplastic angioendotheliosis Hairy cell leukemia Angiocentric endothelial lymphomatosis
Differential Diagnosis of Isolated Angiitis of the CNS
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Necrotizing vasculitis HZ Hodgkin’s disease HIV Sarcoid Hypersensitivity arteritis PAN Lymphomatoid granulomatosis Methamphetamine Sympathomimetic drugs Coll.’s Disease Wegener’s granulomatosis
Differential Diagnosis of Systemic Vasculitis Resembling Isolated Angiitis of the CNS
1. Vasculitis with connective tissue disease 2. PAN
3. 4. 5. 6.
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Wegener’s granulomatosis Giant cell arteritis Takayasu’s Disease Behçet’s Disease
Differential Diagnosis of Vasculitis Associated with Granulomatous Parenchymal Lesions
1. Wegener’s granulomatosis 2. Sarcoid 3. Lymphomatoid granulomatosis 4. Granulomatous angiitis Differential Diagnosis of Granulomatous Angiitis of the CNS 1. Hodgkin’s Disease 2. Sarcoid 3. HZ 4. Methamphetamine 5. Sympathomimetic drugs 6. Coll.’s Disease Differential Diagnosis of Vasculitis By Characteristic Sites of Involvement 1. Takayasu’s Disease: a) Arch of the aorta b) Mid common carotid artery c) Mid descending aorta 2. Sneddon’s Syndrome a) Skin (livedo reticularis) 3. Köhlmeier–Degos Syndrome a) Atrophic skin lesions 4. Giant cell arteritis a) Primarily external carotid system b) May affect the ICA, and arch of the aorta
Differential Diagnosis of Vasculitis by Topography
1. Focal a. Herpes Zoster 1) Proximal MCA; ACA (side of the skin lesions) 2. Multifocal a. SLE b. Primarily separate areas of the cortex 3. Disseminated a. Isolated or primary angiitis of the CNS
Differential Diagnosis of Vasculitis of Medium Sized Arteries
1. PAN 4. Sjögren’s Syndrome 2. SLE 5. Buerger’s Disease 3. RHA
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SECTION I. Vascular Disease
Differential Diagnosis of Vasculitis of Small Sized Arteries
1. 2. 3. 4.
Churg–Strauss Polyarteritis nodosa (microangiopathic variant) Wegener’s granulomatosis Hypersensitivity arteritis
Differential Diagnosis of Segmental Narrowing of Cerebral Arteries on Arteriogram
1. Arteritis (infective; inflammatory; necrotizing) 2. Leptomeningitis (infective, chemical, carcinomatous) 3. Vasospasm (SAH, migraine, hypertensive encephalopathy) 4. Atherosclerosis 5. Fibromuscular dysplasia 6. Recanalization of emboli 7. Sickle cell disease 8. Sympathomimetic drug abuse 9. Neoplasms (angioendotheliosis, glial and meningeal tumors, atrial myxoma) 10. Closed head injury 11. Radiation therapy (X-RT) 12. Neuroectodermal dysplasia (neurofibromatosis; tuberous sclerosis)
Differential Diagnosis of Infectious that Cause Stroke
The differential diagnosis of the infections that cause stroke rests on the specific pathologic mechanisms induced or associated with each infection. The neurology of each infection is different and often the extracranial manifestation of the infection provides the clue to the specific diagnosis. Bacteria viruses and fungi cause stroke as due spirochetes and protozoa. Stroke may occur in the setting of bacterial meningitis. Pus may directly involve the pial vessels that encases them on the cortex. Pneumococcus may concomitantly infect heart valves and mycotic aneurysm with hemorrhage and stroke may occur 6–8 weeks after the primary infection. Meningococcal infection occurs frequently in settings in which young healthy adults are living in close quarters. The speed of the infection (headache to coma) within hours is characteristic. The course is dominated by the meningitis. Stroke is rare. Listeria infections occur following head and neck surgery and during pregnancy and delivery. The seminal feature is brainstem infarct with dorsal pontine involvement. Bartonella henselae infection follows exposure or inoculation from cats. Seizures and retinitis are the seminal features following extremity lymphadenitis.
Syphilis has made a comeback as a serious cause of infection due to HIV. It may be telescoped where all three stages are seen within a short period of time. In the past, brainstem strokes were noted in the meningovascular stage. This pattern persists, but may be more associated with gumma formation and less with clonic syphilitic optic nerve and pretectal involvement (Argyl Robertson pupils). If meningitis is seen concomitantly the CSF sugar is usually normal. Lyme disease is the most common vector borne infection in the United States and has protein manifestations. If VIIth nerve palsy and characteristic rash and large joint arthritis is present diagnosis is straight forward. Unfortunately, many patients present in later stages with asthenia and low grade encephalopathy weeks or months after the infection. Strokes are rare, but are described. Tuberculosis causes strokes because of cortical and basilar exudates. It is a more chronic illness in Western countries and is often seen as a low grade dementing illness. It should always be suspected in HIV infected patients with lower cranial nerve abnormalities (particularly the VIIIth nerve). Fungal infections occur most frequently in the immunocompromised host. Disorders of B-lymphocyte function are associated with encapsulated bacterial pathogens. Impaired T-lymphocyte or macrophage function causes infection by intracellular pathogens such as aspergillus and fungi, nocardia (bacterial) viruses and parasites (toxoplasmosis gondii). Extra CNS sites of infection suggest aspergillus and nocardia that may present subacutely or chronically. T-lymphocyte dysfunction with meningitis is Listeria or cryptococcus. Aspergillus can present as a CNS mass lesion or stroke but most often as meningitis. Mucormycosis is associated with all forms of immunosuppression, but particularly with diabetic ketoacidosis and renal failure. The fungus is associated with sinus infection and venous infarction. It should be suspected in this circumstance in a patient with ophthalmoplegia. Aspergillosis infects isolated lung abcesses and is associated with osteomyelitis of the base of the skull. It is notorious for fungal hyphae occluding cerebral conducting vessels. Fungal balls from valve leaflets are large enough to occlude peripheral extremity arteries. Cryptococcus usually presents as a chronic dementia in the setting of immunocompromise. It spreads through the Virchow–Robin spaces to involve the basal ganglia. This is most helpful in setting of stroke and T2 enhancement of the caudate and putamen. Proximal MCA branches and vessels in the posterior perforated substance are most frequently involved. Coccidiomycosis is common in the American SW. Extracranially it affects lungs and joints. Sacral involvement is frequent as is involvement of the jaw. Proximal MCA and the arteries of the perforated posterior substance are most often involved. Histoplasmosis is most often encountered in the Mississippi Valley. It may be associated with adrenal failure with
Chapter 3. Medical Causes of Stroke
concomitant splenic calcification. Arteries are inflamed in the chronic basilar exudate. Viral infectious cause stroke by direct invasion of the vessel wall or its endothelium, an immune response triggered by vessel epitopes or immune complex deposition. Herpes Zoster causes a middle cerebral artery stroke of the ipsilateral MCA on the side of the Vth nerve involvement. This characteristically occurs 6–8 weeks following the rash, but has been seen within two weeks. Both anterior and posterior circulation large vessels may be involved. Immune compromised HIV patients may suffer small vessel disease. One mechanism is involvement of vessel wall endothelial antithrombotic systems. HIV itself is associated with stroke from various mechanisms: 1. Immune complex formation 2. Cell mediated vasculitis 3. Inflammation from direct viral invasion 4. Associated infections that cause stroke Most often the pathology is in medium sized arteries. The clinical manifestations of severe HIV infection suggest the diagnosis. Cerebral malaria may be the most widespread CNS infection with stroke as a consequence. It most often occurs with plasmodia falciparum and occurs due to obstruction of main capillaries by parasitized RBC. The following is a more detailed description of the various infections that cause stroke.
Infections that cause stroke
1. Bacterial meningitis a. Pneumococcus: 1) Early hematogenous spread from the lung 2) Simultaneous infection of the heart valve (may occur); later SBE 3) Stroke of superficial pial vessels 4) Course clinically dominated by meningitis b. Meningococcal infection: 1) Early headache, nausea and vomiting; “flu-like” 2) Rapid progression to lethargy in 6–12 hours 3) Pial artery strokes 4) Adrenal failure (Waterhouse–Frederickson Syndrome) 5) Clustered infection a) Close living quarters (army barracks’ camp, college dormitories) 6) Bacteria may be seen in cerebral spinal fluid prior to neutrophils c. Listeria monocytogenes 1) Head and neck cancer patients 2) Abrupt onset of symptoms 3) Clinical involvement of: a) Medulla
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b) Pontine tegmentum (seminal feature) c) Lower cranial nerve palsies d) Arteritis of the brainstem with multiple infarcts e) Focal encephalitis f) Monocytic cerebral spinal fluid pleocytosis d. Bartonella henselae (cat-scratch fever) 1) Lymphadenopathy in drainage area of the scratch 2) Seizures (generalized) 3) Retinitis 4) Intracranial stenosis and arteritis
Syphilis
1. Arteritic attacks occur in stage II disease (meningovascular syphilis) a. Many brainstem syndromes were originally described in patients with syphilis b. “Heubner’s arteritis” 2. A proliferative endarteritis 3. Primarily occurs in small penetrating vessels of the brainstem 4. Pupillary abnormalities: a. Oval pupil b. Argyle–Robertson pupil c. Paralytic tabetic pupil 5. Associated retinitis pigmentosa a. Pigmentary migration around choroidal blood vessels 6. Concomitant neurologic manifestations: a. Progressive encephalomyelitis b. Meningovasculitis (syphilitic) c. Peripheral unilateral > bilateral VII nerve palsies (Bernhardt’s disease) d. Peripheral neuropathy e. Headache with meningitis 1) Skin rash involving the palms and soles f. VDRL in cerebral spinal fluid is positive 1) Sugar is normal 2) Acute meningitis with neutrophiles 3) Protein moderately elevated g. Spinal cord strokes occur h. Infection more virulent in HIV patients: 1) Telescoped spinal fluid (3rd stage CSF, lymphocytes, may be seen early in infection)
Lyme Disease
General Features 1. The most common vector borne infection in the United States: a. 15,000 cases/year b. Three distinct foci 1) Maine to Maryland 2) Wisconsin and Minnesota
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SECTION I. Vascular Disease
3) Northern California and Oregon 2. Borrelia burgdorferi: a. Tick borne spirochete 1) Ixodes ricinus complex b. Vectors are: 1) Deer; white footed mice; dusky footed wood rats 3. Medical Complications: a. Early infection 1) Localized erythema migrans (stage 1) 2) Disseminated infection (stage 2) a) Nervous system b) Heart c) Joints d) Occurs within days or weeks of infection 3) Late or persistent (stage 3) a) Weeks or months after infection 4. Medical system involvement: a. Skin 1) Erythema migraines b. Cardiac 1) AV block; subtle myocarditis c. Joints 1) Oligoarticular arthritis 2) Treatment resistant arthritis in 10% of patients d. Asymptomatic infection about 10% of patients 5. Neurological complications: a. Acute phase: 1) Severe headaches 2) Meningitis (lymphocytic) 3) Neck stiffness 4) Radiculoneuritis 5) Mononeuritis multiplex 6) Cerebellar ataxia 7) Myelitis b. Chronic phase: 1) Uni or bilateral VII nerve palsy 2) Encephalopathy 3) Cognitive dysfunction 4) Sensory polyneuropathy a) No acrodermatosis Laboratory evaluation: 1. An antibody response to B. burgdorferi by enzyme-linked immunosorbent assay (ELISA) 2. Western blotting of CSF (positive) 3. Intrathecal production of IgM, IgG or IgA antibody 4. After antibody treatment: a. Antibody titers fall slowly and may persist for years
Tuberculosis
1. Infarction of arteries within cortical and basilar exudates a. Superficial pial arteries most often affected 2. Exudates at the base of the brain 3. Seizures (focal or generalized)
4. Cranial nerve VIII and lower cranial nerves most frequent affected 5. Frequently associated with HIV 6. Chronic dementia
Cerebral Nervous System (CNS) Infections in the Immunologically Compromised Host
1. General neurological manifestations: a. Meningeal signs d. Seizures b. Mass lesions e. Stroke-like presentation c. Encephalopathy 2. Presentation depends on specific characteristics of the organism 3. CNS mass lesions a. Subacute or chronic presentation 4. Meningitis and encephalitis a. Acute presentation 5. Disorders affecting B-lymphocyte function: a. Meningitis caused by encapsulated bacterial pathogens b. Bacterial meningitis similar presentation in normal and compromised hosts 6. Impaired T-lymphocyte or macrophage function: a. Infection caused by intracellular pathogens 1) Aspergillus and fungi 2) Nocardia (bacteria) 3) Viruses a) HSV b) JC c) CMV d) HH-6 4) Parasites a) Toxoplasmosis gondii 7. Extra-CNS sites of infection a. Lung and brain infection 1) Aspergillus 2) Nocardia 3) Subacute or chronic presentation 8. T-lymphocyte dysfunction with meningitis: a. Listeria b. Cryptococcus 9. Failure of anti-toxoplasmosis on the therapy for a mass lesion: a. Probable central nervous system lymphoma 10. Aspergillus presentation: a. Mass lesion c. Rare as meningitis b. Stroke
Fungus Infections
A. Mucormycosis
Chapter 3. Medical Causes of Stroke
1. Associated with ethmoid, sphenoid, maxillary sinus infection 2. Ophthalmoplegia (cavernous sinus involvement) 3. Black palate (associated with lateral sinus thrombosis with cyanotic congested palate) 4. Occurs in immunocompromised patients: a. Diabetic ketoacidosis b. Renal failure c. HIV 5. May have indolent cause with ophthalmoplegia 6. Basilar arteritis a. Pontine infarction b. Skull base involvement 7. Intracranial hemorrhage 8. Large vessel stroke 9. Involvement of intracranial vessels B. Aspergillosis 1. Immunocompromised patients a. Inhalation of spores b. Aspergillomas in lung cavities c. Disseminated after bone marrow transplantation d. Common after ENT surgery (paranasal sinus) e. Involves blood vessels f. Associated mycotic aneurysms g. Intraluminal extension of fungal hyphae with ischemic stroke h. Aspergillomas occur in sphenoid sinus 1) Associated skull base osteomyelitis 2) Cranial nerve involvement 3) Cavernous sinus thrombosis 4) Rare spinal cord involvement C. Cryptococcus 1. Meningitis a. Sugar 30–40 mg% b. Lymphocytic pleocytosis c. PCR positive d. Moderate protein elevation of 50–80% 2. Chronic dementia with headache 3. Common in all immunocompromised patients (especially those with HIV) 4. Affects cranial nerve II accumulate (under optic nerve dura) 5. Basal ganglia and midbrain involvement (spreads through Virchow Robin space) 6. Proximal MCA and arteries in the posterior perforated substance most frequently involved 7. Occasional pial artery stroke D. Coccidia mycosis (coccoides immitis) 1. Spores inhaled from the soil 2. Endemic in deserts of SW USA 3. Pulmonary route of infection a. “flu-like” illness 4. Propensity to invade bone a. Jaw b. Lumbosacral area
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5. Chronic basilar meningitis a. Inflammation of arteries within the inflammatory exudate b. Proximal MCA and arteries of the posterior perforated substance involved
Histoplasmosis
1. 2. 3. 4. 5.
Endemic in the Mississippi Valley Pulmonary route of infection Adrenal failure (rare) Skin manifestations Central Nervous System: a. Basilar meningitis b. Proximal great vessel involvement
Fungal Aneurysms
1. Fusiform in shape 2. Involve longer and more proximal segments of intracranial vessels 3. Intradural portion of the carotid artery most common site of fungal neurysm 4. Vessel invasion occurs from extension of the hyphae into the lumen which cause: a. In situ thrombosis b. Embolization of hyphal masses c. Major portions of vessels involved 1) Large infarctions CT Signs of Fungal Infection of a Sinus
1. Sclerotic thickening 2. Erosion 3. Remodeling a. All rare in bacterial infections 4. Central area of high density within the sinus cavity 5. Low signal on MRI in all sequences a. paramagnetic substances within fungal mycetomas 6. Aggressive extension of fungus form the sinus to: a. Orbit c. Intracranial cavity b. Facial tissues 7. Vascular invasion
Viral Infections and Stroke
1. General features: a. Vasculitis from a viral infection effected by: 1) Direct invasions of central nervous system vessels 2) Triggering an immune response to epitopes of the vessel wall 3) Immune complex deposition
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SECTION I. Vascular Disease
Herpes Zoster
1. General vascular manifestations a. Delayed brain infarction following infection 1) Contralateral hemiplegia form ipsilateral MCA involvement 2) Days to 6–8 weeks following onset of the rash 3) Occlusion or stenosis of the carotid siphon, ACA or MCA a) May be preceded by a TIA b) Usual clinical onset in that of an abrupt stroke 4) Concomitant encephalitis 5) Recurrent and multiple infarcts 6) rash may occur in V2, V3 or vertebrobasilar territory 7) Rare involvement of PCA or vertebrobasilar territory 8) Infarct and stenosis may occur in young adults b. Arteriographic evaluation 1) Stenosis of proximal MCA and basilar artery a) Induce large infarction 2) Occlusion of the supraclinoid ICA 3) Stenosis of intracranial large conducting vessels
2.
3.
4.
5.
6.
HZ Cerebral Infarctions in HIV-Infected Patients
7. 1. HZ ophthalmicus: a. Delayed contralateral hemisphere stroke 1) Granulomatous arteritis 2) Patient’s may have no preceding rash prior to stroke 3) Similar pathology to non-infected patients a) Segmental arteritis of the carotid siphon 4) Concomitant acute retinal necrosis 2. Immune competent HZ patients a. Large vessel disease 3. HIV patients a. Small vessel diseases b. Leukoencephalitis c. Ventriculitis 4. Children with concomitant HIV and HZ a. Dilatation arteriopathy with fusiform aneurysms of intracranial arteries b. Subarachnoid hemorrhage 5. Children with non-HIV, VZV stroke a. Typical delayed proximal intracranial arteritis
HIV
1. General features: a. Approximately 25% of HIV infected patients have cerebrovascular involvement 1) Concomitant infections that cause vasculitic syndromes are:
a) Ebstein–Barr virus c) Hepatitis B b) CMV d) HZ Vasculitis due to: a. Infections (viral, bacterial, fungal, parasitic) b. Lymphoma c. Lymphomatoid granulomatosis 1) Primarily affects the lungs 2) Angiocentric mixed inflammatory infiltration of central nervous system vessels 3) May involve into non-Hodgkin’s lymphoma Mechanism of vasculitis in HIV: a. Immune complex formation b. Cell mediated vasculitis c. Inflammation due to direct injury Clinical associations with HIV vasculitis a. Encephalitis c. Peripheral neuropathy b. Myelopathy d. Myopathy Types of vasculitis with HIV infection a. Necrotizing c. Granulomatous b. Eosinophilic MRA evaluation of HIV arteritis: a. Vascular abnormalities seen in medium sized blood vessels 1) Aneurysmal dilatation 2) Thickening and contrast enhancement of vessel walls Primary angiitis of the central nervous system in an HIV infected patient: a. All other etiologies ruled out b. Clinical features: 1) Acute or subacute recurrent focal deficits 2) Background of global central nervous system dysfunction
Parasitic Infections
Cysticercosis
1. General features: a. Infection with the larvae (cysticerci) of Taenia solium (pork tapeworm) 2. Types of infection a. Ventricular cysts (racemose form) b. Parenchymal involvement c. Subarachnoid space 3. Vascular manifestations a. Occurs primarily in the subarachnoid form of the disease 1) Meningitic spread to basal intracranial blood vessels a) Endarteritis of small vessels in the vicinity of the parasite 4. Patterns of infarction a. MCA > PCA > ACA infarcted
Chapter 3. Medical Causes of Stroke
b. Rarely involves the basilar territory c. Subcortical small infarcts d. Large cortical-subcortical strokes e. Intracranial hemorrhage (rare) 5. Clinical features: a. Stenosis of arteries may spontaneously improve b. Stroke may be precipitated by treatment with praziquantel c. Treatment may precipitate an inflammatory response that exacerbates the endarteritis Cerebral Malaria
1. General manifestations: a. Plasmodium falciparum b. Neurologic manifestations occur in 2% of all malarial infections c. RBC’s parasitized by P1 falciparum 1) Occurs maximally in brain capillaries 2) Clinical manifestations a) Prodrome of fever and headache b) Intracranial hypertension 1) Distention of capillaries and vessels 2) Cerebral edema c) Generalized petechial brain hemorrhages d) Hemiparesis and seizures most common neurological focal complications 3) Focal infarctions more common in children than adults 2. CT findings a. Severely ill patients demonstrate: 1) Thalamic and cerebellar attenuation 2) Cerebral edema b. Mildly affected patients may have normal initial CT scans c. Angiography and TCD in children 1) Demonstrate focal stenosis of the basal intracranial arteries d. Areas of petechial hemorrhage 1) Hallmark of cerebral malaria pathologically 2) Not demonstrated by CT e. Focal infarcts of the ophthalmic and major cerebral arteries are rare in adults MRI Evaluation of Cerebral Malaria
1. Cortical infarcts 2. T2-weighted and FALIR hyperintense lesions a. Diffuse or symmetrical
Stroke in Association with Named Syndromes
It is surprising how many named stroke syndrome have seminal skin manifestations. Köhlmeier Degos syndrome is associated with characteristic whitish or erythematous papules
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with a porcelain white center. Associated severe gastrointestinal symptoms are diagnostic. Mencke’s syndrome has diagnostic course, stiff hair associated with severe hypotonia, seizures, and branch artery occlusion. There is often survival to early adulthood. Vogt–Koyanagi disease is distinguished by a white forelock, eye lashes and eyebrows. The skin manifestations are noted with a uveal meningeal presentation, ocular and brainstem signs and symptoms of the VIIIth nerve is involved the syndrome becomes Voigt–Koyanagi–Harada. Sneddon’s syndrome is characterized by severe livedo reticularis in the extremities and is associated with stroke in young adults. Divry Von Bogaert disease is seen in older patients has livedo reticularis and is associated with seizures and dementia. The skin is clearly hyperelastic in pseudoxanthoma elastica (Grönblad–Strandberg disease) and has a characteristic cigarette paper thinness in the posterior neck area. Hyperelastic skin may also be noted in Ehlers Danlos Type I and IV as well as Marfan’s Syndrome. Characteristic dissections of extracranial arteries (often bilateral), aortic disease and aneurysms distinguish these entities. Fabry’s disease has characteristic angioma in the bathing suit distribution and other seminal feature of heat sensitivity, renal failure, premature coronary artery disease and painful neuropathy. Hemorrhage rather than stroke syndrome are characteristic of Van Hippel Lindau disease, Sturge Weber, Cobb’s disease and Klippel–Ternary–Weber Syndrome. The strawberry hemangioma must cover the upper eyelid (V1) distribution in Sturge–Weber Syndrome. Its most characteristic features are intractable seizures, mental retardation and trans-track calcification of the parieto occipital cortex. Von-Hippel Lindau has characteristic retinal artery venous malformations with lesions also noted in the cerebellum and spinal cord. Associated renal carcinoma is expected. Wyborn–Mason is characterized by strawberry hemangioma on the face or trunk with a midbrain hemangioma Cobb’s Syndrome presents with massive truncal hemangioma and hemispheric AVM. Osler Weber Rendu often presents with telangiectasia of the lower lip, conjunctiva and nasal mucous membrane. Stroke may be emboli from pulmonary shunts. Thrombophlebitis with dilated veins in the upper extremity or chest wall (Mondor’s syndrome) suggests nonbacterial thrombophlebitis from an underlying malignancy. Well known in this regard is pancreatic cancer. Petechiae and purpura are frequently associated with syndromic stroke. Thrombotic thrombocytopenic purpura (Moschowitz’s syndrome) presents with generalized purpura, seizures, hallucinations, focal neurologic signs and renal failure. Waldenström’s macroglobulinemia may be associated with rheological causes of stroke difficulty with perfusion of capillaries, due to high concentrations of IgM. The petechiae are characteristically noted below the knee. Cryoglobulinemia may present similarly, but often with acrocyanosis. The Bing Neel Syndrome is inclusive of all disease processes that interfere with cerebral perfusion. Bleeding from the gums,
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SECTION I. Vascular Disease
petechiae and depressed consciousness are diagnostic. Small cortical strokes may occur. Kawasaki’s disease frequently presents with an explosive course and mucous membrane involvement. Unusual coronary artery occlusion and stroke occur. Behçet’s Syndrome may present with painful erythematous, well demarcated skin lesions and stroke. Most frequently mouth and genital ulcers are seen concomitantly. Eye findings and named stroke syndromes are common. Susac disease is a combination of retinitis and VIIIth nerve involvement with stroke. It is a microangiopathy of the main vestibulocochlear complex and retina. There is striking obliteration and amputation of retinal vessels. Acute posterior multifocal placoid pigment epitheliopathy affects young adults and is a putative autoimmune process. The patients may suffer arteritic strokes. The major pathology is in the retinal pigment epithelium although the optic nerve may be involved concomitantly. Cogan’s syndrome and its variants affect young adults and cause an acute interstitial keratitis as well as vestibular and auditory dysfunction. Central retinal artery or vein occlusion occurs in association with pial artery stroke. Atypical variants have vasculitis and systemic manifestations. Eales disease occurs in young men and is prevalent in the Middle East and India. Retinal periphlebitis and vitreous hemorrhage are common with occasional large vessel stroke. The ophthalmologic symptoms predominate. Eye findings in association with stroke occur in osteogenesis imperfecta (robin’s egg blue sclera); PXE (angioid streaksdisruption of Bruch’s membrane), homocystinuria and Marfan’s syndrome (lens dislocation), cat scratch fever (infectious retinitis) syphilis (retinitis pigmentosa, argyle Robertson pupil, optic atrophy). The defects in Ehler Danlos disease causes arterial dissection, intracerebral an extracranial aneurysm and cavernous sinus fistula. Gastric hemorrhage, skin manifestations, mitral valve prolapse due to elongated chordae tendinea and aortic root ectasia occur. Marfan’s osteogenesis imperfecta, Ehlers Danlos type I and IV are the primary named entities. Strokes and bowel defects are related most often due to protein losing enteropathy known as Ménétrièr’s syndrome. Ulcerative colitis and regional enteritis are associated with large vessel stroke due to loss of protein C and S. Behçet’s may affect the gastrointestinal tract with mucosal ulcers. Köhlmeier–Degos disease frequently is initiated by abdominal pain and diarrhea. Henoch–Schönlein purpura may be attended by early and severe joint and abdominal pain. Loeffler’s syndrome and Churg–Strauss disease are associated with pulmonary intersitial disease, eosinophilia and stroke. Pituitary infarction is peculiarly common with Churg– Strauss disease. Vasculitic sarcoid affects the lung and cerebral vessels as does the hyper eosinophil syndrome (20,000 eosinophil/mm3 ). Arterial involvement as the primary disease process occurs in both Moya-Moya syndrome and Buerger’s syndrome.
In Moya-Moya disease there is progressive relentless occlusion of the origin of the carotid arteries. The resulting collateral circulation and exuberance of lenticulostriate arteries produce the characteristic “puff of smoke” on arteriograms. In the United States it is seen with sickle cell disease, tuberculosis that affects the origin of the great vessels as well as X-ray therapy. Frequently it is idiopathic. Surprisingly, it may present in elderly patients and as a primary subarachnoid hemorrhage rather than occlusive ischemic stroke. Buerger’s disease often presents with severe occlusive disease below the knee rather than the distal 1/3 of aorta or iliac arteries that is characteristic of atherosclerosis. A dementia secondary to a generalized granular cortical atrophy is more common than conducting vessel stroke. Erdheim–Gesell syndrome is medial cystic necrosis. Dissection of the great vessel is common. Arterial thickening of the radial artery at the wrist and aortic insufficiency bolster the diagnosis. As noted above, osteogenesis imperfecta, Marfan’s syndrome and homocystinuria (accelerated atherosclerosis) all present as primary disease of blood vessels. May Turner Disease is iliofemoral deep vein thrombosis that is associated with embolus to the top of the basilar artery. Takayasu’s disease dramatically affects the blood vessels emanating from the aortic arch and the aorta itself. Subclavian steal is prominent arteriographically, but rarely clinically significant. Cataracts and facial atrophy are prominent due to loss of nutritive blood supply to the face. The strokes are primarily in the anterior circulation. Claudication of vision occurs with head position and walking due to the tenuous blood supply to the retina. It occurs with rheumatic diseases as reported from Scandinavia. HERNS disease is a hereditary stroke syndrome associated with endotheliopathy, renal disease neuropathy and stroke. Polyarteritis and polyangiitis are the other vascular arteritides which is associated with renal disease. Cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy is a named disease associated with dementia. Severe migraines are common. Binswanger small vessel microangiography also is associated with dementia. Mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes are also associated with dementia and migraine. Posterior leukoencephalopathy is characteristic in parietal occipital areas. In a similar syndrome reported in French Canadians Saquenay Lac St. John Syndrome, the leukoencephalopathy is frontal rather than parieto occipital. Divry Von Bogaert’s disease is also associated with dementia. Stroke in Association with Named Syndromes 1. Eales disease 2. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) 3. Buerger’s disease (thromboangiitis obliterans) 4. Ehlers–Danlos syndrome (type IV) 5. Homocystinuria
Chapter 3. Medical Causes of Stroke
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
Moyamoya disease Antiphospholipid antibody syndrome (aPL) Sneddon’s syndrome Susac syndrome (microangiopathy of the retina, inner ear, and brain) Takayasu’s disease Divry von Bogaert syndrome Grönblad–Strandberg Disease (pseudoxanthoma elasticum) PXE Kohlmeier–Degos disease (malignant atrophic papulosis) Behçet’s Disease Moschowitz syndrome (thrombotic thrombocytopenic purpura) TTP Disseminated intravascular coagulation (DIC) Sturge–Weber Disease Osler Weber Rendu Bing Neel syndrome Kawasaki syndrome Loeffler’s syndrome Ménétrièr’s syndrome Acute posterior multifocal placoid pigment epitheliopathy Voigt Koyanagi disease Hereditary endotheliopathy renal neuropathy syndrome (HERNS) Fabry’s disease Sanguinary Lac St. John Syndrome Erdheim–Gesell Syndrome (medial cystic necrosis) May Turner Syndrome Cogan’s Syndrome Churg–Strauss
Eales Disease
A. General characteristics 1. Disease of young men 2. Prevalent in the Middle East and India 3. No systemic symptoms 4. Eye symptomatology is dominant B. Ophthalmological Manifestations 1. Retinal periphlebitis 2. Vitreous hemorrhage 3. Retinal capillary ischemia 4. Retinal revascularization 5. Perivenous and periarterial sheathing 6. Macular arteries are less severely affected a. relative sparing of central vision 7. Uveitis C. CNS Manifestation 1. Meningitis 2. Stroke (a) Focal infarcts (b) Occasional large vessel involvement
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CADASIL
General characteristics 1. AD inheritance chromosome: 19q12 2. Onset 30–50 years of age; notch 3 gene mutation 3. Migraine like headaches 4. Depression 5. Diffuse leukoencephalopathy (MRI) 6. Recurrent stroke-like episodes 7. Basophilic granular material replaces the smooth muscle cells of the media a. Small medium sized vessels 8. Strokes in basal ganglia; thalamus, brainstem, meninges and cerebellum 9. Blood vessel changes: myocardium, spinal cord, muscle 10. Unusual neurologic features: a. Seizures b. Small cortical infarcts 11. Gradient ECHO sequence demonstrates the hemosiderin of old infarcts 12. APOE e2 allele a. More hemorrhage b. Vasculopathy 13. May involve external capsule a. Longest penetrating blood vessels 14. A3243G mutation a. Occipital infarcts are prominent Neurologic manifestations: a. Small lacunar infarcts; brainstem, thalamus, basal ganglia, meninges and spinal cord b. Ischemic atherosclerotic white matter changes with posterior predominance c. Strokes may involve the external capsule (longest penetrating arteries) d. Recurrent stroke-like episodes e. Most frequent presentation is hemorrhage 1) Lobar (superficial) 3) Recurrent 2) White matter f. Progressive 1) Gradual 2) Step-wise g. Gait disturbances h. Seizures and small cortical infarcts are rare Japanese variant a. Occurs in young men b. Alopecia c. Back pain d. Affects small arteries 1) Hyalinosis 2) Deterioration of internal elastic membrane MRI evaluation a. Diffuse leukoencephalopathy (posterior predominance) b. T2 weighted lesions may be seen prior to symptoms c. Gradient ECHO sequences demonstrate hemosiderin from prior bleeds
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SECTION I. Vascular Disease
Differential diagnosis 1. Binswanger 5. Vasculitis 2. MS 6. Hexosaminidase A deficiency 3. HIV 7. Adrenomyeloneuropathy (AMN) 4. Neurosyphilis 8. Adrenoleukodystrophy (ALD) Mitochondrial Encephalomyelopathy with Lactic Acidosis Stroke-Like Episodes (MELAS) 1. General features: a. Ischemic brain lesions 1) Metabolic dysfunction of mitochondria 2) Decreased COX activity (mitochondrial complex III) 3) Arteries supplying (ischemic areas) are open 2. Maternal mutation of mtDNA 3. Clinical features: a. Short stature f. Hemiparesis b. High incidence of diabetes g. Seizures c. Migraine – like headaches h. Ataxia d. Sensorineural hearing loss i. Fatigue with exercise e. Visual dysfunction 4. Point mutation A3243G a. Severe occipital infarcts 5. Laboratory evaluation: a. Elevated resting pyruvate/lactate levels b. Ragged red fibers; COX deficiency on muscle biopsy 6. MRI evaluation: a. Multifocal lesions b. Parieto-occipital predominance c. Cortex and underlying white matter affected d. High incidence of basal ganglia calcification 7. Other MtDNA diseases such as MERFF and KSS a. Demonstrate leukoencephalopathy
Buerger’s Disease (Thromboangiitis Obliterans)
A. General Manifestations: 1. Severe peripheral vascular disease. Extremity lesions are typically below the knee in the posterior and anterior arteries rather than the distal 1/3 of the aorta or the iliac arteries 2. Intermittent claudication often presenting in the medial foot (in step) 3. Coronary and renal arteries may be affected B. Neurological Manifestations 1. Large vessel stroke 2. Granular cortical atrophy a. Dementia
b. Affects young women c. Most prevalent in second to fourth decade 2. Clinical manifestations: a. Retina 1) Large retinal arteries are involved: a) Obliteration and amputation of vessels b) Increased light reflex c) Narrow attenuated arteries b. Bilateral visual loss c. Tinnitus and hearing loss d. Bilateral pyramidal tract dysfunction e. Cerebellar ataxia f. Dementia g. Gradual or step wise progression 3. Laboratory evaluation a. CSF 1) Minor lymphocytic pleocytosis 2) High protein 1g/dl 4. Pathology a. Obliteration of small intracranial arteries b. No inflammation or granuloma formation
Acute Posterior Multifocal Placoid Pigment Epitheliopathy
1. General characteristics: a. Affects young adults b. Precedent flu-like febrile illness 2. Clinical features: a. Both eyes are affected simultaneously; ocular involvement may occur seriatim b. Visual blurring; scotoma and distortion of vision c. Vision recovers after several weeks; deficits may be permanent d. Funduscopic examination 1) Pathology in the retinal pigment epithelium 2) Well circumscribed grey-white flat lesions 3. Neurologic features: a. Optic neuritis b. Headache c. Stroke 1) May have arteritis pattern 4. Pathology a. Focal granulomatous inflammation of medium sized blood vessel (one patient)
Takayasu’s Disease Susac Syndrome
1. General Characteristics a. Microangiopathy of the brain, vestibulo-cochlear complex and retina
A. General characteristics 1. Most common in Asia; may be seen sporadically in the West 2. Prodrome of fever and night sweats 3. High sedimentation rate; anemia
Chapter 3. Medical Causes of Stroke
4. Gradual obliteration of: a. Major arterial branches of the arch of the aorta b. Vertebral arteries are relatively spared B. Neurological manifestations 1. Loss of extremity and neck pulses 2. Asymptomatic subclavian steal 3. Intermittent claudication of vision a. Tenuous blood supply to the optic nerve and retina 4. Early onset of cataracts 5. Facial atrophy 6. Headache 7. Dizziness 8. Hypothyroidism a. Increase thyrocervical trunk collaterals destroy the gland 9. Arm and leg claudication C. Stroke 1. Ischemic stroke a. Less frequent than expected from the radiologic evaluation b. Media and adventitia of blood vessels involved in an inflammatory response c. Late stage fibrosis d. Etensive collateral circulation associated with 1) SAH 2) ICH D. Arteriographic evaluation: 1. Occlusion, stenosis, ectasia, aneurysm formation at vessel origins of the aortic arch 2. Most common sites of involvement: a. Mid portion of the left common carotid artery b. Left and right subclavian arteries c. Mid portion of the innominate artery
Behçet’s Disease
A. General Characteristics 1. Relapsing remitting course 2. Major features a. Oral ulcers c. Uveitis b. Genital ulcers 3. High incidence in Turkey and Japan a. World-wide distribution 4. Systemic involvement: a. Skin: 1) Aphthous mouth ulcers 2) Folliculitis 3) Erythema nodosum 5. Ulcerative lesions of bowel/bowel mucosa 6. Stomach ulcers 7. Synovitis 8. Large joint arthritis 9. Thrombophlebitis 10. Affects young adults 11. Male > female 2 : 1
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12. Neurologic involvement large vessel 2. Dural venous sinus thrombosis 3. Primarily ocular manifestations 4. Brainstem syndrome (rhombencephalitis) 5. Neurologic signs and symptoms are frequently relapsing and remitting 6. Spinal cord may be involved E. MRI Evaluation: 1. Topography of involvement a. Pons > midbrain > basal ganglia > thalamus 2. Small well delineated T2 weighted lesions a. Brainstem lesions 1) Not in arterial territories b. Grey and white matter lesions c. 10 mm sharply marginated irregular and confluent lesions in affected areas
Cogan’s Syndrome
A. General Characteristics 1. Occurs in young adults 2. Clinical features: a. Acute interstitial keratitis b. Vestibular auditory dysfunction 1) Inflammation of the labyrinths
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SECTION I. Vascular Disease
c. Stroke (pial arteries) B. Typical Cogan’s 1. Photophobia, lacrimination, eye pain 2. Blurred vision 3. Intermittent symptoms for years 4. Ménière’s like attacks may precede eye pain 5. Total deafness and absence of vestibular function C. Atypical Cogan’s Syndrome 1. Vasculitis and systemic manifestations 2. Eye pathology includes: a. Retinal hemorrhage b. Papilledema c. Orbital pseudotumor d. Central artery or vein occlusion 3. Vestibula auditory dysfunction may occur >2 years after onset of eye symptoms 4. Vasculitis a. Occurs in atypical disease b. Aortitis and aortic insufficiency in the classic syndrome c. Neurologic symptoms 1) Stroke 2) Encephalopathy 3) Seizure 4) Myelopathy 5) Mononeuritis multiplex 6) Cavernous sinus thrombosis d. Differential diagnosis includes syphilis
Ehlers Danlos Syndrome
A. General features 1. Hyperelastic skin 2. Hyperextensible joints 3. Increased scarring after injury 4. Platelet dysfunction 5. Cardiac defects B. Nine subtypes of the syndrome 1. Major types are I, II, or III (approximately 50% of patients) C. Subtype IV most important for cerebrovascular lesions: 1. Decreased synthesis of type III collagen a. All of these patients demonstrate AD inheritance b. COL 3A1 gene (mutations); chromosome 2 1) Codes for alpha-1 chain of type III collagen D. Neurological features: 1. Aneurysms (IV; rarely type I) a. Intra and extracranial aneurysms b. Multiple aneurysms c. Most common aneurysm is of the ICA 1) In the cavernous sinus 2) At the site of emergence from the sinus d. Presentation of aneurysms: 1) SAH 2) Carotid cavernous fistula (rupture of the cavernous sinus aneurysm)
Differential Diagnosis between Marfan’s Syndrome and Ehlers Danlos Buerger’s Disease (Thromboangiitis Obliterans)
1. General Characteristics a. Vasculitis of medium and small vessels b. Primary involvement in distal extremity vessels c. Rarely affects veins d. Onset prior to age 45 2. Brain vessel topography: a. Watershed zones between ACA/MCA and MCA/PCA territories b. Possibly two vessel size involved: 1) Arteries 15 years a. Late neurological presentations occur b. Girls > boys 50 : 1 c. Adult present 3–5th decade B. Pathology 1. Endothelial fibrosis and hyperplasia 2. Abnormalities of the internal elastic membrane 3. No inflammatory changes C. Neurological features: 1. Childhood presentation: a. Transient hemiparesis precipitated by exercise or hyperventilation b. Cognitive decline c. Rare intermittent choreoathetosis d. Headaches e. Seizures 2. Adult presentation: a. Brain hemorrhages 1) Thalamus, basal ganglion, deep white matter 2) Aneurysmal dilations of the collateral vessels with rupture b. SAH and intraventricular hemorrhage c. Aneurysms of the circle of Willis develop. Predilection for: 1) Anterior communicating artery 2) Basilar artery d. Unusual prominent collaterals: 1) Ethmoidal arteries (from carotid) 2) Superficial temporal and middle meningeal arteries to transdural arteries e. Process may stabilize with age MRI/MRA Evaluation
1. Collateral flow voids are prominent 2. Multiple bilateral infarctions of: a. Basal ganglia 3. Subcortical white matter infarctions
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4. Cortical atrophy and hydrocephalus ex vacuo 5. Conventional arteriography a. Demonstrates typical lenticulostriate collaterals (“puff of smoke”) b. Terminal carotid proximal ACA and MCA occlusions c. Dilated collateral vessels Antiphospholipid Antibody Syndrome (APL)
Sneddon’s Syndrome
A. General Characteristics 1. Young patients; pial artery strokes 2. Livedo reticularis of the skin a. Reticulated skin pattern b. Involves trunk and all extremities 3. Cold extremities 4. Diminished pulses 5. Differential diagnosis a. Sympathically maintained pain patients: 1) Usually have concomitant allodynia, hyperalgesia, autonomic dysregulation
Differential Diagnosis between Sneddon’s Syndrome and APL (antiphospholipid syndrome)
1. Antiphospholipid antibody titers (APL) approximately equal in both 2. APL Sneddon’s patients are older than APL patients 3. Miscarriages more frequent in APL patients 4. Cardiac valve abnormalities APL > APL patients (marantic endocarditis) 5. Venous thrombosis more common in APL than APL patients
Differential Diagnostic Points between Sneddon’s vs. APL Patients
1. Digital artery narrowing and dilation demonstrated angiographically; acrocyanosis (Sneddon’s) 2. Early inflammatory skin lesions (Sneddon’s) a. Medium-sized arteries between the dermis and subcutis affected 3. May be familial (Sneddon’s) 4. May have antiphospholipid antibodies (Sneddon’s) 5. Valvular cardiac defects less common than APL+ 6. Neurological manifestations of Sneddon’s a. Multifocal cortical infarcts b. Lesions in the cerebral white matter c. Intranuclear ophthalmoplegia 7. Arteriography a. Branch occlusions of intracranial arteries
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SECTION I. Vascular Disease
Differential Diagnosis of Livedo Reticularis
1. Collagen vascular disease a. SLE b. Rheumatoid arthritis c. PAN 2. Tuberculosis 3. Syphilis 4. RSD (usually allodynia/hyperalgesia associated) 5. APL syndrome 6. TTP 7. Thrombocythemia 8. DIC 9. Oral contraceptives 10. Neoplasm 11. Cryoglobulinemia (legs) 12. Cholesterol emboli syndrome (legs and toes are blue) 13. Divry Von Bogaert Syndrome
Susac’s Syndrome (Retinocochleocerebral Syndrome)
A. General characteristics 1. Obliteration of large retinal arteries 2. Gradual bilateral visual loss 3. Effects young women in second to fourth decade B. Neurological manifestations 1. Tinnitus and hearing loss 2. Bilateral pyramidal tracts signs 3. Cerebellar dysfunction 4. Dementia (paranoid, bizarre behavior) 5. Stepwise or gradual progression 6. Self-limiting 1–2 years C. CSF Evaluation 1. High protein; rarely >1 gram/dl 2. Minimal pleocytosis D. Pathology 1. Obliteration of small arteries E. Forme Frustes: 1. Branch retinal occlusions 2. Multifocal small infarctions 3. No VIIIth nerve deficits 4. Retinal and VIIIth nerve involvement a. no other neurological deficit
Acute Posterior Multifocal Placoid Endoheliopathy
A. General characteristics 1. Preceding “flu-like” illness 2. Disease of young adults 3. Eyes may be affected singularly or sequentially 4. Ophthalmological findings a. Scotomata b. Lesions of the retinal pigment epithelium
c. Vision recovers within weeks. An occasional patient has permanent visual loss d. Choroidal vasculitis B. Neurological manifestations 1. Headache 2. Optic neuritis 3. Stroke 4. Visual blurring, distortion and scotomata C. Arteriogram 1. Endarteritis
Mencke’s Disease
A. General characteristics: 1. X-linked recessive 2. Mitochondrial dysfunction (lack of copper) a. Impaired intestinal copper absorption 1) Low copper in serum; high excretion in feces b. Mutation in gene encoding metal transporter (MNK ATP 7Ap ) 3. Occipital horn syndrome (OHS) a. Milder phenotype b. Caused by ATP7A P-type gene mutation B. General Clinical Features 1. Coarse, stiff hair (triangular) 2. Hypothermia 3. Onset and death usually early childhood C. Neurologic Features 1. Hypotonia 3. Failure to thrive 2. Seizures D. Diagnostic Features 1. Muscle COX deficit; RRF (ragged red fibers) 2. EM: abnormal mitochondria E. Pathology 1. Microinfarcts 2. Occlusion of branch arteries 3. Cerebral atrophy
Vogt–Koyanagi Harada Syndrome
A. General characteristics: 1. Uveomeningeal process 2. White forelock and eyelashes 3. Alopecia 4. Iridocyclitis 5. Choroiditis B. Neurological manifestations 1. Meningeal signs (cause of recurrent meningitis) 2. Adhesive arachnoiditis 3. Papilledema 4. Increased intracranial pressure 5. Dementia 6. Cerebellar signs
Chapter 3. Medical Causes of Stroke
7. May remit after 6–12 months C. Laboratory Evaluation 1. CSF lymphocytic pleocytosis
Divry Von Bogaert Syndrome (DVBS)
A. General characteristics: 1. Presents in adults between 18–40 2. May be familial or sporadic in the adult form 3. Affects males in the adult form 4. Juvenile form may follow vaccination or viral illness 5. Livedo reticularis is present 6. Death usually occurs in 20 years B. Neurological manifestations 1. Presenting symptoms: a. Seizure b. Dementia c. Rigidity d. Hyperreflexia e. Ataxia f. Multiple deep and superficial infarction that leads to: 1) Pseudo bulbar palsy 2) Corticomeningeal non-calcifying angiomatosis of vessels; arteries develop fibrous thickening
Sanguinay Lac St. Jean
A. General characteristics 1. AR 2. Decreased COX (cytochrome oxidase) in tissues B. Neurological manifestations 1. Frontal cortical lesions 2. Stroke-like episodes C. Differential point: 1. MELAS affects parietoccipital areas primarily
Disseminated Intravascular Coagulation (DIC)
A. General characteristics 1. Occurs in a setting of: a. Septicemia b. Cancer c. Obstetrical procedures with release of amniotic fluid into the circulation d. Neurosurgical procedures (release thromboplastin) e. Chemotherapy f. Viremia: 1) HIV 3) Varicella 2) Hepatitis g. Intravascular hemolysis h. Heat stroke
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i. Burn patients j. Liver disease k. Prosthetic devices l. Collagen vascular disease 2. Clotting and fibrinolytic system are activated simultaneously 3. Usually systemic hemorrhage and thrombosis: a. Hypotension b. Fever c. Hypoxia d. Acidosis e. Shock f. Acrocyanosis g. Bleeding from all punctures sites B. Neurological manifestations 1. May present in coma with a nonfocal neurological exam 2. Large vessel occlusion 3. Lethargy; stupor 4. Cranial nerve palsies 5. Seizure 6. SAH 7. Emboli from NBTE 8. Multifocal hemorrhage and infarction C. Laboratory evaluation 1. Peripheral blood smear: a. Schistocytes (fragmented RBC’s) in 50% of patients b. Thrombocytopenia legs and trunk e. Anterior tongue f. Retina (10%) 3. Telangiectasia a. Enlarge and multiply 4. Telangiectasia occur in internal organs a. Lungs c. Genitourinary tract b. GI tract B. Neurological manifestations: 1. CNS affected in 8–12% of patients 2. Increased incidence of migraine 3. 67 3. Hemoglobin at 18–22 grams/ml 4. Bleeding from the gums 5. Dilated tortuous retinal veins a. Box car phenomena (pressure on the globe with clumping of RBC’s in the central retinal veins) 6. Petechiae of the lower extremities 7. Associated with: a. IgM > IgG monoclonal gammopathy b. Waldenström’s macroglobulinemia B. Neurological manifestations 1. Encephalopathy a. Poor cerebral perfusion b. Cerebral small vessel ischemia
Grönblad–Strandberg Disease (Pseudoxanthoma Elasticum) PXE
A. General characteristics 1. Angioid streaks in the retina a. Grey streaks radiating from the disk b. Break in Bruch’s membrane 2. Thickened soft skin in general and particularly in the lower abdominal area 3. Angioid streaks are present in 85% of patients 4. Chorioretinal scarring 5. Macular degeneration 6. Leukoencephalopathy 7. Genetics a. AR most common
Chapter 3. Medical Causes of Stroke
b. AD c. Sporadic forms 8. Female > male predominance 9. Progressive disease 10. Systems involved prematurely: a. Cardiovascular c. Skin b. Ocular 11. Arterial disease: a. Accelerated atherosclerosis b. Calcification c. Large and medium size vessels affected 12. Hypertension 13. Gastrointestinal hemorrhage a. Intestinal and gastric mucosal vessel involvement B. Neurological manifestations 1. Stroke a. Large artery infarction 2. Hemorrhage a. Hypertension c. Saccular aneurysm b. Microaneurysm d. SAH 3. Cavernous artery aneurysm.
Köhlmeier Degos Disease (Malignant Atrophic Papulosis)
A. General characteristics 1. An occlusive endarteropathy a. Involves small and middle size arteries and veins b. Proliferative vasculopathy 2. Affects young adults a. May be a more benign childhood form 3. Skin manifestations are pathognomic a. May be absent early b. Whitish or erythematous papules c. Involve the trunk and limbs d. Central part of the lesion is atrophic 1) Porcelain white 4. Gastrointestinal lesions a. Early stages associated with abdominal pain and diarrhea b. Intestinal obstruction c. Perforation (often the cause of death) 5. May affect all organ systems B. Neurological manifestations 1. Stroke may precede other systemic manifestations 2. CNS dysfunction a. Cranial nerve involvement b. Cognitive decline c. Ophthalmoplegia d. Focal motor or sensory deficit e. Multifocal infarction and hemorrhage f. SAH (rare) g. Dural sinus thrombosis 3. Peripheral nerve involvement a. Demyelinative peripheral neuropathy
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b. Rare polyradiculopathy C. Ophthalmological involvement of: 1. Conjunctiva 5. Urea 2. Sclera 6. Pupils 3. Retina 7. Optic nerve 4. Choroid 8. Optic tracts D. Angiography 1. Occlusions and beading a. Distal branches of intracranial vessels Cogan’s Syndrome
A. General characteristics 1. Affects young adults 2. Autoimmune vasculitis (putative) 3. Presents with visual symptoms: a. Red eyes d. Interstitial keratitis b. Photophobia e. Uveitis (rare) c. Reduced vision 4. Vasculitis of small and medium sized blood vessels 5. Fever 6. Aortitis and bowel disease 7. Aortic aneurysm B. Neurological manifestations 1. Blindness (corneal opacification) 3. Vertigo 2. Hearing loss 4. Ataxia Erdheim–Gesell Disease (medial cystic necrosis)
A. General characteristics 1. Medial cystic necrosis B. Neurological manifestations 1. Spontaneous arterial dissection 2. Pathology a. Necrosis of smooth muscle of the lamina media May Turner Disease
A. General characteristics 1. Iliac vein/artery compression 2. Iliofemoral deep vein thrombosis B. Neurological manifestations 1. Embolus to basilar apex Vasculopathy
The term vasculopathy as used for this section denotes an abnormality of the vascular wall that predisposes to occlusion, emboli, hemorrhage or compression of neighboring structures. They most frequently occur in younger patients and are a significant component of the differential diagnosis of stroke in the young. The following is a description of the major vasculopathies and their differential diagnosis.
SECTION I. Vascular Disease
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Differential Diagnosis of Vasculopathy
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
Antiphospholipid syndrome Recanalization of atherosclerotic emboli Fibromuscular dysplasia Thrombotic thrombocytopenia purpura Sarcoid Neurofibromatosis 1 Tuberous sclerosis SLE X-RT (irradiation treatment) Pseudoxanthomata elastica (PXE) Marfan’s Disease Medial cystic necrosis – Cerebral arterial ectasia and dolichoectasia Congophilic amyloid angiography –
Neurological manifestations of FMD
1. 2. 3. 4. 5. 6. 7.
TIA Stroke Dissection Horner’s syndrome Headache Syncope Intracranial hemorrhage a. Renal hypertension 8. Neurological complications of dissection 9. Stroke recurrence is rare 10. Internal carotid involvement a. Periorbital pain
Neurofibromatosis Type I Recanalization of Embolus with Thrombus
1. Embolus: a) Fragments and moves distally b) Movement occurs most often in the first 48 hours 2. recanalization of a thrombosed intracranial artery: a) Evident by 14–21 days b) Irregular vascular wall of the affected vessel
1. General characteristics: a. vasculopathy in the setting of other general manifestations of the disease b. may also overlap with tuberous sclerosis that also demonstrates arteriopathy 2. dilated vascular wall 3. rarely causes stroke
Fibromuscular Dysplasia (FMD) X-RT
1. General characteristics: a) Affects systemic arteries: 1) Renal arteries with consequent hypertension b) May involve the entire arterial wall c) Incidence of 6% in selected arteriogram d) Most common in middle aged women e) Bilateral ICA involved in 86% of patients f) Spares the carotid bifurcation: 1) Most common in the pharyngeal carotid artery 2) Spares the in the intracranial carotid artery g) 20% of patients have concomitant extracranial vertebral artery involvement (ECVA) h) The media most often involved 1) Constricting bands (MRA; arteriogram) 2) Proliferation of smooth muscle cells that alternate with media thinning and disruption of the elastic membrane 3) Hypertrophy of fibrous tissue leads to focal stenosis 4) Band-like diaphragms within enlarged carotid bulbs (mega bulbs) (a) Embolic source 5) Affects medium sized muscular intracranial arteries 2. Associations: a) Aneurysms of intracranial arteries b) Arterial dissections
1. General Characteristics: a. Occurs following >3000 rads delivered to the arterial wall b. Carotid artery involvement most frequent after the irradiation of: 1) Pharyngeal tumors 2) Hodgkin’s and other lymphomas 3) Little soft tissue mass to protect the artery in the neck c. Characteristics of bifurcation atherosclerosis d. Arterial calcification 2. Neurological manifestations: a. TIA in the carotid and MCA territory b. Stroke in similar distributions 1) Embolic 2) Thrombotic 3) Distal field ischemia
Tuberous Sclerosis
a. Overlaps syndromically with NF-I b. Arteriopathy is usually asymptomatic
Chapter 3. Medical Causes of Stroke Cerebral Arterial Ectasia
1. General Characteristics a. May be seen in children b. Often involves several arteries c. Familial tendencies noted: 1) One family with alpha-glucosidase deficiency d. If severe the condition is known as dolichoectasia 2. Most frequent location: a. Posterior fossa b. Basilar and vertebral artery c. Middle cerebral artery d. Both anterior and posterior circulations may be involved concomitantly 3. Pathology: a. Gaps in the internal elastic lamina b. Decrease in the muscularis layer c. Fibrotic arterial segments d. Elastic tissue degeneration and increase in the vasa vasorum 4. Neurological manifestations: a. Spasticity (ventral pontine compression) b. Dysarthria (XIIth nerve compression) c. Hydrocephalus (pressure on the IIIrd ventricle); obliterates the prepontine cistern d. Ischemia in the distribution of the affected arteries: 1) Emboli from thrombi in ectatic aneurysms 2) Plaque or clot obstruction in penetrating arteries 3) Rare rupture of aneurysms with SAH 4) Distortion and elongation of arteries cause reduced blood flow 5. Transcranial Doppler Evaluation: 1) Reduced mean-flow velocities 2) Preserved peak-flow velocities 3) Reduced antegrade flow a) To and fro movement within the dilated vessel 6. Imaging Evaluation 1) CT, MRA > MRI are diagnostic a) Reveal dilated, enlarged tortuous vessels
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c. Younger at first hemorrhage d. Rare association with isolated cerebral angiitis 2. Genetic Groups Affected: a. Hereditary cerebral amyloidosis (Dutch); Icelandic b. chromosome 21 p11 c. APP gene (amyloid precursor protein) gene d. Clinical manifestations: a) Ocular vessels involved b) Leptomeningeal deposits of amyloid c) Lobar hemorrhages e. Icelandic 1. Cystatin C gene (chromosome 21 p11) 3. Clinical manifestations: a. Cerebral hemorrhages 1) Multiple 2) Superficial 3) Subcortical lobar 4) Recurrent b. Rare TIA c. Multiple infarcts d. SAH e. Leukoencephalopathy 1) Concomitant multiple infarcts 2) Clinically similar to Binswanger microangiopathy f. Dementing illness from: 1) Concomitant multiple infarcts 2) Alzheimer’s pathology 4. Imaging studies a. Gradient ECHO MRI 1) Demonstrates old hemorrhages (residual hemosiderin)
Rare Causes of Vasculopathy
1. Familial occipital calcification: a. Optic atrophy c. VIII nerve involvement b. Dementia by age 33 d. Hemorrhagic stroke
Vasoconstriction and Stroke Occulo Meningeal Amyloid
1. 2. 3. 4.
Primary uveal veil (vitreous) SAH with secondary vasospasm and stroke Thickened dura Acquired factor V deficiency
Cerebral Amyloid Angiopathy (congophilic angiopathy)
1. General characteristics: a. Increase of E2/E4 alleles b. Amyloid AB 39–43 amino acids 1) Usual vascular amyloid 39–40 aa
Migraine headache and vasoconstriction following subarachnoid hemorrhage are the two most common causes of cerebral artery vasoconstriction and consequent stroke. During migraine headache there is frequently demonstrated arteriographic vasoconstriction; a reduced cerebral blood flow and increase velocity measurement by TCD. F18-2DG PET studies have also demonstrated a spreading posterior to anterior Oligemia often preceding change in blood vessel diameter. This spreading cortical depression of metabolic activity with consequent lessened production of H+ from decreased production of lactic acid may also cause vasoconstriction. The DRASC receptor on cerebral blood vessels interacts with H+ to dilate the vessel. This autoregulation with a match between
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SECTION I. Vascular Disease
lCMR glu (and production of H+ ) and ICBF may determine the caliber of cerebral blood vessels during migraine attacks. The locus ceruleus (norepinephrine) may contract proximal cerebral blood vessels whereas out flow from the superior nucleus salivatorius may dilate cerebral blood vessels during a migrainous attack. The relationship between spreading depression and cerebral blood flow has not been fully elucidated. Migraine has been associated with severe intense vasoconstriction with infarction. Vasoconstriction in migraine may cause ICH and arterial dissection. Reversible cerebral segmental vasoconstriction usually affects young women following delivery, but may occur during their menopause. It may occur after carotid endarterectomy and involves large, medium and small vessels. There are focal regions of vasodilation and vasoconstriction. Vasoconstriction following subarachnoid hemorrhage is a major cause of death and morbidity from this event. It is most often seen at 4–7 days following the bleed and is correlated with the amount of blood surrounding the affected vessels. Mechanisms and characteristics will be discussed in the section on subarachnoid hemorrhage from aneurysms.
Migraine
1. General characteristics: a. Affects all age groups b. During attacks: 1) Vasoconstriction of intracranial blood vessels does occur 2) Spreading depression a) Occipital to frontal b) More important as basic mechanism than vasoconstriction for auras 2. Clinical manifestations 1. Ischemic symptoms a. Precede, are concomitant with or follow attacks b. Usually occur 10–20 minutes prior to the headache 2. Small vessel infarction a. Intense vasoconstriction with thrombosis b. Activation of platelets c. Vasoconstriction per se: 1) Stimulates endothelium to promote thrombosis 3. Migraine and possible association with reversible cerebral segmental vasoconstrictions 4. intracranial hemorrhage a. Reported during migraine attack b. Possible reperfusion etiology 5. Associated with carotid dissection
Differential Points of Migraine Versus Ischemia Stroke
1. Sensory modalities involved sequentially a. Vision, sensory, speech
2.
3.
4.
5. 6. 7.
8.
1) Several modalities involved concomitantly in stroke 2) Negative symptoms predominate in stroke Symptoms are positive in migraine: a. Scintillating scotomata c. Teichopsia b. Paresthesia d. Brightness in a VF Positive symptoms followed by negative symptoms in migraine a. Brightness followed by scotomata Headache follows neuralgic symptoms by 10–15 minutes in migraine a. Sometimes headaches precede symptoms b. Rarely headache and symptoms are concomitant Average attack lasts 20 minutes in migraine Women > men in migraine Attacks lasts over life time of the patient a. Acephalgic form of migraine occurs more frequently in older patients No atheromatous risk factors in migraine
Ischemic Symptoms in Stroke
1. 2. 3. 4. 5. 6. 7. 8. 9.
Several modalities involved concomitantly Negative symptoms predominate Deficits in two modalities occur simultaneously Headache often concomitant with deficits Small white platelet fibrin emboli cause deficits of 5 minutes Distal field ischemia-same territory involved with each attack men > women Attacks height 3) Lateral lens dislocation (50% of patients) 4) Pectus incurvatum 5) Hyperextensible joints b. Enlarged aortic root c. MVP associated d. Aortic insufficiency 3. Neurological manifestations a. Giant intracranial aneurysm (internal carotid) b. bBerry aneurysms occur with higher frequency than expected c. Rare vascular thrombotic or embolic stroke (MVP); emboli also from giant aneurysms d. Increased incidence of dissection
Cystic Medial Necrosis (Erdheim–Gesell Disease)
1. General Characteristics a. Focal fragmentation of elastic fibers b. Loss of smooth muscle cells of the media c. Deposits of mucopolysaccharides d. Similar lesions also noted in: 1) Ascending aorta of Marfan’s patients 2) Advancing age 3) Possible relationship to hypertension 2. Clinical Features: a. Coronary artery dissection b. Carotid artery aneurysm c. Giant aneurysm of the ascending aorta
Chapter 3. Medical Causes of Stroke
Fibromuscular dysplasia affects the media of the vessel wall with constricting bands that are composed of virous dysplastic tissue and proliferating smooth muscle cells. There are alternating areas of vessel wall dilatation related to medial thinning and disruption of the internal elastic membrane. The process affects renal vessels with consequent arterial hypertension. The entity will be discussed more completely under arterial dissection. Enzyme Deficiencies and Stroke
Enzyme deficiencies cause stroke by: 1. All acclerating atherosclerosis 2. Deposition subendothelial or the surface of vascular tissue 3. Clotting factor and platelet abnormalities Rarely, defects that cause hypertension (adrenal steroid enzymes) cause stroke by the induction of hypertension. The major enzyme deficiencies that cause stroke are: 1. Fabry’s disease 2. Homocystinuria 3. Paroxysmal nocturnal hemoglobinuria 4. Ehlers–Danlos syndrome
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Homocystinuria
1. General Characteristics: a. Definition: homocysteine is found in the urine b. Seven biochemically different entities have been identified c. Major categories of entities causing deficit: 1) Enzymopathies 2) Deficiencies of: a) B6 b) Tetrahydrofolic acid 2. Pathology of Elevated Homocysteine Levels 1. Related to: a. Stroke b. Premature atherosclerosis c. Myocardial infarction d. Venous thromboembolism e. More severe carotid disease 2. Injury to the vascular endothelium a. Platelet activation b. Formation of thrombi 3. Vascular smooth muscle proliferation
Fabry’s Disease
A. General Characteristics 1. X-linked 2. Deficiency of alpha-galactosidase A a. Deficiency of alpha activator protein 3. Primarily a small vessel disease 4. Larger vessel ectasia in posterior vessels of the posterior circulation a. TCD demonstrates elevated CBF velocities 5. Ceramide trihexoside accumulates in cerebral and somatic arteries B. Systemic Clinical Features 1. Decreased ability to sweat 2. Severe acroparesthesias 3. Cutaneous angiokeratomas a. Predilection for perineal areas 4. Renal failure 5. Severe heat intolerance (failure to sweat normally) a. Coma with increased temperature 6. Facial swelling (during heat stress) 7. Lumbosacral bone and disc disease in carriers 8. Exercise intolerance 9. Cardiomyopathy (percentage of patients) C. Neurologic Features 1. Large vessel strokes 2. Vertebrobasilar insufficiency (rare) 3. Autonomic nerve dysfunction (small fiber neuropathy a. Decreased sweating (hypotension) b. Syncope 4. Retinal angioid streaks 5. Aneurysmal dilatation of posterior circulation
Cystathionine Beta-Synthetase Deficiency
1. General Characteristics a. Common in Ireland b. AR; chromosome 21q c. Homocysteine interferes with the cross-linking of collagen 2. Systemic manifestations a. Mental retardation b. Osteoporosis c. Dislocation of the lens d. Occlusion of coronary and renal arteries e. Marfan habitus f. Premature atherosclerosis 3. Neurological manifestations: a. Thrombotic strokes may occur in the first decade; usually 30 minutes to hours. Deficits from the smaller cholesterol platelet-fibrin emboli in general last from 30 seconds to five minutes. Fluctuations and deterioration within specific territorial involvement occurs with distal migration of embolic material. Approximately 90% of emboli migrate in 2–3 weeks or recanalize. Emboli from the heart or venous system have no prior TIA in the affected arterial territory but may have caused TIA’s in another arterial territory. The most common symptoms of emboli are non-specific headaches or dizziness which are hard to document. Seizures occur in 10–15% of patients, 25% of patients have focal symptoms. The sudden onset of a pure Wernicke’s aphasia in the setting of AF suggests an embolus to the inferior division of the left MCA. Muteness may be caused by an embolus to the stem of the MCA or an ACA embolus that affects the supplementary motor area. Thalamic aphasia may occur with a top of the basilar embolus. Ten percent of patients suffer loss of consciousness at ictal onset. Many cerebral emboli are asymptomatic which has been clearly demonstrated by evidence of old lesions at presentation during the first ictus and by multiple emboli detected by TCD during carotid endarterectomy. Simultaneous involvement of ACA and MCA territories suggest a top of the carotid siphon localization. In approximately 50% of patients there are RBC’s in the CSF (80–100/mm3 ) at presentation.
Cardiogenic Embolic
The general clinical features of cerebral emboli are a sudden neurological deficit maximum at onset. There is usually some degree of recovery within 24 hours. Carotid crescendo TIA’s are caused by emboli from an area of critical stenosis associated with a burst plaque. The lipid core of the burst plaque activates platelets and the coagulation cascade with consequent detachment of platelet plugs and red cell fibrin material into the carotid territory. Frequently, the crescendo carotid TIA from emboli results in repeated monocular blindness described as blurry vision or dimness which is different from a patient with severe carotid stenosis. Sudden exposure to light in these patients may cause scotomata due to failure of replenishment of retinal pigments. Distal field ischemia with blindness, contralateral sensory loss or weakness may occur with postural lowering of perfusion pressure. These attacks are more frequent than those that occur following a burst plaque. Distal field ischemia may be manifest by shaking of the contralateral area with decreased perfusion. Similar attacks occur in the posterior circulation. These are rapid and clear quickly without a clinical deficit. Emboli most often occur during the usual activities of daily living. Often an embolus occurs during a Valsalva maneuver which suggests a PFO, atrial septal defect or ventricular septal defect. Getting up to urinate in the middle of
The majority of patients that suffer cerebral cardiogenic emboli have ischemic heart disease, non-valvular atrial fibrillation, prosthetic heart valves and various forms of dilated cardiomyopathy. The rarer causes of cerebral cardiogenic emboli are heart tumors, congenital right to left shunts, subacute bacterial endocarditis, mitral annulus calcification, mitral valve prolapse, venous clots that pass through a patent foramen ovale (PFO), atrial septal aneurysm, fat, air, septic material and fibromyxomatous degeneration of heart valves. Clinical Features of Cardiac Emboli 1. An abrupt onset of hemiparesis, aphasia (particularly Wernicke’s in a setting of AF), sensory deficit or hemianopic visual field loss. 2. MCA > PCA > ACA are the most frequent territories affected a. Some lacunar strokes may be embolic (several vessels affected that produce large lacunes) Preceding Symptoms and Signs 1. 10% may have prodromal symptoms prior to the presenting ictus: a. Stuttering focal deficits occur due to: 1. Distal movement of prior embolus 2. Collateral circulation
Chapter 4. Cerebral Emboli
3. Recanalization b. Cerebral infarction from cardiac emboli may be preceded by TIA’s that are longer with a more severe neurologic deficit than artery to artery emboli. 1. Cardiogenic emboli cause minutes to hours of deficit 2. Artery to artery 60 have AF b. 35% of patients with AF will have an ischemic stroke over their life time c. Approximately 4% of AF patients suffer a stroke each year d. AF with no associated risk factors 70 years of age have nonvalvular AF h. NVAF – 3× greater risk of stroke related death i. Left atrial enlargement and decreased function causes increased risk of cardiac emboli j. Embolus rate highest after the onset of dysrhythmia k. 12% of patients’ cardioverter for AF suffer an embolus within the first few days of the procedure. 3. Causes of AF: a. 10–30% of AF no identifiable cardiovascular disease b. Identified causes 1. Dilated left atrium in mitral stenosis 2. Thyrotoxicosis 3. Pericarditis 4. Ischemic cardiac disease 4. Origin of embolic material: a. Left atrium or the left atrial appendage 1. 15–50% of valvular atrial fibrillation (VAF) have thrombi in the left atrium 2. Autopsy evidence of arterial emboli in 40% of nonvalvular atrial fibrillation (NVAF) b. Valvular disease with AF 1. 9–29% have left atrial thrombi
Recurrent Embolism in Non-Valvular AF (NVAF)
1. 50% of patients with cerebral embolism from AF suffer a second embolic stroke 2. Recurrence is greatest the first days to weeks (15–20% of patients); some evidence that the greatest risk is at 12–24 hours Paroxysmal Atrial Fibrillation
1. 2. 3. 4.
Cerebral emboli occur during a paroxysm of AF Thrombi form during the arrhythmia Cerebral rather than peripheral arteries are affected 2% may occur at the time of cardioversion
Sick Sinus Syndrome
1. Chaotic atrial activity 2. Changing p wave contour 3. Bradycardia with: a. Multiple recurrent ectopic beats b. Runs of atrial and nodal tachycardia 4. Associated arrhythmias: a. AF or atrial flutter with slow rate of response (70 beats per minute) b. Sinoatrial arrest c. Atrial tachycardia d. Sinus bradycardia 5. 29.9% of men and 1.5% of women >75 years may suffer the syndrome a. 14–18% of patients suffer cerebral emboli 6. The sinoatrial disease at greatest risk for embolism is the brady-tachy syndrome. A greater risk than sinoatrial disease without tachycardia or atrioventricular block a. Emboli are more common with prolonged atrial asystole b. Tachyarrhythmias > bradyarrhythmias are more likely to embolize Rare Causes of Emboli with Arrhythmia
1. Romano Ward Syndrome (AD) 2. Long QT Syndrome a. Jervell b. Lang–Nielsen
Chapter 4. Cerebral Emboli
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Rheumatic Heart Disease
Cardiogenic Site of Origin
1. Majority of RHD patients with cerebral emboli have mitral stenosis (10–20%) 2. Mitral insufficiency (MI) and aortic valve disease are the second most common cause of cerebral emboli in RHD 3. Mitral stenosis: a. Thrombi form in the left atrium b. Rarely on the valve 4. 50–75% of RHD patients have AF or other arrhythmias at the time of an embolus 5. Majority of RHD patients with mitral stenosis have a normal sinus rhythm a. AF greatly increase stroke risk 6. Systemic emboli occur in 10–49% of patients with RHD
General Features 1. Ejection fraction less than 40%: a. Contact factors of clotting mechanisms are activated (slow blood flow) b. Large atria c. Areas of muscle hypokinesia in the ventricles 2. Valve leaflets: a. Activation of platelets by shear forces b. Consequent dilatation of left atrium with arrhythmia c. Nidus for infection d. Platelet fibrin deposition from prothrombotic conditions 1. Non-bacterial thrombotic emboli e. Myxomatous valve and chordae tendinea degeneration f. Calcific aortic valve degeneration 3. Patent foramen ovale (PFO) 4. Atrial septal aneurysm (ASA) 5. Combination of PFO + ASA 6. Cardiac tumors: 1. Primary 2. Metastatic 7. Less common types and sources of emboli: a. Lodge in the carotid artery (Calcium; cartilage) b. Vertebrobasilar arteries at sites of narrowing
Sites of Origin of Artery-to-Artery Emboli
A. Site of Origin a. Artery-to-artery embolism 1. Carotid System a. Bifurcation of common and external carotid arteries b. T-portion (ACA and MCA) at the siphon c. From giant distal aneurysms (carotid; MCA) d. Embryologic connections from the basilar artery to the carotid (rare cause of posterior circulation embolus to reach the anterior circulation) 1) Trigeminal 3) Hypoglossal 2) Otic 4) Proatlantal 2. Intimal tears from dissection of the carotid are a source of emboli a. repair of carotid ulcers or stenosis b. Vertebrobasilar system sources: a. Arch of the aorta (mobile plaques) b. Vertebral artery c. Basilar artery d. Dolichoectatic vertebral basilar artery e. Giant aneurysms 1. Tip of the basilar c. Predilection for specific sites of embolic termination a. Arterial bifurcations b. Pial superficial MCA branches c. Upper and lower trunks of the MCA d. Distal basilar artery (top of the basilar) e. Posterior cerebral arteries f. Areas of greatest CBF: 1. 40% of anterior circulations emboli go to MCA territory g. Tendency to affect same location within an arterial territory 1. Laminar flow h. Aortic arch is the source of 25% of posterior circulation emboli i. 25% of emboli go to VB system (less than 20% of blood flow goes to this circulation)
Valvular Heart Disease as a Source of Emboli
General Characteristics: 1. Approximately 10–20% of patients with valvular heart disease embolize 2. Valvular outlet obstruction is caused by: a. Commisural adhesions b. Leaflet dystrophic calcification 3. Functional properties of stenotic valves: a. Decreased pliability b. Irregular surfaces c. Turbulent blood flow 4. Platelets are activated by turbulence 5. Thrombus formation is related to valve device turbulence 6. Abnormalities of blood flow distal to stenotic or incompetent valves cause: a. Prolonged contact of blood and platelets b. Formation of platelet and red cell fibrin thrombi 7. Atrial and ventricular enlargement from stenotic or incompetent valves: a. Enlarged left atria (mitral stenosis or incompetence) b. Prolonged contact of blood and platelets with cardiac and valve surfaces induces thrombus formation
Cause of Valvular Heart Disease Associated with Emboli
1. Rheumatic mitral and aortic valve stenosis and incompetence
SECTION I. Vascular Disease
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2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Bicuspid aortic valve (congenital) Mitral annulus calcification Calcific aortic stenosis Mitral valve prolapse Bacterial endocarditis Non-bacterial thrombotic endocarditis Prosthetic heart valves Left ventricular assist devices (LVAD) Anti-phospholipid syndrome Fibrin valvular excressences
Aortic Valve Disease
a. General Characteristics 1. Progressive calcific aortic stenosis: a. Develops in patient’s with congential bicuspid valves; becomes symptomatic in the 4–5th decade b. Rheumatic valvulitis c. Idiopathic 1. Develops in 6–8th decade 2. An atherosclerotic degenerative process 2. Microthrombi in 53% of stenotic valves at necropsy 3. Neurologic complications a. Emboli possibly as high as 33% of patient’s with calcific stenosis b. Associated emboli to: 1. Retina (white and irregular, calcium deposits) 2. Coronary arteries 3. Renal arteries c. Embolization more common after cardiac catheterization or surgery than spontaneously d. Mitral valve > aortic valve embolization e. Incidence and clinical features of aortic insufficiency are unknown
a. Variable obstruction of left ventricular outflow from systolic anterior displacement of the mitral valve b. Concomitant structural abnormality of the mitral valve 2. Clinical Features a. Syncope with prolonged exercise: 1. Release of norepinephrine that constricts the myocardial septum 2. Epinephrine release from the adrenal that dilates skeletal muscle arteries; norepinephrine constricts the hypertrophied segment 3. Combination of peripheral vasodilation and ventricular outflow obstruction that induces hypotension after exercise b. Atrial fibrillation associated with left atrial enlargement occurs late in the course of the disease with a low rate of cerebral embolization c. Rare concomitant SBE of mitral valve or of the annulus calcification or may be causative
Mitral Annulus Calcification (MAC)
1. General characteristics a. Degeneration of the fibrous support of the valve b. Common in the elderly c. Women > men 2. Clinical symptomatology: a. Increased risk of stroke 1) Each millimeter of thickening on the echocardiogram increases the relative risk of stroke (RR) by 1.24 b. Calcification occurs 1. Posterior portion of the mitral annulus ring 2. May project into the cavity of the left ventricle c. Often MAC is accompanied by MI and AF d. May develop superimposed SBE
Mitral Valve Disease
Mitral Valve Prolapse
1. Valve most often involved in rheumatic fever a. Often concomitant aortic valve disease 2. Embolism in mitral stenosis: a. Occurs in 10–20% of patient’s; approximately 50–75% of these are to the brain b. Atrial fibrillation greatly increases the risk of embolism c. Incidence of embolization possibly 1.5% per year 3. Mitral insufficiency is a rare cause of cerebral embolism: a. Increased risk occurs with atrial enlargement and AF
1. Mid Systolic murmur a. Failure of mitral valve leaflet to coapt b. Some patients have abnormal left ventricular contractions 2. Most commonly diagnosed cardiac valve lesion: a. Prevalence of 5–20% in the general population b. Women > men 3. Pathology a. Disruption of valve collagen by infiltration of myxomatous material b. Thickened and elongated chordae tendinea c. Infiltration of the mitral valve annulus d. Fibrosis and thickening of the endocardial surface of the valve leaflets 4. Clinical symptomatology:
Idiopathic Hypertrophic Subaortic Stenosis
1. Asymmetric hypertrophy of the left ventricular septum that causes:
Chapter 4. Cerebral Emboli
a. Small percentage of patients develop severe mitral insufficiency with CHF b. AF may develop in elderly patients with MI and enlarged left atria c. Associated with Marfan’s syndrome, osteogenesis imperfecta and Ehlers–Danlos syndrome d. Rare endocarditis on myxomatous valves e. Low rate of cerebral embolization 5. Echocardiographic evaluation a. 2 mm or greater movement of the coapted anterior or posterior valve leaflets b. Valve leaflets are displaced into the left atrium during systole c. Mitral valve thickening or redundancy d. Regurgitation Neurologic Features 1. Emboli occur in young patients often without other associated risk factors 2. Strokes and TIA occur 3. Approximately 10% of patients have AF concomitantly with the stroke 4. Platelet dysfunction is reported in some patients with MVP: a. Shortened survival time b. Increased levels of beta-thromboglobulin and platelet factor IV 5. Recurrent embolic stroke is rare
Prosthetic Heart Valves
1. General Characteristics a. Dacron rings are a nidus for platelet activation and adhesion b. Prosthetic material activates intrinsic clotting cascade; erythrocyte-fibrin thrombi form c. Degeneration of bioprosthetic valves: 1. Deposition of white platelet fibrin thrombi 2. Cusp sinuses of bioprosthetic mitral valves: a. Undergo fibrosis and calcification b. Nidus for thrombi 2. Mechanical valves are: a. Metal and carbon alloys b. Bioprosthetic valves: 1. Heterography from pig and cow pericardium or valves 3. Non-tissue valves: 1. Thrombus forms at the component tissue interface or in areas of stenosis 4. Incidence of embolization is related to the degree of thrombogenicity: a. Non cloth covered prosthetic valves > cloth covered prosthetic valves > tissue valves 5. Increased risk for embolization:
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a. Caged ball valve prosthesis b. Mitral valve (associated with AF) c. Multiple prosthetic valves d. Age > 70b years e. AF f. Decreased left ventricular ejection fraction g. SBE h. Pregnancy and the puerperium 6. Mitral valve embolize > aortic valves 7. Risk of bioprosthetic valve embolization equals that of mechanical valves that are adequately anti-coagulated 8. Size of the cerebral infarction is due to: a. Size of the embolus b. Stability of the embolus c. Adequacy of the collateral circulation
Subacute Bacterial Endocarditis
1. General Characteristics: a. Natural valves: staph aureus and group D streptococcus are the most common organisms b. Prosthetic valves: aspergillus most common for early emboli; strep viridans for late emboli 2. New epidemiology: a. Older patients b. Intravenous drug abuse patients c. Tricuspid valve is more frequently involved 3. 20% of patients with endocarditis suffer cerebral emboli: a. Small cortical or subcortical bland infarcts b. Large infarcts are secondary often to staph aureus 4. Valve pathology: a. Calcified valves d. Mitral valve prolapse b. Prosthetic valves e. Myxomatous mitral valves c. Rheumatic valves 5. 30–40% of emboli may occur from normal valves a. Aortic > mitral 6. 50% of infected prosthetic valves cause cerebral emboli 7. Neurologic complications are similar for native and prosthetic valves Clinical Characteristics 1. Systemic symptoms: a. Intermittent fever and fatigue b. Backache is common, early c. Embolization to other organs; large artery occlusion suggests fungus d. Sterile vegetations may embolize Systemic Symptoms 1. Intermittent fever and fatigue 2. Backache 3. Loss of weight and appetite Neurologic Signs and Symptoms 1. Cerebral and retinal TIA a. Most common early in the course of the infection 2. Brain ischemia
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SECTION I. Vascular Disease
a. 15–19% of patients 3. Ischemic stroke may occur after treatment has started 4. Intracranial Hemorrhage a. 2.8–7% of patients b. Hemorrhagic transformation of bland infracts c. Large hemorrhages occur: 1. Concomitant use of anticoagulants d. Rupture of septic arteritis e. Rupture of mycotic aneurysms 1. Occur in peripheral subpial vessels f. ICH occurs at or near time of presentation 1. May have had a preceding TIA g. Mycotic aneurysms may rupture after bacterial treatment
5. Early endocarditis: rapid hemodynamic deterioration, conduction defects, poor peripheral perfusion 6. Mortality for prosthetic valve endocarditis is 30–80% for the early form and 20–40% for the late form. 7. Infection with organisms other than streptococcus usually results in valve replacement.
CSF
1. Pleocytosis < 300 cells/mm3 ; neutrophilic early and lymphocytic late 2. Slight increase of protein 3. Normal sugar 4. May have normal CSF
Encephalopathy Non-Infective Endocardial Lesions
1. Most common with staph aureus: 1. Toxic metabolic factors 2. Secretion of interleukins (IL-6) with subsequent cerebral edema 3. Associated brain infarcts and microabscesses
Meningitis
a. Embolization of bacteria to meningeal arteries: 1. Presentation with neck and back pain prior to neurologic symptoms 2. 1.1–6.4% of patients with endocarditis have meningitis Vegetations 1. Millimeters to centimeters in size a. fungi are the largest 2. Potential for embolization is related to: a. Size b. Friability 3. Valve most like to embolize 1. Mitral > aortic > tricuspid
Endocarditis on Prosthetic Valve
a. Occurs in 3–6% of patients: 1. Early endocarditis 60 days post operatively; streptococci, staph epidermidis. 3. The risk of endocarditis is similar for mechanical and bioprosthetic valves. 4. Most common symptoms and signs; fever, new or changing murmur, systemic embolization or congestive heart failure.
1. General Characteristics a. Occur primarily in SLE, the APLA syndrome and NBTE b. Probable similar pathogenesis c. All three entities are associated with: 1. Hypercoagulability 2. Thrombocytopenia 3. Embolic stroke 4. Platelet thrombi on valve and endocardial tissues 2. Noninfective valve lesions are associated with: a. Ergotamine b. Methysergide c. Dexfenfluramine d. Phentermine e. Carcinoid (high serotonin levels) f. Leukemia 3. Strands a. Trans esophageal echo cardiography may demonstrate: 1. Strands of mobile tissue attached to valve and endocardial surfaces b. Filamentous strands are known as Lambl excrescences: 1. Located on the atrial surfaces of mitral valves or the ventricular surfaces of aortic valves 2. Strands are composed of: a. Cellular connective tissue core covered by epithelium b. 1–10 mm in length c. May be related to fibrinous deposits on valve surfaces d. May spread to the endocardium and papillary muscles 3. Prevalence by TEE (transesophageal echocardiography) a. Approximately 4% on mitral valves
Chapter 4. Cerebral Emboli
b. 1.7% on aortic valves c. Incidence possibly 10% in patients who have suffered embolization 4. Association of stroke and strands: a. Young patients b. Mitral and aortic strands c. Low recurrent stroke risk d. Patients with SLE, APLAS and NBTE
Antiphospholipid Antibody Syndrome
1. General Characteristics a. Associated with: 1. Recurrent abortion 2. Phlebothrombosis (including the upper extremities) 3. Myocardial infarction 4. Thrombocytopenia 5. Pulmonary emboli b. Cardiac valvular lesions: 1. High frequency 2. Similar to the verrucous lesion of SLE 3. Mitral > aortic valves 2. Phospholipids are important constituents of: a. Platelets c. Coagulation factors b. Cardiac valve endothelium 3. Laboratory evaluation: a. Patients demonstrate lupus anticoagulant b. Anticardiolipin antibody (IgG or IgM) c. Patients with clinical features of APLAS may have embolic stroke and a negative screen for antibodies
Non-Bacterial Thrombotic Endocarditis
1. Associated most often with cancer (particularly mucinous adenocarcinoma, prostate, lung, or melanoma) 2. Other Associations: a. SLE b. APLAS c. Pneumonia d. Perforated ulcer e. Wasted, immunosuppressed patients f. Severe gram negative infection g. Pheochromocytoma 3. Order of valve involvement: a. Mitral > aortic > tricuspid > pulmonary b. Deposits are along lines of valve coaptation and consist of degenerating platelets, fibrin and leukocytes c. Bivalvular lesions occur d. Vegetations are bland and less than 5 mm in size 4. Both small and large vessel occlusions occur in the cerebral or systemic circulation a. Cerebral emboli with stroke occur in 50% of patients with valve lesions
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5. Often associated with DIC but also occur concomitantly with SAH, ICH and thrombotic stroke a. Elevated D-dimer seen in this context
Lupus Verrucous Endocarditis
1. Fibrous thickening of valves 2. Vegetations prominent along valvular closure lines and leaflets 3. Spread to the papillary muscles and endocardium 4. Associated with cerebral embolism
Cardiomyopathy
1. General Characteristics a. Embolism most common in dilated cardiomyopathies; ejection fraction less than 50% b. Loss of normal subendocardial trabeculations c. Stasis of blood; prolonged contact of platelets and contact factor XIII d. Mural thrombi form within the trabeculae carnea of the cardiac apex e. Embolism less frequent in hypertrophic cardiomyopathy unless there is concomitant AF f. Associated with the stasis of CHF 2. Cardiomyopathies associated with emboli: a. Idiopathic b. Post partum c. Viral d. Myocarditis (idiopathic) e. Ischemic cardiomyopathy f. Sarcoidosis g. Amyloidosis h. Endocardial fibroelastosis i. Mitochondrial myopathies j. Dystrophinopathy (DMD; Becker’s) k. Inflammatory muscle disease (IBM; DM/PM) l. Nemaline myopathy m. Glycogen: storage disease (debrancher) n. scapuloperoneal dystrophy with mental retardation o. Desmin myopathy p. Myofibrillar lysis q. Fabry’s disease r. Cocaine s. Endocrinopathies (acromegaly, hypothyroidism, adrenal insufficiency) t. Congenital myopathy
Hereditary Cardiomyopathies
I. General Characteristics:
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SECTION I. Vascular Disease
1. Categories of familial dilated cardiomyopathies (FDCM) a. Mutations in contractile protein genes b. Dystrophinopathy 1) Affected boys and men 2) Women carriers of Becker or Duchenne mutations 3) Mitochondrial disorders 4) Sarcoglycanopathies a) Limb girdle myopathies 5) Rare disorders 2. Genetics of FDCM a. Allelic and locus heterogeneity 3. Usual clinical features: a. Syncope b. Palpitations c. Dyspnea d. Heart failure e. Exertion induced sudden death f. Angina 4. Neurologic features: a. Cerebral emboli occur in patients with: 1) Ejection fractions of left ventricle: may have simultaneous origin from both atria c. Attached to atrial wall or are pedunculated and cause valve obstruction d. Gelatinous round, polypoid masses covered with platelet fibrin clots e. Emboli: Tumor fragments or thrombi f. Cardiac symptoms: 1. Syncope (change of cardiac output) 2. Tripopnea a. Right atrial myxoma b. Shortness of breath with position change (blockage of right ventricle outflow) 3. Heart murmur usually MI > MS (with mitral valve disease) 4. Occasionally a cardiac “plop” can be auscultated. Tumor falls into the valve and obstructs it g. Rare bilateral myxomas 1. Project from right atrium to left and through a PFO h. Less than 10% are in the ventricles
Neurological Signs and Symptoms of Myxoma
1. Superficial pial MCA territory most commonly affected 2. Peripheral aneurysm of superficial blood vessels: a. Small b. Multiple c. Rupture with SAH or hemorrhagic infarctions 1. Myomatous tissue grows through the vessel wall d. Rarely large peripheral aneurysms are seen 3. Delayed progressive neurologic signs are seen (rare) 4. 30–50% of cardiac myxomas embolize 5. Rare embolization to the spinal cord 6. Sudden death (possible coronary artery embolus)
Constitutional Symptoms and Signs of Myxoma
1. CHF 4. Weight loss 2. Polyarthralgia 5. Anterior chest wall petechiae 3. Fever
Papillary Fibroelastoma
1. General characteristics a. Multiple papillary bands that are attached to an avascular fibrocartilaginous core b. Arise from the aortic valve 2. Clinical symptomatology a. Angina due to embolization of the coronary arteries b. Multiple brain infarcts
SECTION I. Vascular Disease
106 Rhabdomyoma
1. General characteristics a. Often are multiple b. Arise from the ventricular myocardium with projection into the ventricular chamber c. Associated with tuberous sclerosis and neurofibromatosis (NFI) 2. Emboli consist of tumor fragments
l. Valsalva maneuvers 3. Less than 1% of cerebral emboli are paradoxical 4. The clinical setting: a. Thrombosis of leg or pelvic veins b. Prothrombotic state c. Valsalva maneuvers d. Associated pulmonary embolism 5. Neurological signs and symptoms a. Most common stroke territory is that of the MCA b. Higher than expected vertebrobasilar embolization
Differential Diagnosis of Cardiac Tumors Patent Foramen Ovale
1. Rhabdomyoma 2. Atrial and ventricular myxomas 3. Fibroelastoma 4. Histiocytoma 5. Hemangioma
6. Hamartoma 7. Undifferentiated 8. Fibroma 9. Metastatic tumors
Differential Diagnosis of Intracardiac Lesions
1. Cardiac tumors 2. Metastatic tumors to the heart a. Hypernephroma (through the inferior vena cava) b. Squamous cell lung carcinoma (through the pericardium) c. Malignant melanoma (able to attach to the endocardium) 3. Ball valve thrombus 4. Mural thrombus a. Following myocardial ischemia b. Within ventricular aneurysm 5. Thrombi within septal aneurysms
Paradoxical Cerebral Embolus
1. General characteristics 1. Definition: embolus entering the arterial circulation from the venous side through a right to left shunt 2. Predisposition: a. Patent foramen ovale (20–25% of the population) b. Atrial septal defect’s, VSD, pulmonary AV fistulas c. Anovulatory drugs d. Lower extremity injury e. Prothrombotic states f. Jugular vein catheterization g. Cancer h. Obesity i. Prolonged bed rest j. Any increased source of right heart pressure k. Occurs in some patients with no evidence of right heart disease, thrombophlebitis or increased pulmonary pressure
1. General characteristics: a. Present to some degree in approximately 30% of patients b. Declines approximately 10% with age c. Average size is 4–5 mm; gradually increases with age 2. Neurologic signs and symptoms: a. MCA territory most frequently involved b. Approximately 1/3 involve the VB system which receives approximately 20% of CBF. MCA territory receives approximately 40% of CBF c. Predisposition for paradoxical embolus is the setting 3. Increased risk of paradoxical embolus with PFO by TEE a. Concomitant atrial septal aneurysm b. Larger PFO c. More microbubbles insonated in MCA territory
Atrial Septal Aneurysm
1. General characteristics a. Bulging of septum primum tissue of the atrial septum through the fossa ovalis 1. Into the right or left atria b. Association of atrial septal aneurysms and interatrial shunts c. High incidence of PFO with atrial septal aneurysms d. Atrial septal aneurysm with 10 mm excursion greater chance of embolization e. Thrombi may form within the aneurysm 2. Recurrence rate of stroke for PFO and atrial septal aneurysm when combined is approximately 2% per year; may have severe stroke at onset
Differential Diagnosis of Cardiac Sources of Emboli
A. Ischemic Heart Disease 1. Mural thrombus 2. Congestive heart failure 3. Ejection fraction of less than 30% 4. Ventricular aneurysm
Chapter 4. Cerebral Emboli
5. Akinetic or hypokinetic segments B. Cardiac Arrhythmia 1. Chronic or paroxysmal atrial fibrillation 2. Sick sinus syndrome 3. Brady-tachyarrhythmia 4. Long QT interval syndrome 5. Ward Romano Syndrome (AD) 6. Jervell Syndrome (AD) 7. Lang–Nielsen Syndrome (AR) C. Valvular heart disease 1. Rheumatic mitral stenosis 2. Rheumatic mitral insufficiency (rare) 3. Rheumatic aortic stenosis 4. Bicuspid aortic valve (congenital) 5. Calcific aortic stenosis 6. Mitral annulus calcification 7. Bacterial endocarditis 8. NBTE (marantic endocarditis) 9. SLE (verrucous endocarditis) 10. Antiphospholipid syndrome (APLS) 11. Left ventricular assist devices 12. Prosthetic heart valves 13. Fibrous and fibrinous endocardial lesions D. Cardiomyopathy 1. All dilated cardiomyopathies 2. Idiopathic 3. Post partum 4. Viral 5. Idiopathic myocarditis 6. Ischemic cardiomyopathy 7. Sarcoidosis 8. Amyloidosis 9. Endocardial fibroelastosis 10. Multiple mitochondrial myopathies 11. Duchenne muscular dystrophy 12. Becker’s muscular dystrophy 13. Idiopathic dilated cardiomyopathy 14. Variants of dystrophinopathy 15. Inclusion body myositis 16. Dermatomyositis/polymyositis complex 17. Nemaline myopathy 18. Debrancher glycogen storage disease 19. Scapuloperoneal dystrophy with mental retardation 20. Desmin myopathy 21. Myofibrillar lysis E. Intracardiac Lesions 1. Cardiac tumors (primary) a. Myxoma b. Fibroma c. Fibroelastoma d. Hamartoma e. Hemangioma f. Histiocytoma g. Rhabdomyoma (sarcoma) h. Undifferentiated
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2. Metastatic tumors a. Hypernephroma b. Melanoma c. Squamous cell carcinoma of the lung 3. Ball valve thrombus 4. Mural thrombus 5. Ventricular aneurysm with thrombus 6. Septal aneurysm with thrombus F. Intracardiac defects with paradoxical embolus 1. Atrial septal defects 2. Ventricular septal defects 3. Patent foramen ovale (PFO) 4. Atrial septal aneurysms 5. PFO plus atrial septal aneurysm
The Aorta as a Source of Emboli
General characteristics 1. Average diameter of an aortic plaque is 19 mm 2. Plaques are frequently on the anterior or posterior right side of the ascending aorta 3. The upper and lower half of the ascending aorta are equally involved 4. Aortic arch plaques a. At the edifice of the innominate artery 5. Plaque grading system a. 0 mm – 0 b. 1 mm – grade 1 c. 2 mm – grade 2 d. 3 mm – grade 3 e. 4 mm – grade 4 f. 5 mm – grade 5; mobile complex 6. Complex thick or mobile plaques are most likely to embolize 7. Plaques have disappeared after anti-coagulant therapy 8. Anticoagulants theoretically could potentiate cholesterol emboli by: a. Blocking protective clot thrombi that cover plaque ulceration Neurologic Signs and Symptoms 1. Protruding atheroma a. Related to emboli 2. Ulcerated plaque in the aortic arch may not correlate with atheromatous carotid disease 3. Ascending aorta and arch junction a. Important site for plaque that embolize as is the origin of the innominate artery 4. Frequency of brain infarction correlated with thickness of the aortic wall 5. Complex, thick or mobile plaques > 5 mm have 3× greater incidence of stroke than patients with plaques 1 cm; tip of the basilar, carotid, middle cerebral artery) 9. Tumor material 10. Thrombolytic therapy (lysis of clots that then expose underlying collagen which then forms new less adherent clots) 11. Iatrogenic occlusive therapy (embolization of AVM’s; Gelfoam) 12. Catheters 13. Defoaming agents 14. MAC attack (esophageal fistula to veins-McDonald hamburger fragments to veins) 15. Talc (addicts; increased right heart pressure from pulmonary fibrosis; paradoxical embolus) 16. Fibrocartilage (following orthopedic procedures)
Chapter 5 Hypoxic-Ischemic Encephalopathy General Characteristics
a. Decreased brain perfusion, oxygenation or both b. Decreased perfusion 1. Cardiac arrhythmia or arrest 2. Pump failure The brain is differentially susceptible to hypoxia, hypoglycemia and hypoperfusion. In general, areas most susceptible to hypoxia have the greatest required metabolic rate for glucose utilization and ATP requirement. In the case of cardiac arrest, pump failure, ventilatory failure they suffer first and most severely. In general, respiratory arrest without circulatory compromise carries a better prognosis. Complete circulatory arrest induces rheological changes that include endothelial cell
Chapter 5. Hypoxic-Ischemic Encephalopathy
swelling and viscosity changes that preclude reperfusion of cortical, basal ganglia and thalamic capillary net works. This constitutes the no-reflow phenomena. Hyperglycemia and acidosis at the time of arrest increase neuronal death. Pre arrest vascular compromise leads to distal field ischemia and stroke primarily in the anterior circulation in those under 40 and in the vertebral basilar system in elderly patients. Prolonged hypoperfusion and anoxia lead to border zone infarction (posterior zone between MCA/PCA) territory > anterior zone (MCA/ACA territory). Specific toxins or circumstance involve specific brain areas. Carbon monoxide preferentially affects the medial globus pallidus, cortex and cerebellum. Isolation of speech areas, from perisylvian involvement has also been described. Strangulation or hanging preferentially involves the medial globus pallidus as reversible decerebration. A single hypoxic event may cause a delayed but progressive leukoencephalopathy that begins 4–10 days following the insult. Cognitive dysfunction, irritability and apathy are prominent as is rigidity of the limbs and ataxia of gait. Some patients with delayed hypoxic leukoencephalopathy have reduced aryl sulfatase A activity.
Consciousness
The integrity of the reticular activating system (RAS) is requisite for consciousness. The lateral medullary reticular formation, the dorsal pontine tegmentum, periaqueductal grey of the midbrain, intra laminar thalamic nuclei are the most important nuclear areas that maintain consciousness. Both cerebral hemispheres must be involved to lose consciousness. Bilateral vertebral disease or basilar artery infarction compromise the lateral medullary reticular formation and dorsal pontine tegmentum. Top of the basilar artery embolic stroke or thrombosis affects the midbrain periaqueductal grey or intra laminar thalamic nuclei. Hypoxic insults and prolonged hypoperfusion affect the cerebral hemispheres. Increased intracranial pressure (usually from edema) decreases cerebral perfusion at all levels and is a frequent concomitant of cardiac arrest.
Differential Susceptibility of Neurons to Hypoxia
1. Hippocampus a. Sumner’s section V, amygdaloid complex b. Pyramidal neurons c. CA I zone 2. Medial laminae of the cerebral cortex a. III–V b. Thalamic projecting neurons to the cortex 3. Globus pallidus/caudate/putamen a. Internal segment GPi 4. Thalamus
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a. Anteroventral nuclei c. Pulvinar b. Dorsomedial nuclei 5. Cerebellum a. Purkinje cells 6. Brainstem tegmental nuclei a. V, IX, X; c. Superior alive b. Inferior caliculus d. Vestibular nuclei 7. Spinal cord a. Renshaw cells b. Anterior 2/3 of the cord c. Distribution of the artery of Adamkiewicz
Border Zone Infarction
1. Anterior; ACA/MCA 2. Posterior; MCA/PCA 3. Vascular stripe (between descending pial blood vessels and ascending lenticula striate arteries) 4. Border zone of the cerebellum (level of the dentate) 5. Subinsular cortical areas 6. Cerebellar artery border zones a. SCA/PICA b. SCA/AICA
Clinical Patterns of Circulatory Arrest
Brain-Stem Coma
1. Prolonged hypoperfusion-anoxia a. Dilated pupils b. Absent corneal reflexes c. No doll’s eye response (absent vestibular ocular response) d. No response to ice-water caloric (absent VOR) e. Frequent loss of spontaneous respiration f. No spontaneous movement 1. decorticate or decerebrate posture may be seen 2. Selective necrosis of brainstem nuclei a. Affects children and infants most frequently; (Vth nerve involvement) occasionally seen in adults b. No oculocephalic eye movements (VOR) c. Loss of branchial muscle functioning including the gag reflex d. Stiff extremities; no spontaneous movement e. Automatic movements with stimuli f. Autonomic disinhibition a. Fluctuating blood pressure and cardiac rate g. Loss of spontaneous respiration 3. Brainstem coma secondary to bi-hemispheral coma a. Patients regain brainstem reflexes b. Spontaneous respiration occurs
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Coma due to Bilateral Hemispheric Dysfunction
a. b. c. d. e.
Unresponsive to noise, bright light or voice Respond to painful stimuli Spontaneous movements of the extremities Pupils are normal or small; react to light Eye movements: 1) Roving from side to side 2) Midline 3) Deviated upward 4) Hyperactive doll’s eyes a) Loss of ocular fixation reflexes that inhibit the vestibular ocular reflex 5) Vertical eye movements present to VOR maneuvers: a) May be difficult to deviate downward if patient has fixed upward deviation f. Gag reflex intact g. Branchial innervated movements are intact 1. Spontaneous blink and swallow reflexes
Posterior Border Zone Infarction
1. Bilateral infarction of the MCA/PCA overlap territory a. Parieto-occipital junction 2. Complete or partial Balint’s Syndrome a. Simultagnosia 1. Inability to see all objects in the visual field 2. Inability to see all components of one object 3. Inability to maintain components of an object into a whole 4. Optic ataxia: a. Damage to parietal area 5 and 7. Patients under reach for objects. They have poor eye/hand coordination 5. Apraxia of gaze a. Poor initial scanning of a visual field b. Inability to look at a specific object on command c. Inability to break a fixed gaze
Anterior Border Zone Infarction Corticospinal Tract Dysfunction
1. Patients may have preserved: a. Adduction/flexion of the shoulder, arms and wrists 2. Noxious stimulation of extensor or flexor upper extremity surface: a. Elicits flexion/adduction of the arms and shoulder 3. Noxious stimulation of lower extremities a. Extension/adduction of the lower limbs 4. External rotation of the foot; cortical thumb
Intact Corticospinal Tract Signs
a. Noxious stimuli elicits movements away from afferent input b. Movement of individual fingers c. Spontaneous or reactive extension of the upper extremity d. Abducting movements of the arm or forearm e. Lower limb noxious stimuli elicits 1. Flexion/adduction f. Supination of the arm at rest and normal position of the foot (extension) g. Thumb abducted
Progression from Bi-Hemispheral Coma
Specific features of selective vulnerability to the anoxicischemic episode may become prominent. Many patients demonstrate agitation, restlessness, confusion and delirium as they regain consciousness. If the insult has been primarily hypotensive with less generalized anoxia, border zone infarction may be prominent.
1. Bilateral infarction of the anterior and middle cerebral artery border zone territories 2. “Man in the Barrel” Syndrome a. Shoulder and arm are primarily affected; hand stronger than shoulder; legs spared b. Frontal eye fields involved (area 8, 10) 1. Roving cortical eye movements (disinhibited from gaze centers) 2. Too easily obtained doll’s eye maneuvers (uninhibited VOR) 3. Asymmetries have been described: a. Unilateral arm paralysis b. Head and eye deviation to the more affected side 4. Stupor from extensive bilateral lesions
Memory Loss
1. Severe damage to the pyramidal cells of the hippocampus a. CA I; Sumner’s section V b. Amygdaloid complex c. Medial temporal lobes 2. Clinical sequelae a. Severe short term memory loss. Poor encoding of new memories over 3 minutes. Registration is intact (object recall 15 seconds). Long term memory and retrieval relatively spared
Laminar Necrosis
1. Layers III–V of the cortex are damaged throughout. Speech, motor, and visual areas affected clinically more prominently than the parietal lobe.
Chapter 5. Hypoxic-Ischemic Encephalopathy
2. Isolation of the speech areas a. Combination of laminar necrosis and anterior and poster border zone infarction b. Transcortical motor and sensory aphasia c. Complete perisylvian involvement 1. Patient can only repeat; cannot initiate or perceive speech d. Severe dysarthria 1. Damage to corticobulbar fibers for speech emanating from the frontal operculum 3. Clumsiness and dysarthria 4. Ideomotor, limb kinetic, ideational apraxias a. Laminar necrosis of area 6, 8 (ideomotor; callosal apraxia); posterior parietal areas (ideational apraxia) 5. Cortical blindness a. Laminal necrosis of the occipital cortex b. Anton’s Syndrome 6. Seizures a. Most often generalized b. Difficult to treat 7. Myoclonus a. Multifocal b. Generalized c. Exaggerated by stimuli or movement d. Repetitive and generalized > 30 minutes a bad prognostic sign following cardiac arrest 8. Persistent Vegetative State a. Severe laminar necrosis 1. Appear awake and have brain stem function 2. No response to stimuli a. Eyes may track a moving object 3. Retain sleep-wake cycle 4. Eyes are open 9. Cerebellar dysfunction a. Metronomic eye movements; eyes rhythmically oscillate side to side b. generalized ataxia c. Lance Adams Syndrome 1. Spontaneous, arrhythmic fine and course movements 2. Exaggerated by voluntary movement 3. Action myoclonus 4. Associated with gait ataxia 5. Damage to dorsal raphe serotonergic neurons in addition to Purkinje cells and cerebellar pathways 6. Probable associated border zone cerebellar infarcts of the PICA/SCA and AICA 7. May progress after the initial insult
Basal Ganglia and Thalamus
1. Prolonged partial ischemia: a. Hypoxia precedes circulatory insult
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b. Damage most severe in globus pallidus interna, caudate, putamen AV, DM and pulvinar nuclei of the thalamus c. Hanging, strangulation, carbon monoxide produce a similar dissociation between blood flow and oxygenation d. Clinical sequelae 1. Eyes open and fixate 2. Abnormal twitches and movements 3. Rigidity of extensor and flexor muscles 4. Decorticate posturing 5. Mute and unresponsive
Delayed Leukoencephalopathy
1. Generally young patients who have suffered strangulation, drowning, inhalation of noxious gases or carbon monoxide poisoning 2. Pathology: a. Diffuse demyelination to hemorrhagic white matter necrosis b. Basal ganglia involvement (GP) c. Possible relationship to decreased Arylsulfatase A in some patients 3. Clinical features: a. Initial coma associated with: 1. Quadriparesis 3. Involuntary limb movements 2. Atonia b. Progression to: 1. Dystonic rigid state a. Relative preservation of the cortex b. Severe damage to basal ganglia c. Generalized demyelination c. Delayed deterioration started between 4–10 days in some patients
Hypoxic-Ischemic Spinal Cord Damage
1. Selective vulnerability of the spinal cord a. Upper and lower thoracic cord most often involved b. Territory of the great radicular artery of Adamkiewicz 1. Origin T10–T12 to L-2; supplies lumbar cord and the conus medullaris c. Upper and lower thoracic regions border zones of anterior feeding vessels (those that comprise the unpaired anterior spinal artery) ASA d. Sulcal arteries from the ASA supply the ventral horns; circumferential arteries from the posterior paired spinal arteries and the circumferential branches of the ASA supply the lateral components of the cord. The internal spinal cord watershed is the corticospinal tracts, the border zone between the sulcal and circumferential arteries. Paired dorsal spinal arteries supply the posterior columns
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e. Clinical Sequelae: 1. Spinal cord hypotensive damage is unusual as the cord is perfused at a much lower pressure than the cerebral circulation (approximately 60 mg Hg) 2. Ischemic injury involves the anterior 2/3 of the cord 3. Flaccid paralysis of the lower extremities is noted early; spasticity supervene: a. Loss of bowel and bladder continence b. Sensory level to temperature and pin prick at lower thoracic levels c. Atrophy and fasciculation of the legs/supervenes 4. Rare acute rigidity: a. Renshaw cell involvement b. Loss of glycine spinal cord inhibition
Prognostic Indicators In Patients that Have Suffered Ischemic-Hypoxic Injury
A. Early (minutes to 6 hours) Vital signs 1. Blood pressure a. Severe hypertension 1. Increased ICP 2. Normal cardiac function b. Profound hypotension 1. Severe cardiac damage 2. Vasomotor center damage (brainstem) c. Fluctuating blood pressure 1. Vasomotor center or connections are damaged (dorsolateral medulla) 2. Autonomic disruption (posterior hypothalamus afferents to inter mediolateral column of the spinal cord) d. Herniation 1. Hypertension to sudden hypotension a. Disruption of the vasomotor center and its connections in the dorsolateral medulla 2. Pulse a. Regular full slow pulse (50–60/min) 1. Kocher–Cushing reflux of ICP b. Thready rapid pulse (120 minute) 1. Cerebral herniation 2. Cardiac failure 3. Disruption of vasomotor center and its connections at a brainstem level 3. Respiratory pattern by CNS Level a. Cheyne’s–Stoke-basal ganglia/thalamic b. Periodic breathing-BG/thalamic c. Central neurogenic-hyperventilation-midbrain a. Acidosis b. Low pO2 c. Uninhibited Kölliker–Fuchs nucleus 1) Pneumotaxic center d. Apneic-pons (grave sign)
e. Cluster-medullary f. Ataxic-medullary g. Biot’s – medullary (couplet breathing) 4. Temperature General rule is that temperatures above 105 degree F◦ are central rather than from sepsis
Hyperthermia
a. Anterior hypothalamic damage b. Drugs: D2 (dopamine receptor D2 agonists or their sudden withdrawal) agonists, INH cocaine, amphetamine, phenothiazine (rare) c. Blood in the 3rd ventricle
Hypothermia
a. 92–93 degree F◦ (posterior hypothalamic damage) 1. Hypothyroidism; pan hypopituitarism 2. Drugs (phenothiazine based) b. 97–98 degrees 1. Endocrine failure 3. Liver and renal failure 2. Hypoglycemia 4. Phenobarbital Level of Consciousness
Profound coma implies damage to the lateral medullary reticular formation, the dorsal pontine tegmentorum periaquaductal grey of the midbrain, intralaminar nuclei of the thalamus or bilateral cerebral cortex. The brainstem is much less vulnerable to hypoperfusion and anoxia than the cortex and therefore severe brainstem dysfunction implies hemispheric damage with a poor prognosis for a good functional recovery. A patient who is fully alert and awake 6 hours after a cardiac arrest or hypoxic-ischemic event improves rapidly over twelve hours and has a good prognosis. Twenty four hours to alertness may be a very important prognostic assessment time. Levels to be assessed are: 1. Fully alert 4. Stuporous 2. Lethargic 5. Comatose 3. Obtunded
Brainstem Reflex Assessment at 6 hours
1. Gag reflex – IX, X (medulla) 2. Corneal – V – pons 3. Vestibuli ocular reflexes (VOR) a. VIII nerve b. Medial longitudinal fasciculus c. VI and III nerve 4. Pupils
Chapter 6. Chronic Small Vessel Disease
1. Dilate to 4–5 mm after 3–4 minutes of cardio-pulmonary arrest a. Rule out atropine or sympathomimetics during resuscitation 2. Cortical or pretectal level a. Non-reactive to light 3. 3 mm and non-reactive to light or noxious stimuli a. Midbrain b. cadaveric 4. 2–3 mm a. Reactive to light b. Thalamic basal ganglia level 5. 0.5 mm a. Pontine level b. Reactive to light 6. 1 mm a. Medullary level b. Sympathetically denervated R/O narcotics 1) Demerol may not affect pupils. 1/3 of the time it does. R/O drugs with parasympathomimetic action 5. Persistent pupillary dilatation poor prognostic indicator. Return of brainstem reflexes early is a good prognostic sign.
Evoked and Spontaneous Limb Movements
1. Spontaneous limb movement – good prognostic sign 2. Evoked decerebration and decortication – poor prognostic indicator 3. Myoclonus: a. Persistent and stimulus sensitive – poor prognostic sign 1. Loss of cortical inhibition 2. Damage to the nucleus gigantiocellularis of the brainstem 4. Seizure a. First 24 hours not prognostic b. Status epilepticus – poor prognostic sign at anytime after an ictus Late Prognostic Signs > 24 hours
Good 1. Awake and alert 2. Return of brainstem reflexes 3. Eye opening with ocular fixation reflexes 4. noxious stimuli evoke withdrawal reflexes Bad 1. Persistent depressed level of consciousness 2. Absent brainstem reflexes 3. Noxious stimulation evoke decortication or decerebration 4. Eyes open with: a. Roving eye movements b. Uninhibited doll’s eye maneuver c. Persistent vertical ocular deviation
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5. Spontaneous and evoked myoclonus 6. Status epilepticus 7. Persistently dilated pupils Laboratory Evaluation
1. MRI: a. Watershed infarcts of cortical and deep territories b. Cortical infarcts c. Blurring of the grey white junction d. Obliteration of the perimesencephalic cisterns with midbrain compression e. T2 weighted signal abnormalities of laminar necrosis 2. EEG a. Diffuse slowing in the delta and theta range 1. All survivors at some point b. Periodic lateralizing epileptiform discharge 1. Isolated areas of cortex c. Epileptiform activity d. Alpha coma (bad prognostic sign) 1. 9–12 cycles/second 2. Transitory 3. Frontal central parietal rather than occipital distribution 4. Does not vary with external stimuli 3. Brain Death a. Absence of intracranial circulation by angiography, Doppler or SPECT
Chapter 6 Chronic Small Vessel Disease Poorly controlled hypertension and diabetes are associated with small vessel disease both by MRI and neuropathologically. The aging process itself and chronic migraine also are associated with probable microinfarctions. CADASIL, Binswanger’s Disease and amyloid angiopathy are well delineated syndromes associated with small vessel disease. Multiple small vessel infarction is associated with a subcortical dementia characterized by apraxia and slowness of information processing. Pseudobulbar palsy and spasticity are common concomitant features. Congophilic angiopathy is usually differentiated from just small vessel infarction by superficial cortical hemorrhages. Binswanger’s Disease frequently is preceded by severe uncontrolled hypertension and is posterior periventricular predominant. Migraine most frequently presents with the T2 weighted lesions rarely associated with neurological deficit. CADASIL is associated with severe migraine and early onset dementia. 1. Most patients with lacunar infarction suffer more than one lacune a. Multiple penetrating arteries are involved
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2. Extensive lacunar infarction a. Cystic lesions of the basal ganglia, thalamus, internal capsule and pons known as “état lacunaire.” 3. Traditional clinical feature of “état lacunaire” a. Pseudobulbar palsy 1. Emotional dyscontrol; “laughter without mirth”, “crying without tears” inappropriate to the patients environment 2. Difficulty with swallowing combined with hyperactive gag reflex 3. Subcortical dementia 4. Rigidity 5. Cautious small stepped gait (Well’s dementia gait) 6. Bilateral Babinski signs b. Mild focal motor or sensory signs 4. Evolving concepts: a. Many patients with multiple lacunes are asymptomatic (common) b. Severe generalized while matter disease: 1. Associated with subcortical dementia 2. Spasticity c. Ventriculomegaly (ex vacuo) d. New concept: 1. Lacunes, white matter gliosis and atrophy exemplified by ventriculomegaly occur concomitantly and constitute a chronic brain micro vasculopathy
a. Fibrous thickening b. Hyaline degeneration of the intima c. Reduplication of the internal elastic lamina d. PAS positive material deposition in the vessel 2. Clinical features: a. Onset in the early 40’s b. Migraine headaches c. Chromosome 19q 12 d. Dementia; abulia; behavioral disturbances 1. subcortical > cortical type e. Lacunar strokes f. Pseudobulbar palsy g. Long periods of clinical stability 3. MRI evaluation a. Periventricular T2 -weighted lesions are prominent b. Patchy areas of myelin abnormality
Amyloid Angiopathy
1. Clinical features: a. Subcortical lobar hemorrhages b. Multiple lobes c. Rare TIA during the course of the illness d. Seizures more common than with HCVD
MRI White Matter Lesions from Microangiopathy Chronic White Matter Changes of Micro Vasculopathy (Binswanger’s Disease)
1. Occipital lobes and periventricular white matter involvement are predominant location a. Anterior ventricles are affected. The lesions are close to the ependymal surface 2. Patchy demyelination that may be confluent 3. Cerebellar white matter affected 4. Thin corpus callosum 5. Cortex is relatively spared
1. Vascular stripe a. Periventricular internal border zone 1. Between arterial penetrating vessel from superficial pial arteries and ascending lenticulostriate arteries 2. Ventricular caps of increased T2 -weighted lesions a. Anterior and occipital horns of the lateral ventricles 3. Periventricular rims a. Gliosis possibly secondary to trans ependymal CSF flow (approximately 30% of all CSF bulk flow) 4. Centrum semiovale and corona radiata lesions a. Multiple and discrete b. Rarely syncytial
Pathology
1. Islands of pallid decreased myelinization surrounded by normal myelin a. Necrosis and cavitation occur in severe cases 2. penetrating arteries are thickened and hyalinized a. Usually patent b. Rare amyloid deposition in vessels of hemisphere, cortex and leptomeninges
CADASIL (Cerebral AD Arteriopathy with Subcortical Infarcts and Leukoencephalopathy)
1. Pathology of penetrating arteries:
Epidemiology of Hemorrhagic Vascular Disease
Hypertension is the major cause of intracranial hemorrhage. The age of the patient and underlying medical condition point to the specific etiology of hemorrhagic vascular disease. Spontaneous intracranial and subarachnoid hemorrhage cause approximately 10% of strokes. In patients less than 40 years of age, vascular malformations, aneurysms, cavernous angioma, illicit drugs and head trauma are the usual causes. In elderly patients, congophilic angiopathy accounts for approximately 10% of hemorrhages. Approximately 10% of patients treated with fibrinolytic agents after myocardial infarction bleed. Approximately 5–10% of patients on warfarin or
Chapter 7. Hemorrhagic Vascular Disease
heparin bleed at some point during their therapy. The rate of ICH on anticoagulation is approximately 0.3% per year. Evidence of prior vascular disease is common as patients with ICH have T2 weighted hyper intensities in cerebral white matter, lacunes and old infarction 68% of the time. There is a correlation of spontaneous ICH with small chronic hemorrhage and ischemic lesions in elderly patients.
Chapter 7 Hemorrhagic Vascular Disease The major categories of hemorrhagic vascular disease are: 1. Hypertension 2. Aneurysm, arteriovenous malformation, venous malformation, cavernous hemangioma 3. Medical causes of platelet or clotting factor dysfunction 4. Hemorrhagic transformation of ischemic stroke 5. Anticoagulation 6. Drug abuse (methamphetamine, cocaine, PPA) 7. Thrombolytic agents 8. Congophilic angiopathy (CCA) 9. Cold exposure 10. Post carotid endarterectomy syndrome 11. Severe migraine 12. Tumor 13. Surgery 14. Moyamoya disease 15. Trauma 16. Alcohol
Hypertensive Hemorrhage
Hypertensive hemorrhage occurs in very specific places the most common of which are: a. Basal ganglia – 60% (caudate 10%; putamen 50%; GP1 40%) b. Thalamus – 20% c. Cerebellum – 15% d. Pons – 5% e. Lobar – 10% f. Pontine – 5% g. Medulla – rare dysmetria 6. collapse 6. severe gait ataxia 7. Early Central Neurogenic 7. late CNH Hyperventilation 8. Early pupils changes 8. 1 mm pupils ipsi > 5 on Coumadin) Ischemia transformation of infarct Trauma Venous malformation (usually don’t bleed)
Primary Pontine Hemorrhage
1. Location: a. Midventral pons (at the level of Vth nerve or junction of basis pontis and tegmentum) b. Oval shape: destroys the center of the ventral tegmentum and basis pontis c. Dissects: 1) Rostrally to the midbrain 2) Rarely to the medullary 3) Commonly into the IVth ventricle 4) Rarely ruptures through the pial surface with spread to the clivus 2. Caused by rupture of paramedian basilar penetrating artery Clinical Signs and Symptoms:
1. Decreased level of consciousness or coma early in the course 2. Hypertension early to vascular collapse during evolution (pressure on vasomotor center of lateral medulla) 3. Central neurogenic ventilation early (20–40 breaths/min to apneustic gasp prior to death) 4. Early hemiparesis 5. Quadriplegia with increased tone of all extremities during evolution 6. Headache (basiocciput) and vomiting (occasional) 7. Gradual asymmetric onset (occasional) 8. Asymmetric weakness of face and extremities 9. Abnormal movements: a. Shaking tremors (partial decerebration) b. Shivering and fasciculation (chest wall) c. Dystonic posture versus decerebration 10. Weakness or paralysis of the face, pharynx, palate and tongue 11. Ocular manifestations a. Pinpoint pupils 105◦ Fahrenheit) Prognosis 1. Most often death in 24–48 hours, rarely a patient survives 7–10 days Unilateral Basilar or Tegment basilar Hemorrhage
A. Paramedian hemorrhage 1. Exclusively or predominantly on one side of the pons 2. Basotegmental hemorrhage is usually larger than those confined to one side of the pons 3. Small lateral basal hematomas a. Present as: 1) Pure motor hemiparesis 2) Ataxic hemiparesis 3) Clumsy hand dysarthria syndrome b. Dissection of lateral basal lesions into the tegmentum 1) Cranial nerve V, VI, VII deficit 2) Contralateral hemiparesis Differential Diagnostic Points Separating Hemorrhage Versus Lacunar Strokes 1. Occipital headache (hemorrhage) 2. Nausea or vomiting (hemorrhage) Paramedian Tegmental Hemorrhage
1. Position and higher sensory modality loss in the contralateral arm, face and leg 2. Ipsilateral 1½ syndrome 3. Motor dysfunction of the contralateral extremities a. Ataxia c. Dystonia b. Decerebration Lateral Pontine Tegmental Hemorrhage
1. Rupture of small penetrating vessels from long circumferential arteries 2. Pupillary defects: a. Anisocoria (smaller ipsilateral pupil, normal reactivity) 3. Ocular motility defects: 1. Paralysis of ipsilateral conjugate gaze 2. 1½ syndrome (if posterior MLF affected) 3. Intranuclear ophthalmoplegia (posterior type) 4. Ipsilateral VIth nerve deficit 5. Pontine exotropia 6. Ocular bobbing, dipping 4. Cranial nerve deficits: a. V, VI, VII 5. Moderate hemiparesis a. Bilateral weakness may occur at ictus; ipsilateral deficit clears b. Limb and truncal ataxia, ipsilateral > contralateral, may be bilateral
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Clinical Differential Points of Lateral vs Paramedian Lesion
1. Quadriparesis or quadriplegia (paramedian) 2. Contralateral hemisensory deficit: (lateral) a. Lemniscal modalities and spinothalamic deficits contralaterally 3. Rare findings: a. Decreased hearing (trapezoid body); paramedian lesion b. Dysarthria (posterior 1/3 of ventral tegmentum) c. Dysphagia (corticobulbar fibers X, XII) d. Decreased ipsilateral V (corresponding decrease of corneal reflex) e. Bilateral ptosis (rare) f. Convergent and divergent eye movements associated with: 1) Ipsilateral facial numbness 2) Contralateral sensory deficits 3) No motor abnormality Differential Diagnosis of Primary Pontine Hemorrhage
1. Hypertensive cardiovascular disease a. Middle aged patients 2. Vascular malformations (younger patients) a. Von Hippel Lindau disease b. Zona Bannayan syndrome c. Cobb’s syndrome d. Cavernous angioma e. Capillary telangiectasia (rarely bleed) 3. Anticoagulation 4. Coagulopathy 5. Trauma (associated with basilar skull fracture) Medullary Hemorrhage
1. Approximately 0.5–1% of ICH 2. Bleeding can occur from: a. Direct penetrating arteries of the distal vertebral artery b. Branch arterial rupture from PICA, AICA or anomalies of the vertebral artery (basilarization of the vertebral artery) 1) Hemorrhage may be involved with concomitant cerebellar infarct c. Dorsal branches of PICA 1) Supply the dorsal medulla 2) Concomitant cerebellar infarction if these arteries rupture Clinical Signs and Symptoms 1. Partial or complete lateral medullary syndrome depending on specific arterial rupture Secondary Pontine Hemorrhage
1. Diencephalic herniation a. Sretch and rupture of paramedian pontine penetrators from the basilar artery (Duret’s hemorrhage)
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b. Associated midline thalamic and midbrain hemorrhages 2. Blood dyscrasia 3. Coagulopathy 4. Sudden severe increase of intracranial pressure Prognostic Factors for Intraparenchymal Hemorrhage
1. Size and level of consciousness a. 85 cm3 – death 2. Other predictors of prognosis a. intraventricular hemorrhage c. edema b. hydrocephalus 3. 30 day mortality – approximately 45% a. 50% of deaths occur in the first 48 hours 4. Pineal displacement laterally – 78% deteriorated b. 20–50 ml – 33% deteriorated c. frontal > temporal lobe B. Clinical Signs and Symptoms: 1. 48% present with seizures 2. 2% have progressive neurologic deficits 3. Chronic headache: a. Migrainous; often are stereotyped and do not switch sides b. May have associated increased ICP and papilledema 4. Rare presentation with hydrocephalus: a. Common with great vein of Galen location in children b. Prior small bleeds block CSF absorption 5. Fluctuating bruit: a. Concomitant with heart beat b. Rarely heard over the malformation c. Jugular venous hum (heard in the neck) 6. Hemi asymmetry of the side opposite the lesions a. Most severe if the parietal lobe is involved 7. Hemorrhage is not strictly limited to the subarachnoid space 8. Cortical or ventricular surfaces most likely to rupture 9. Focal deficits specific to location 10. May have asymptomatic bleeds (hemosiderin deposits on gradient ECHO MRI sequence) 11. Rupture 2.2% per year 12. Mean risk of death from rupture is 29% 13. Meningeal signs if rupture is primarily in the subarachnoid space
Imaging Evaluation
1. MRI a. Honey combed areas
2.
3.
4.
5.
b. Serpiginous flow voids c. Brain atrophy and ventricular dilatation d. Adjacent cysts f. Intralesional calcification Arteriographic features definitive a. Enlarged feeding vessels from several circulations (most frequent) b. Tortuous enlarged draining veins c. Central arterial venous complex of vessels d. Rapid arterial to venous shunts Negative arteriogram with AVM malformations: a. Spontaneous thrombosis b. Obliteration with hemorrhage c. Cavernous angioma or dural anterior venous malformation 1) No feeding arteries d. Spinal AVM 1) May mimic intracranial signs and symptoms a) Headache and stiff neck Features Increasing the Risk of Hemorrhage: a. Small malformation b. Exclusively deep venous drainage c. High intranidal pressure AVM of the lateral ventricle: a. males 2 : 1 with thrombosis of the lateral sinus and increased venous drainage enlarging dural veins. 4. May become symptomatic with pregnancy. 5. Thrombosis or stenosis within the draining dural sinus: a. Enlarges the DAVM. b. Increases venous hypertension. Clinical Signs and Symptoms
1. Headache (global and frontal); may be migrainous or localized to the side of the lesion. 2. Increased intracranial pressure. 3. Hydrocephalus. 4. Hemorrhage. a. Signs and symptoms depend on the drainage pattern: 1) Solely dural 2) Drainage pattern into the cortical or deep venous system b. Intraparenchymal > subdural > subarachnoid in location c. 30% mortality d. Pulsatile tinnitus. e. Seizures. f. Cerebral edema with venous hypertension and sinus occlusion. g. Postural headache (worse in supine position). Location of DAVM
1. Most common are related to the lateral sinus and involve the transverse or sigmoid portions; approximately 60% of DAVM’s. a. Feeding vessels of lateral sinus fistulae: 1) Occipital, middle meningeal, accessory meningeal from the external carotid. 2) Ascending pharyngeal (arch of the aorta) 3) Meningohypophyseal trunk of the cavernous carotid artery. 4) Dural branches of the vertebral arteries.
Cavernous Sinus DAVM
General Features: 1. Occur in approximately 16% of DAVM; 2% of patients with head trauma. 2. Abnormal shunting of blood from the internal and external carotid into the cavernous sinus. a. Type A 1) Direct carotid cavernous fistula
3.
4. 5. 6.
7.
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2) Large shunted blood volume 3) Dramatic symptoms b. Type B; indirect CCF 1) No direct communication between ICA-cavernous sinuses 2) Branches of ICA or ECA and the cavernous sinus 3) Type C a) Fed by dural branches of ECA 4) Type D a) Branches of ICA/ECA c. Orbital venous hypertension causes: 1) Proptosis 2) Scleral arterialized venous blood; the arteries reach the iris whereas in infection they don’t. 3) Chemosis. 4) Papilledema. 5) Glaucoma. d. Cavernous sinus drainage into: 1) Petrosal veins and sinuses 2) Basal vein of Rosenthal 3) Results in brainstem venous hypertension e. Cranial nerve III, IV, VI and first division of V (V1) may be compromised. f. Etiology. 1) Trauma. a. MVA with head injury b. Gunshot wounds 2) Rupture of ICA infraclinoid aneurysm. Etiology a. Ehlers Danlos type IV c. Arteriosclerosis b. FMD d. HCVD Indirect Fistulas a. Post menopausal b. Spontaneous Direct Fistulas a. Trauma Differential Diagnosis Tumors a. Pituitary adenoma d. Nasopharyngeal cancer b. Metastasis e. Hyperthyroidism c. Craniopharyngioma f. Retrobulbar masses 1) Hemangioma 3) Mucocele 2) Bone tumor Rare DAVM’s a. Incisura of the tentorium 8% b. Cerebral convexity – sagittal sinus c. Orbital-anterior falx d. Drainage into the vein of Galen, straight sinus or posterior falx e. Acquired adult vein of Galen – DAVM 1) Related to dural sinus occlusion 2) Supplied by middle meningeal and vertebral artery, PCA and meningohypophyseal branches of the ICA 3) Shunt is into the wall of the vein of Galen 4) Occasional association of a vein of Galen aneurysm with DAVM has been noted
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Prognosis and Natural History
1. An aggressive course is correlated with a. Drainage into subarachnoid and parenchymal veins b. Retrograde flow away from the lesion 2. Spontaneous closure may occur 3. Minimal symptoms for prolonged periods a. Headache b. Pulsatile tinnitus
Spinal AVM
General Features: 1. Subarachnoid bleeding may occur with cervical dural AVM a. Vertebral artery blood supply b. Cervicomedullary junction in location 2. Thoracic, lumbar and sacral malformations rarely bleed; epidural hemorrhage is presentation if they rupture Some dural fistulas are located in the in spine or paravertebrally. 3. Clinical signs and symptoms: a. Pain occurs in approximately 40% of patients; may be radicular b. Symptoms may worsen after exercise c. May present with Brown-Sequard distribution d. Usual course is progressive weakness with bladder involvement e. Local back pain f. Headache (intracranial meningeal irritation) g. Those in spine or paravertebral location 1) Compressive myelopathy 4. Hemorrhage may be initiated by coagulopathy or anticoagulation 5. Blood may be seen: a. Intraventricularly b. Basal cisterns c. Re bleeds occur in 50% of patient d. 90% of patients have neurologic deficits Type I Malformation Dural Form of Spinal AVM
1. Dural location most frequent 2. Blood supply derives from arteries located in the dural sleeves of spinal roots 3. Arteriovenous malformation fed by dural branches of a radicular artery 4. Fistula drained intradurally by: a. Enlarged tortuous vein (seen partially on the dorsal cord) b. Usually above the arterial feeder 5. Men > women 4 : 1 6. Age at onset of symptoms between 40–70 7. Usually located at lower thoracic and lumbosacral levels 8. Not associated with arterial or venous aneurysms a. Low flow
Cavernous Angiomas
A. General Features: 1. No entrapped brain parenchyma (well encapsulated) 2. Hyalinization and thickening of peripheral vessels 3. Often multiple 4. Familial (Mexican-American) 5. Zonula – Bannayan syndrome 6. Higher incidence of associated cavernous hemangioma 7. Cavernous hemangiomas are located in the posterior fossa in this circumstance 8. Associated with dural AVM a. Most common location in this instance is the posterior fossa 9. May appear anywhere in brain parenchyma 10. Often periventricular location 11. May occur: a. Spinal cord b. Subarachnoid space c. Dura d. Multiple locations simultaneously 12. Compact sinusoidal vessels Clinical Signs and Symptoms
1. Recurrent bleeding with focal neurologic deficit (parenchymal) 2. Seizures 3. SAH 4. Usually no correlation with vascular type headache 5. Rare occurrences: a. Visual loss from chiasmatic lesions b. Simultaneous bleeding from two lesions c. Hemigeusia from pontine lesions d. Associated with hippocampal sclerosis 6. May bleed intraventricularly MRI Imaging
1. Multiple lesions 2. “Pop corn” appearance of the lesion a. Mixed signal on T1; old blood (10–14 days) and new blood (90 years of age
Associated Other Diseases
a. Coarctation of the aorta b. Congenital anomalous blood vessels c. Arteriovenous malformation (arteries feeding the malformation) d. Moyamoya syndrome e. Takayasu syndrome The Defect Underlying Aneurysm Formation
a. Occur at branch points of arteries of the Circle of Willis b. Decrease of type III collagen c. Defect of the arterial media and localized loss of muscular elements d. Loss or breakage of the internal elastic membrane Familial Aggregation of Congenital Aneurysms
a. 7–10% of patients with aneurysmal rupture have first or second degree relatives with an aneurysm b. Among first degree relatives of those with ruptured aneurysms risk of SAH is four times that of the population at large c. Risk highest among siblings of the index patient d. Most families have 2–3 members that are affected if there is familial aggregation e. Inheritance patterns are unclear; autosomal dominant most probable Incidence of SAH with Aneurysms
a. 1/10,000 people b. At risk for development of new aneurysm (after rupture of the first)
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SECTION I. Vascular Disease
c. Each year: new aneurysms develop in 2% of patients with previously ruptured aneurysms, this group ruptures at an incidence of 6/10,000 in the general population d. Morbidity and mortality 1. 12% die prior to medical attention 2. 40% die in the hospital within 1 month after the ictus 3. 1/3 of survivors suffer major neurologic deficits Associated Clinical Features of Aneurysms with Underlying Collagen Defects
1. 2. 3. 4. 5. 6.
They are in typical locations Bilateral Associated with enlarged tortuous extracranial vessels Occur at supra clinoid level Associated with A-V fistulas Associated with dural ectasia
Familial Aneurysms
a. Rupture at an earlier age than sporadic aneurysms b. Smaller when they rupture c. More often followed by the formation of new aneurysms Multiple Aneurysms
a. b. c. d.
Usually 2–3 in patients Occur in 20–30% of patients Rarely > 10 Occur with AVMs and other associated congenital anomalies of blood vessels
1. 9% risk in first degree relatives if 2 or more members have aneurysms 2. Life time risk for SAH in persons with an affected first degree relative is 1% at age 50; 2% at age 70 i. Familial predisposition 4.0% (2.7–6%) j. Atherosclerosis 2.3% k. 8% of aneurysms detected >8 mm in size l. Incidence of rupture increases after the third decade; average age of rupture is fifty years of age, increases with age until 80 1. Female > male risk of rupture after 40 2. Male > female risk of rupture < 40 a) Anterior communicating aneurysms female > male m. 75% of unruptured aneurysms in women than men e. Incidentally found aneurysms lower risk of rupture than those found in addition to one that has ruptured f. Aneurysmal SAH; male > female 1. Premenopausal female low risk of rupture 2. Postmenopausal female with hormone replacement (intermediate risk) 3. Postmenopausal female without hormone replacement (highest risk) 4. Alcohol consumption g. Cigarette smoking; 3–10× greater risk than nonsmoker 1. Smoking increases chance of developing a new aneurysm 2. Decreases alpha antitrypsin (inhibits proteases) 3. Inherited decrease of alpha antitrypsin causes increased risk of aneurysms h. ADPCK disease (autosomal dominant polycystic kidney disease) 4.4% (2.7–7.2%) chance of aneurysm
1. 2. 3. 4. 5. 6. 7. 8.
Valsalva maneuvers Pregnancy (release of elastases) Sleep (30% rupture during sleep) extreme sudden hypertension (amphetamines; cocaine, PPA) Weight lifting Coitus Defecation 30% rupture during normal activity
The Clinical Spectrum of Unruptured Intracranial Aneurysms
1. Mean age at diagnosis 50 years (11–77 years) 2. Mean aneurysm diameter 2.1 cm Group I – Acutely Symptomatic Patients
1. Headache a. Sentinel hemorrhage 1) Possibly 30% of aneurysmal SAH 2) Minute tear of the aneurysm: a) Sudden onset “thunderclap” headache b) Maximum intensity instantly
Chapter 7. Hemorrhagic Vascular Disease
c) Resolves in 48 hours, but may last weeks d) Radiation to shoulder, neck and back; “flu-like” symptoms (with SAH) e) Aneurysm thrombosis; meningeal inflammation 3) Ischemia (vasoconstriction of the parent vessel) 4) Seizure (rare) 5) Cranial neuropathy (III most common) Group II – Chronic Symptoms (giant aneurysms)
a. b. c. d. e. f.
Average size of giant aneurysms 2.1 cm Headache (mass effect) Visual loss (optic nerve or chiasmatic compression) Pyramidal tract dysfunction (MCA giant aneurysm) Facial pain (V1 involvement in cavernous sinus) Diplopia 1. III and IV nerve – giant basilar tip aneurysm 2. P-COM; III nerve compression 3. AICA – VI nerve rare 4. Cavernous sinus VI nerve > III > IV nerve
Asymptomatic Patients
1. Aneurysm size 1.1 cm Unruptured Aneurysm Major Clinical Presentations
a. b. c. d. e. f.
Mass lesion Stroke Seizure 77.4% at ICA and PCA sites More common in women than men MCA aneurysms; approximately 15% are symptomatic
Clinical Presentation of SAH From A Ruptured Aneurysm
1. General manifestations a. Severe headache (noted above) b. 50% of patients lose consciousness or are stunned c. Photophobia d. 30–50% have suffered a sentinel headache days to weeks prior to the rupture e. Neck stiffness 1) Kernig’s sign 2) Brudzinski’s sign f. Subhyaloid hemorrhage (Torsten’s syndrome) 1) Side of the ruptured aneurysm (if there are multiple); sudden increased ICP with rupture of the preretinal veins 2) Shoulder, back or sciatic pain 3) Pain across the shoulders with “flu-like” symptoms g. leg f. Aneurysm may be > 2 cm (giant aneurysm) g. Large amount of blood in Sylvian fissure, vasoconstriction of MCA h. Giant MCA aneurysm: seizures, dysphasia, hemiparesis
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SECTION I. Vascular Disease
Internal Carotid Artery Aneurysm
Superior Cerebellar-Basilar Artery Aneurysm
a. b. c. d. e.
a. b. c. d.
Pain behind the eye Ptosis (partial) and pupillary paresis Rare complete IIIrd nerve palsy Contralateral hemiparesis and hemisensory deficits Nasal visual field deficit 1) Homonymous 2) Compression of the lateral chiasm
Ophthalmic artery aneurysm
a. b. c. d.
Pain in or behind the eye Painless loss of central vision Rare bitemporal VF deficit Chiasmatic syndrome (anterior)
Anterior choroidal artery aneurysm
a. b. c. d. e. f. g.
Contralateral hemiparesis Contralateral hemisensory defect Central sector VF deficit Transient focal ischemia of the internal capsule Limb shaking (ischemia of internal capsule) Tonic spasm (ischemia of internal capsule) Rupture with: 1. Intracranial or intraventricular hemorrhage
III nerve palsy Ipsilateral dysmetria Dysarthria Blood in the perimesencephalic cistern
Top of the Basilar-PCA Bifurcation
1. 2. 3. 4.
Pain in the back of the neck or basiocciput III nerve palsy (peduncular) Visual field deficit (embolus to PCA) Hemiparesis or quadriparesis (emboli or pressure on the cerebral peduncles) 5. Movement disorder (emboli or vasoconstriction of the thalamoperforate artery) 6. Thalamic sensory deficit (emboli or vasoconstriction of the thalamogeniculate artery) 7. Blood in the perimesencephalic cisterns; intra peduncular blood PCA-P1 (posterior communicating artery)
1. Similar to top of the basilar–PCA aneurysm Specific Clinical Signs Denoting Specific Aneurysms
Posterior Circulation Congenital Aneurysm
A. Vertebral Artery Aneurysm 1. PICA symptoms 2. Anterior spinal artery symptoms (VA-ASA) a. Hemiparesis b. Proprioception and vibration loss 3. Pain in the side of the neck 4. Rarely pain radiates to lateral eyebrow 5. Acute blood in the IV ventricle B. PICA-Vertebral Artery Aneurysm 1. Dysphagia and hoarseness 2. Lateral pulsion (ipsilateral side) 3. Inability to stand 4. Nausea and vomiting 5. Pain in the basiocciput; lateral eyebrow or side of the face 6. Crossed hemisensory loss to pain and temperature 7. Oscillopsia 8. Acute rotary nystagmus (greatest ipsilaterally) 9. Ipsilateral Horner’s syndrome 10. Blood in the IV ventricle and the posterior fossa AICA-Basilar Artery Aneurysm
1. 2. 3. 4.
Sudden hearing loss or tinnitus Peripheral ipsilateral facial weakness Ipsilateral pain in the face Contralateral pain and temperature loss (below the clavicle) 5. Contralateral hemiparesis 6. Blood in the posterior fossa
1. Giant MCA aneurysm a. Seizure (focal motor) c. Hemiparesis b. Dysphasia 2. IIIrd nerve compression a. ICA (hemiparesis often associated) b. P-COM c. Superior cerebellar artery 3. Isolated VIth nerve following aneurysmal SAH a. Blood b. Increased intracranial pressure 4. Cavernous sinus aneurysm a. VIth nerve first sign b. Severe Vth nerve facial pain c. Late: IIIrd, IVth, VIth 5. Basilar tip a. Forward pointing 1) Destroys the pituitary (endocrine failure) 2) Visual field deficits b. Vertical 1) IIIrd, IVth nerve 2) Compresses the IIIrd ventricle
Rare Clinical Signs of Aneurysms
1. Transient neurologic signs: a. Ischemia of the parent vessel b. Embolization: 1) Usually from giant aneurysms 2) Cause strokes in the affected territory 2. Torsten’s syndrome
Chapter 7. Hemorrhagic Vascular Disease
a. b. c. d.
Subhyaloid hemorrhage (preretinal) Hemorrhage is moveable with changing head positions Due to sudden increased pressure Occurs on the side of the ruptured aneurysm (20% of patients harbor two or more aneurysm) e. Secondary to rupture of a preretinal vein 3. Prognosis of SAH from an aneurysm is better if no aneurysm is demonstrated Radiological features of an aneurysm that has ruptured if more than one is present by arteriography: 1. The largest aneurysm most often has bled a. Most commonly between 7–10 mm b. Giant aneurysm usually do not bleed 2. Aneurysm with the most excrescences 3. Local vasospasm 4. Local hemorrhage or hematoma
Aneurysmal Rebleeding
1. Clinical manifestations a. Sudden abrupt severe headache (described above) b. Meningismus c. Focal signs secondary to early hemorrhage d. Late 1) Vasospasm of the parent vessel with focal expected signs and symptoms e. Associated ICH leads to rapid coma f. Aneurysms that cause neurologic symptoms rupture at a higher rate 1) 15% of rebleeding within 6 months g. Fewer re bleeds in patients with Hunt grades I and II 2. Time of aneurysmal rebleeding a. 0.8–4% re bleed the first 24 hours b. 20% re bleed the first 2 weeks c. 30% re bleed by the end of the first month d. 40% by the end of 6 months e. >6 months 3%/year 3. Vasospasm concurrent with rebleeding a. Occurs from day 3–5 b. Peaks between days 5–9 c. Resolves after the second week d. Directly related to the amount of blood surrounding the artery e. Configuration of the arteries 1) Focal vasoconstriction approximate to area of the bleed 2) Diffuse vasoconstriction of the artery f. Lumen of the affected artery arms
Medical Complications of Aneurysmal Subarachnoid Hemorrhage
1. General manifestations a. Seen at 3 months 1) Symptomatic vasospasm – 46% 2) Rebleeding 7% 3) Total mortality 19% b. Frequency of at least one severe (life threatening) medical complication 1) 40% 2) Death from medical complications 23% (of those that die) a) Rebleeding 22% of these deaths 3) Vasospasm with stroke 23%
Cardiac Arrhythmia
1. 50% have an abnormal admission EKG 2. 25% have ST segment or T wave abnormalities 3. 15% have prolonged QT interval associated with at least one episode of moderate or severe arrhythmia 4. 35% of all aneurysms have one episode of cardiac arrhythmia on day 0–14; 66% of these are mild; 29% moderate and 5% are severe 5. Onset of arrhythmias usually first 7 days (peak day 2–3) 6. 17% of patients suffer moderate or severe arrhythmia on the day of rupture 7. Cardiac arrhythmia on the day after surgery a. Life threatening 5% of patients b. Less serious 30% of patients 8. Moderate arrhythmias a. Sinus bradycardia c. Atrial extrasystole b. Sinus tachycardia d. Atrial fibrillation 9. Severe arrhythmia a. Asystole b. Ventricular tachycardia c. Atrial fibrillation with hypotension d. AV block e. Supraventricular tachycardia f. Ventricular extrasystole 10. EKG changes with SAH a. ST depression or elevation without q waves
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b. c. d. e.
Deeply caved T waves (Pardee T waves) V3–V6 u waves Hyperpolarized T waves Pathogenesis 1) Myocytolysis a) Contraction band necrosis b) Myofibrillar degeneration c) Effects of increased sympathetic discharge
Grading Scale for Subarachnoid Hemorrhage
Grade I Grade II
15 13 or 14
Grade III Grade IV
12 or 13 7–12
Grade V
3–6
Glasgow Coma Scale headache only no motor deficit, may have cranial nerve deficit motor deficit, cranial nerve deficit motor deficit, cranial nerve deficit, obtunded cranial nerve and motor deficit, comatose
Pulmonary Edema
1. Occurs in 6% of patients (day 3 to 7) 2. Probable sudden increase in ICP 3. Water and electrolyte disturbance a. Particularly with anterior communicating artery aneurysms 4. Increase of atrial natruretic factor 5. Discharge of substance P containing afferents in lung capillaries
Hepatic Dysfunction
Giant Aneurysms > 2 Centimeters
1. General characteristics a. Do bleed but rarely b. Symptoms are caused by: 1) Pressure on local structures 2) Emboli distally 3) Seizure activity 4) Endocrine dysfunction (erosion into the pituitary)
Giant Carotid Aneurysm
1. Occurs in 7% of patients 2. Usually 24% of patients have mild enzyme abnormalities 3. 4% severe hepatic impairment
1. Pain behind or around the eye 2. May erode into the pituitary with endocrine failure 3. Compression of the optic chiasm with nasal VF deficit or chiasmal syndrome 4. III nerve palsy
Renal Dysfunction
Middle Cerebral Artery Giant Aneurysm
1. Occurs in 7% of patients 2. 1.2% severe life threatening renal failure
1. Anterior temporal or retroauricular headache 2. Seizure activity 3. Contralateral hemiparesis
Thrombocytopenia
Top of the Basilar Giant Aneurysm
1. Occurs in 4% of patients a. Usually associated with sepsis
Sensitivity of Computed Tomography in Detecting SAH
1. Sensitivity of new generation CT scans for patients screened < 24 hours from the ictus is 93% 2. Sensitivity of new generation CT scans in patients after 24 hours from the ictus is 90% 3. L.P. remains the gold standard to rule out SAH
1. 2. 3. 4. 5.
Occipital headache III, IV nerve palsy (if extends dorsally) Compression or invasion of the III ventricle May cause obstructive hydrocephalus Associated with emboli to the posterior cerebral artery territories with VF deficits 6. Hemiparesis (compression of the cerebral peduncle)
Acquired Aneurysms
1. General manifestations a. Peripheral arterial location (not at the Circle of Willis)
Chapter 7. Hemorrhagic Vascular Disease
b. May be multiple on superficial conducting vessels c. Cause of peripheral lobar hemorrhage 2. Differential diagnosis 1. Fusiform (secondary to hypertension; basilar artery) 2. Subacute bacterial endocarditis 3. Trauma 4. Atrial myxoma 5. Collagen vascular disease 6. Cigarette smoking (women > men)
Basilar Fusiform Aneurysm
1. Occurs in elderly hypertensive patients with associated atherosclerosis 2. Dysarthria (pontine compression) 3. Hydrocephalus (blocks ventral CSF pathways) 4. Spastic gait (pressure on ventral pontine motor fibers) 5. XII nerve palsy (dysarthria) 6. Spastic quadriparesis (ventral pontine compression)
Closed Head Injury
1. Aneurysms of superficial subarachnoid conducting vessels 2. Rarely basilar artery is traumatized after cervical or basilar skull fracture with aneurysmal formation 3. May be multiple
Atrial Myxoma
1. Multiple peripheral aneurysms 2. MCA territory most common 3. Myxomatous emboli may grow through the wall of the blood vessel
Traumatic Peripheral Carotid Artery Aneurysm (Pharyngeal Portion)
1. Knife or gunshot wound to the neck 2. Sympathetic ocular paralysis (complete Horner’s syndrome) 3. Abnormal neck pulsation 4. Embolization in carotid territory 5. Pain in the side of the face 6. Carotodynia (pain in the artery itself) 7. Associated connective tissue disease: a. Ehlers Danlos type IV and VI b. Marfan’s disease c. COLIA gene mutations d. Fibromuscular dysplasia e. May be bilateral
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Traumatic Vertebral Artery Peripheral Aneurysm
1. Trauma to the neck a. Often minimal and unrecognized when it occurs 2. Pain in the posterior or side of the neck a. Mastoid pain b. Occipital headache 3. Chiropractic manipulation (horizontal C2 portion most vulnerable) 4. Congenital connective tissue disorders (particularly if bilateral) 5. Signs and symptoms: a. Distribution of the vertebral or basilar artery b. Due to emboli at the site of the vessel tear c. Rarely flow limiting pathogenesis for signs and symptoms 6. Cancer or cancer treatment (surgical trauma)
Subacute Bacterial Endocarditis
1. May be multiple 2. MCA territory most frequent locations 3. Hemorrhage is common a. Cause of peripheral ICH b. May be delayed after successful antibiotic treatment (destruction of the vessel wall) 4. Seizures are common 5. Focal motor deficits: the symptomatology depends on location 6. Streptococcus viridans; gram negative organisms most common 7. Following dental work 8. In association with deformed values a. Congenital bicuspid calcified valves b. Rheumatic fever deformed valves c. Rarely mitral valve prolapse Differential diagnosis of subarachnoid hemorrhage without detectable aneurysm 1. General features a. 15–20% of spontaneous SAH no aneurysm is detected by 4 vessels arteriography b. There is a better prognosis in these patients than in those in which an aneurysm is found
Diseases
1. Idiopathic perimesencephalic hemorrhage 2. Venous trauma 3. Diffuse or anteriorly located hemorrhage in the basal cisterns 4. Incomplete visualization of the posterior circulation 5. Occult aneurysm
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6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Carotid artery dissection Vertebral artery dissection Dural arteriovenous malformation Spinal AVM Parenchymal trauma Mycotic aneurysm Cocaine abuse Sickle cell disease Coagulopathies Subarachnoid blood in the basal cisterns a. Pituitary apoplexy b. Cervical tumor c. Rupture of circumferential artery (penetrators) in the pontine cisterns d. Trauma e. Mycotic aneurysm f. Coagulopathies (rare) g. Cocaine or sympathomimetic drug abuse
Incomplete Visualization of the Posterior Circulation
1. Ruptured aneurysm of the posterior circulation is suspected from the early CT scan 2. 85% of patients demonstrate blood in the IV ventricle and to a lesser extent the IIIrd and lateral ventricles 3. IVH is the only abnormality on CT scan in 25% of posterior circulation aneurysms 4. Subarachnoid blood is noted in the midbrain cisterns with spread to the anterior basal cisterns
Occult Aneurysm
1. Approximately 20% of aneurysms are detected on the second arteriogram (after 2 weeks; vasospasm has cleared) 2. Aneurysmal rupture is likely if there is blood in the Sylvian or interhemispheric fissure
Idiopathic Perimesencephalic Hemorrhage
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
Approximately 10% of all SAH Comprise 2/3 of patients with normal arteriograms Occur in older patients (>6th decade) Few patients with HCVD Rarely concomitant with congenital aneurysm 1/3 have history of strenuous exercise prior to the bleed Headache reaches maximum intensity within minutes rather than seconds No loss of consciousness with the ictus No focal neurological deficits No rebleeding or delayed ischemia Normal on admission other than headache 20% have hydrocephalus with no other clinical deficits Excellent prognosis Some evidence of capillary bleed as cause
Venous Trauma
1. Shearing head injury 2. Blood most often seen in the posterior part of the ambient cistern (superior cerebellar-quadrigeminal cisterns) at the level of the tentorium 3. Vein is torn against the tentorium Diffuse or Anteriorly Located Hemorrhage with Rupture into the Basal Cisterns
1. 2. 3. 4.
Patients are lethargic to stuporous Focal neurologic deficits are present Symptomatic hydrocephalus Nidus of bleeding medial frontal lobe a. Blood dissects into the inter hemispheric fissure b. May re bleed 5. Deterioration from associated ischemia
Carotid Artery Dissection
1. Rare cause of SAH 2. Clinical features: a. Severe neck pain; subacute or acute onset b. Facial pain c. Oculosympathetic paralysis d. MCA or carotid embolic stroke e. May be associated with depressed level of consciousness f. Rebleeding may occur within hours of the initial hemorrhage
Vertebral Artery Dissection
1. Autopsy series – comprises 4% of patients who died from SAH 2. Primarily middle aged patients 3. 1/3 have HCVD 4. Common after neck movement or minor trauma a. Patient may be going to a chiropractor because he has neck pain from the dissection 5. Rarely associated with lower cranial nerve palsies; symptoms from occlusion or embolus of the PICA 6. May be bilateral if the cause is an underlying collagen defect 7. Rebleed occurs in 30% of patients; may occur within hours of the initial hemorrhage
Anticoagulation with Warfarin or Heparin
Risk factors for ICH or systemic bleeding
Chapter 7. Hemorrhagic Vascular Disease
1. Prolongation of prothrombin time beyond the therapeutic range a. hemorrhages occur occasionally in the therapeutic range 2. Large size of infarcted area (ischemic stroke) 3. Uncontrolled hypertension 4. Age related (relative risk); primarily for subdural hematoma Clinical Features
1. Gradual and insidious onset a. Hours to days 2. Predilection for the cerebellum and central lobes 3. High morbidity and mortality Patients Requiring Long Term Anti Coagulation after Bleed; Reinstitution of Rx:
1. 10–14 days possibly safe; 2–3 weeks heparin or warfarin probably safe 2. First year of anticoagulation most dangerous MRI Evaluation
1. Inhomogeneous infarction mixed signal on T2 weighted images suggest acute bleeding and clots
Primary Tumors that Hemorrhage
1. Glioblastoma multiforme 1. In general petechial hemorrhage 2. Bleeding and edema may be initiated by minimal trauma 2. Pituitary apoplexy a. Most often MRI demonstrates blood confined to the pituitary 3. General Characteristics a. Bleeding into tumors account for 5–10% of ICH b. 1% of tumors bleed c. Hemorrhagic metastatic tumors 1) Melanoma 2) Choriocarcinoma 3) Papillary Ca of the thyroid 4) Bronchogenic Ca d. Tumors that bleed are overwhelmingly malignant
Clinical Characteristics Suggesting ICH is Secondary to a Tumor
1. Underlying systemic cancer 2. Focal symptoms prior to hemorrhage 3. Unusual site: a. Corpus callosum (glioma) 4. Multiple simultaneous hemorrhages
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Bleeding Diathesis
1. General manifestations a. Platelet abnormalities 1) Associated with petechial hemorrhage in the lower extremities 2) Bleeding from the gums 3) Vaginal bleeding prior to cerebral hemorrhage may occur 4) Hemorrhage starts at 5) c. Thrombolytic treatment (TPA; urokinase) d. Connective tissue disease e. Sickle cell disease Specific Diseases of Blood Vessels That Hemorrhage
1. Cerebral amyloid angiopathy a. AD (Icelandic; Dutch variants) b. Sporadic; incidence increases with age c. Concomitant Alzheimer’s disease and variants 2. Granulomatous angitis of the CNS 3. Lymphomatous granulomatosis 4. Benign appearing immunoproliferative vasculitis 5. Angiocentric lymphoma 6. Periarteritis nodosa 7. SLE (with and without lupus anticoagulant) 8. Connective tissue diseases 9. Sickle cell disease a. 30% of sickle cell disease SAH occur in children b. Blood is in the superficial sulci c. Mechanisms 1) Distal branch occlusions 2) Collateral leptomeningeal vessels 3) Moyamoya disease (bilateral carotid occlusion) d. Adult patients may have: a) Underlying aneurysm b) Blood in the basal cisterns
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SECTION I. Vascular Disease
Thrombolysis Related Intracranial Hemorrhage
1. 2. 3. 4. 5. 6. 7.
Hemorrhages are large (approximate mean of 70 ml) Solitary in 66% Lobar 77% Confluent 80% Intraparenchymal 80% Mortality 44–83% Increased risk of subdural hematoma
Clinical Features
1. 2/3 of hemorrhages are supratentorial and solitary 2. 1/3 subtentorial or multifocal 3. Peri hemorrhage edema is minimal a. Less in those hemorrhages with a blood fluid level b. Mottling and a blood fluid level is indicative of continuing fibrinolysis 4. TPA > hemorrhage risk than from streptokinase Thrombolysis Induced Hemorrhage Occur in 6% of Treated Patients
a. 7% may be asymptomatic; noted on follow-up CT scan b. Main comorbidities associated with ICH thrombosis: 1) History of diabetes melitis and cardiac disease 2) Use of antiplatelet agents other than ASA prior to stroke related hemorrhage 3) Elevated pretreatment blood pressure 4) Age c. Criteria that utilized CT findings and laboratory findings that predict ICH: 1) Ischemic changes on CT exceeding 1/3 of the MCA territory 3) diabetes 4) Elevated serum glucose 5) Low platelet counts d. Pretreatment diffusion-weighted MRI parameters and laboratory values predictive of ICH after thrombolysis 1) High systolic blood pressure 2) Severity of the stroke 3) Elevated serum glucose 4) Volume of initial DWI lesion 5) Voxels with decreased ADC value e. Predictive CT findings for thrombolytic hemorrhage: 1) Large arterial territory involved 2) Obscuration of caudate nucleus 3) Loss of the insular stripe 4) Sulcal effacement
a. b. c. d. e.
Hypertension Size of the ischemic area Age of the patient Embolic > thrombotic stroke Endothelial cells of blood vessels are sensitive to hypoxia 3. Unfavorable prognostic signs a. Intraparenchymal hemorrhage b. Extraparenchymal bleeding (often occurs after streptokinase) c. Cerebral edema d. Size of the hematoma 1) Increased cerebral edema e. Hemorrhagic transformation of an ischemic stroke has a better prognosis than a hematoma for ICH
Recurrent Intracerebral Hemorrhage
1. 1.8–5% of patients in Asia 2. 2–24% of European patients 3. 6% of ICH are recurrent in the USA; 2.4%/year for primary ICH 4. Mean age is 64.7 years 5. Interval between bleeds is 48 months 6. Recurrent hemorrhages occur at different locations 7. Patterns of recurrences a. Basal ganglionic in hypertensive patients b. Lobar in patients with congophilic angiopathy 8. Younger age and lobar hemorrhage increase the risk of recurrence of ICH 9. Recurrent ICH a. Poor prognosis b. Severe cognitive deficits c. Risk is 4× higher in lobar hemorrhage
Post-Partum Cerebral Angiopathy
1. Cause of recurrent intracerebral hemorrhage in young women 2. Rsually a vasospastic process 3. Rsually benign and non-relapsing 4. Several intracranial vessels involved; often bilaterally 5. Similarities to benign isolated CNS angiitis: a. Young women b. Headache, seizures, neurologic deficits c. Angiogram consistent with vasospasm
Hemorrhage After an Acute Ischemic Stroke
Mechanisms of Recurrence of Intracranial Hemorrhage
1. All ischemic infarctions have petechial hemorrhages microscopically 2. Hemorrhagic transformation determinants:
1. Young patients – hypertension 2. Older patients > 65 years – congophilic angiopathy 3. Approximately 50% are secondary to hypertension
Chapter 7. Hemorrhagic Vascular Disease Differential Diagnosis of Multiple ICH
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Underlying malignancy Hypertension Coagulopathies Subacute bacterial endocarditis Vasculitis of collagen disease Congophilic angiopathy Venous sinus occlusion Multiple cardiac emboli Artery to artery emboli Multiple hemorrhage from thrombolysis therapy (IV after myocardial infarction)
Multiple Hemorrhages From Thrombolysis Therapy (IV After Myocardial Infarction)
1. Multiple hemorrhages are unusual in spontaneous ICH 2. Multiple hemorrhages occur earlier than solitary hemorrhages after thrombolytic therapy
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3. Multiple hemorrhages a. 0.47% for streptokinase (CSK) with sc. heparin b. 0.57% for SK with iv heparin c. 0.7% accelerated TPA with iv heparin d. 0.95% for SK with both accelerated TPA and intravenous heparin 4. Time from thrombolytic treatment to ICH a. Streptokinase – 17.5 hours b. TPA – 10 hours c. TPA + SK – 13 hours 5. Factors associated with increased risk of hemorrhage after thrombolysis for MI a. Age b. Congophilic angiopathy c. Facial and head trauma 1) Risk increases if syncope had occurred < 2 days prior to treatment
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Section II EPILEPSY
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Chapter 1. Introduction
Chapter 1 Introduction
Definition: Gordon Holmes
A seizure as defined by the eminent British neurologist Gordon Holmes is a “sudden, involuntary, time limited attenuation in function, secondary to an abnormal discharge of neurons in the central nervous system”. They may be due to an acute systemic or focal neurologic lesion. Idiopathic seizures have no known underlying definitive cause. Modern imaging techniques and volumetric analysis are now revealing various migrational disorders and focal microdysgenesis of the cortex which is shrinking the percentage of truly idiopathic patients. Epileptic Seizures
1. Discrete epileptic events due to transient hypersynchronous abnormal neuronal discharges 2. Epilepsy: recurrent unprovoked seizures General Epidemiology
Overall incidence: 40–70 : 100,000 in developed countries Single seizure; 0.5–5% of the population over a lifetime Greatest incidence occurs during the first year of life Western Europe and USA: a. By the age of 20, 3% of children may have had a seizure; 25% of these will develop epilepsy b. 80% of these children are seizure free within five years; most by one year c. Approximately 20–30% of newly diagnosed epilepsy patients will develop medically refractory seizures d. Secondary rise in incidence after 60 years of age 5. Risk factors for epilepsy: a. Mental retardation b. Perinatal disorders c. Cerebral palsy d. Cerebrovascular disease e. Infection of the central nervous system f. Neoplasm g. Neurodegenerative disease h. Drug abuse i. Men 1–2.4 times at greater risk than women
1. 2. 3. 4.
Classification of Epilepsy
The International Classification of Epileptic Seizures
I. Partial Seizure: The first clinical and or EEG changes indicate initial involvement of one hemisphere. Partial seizures are classified on the basis of impairment of consciousness.
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a. Simple partial: No impairment of consciousness b. Complex partial: Impairment of consciousness c. Partial with secondary generalization II. Generalized Seizures: The first clinical and or EEG changes indicate initial involvement of both hemispheres. Consciousness is impaired. 1. Tonic clonic 4. Myoclonic 2. Absence 5. Tonic 3. Clonic 6. Atonic III. Unclassified: 1. Neonatal seizures IV. Epileptic Syndrome: A. Heterogeneous groups of disorders with specific manifestations. Classification is based on: 1. Cluster of signs and symptoms 2. Seizure type 3. Age at onset 4. EEG findings 5. Prognosis 6. Response to antiepileptic drugs (AED) Seizures Classified by Etiology
1. Idiopathic: Seizures that occur in the absence of an acute precipitating central nervous system insult, systemic metabolic dysfunction or a history of prior neurologic insult. 2. Acute Symptomatic: Seizures that occur only during the first week after an acute central nervous system lesion or are concurrent with: a. Metabolic disturbance c. Alcohol withdrawal b. Febrile episode 3. Remote Symptomatic: Seizures in a patient with a history of central nervous system insult associated with an increased risk of seizure.
Epilepsies, Epileptic Syndromes and Related Seizure Disorders; International League Against Epilepsy Classification
1. Localization-Related (focal or partial) a. Seizure semiology, EEG or MRI implicate a focal origin 2. Primary Idiopathic: a. Definition: an idiopathic disorder is one not preceded by another disorder 1) Benign childhood epilepsy with Centro-temporal spikes 2) Childhood epilepsy with occipital paroxysms 3) Primary reading epilepsy 3. Secondary symptomatic: a. Secondary to a known or suspected central nervous system disorder 4. Chronic progressive epilepsia partialis continua of childhood:
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a. Rasmussen’s Syndrome 5. Epilepsies by cortical localization: a. Temporal lobe epilepsy b. Frontal lobe epilepsy c. Parietal lobe epilepsy d. Occipital lobe epilepsy
Generalized Epilepsies and Syndromes
Idiopathic generalized epilepsies: 1. Benign neonatal familial convulsions 2. Benign neonatal convulsions 3. Benign myoclonic epilepsy in infancy 4. Childhood absence epilepsy (pyknolepsy or petit mal) 5. Juvenile absence epilepsy 6. Juvenile myoclonic epilepsy 7. Epilepsies with grand mal seizures 8. Generalized tonic clonic seizures (GTCS) on awakening
Specific Syndromes 1. Malformations 2. Inborn errors of metabolism Seizures with both Generalized and Focal Features 1. Neonatal seizures 2. Severe myoclonic epilepsy in infancy 3. Epilepsy with continuous spike-and-waves during slow wave sleep 4. Acquired epileptic aphasia (Landau–Kleffner Syndrome) Situation-Related Seizures 1. Febrile convulsions 2. Seizures occurring only when there is an acute metabolic or toxic event 3. Alcohol 4. Drugs 5. Eclampsia 6. Nonketotic hyperglycemia Isolated Seizures or Isolated Status Epilepticus
Epilepsies with Seizures Characterized by Specific Modes of Presentation
Reflex epilepsies: Specific mental or somatic events that trigger seizures: 1. Temperature change 2. Photic stimulation 3. Math (simple calculations) 4. Chess 5. Somatic (proprioception or touching the skin surface) 6. Reading 7. Auditory (specific tones) 8. Chemical smells 9. Eating 10. Walking 11. Singing Symptomatic (age-related) 1. West Syndrome (infantile spasms) 2. Lennox–Gastaut Syndrome (infancy) 3. Epilepsy with myoclonic-astatic seizures 4. Epilepsy with myoclonic absence Symptomatic Generalized Epilepsies and Syndromes: Often Associated with Diffuse Encephalopathy 1. Generalized seizures 2. Supportive EEG findings 3. Many different types of seizures in the same patient 4. Neuroradiological signs may be positive Non-Specific Etiology (age-related) 1. Early myoclonic encephalopathy 2. Early infantile epileptic encephalopathy with suppression bursts
The major problems in the epilepsies suffered by adult patients are major motor seizures and complex partial seizures. The varying auras and descriptions of complex partial seizures make them difficult to diagnose in many instances. Occasionally primary childhood seizure types extend into adolescence and adulthood and will be discussed. Congenital and pediatric seizures will not be discussed in detail, but may be mentioned for completeness.
Chapter 2 Generalized Seizures
Generalized Tonic-Clonic Seizures (GTCS)
Different cortical areas are more likely to initiate the paroxysmal depolarization shift (PDS) that initiates a generalized tonic clonic seizure (GTCS) than others. Approximately 85% of GTCS are secondarily generalized. The usual cortical area that initiates the generalized seizure is the temporal lobe followed by the frontal lobe. Frontopolar and occipital areas of the cortex are less likely to initiate a major motor seizure. The primary motor and sensory area (MI and SI) are very seizurogenic and propagate to the basal ganglia and thalamus quickly. The bilateral projections from the reticular nuclei of the thalamus to the motor cortex initiates the tonic phase of the seizure. Inhibitory interneurons in the cortex and reticular formation and cerebellar volleys terminate the tonic phase and initiate the clonic phase. Oscillatory activity between the cortex and the thalamus sustain the GTCS.
Chapter 2. Generalized Seizures
1. Clinical characteristics of generalized tonic-clonic seizures a. Prodrome: 1) Extreme fatigue several days to a week prior to seizure onset 2) Increase of nocturnal myoclonic jerks 3) Mood change 4) Increased irritability and headache b. Pretonic-clonic phase (at the initiation of the seizure): 1) Myoclonic jerks 2) Brief clonic seizures 3) Deviation of the head and eyes (frontal and rarely occipital cortical focus) c. Tonic phase: 1) Tonic contraction of the axial musculature 2) Upward eye deviation 3) Pupillary dilatation 4) Tonic limb contraction 5) “Epileptic cry” a) Sudden contraction of intercostal muscles forcing air through the larynx 6) Tongue and jaw contraction a) Tongue biting (side opposite a focal lesion) 7) Cyanosis d. Clonic phase: 1) Gradual onset 2) Low amplitudes of clonic activity 3) Frequency of eight jerks per second 4) Progressive increase in amplitude that then decreases in frequency to four jerks per second 5) Atonic inhibition supervenes: a) Loss of continence b) Atonia of somatic muscles 6) Seizures usually lasts 30 seconds to 1 ½ minutes e. Post ictally: 1) Post ictal sleep (30 minutes to one hour) 2) Confusion on awakening (minutes to one hour) is usual; may last for 1–2 hours 3) Dull pounding headache (occipital predominance) 4) Todd’s paralysis (if there is underlying structural lesion) 5) Tongue biting (more severe the side opposite a focal onset) 6) Soreness of the paraspinal muscles and large leg extensor muscles 7) Rarely bilateral posterior dislocation of the shoulders (younger patients) 8) Fracture of a thoracic vertebrae (older patients) 9) Increased blood pressure (during a seizure) 10) Severe hyperhydrosis for minutes to hours 11) Temperature to 101◦ F (sustained seizure) 12) Cerebral spinal fluid (cells up to 100 neutrophils per mm3 ) 13) Post ictal psychosis (fighting constraint)
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14) Myoglobinuria and renal failure (prolonged seizure) 15) May briefly awaken and then fall back asleep 16) Rarely trismus or opisthotonos is maintained 17) Tonic seizure more common with secondary generalized epilepsy 18) Tonic seizures of adults usually a variant of GTCS 19) Increased prolactin levels (temporal lobe focus) f. Some generalized seizures are just tonic or clonic. Sudden death may occur during sleep Rare Sequelae: 1. Neurogenic pulmonary edema 2. Cardiac arrhythmias with EKG abnormalities 3. Bleeding from the first portion of the duodenum (through and through penetrating ulcer) 4. Myoglobinuria with renal failure 5. Severe acidosis pH < 7.0 6. Posterior shoulder dislocation 7. Sudden unexplained epileptic death (SUDEP) a. Tonic clonic seizures are important proximate cause b. Incidence is 0.7–1.3/10,000 patient years c. Disease severity is the primary determining factor for sudden death d. Independent risk factors: 1) Mental retardation 2) Number of anticonvulsant drugs used 3) Increased seizure frequency Differential Diagnosis of Causes of GTCS
Generalized Epilepsy with Febrile Convulsions 1. Genetics: a. Reported loci for febrile convulsions with GTCS 1) Chromosome 5 q 14–15 2) Chromosome 8 q 13–21 3) Chromosome 19 p 13.3 (SCN 1B) 4) Chromosome 2 (SCNIA/2A genes) 2. SCN 1B and SCN 2B genes a. Modulate the expressions of Na channel alpha-subunits 3. Clinical Features: a. Benign childhood onset b. Tonic-clonic seizure without fever c. 1/3 of patients have: 1) Atonic; myoclonic; astatic seizures d. Seizures with fever after six years of age e. Simple febrile seizure (FS) 1) Followed more frequently by GTCS f. Complex FS 1) Prolonged duration 2) Followed by TLE in 25% of patients g. AD febrile seizures 1) Occur after six years of age (noted above) Generalized Epilepsy with Focal Seizures Plus (GEFS+) 1. Genetics: chromosome 19q 13.1
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a. Codes for a voltage gated sodium channel (subunit B1) b. Na channel mutation cause febrile convulsions 2. Associated with afebrile seizures 5. Metabolic Disease
1. Hypoglycemia: cerebral spinal fluid sugar is approximately 2/3 of blood sugar. Patients will have seizures when the cerebral spinal fluid sugar is less than 30 mg/dl. This occurs between 40–60 mg/dl of peripheral blood sugar. The rate at which the sugar falls may also be a determinant if a seizure will be provoked. As the blood sugar starts to fall, a nonadrenergic response causes hunger, piloerection, hyperhidrosis and abnormal behavior. Parasympathetic discharge occurs frequently when the peripheral sugar is 30 mg/dl. The temperature of the patient may drop to 97◦ Fahrenheit. 2. Hypocalcemia: a. The usual setting is renal failure b. Fasciculation of muscle may occur spontaneously or with mechanical stimuli c. Peripheral nerves may discharge to mechanical stimuli (Chvostek’s sign VIIth nerve) or to ischemia (Trousseau’s sign) d. Long QT interval; non-specific T wave change on EKG 3. Hypomagnesemia: a. Often occurs concomitantly with hypocalcemia b. Secondary to prolonged enteral feeding c. Burn patients d. Clinically similar to hypocalcemic seizures e. Increased neuro excitability; increased reflexes throughout f. EKG changes similar to hypomagnesemia; often both electrolyte abnormalities occur concomitantly. 4. Uremia: a. BUN usually between 90–120 dl% when seizures occur b. Following rapid osmotic shifts (post dialysis) c. Need to rule out intracranial blood: 1) Uremic platelet dysfunction 2) Hypertensive hemorrhage from the uremic state 3) Incomplete reversal of anticoagulation (following hemodialysis) 4) Subarachnoid hemorrhage (platelet dysfunction; combination of pathologies) d. Infection (gram bacilli negative, fungus, HIV) as cause of seizures e. Seizures are often short f. Pupillary abnormalities may occur; (usually dilated) and are often associated with uremic optic neuritis (pallor, loss of the cup) which may complicate the exam
6.
7.
8.
9.
g. Rare central pontine myelinolysis occurs (if low sodium corrected too rapidly); which may be seen in ectopic areas: midbrain, thalamus, periventricularly; and is rarely associated with seizures Hepatic encephalopathy: a. May occur with anticonvulsant medications (valproic acid and phenobarbital) b. Dilantin (Steven Johnson’s syndrome, severe arteritis with lobar hepatic infarction) c. Carbamazepine: 1) Hepatotoxicity 2) Seizures also caused by inappropriate antidiuretic hormone secretion d. Valproic acid (VPA) 1) May have hyperammonia without hepatic failure; accompanied by seizures and worsening EEG 2) Phenobarbital, phenytoin valproic acid induced encephalopathy occur with combined use 3) Vigabatrin, gabapentin and topiramate all can contribute to Valproic acid encephalopathy 4) VPA and topiramate cause hyperammonemic encephalopathy 5) Clinical features of VPA induced encephalopathy: a) Acute onset of impaired consciousness b) Focal neurological signs c) increased seizure frequency d) EEG; pronounced slowing and increased epileptiform discharges e) Patients at most risk: those with liver disease, congenital enzyme deficiencies 6) Cirrhosis Hyponatremia a. Frequently seizures are dependent on the rate at which the sodium falls b. Seizures usually occur at levels less than 110 mEq/ml c. Hyporeflexia: severe weakness are concomitant features Acute intermitted porphyria: a. Major motor seizures occur due to porphyrins themselves (mechanisms not certain) b. Inappropriate ADH c. May cause status epilepticus d. Usually associated with abdominal pain and severe motor neuropathy Inappropriate ADH: a. Usually serum sodium is between 120–130 mEq/dl b. Initiated by: 1) Head trauma 2) Metabolic abnormalities 3) Drugs (carbamazepine) 4) Paraneoplastic (rare) 5) Intracranial surgery c. May cause status epilepticus Hyperosmotic states:
Chapter 2. Generalized Seizures
a. Nonketotic-diabetic coma (blood sugar often between 2000–3000 mg/dl) b. Renal failure c. Hyperlipidemia d. Insufficient free water with PEG feedings e. Clinical manifestations: 1) Multiple movement disorders; often segmental myoclonus 2) Asterixis 3) Focal and generalized seizures 10. Pulmonary failure: a. pCO2 > 70 torr; pO2 < 80 torr b. Clinical manifestations: 1) Suffused optic disease; dilated veins; papilledema 2) Asterixis 3) Fasciculations, muscle hyperexcitability 4) Generalized seizures 11. Drugs/Toxin-associated features with GTCS: a. Often osmotic gap noted on electrolyte evaluation (with toxin) b. Specific features of different drugs and toxins: 1) Methanol: hemorrhagic optic neuritis 2) INH: hyperthermia: hyperglycemia 3) Phenothiazine: hypo or hyperthermia 4) Insulin: severe hypoglycemia 5) Anesthetics a) Propofol c) Enflurane b) Halothane d) Sevoflurane 6) Theophylline (jitteriness) 7) Disopyramide 8) Amphetamine (psychosis) 9) Tricyclic anti depressants (parasympathomimetic effects 10) Lithium (tremor) 11) Antimalarials (muscle and macular degeneration) 12) Cocaine: a) Hypertension with cerebral hemorrhage b) Severe cortical and coronary artery vasospasm c) Hemorrhage if underlying vascular abnormality is present 13) Heroin: pulmonary edema, transverse myelitis 14) PCP: hallucinations, self destructive behavior, changing nystagmus 15) Anticonvulsants: liver failure, ophthalmoplegia (phenytoin; rarely carbamazepine) 16) Penicillin: large IV doses; setting of renal failure 17) Alcohol withdrawal: hypothalamic disinhibition, delirium, tremens
Infections Associated with GTCS
1. The cortex must be involved to initiate a major motor GTCS
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a. Diffuse inflammation of the meninges occurs with infections that spread to the arachnoid and pia mater b. Cortical stroke is caused by: 1) Tuberculosis (endarteritis, meningeal involvement) 2) Cryptococcosis (meningeal) 3) Mucormycosis (sinus spread) 4) Aspergillus (venous spread); often lung abscess is the source 5) HIV (blood vessel involvement directly; endothelial cell damage) 6) Syphilis (proliferative endarteritis); often brainstem 7) Subacute bacterial endocarditis (aneurysms; late focal hemorrhage) 8) Cysticercosis (calcification with adjacent cysts) 9) Toxicants (toxocana canis); primarily children 2. Direct cortical involvement: a. SBE (gram negative or positive) b. HIV c. Toxoplasmosis d. Opportunistic infections in an HIV infected patient e. Parasitic infections (tropical) (setting of metabolic dysfunction) 3. Other causes of GTCS: a. Venous infarction (often postpartum) b. Vascular (infarction, hemorrhagic, malformation) c. Tumor (primary and metastatic) d. Head injury (acute or distant past) e. Prior cortical scar (setting of metabolic dysfunction) f. Prior stroke (at least 10% of stroke patients) g. Anticonvulsant withdrawal h. Alcohol withdrawal 4. Precipitating factors for GTCS: a. Failure of drug compliance b. Alcohol withdrawal c. Specific drugs that cause seizures: 1) Cocaine 2) Antihistamines 3) High doses of penicillin (renal failure) 4) Phenothiazine (particularly if there is a preexisting structural lesion) 5) Phosphodiesterase inhibitors (asthma) d. Hypoglycemia (missing breakfast then administering insulin in a diabetic) e. Stress f. Lack of sleep Differential Diagnosis of GTCS by Age
1. Adolescent: a. Idiopathic b. Noncompliance with drug therapy c. Drugs (cocaine, PCP, barbiturate, and alcohol withdrawal) d. Metabolic (hypoglycemia) e. Vascular (infarction embolus, hemorrhage malformations)
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f. g. h. i.
Tumor (rare) Encephalitis Head injury Migrational disorders (nodular and band heterotopia; microdysgenesis) j. Hippocampal sclerosis with secondary generalization k. Syndromic (tuberous sclerosis); Chromosal defects l. Mitochondrial disease 2. Adult < 40 a. Lack of AED drug compliance b. Drugs (cocaine) c. Vascular (embolus, hemorrhage, infarction) d. Tumor (primary greater than secondary) e. Infection (HIV associated) f. Head injury g. Cardiac arrhythmia (global cerebral ischemia) h. Metabolic causes i. Migrational disorders 3. Adult > 40 a. Vascular; embolus > infarction > hemorrhage b. Lack of drug compliance (AED’s) c. Cardiac arrhythmia d. Tumor (metastatic > primary) e. Metabolic causes f. Drugs (hypnotic sedative withdrawal; elicit) g. HIV (associated opportunistic infection) h. Herpes simplex infection (TLE with secondary generalization) i. Migrational disorders 4. Adult > 60 a. Cardiac arrhythmia b. Cerebrovascular disease (infarction > embolus > hemorrhage) c. Metabolic dysfunction d. Prior CNS structural lesion e. Tumor (metastatic > meningioma > lymphoma) f. Herpes simplex infection (bitemporal and frontal lobe involvement) g. Rarely migrational disorder
Absence Seizures
1. General features: a. Onset between 3–6 years of age b. Most prevalent in first 10 years of life c. Rarely persist into adulthood d. Petit mal status is rare in adults e. Seizures are short, less than 30 seconds f. Never associated with an aura or post ictal confusion 2. Clinical Types: a. Simple typical absence: 1) Sudden onset of impaired consciousness associated with absence of facial expression and without motor or behavioral manifestations
2) Approximately 10% of absence seizure patients have this type b. Complex typical absence seizure: 1) Accompanied by motor, behavioral or autonomic features 3. Clinical features: a. Sudden onset of a blank stare b. Arrest of motor activity c. Clonic components: eye blinking, nystagmus, rapid jerking of the arms d. Tonic postural contraction causing flexion or hypertonic extension postures e. Loss of tone causes head nodding or dropping of objects f. Patients rarely fall g. Automatisms: 1) Occur in approximately 40% of typical absence seizures 2) Automatisms are semi-purposeful movements and behaviors which the patient cannot recall. They are perseverative or de novo: a) De novo: simple acts such as hand rubbing, licking the lips, chewing, scratching, picking at clothes b) Perseverative: dealing cards, handling an object or playing a hand game c) Speech is usually dysarthric, it may be normal or perseverative h. Autonomic manifestations: 1) Pupillary dilation 4) Piloerection 2) Hyperhidrosis 5) Urinary incontinence 3) Salivation 4. Atypical Absence Seizure: a. Onset prior to age 5 b. Associated with other generalized seizure types and mental retardation EEG: 1.5–2.5 Hz spike-and-wave discharges or multiple spike-and-waves that are irregular or asymmetrical; interictal EEG is unusually slow and demonstrates multifocal epileptiform features. c. Average seizure is longer than typical absence; onset is less abrupt d. Diminished postural tone; tonic or myoclonic activity is more frequent than in typical absence seizures: 1) Automatisms are more perservative in atypical absence seizures than in typical absence seizures (AS) 2) Postural tone changes are more frequent in atypical absence seizures (AAS) than typical absence seizures (TAS) 3) A blank stare or change in facial expression > AAS than TAS 4) Smiling automatism common in AAS 5) Hyperventilation may induce absence seizures; this rarely occurs in CPS or GTCS 6) Photic stimulation may induce GTCS, absence, atypical absence or CPS
Chapter 2. Generalized Seizures
e. Adult petit-mal status occurs rarely and usually presents as confusion or stupor f. Between 40–60% of patients with TAS have GTCS 1) First absence to first CTS: 1 to 16 years 2) AAS: almost always have GTCS’s, myoclonic, tonic and TAS seizures concomitantly 3) Partial seizures are uncommon in AAS and TAS 5. Absence Syndromes: a. Generalized idiopathic epilepsies: 1) Childhood absence 2) Juvenile absence 3) Juvenile myoclonic b. Generalized symptomatic epilepsies: 1) Lennox–Gastaut Syndrome 2) Epilepsy with myoclonic astatic seizures 3) Epilepsy with myoclonic absences 6. Generalized idiopathic Epilepsies: a. Childhood absence: 1) Typical absence (simple and complex) 2) Onset: 3–5 years and puberty 3) Genetic predisposition 4) Girls more frequently affected 5) Frequent: up to several hundred per day and may cluster 6) EEG: bilateral symmetrical synchronous 3 Hz spikes and wave discharges; normal interictally 7) Absences may remit during adolescence: 25–30% develop GTCS b. Juvenile absence Epilepsy: 1) starts around puberty 2) seizures are more sporadic 3) fewer retropulsive movements 4) generalized tonic-clonic and myoclonic seizures occur upon awakening 5) males equally affected 6) EEG: spike-and-wave is faster than 3 Hz Juvenile Myoclonic Epilepsy of Jansen: 1. Starts 12–18 years of age (few patients start in the late 20’s) approximately 4–10% of epilepsy 2. Genetics: a. AD b. Chromosome 6q; 15q 3. Early morning: mild to moderate myoclonic jerks of the neck, shoulders and arms 4. Patients may just notice shakiness or nervousness upon awakening or drop or throw objects (hair brush) 5. GTCS occur in 90% of patients: 1/3 suffer absence seizures 6. Myoclonic jerks may culminate in GTCS 7. Seizures precipitated or increased by awakening, fatigue, alcohol or by recreational drugs; 30–35% of patients suffer absence attacks 8. EEG: interictal 3.5 to 6 Hz, irregular spike and wave and multiple spike and wave complexes 9. Rapid 10–16 Hz spikes followed by irregular slow waves are noted during the myoclonic seizures
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10. EEG activated by sleep deprivation and photic stimulation 11. JME persists for life 12. Drinking on the weekend in adults may initiate myoclonic seizures with GTCS on Monday morning Epilepsy with Generalized Tonic-Clonic Seizures on Awakening 1. General features: a. Onset occurs in the second decade b. 90% of seizures occur on awakening at any time of the day c. May occur with relaxation in the evening d. Associated with absence and myoclonic seizures
Generalized Symptomatic Epilepsies Lennox–Gastaut Syndrome
1. Onset usually prior to age 5 (may start as late as age 8) 2. Tonic, atonic and absence seizures are most typical. May also have myoclonic, GTCS or partial seizures 3. EEG: slow spike-and-wave less than 3 Hz; abnormal background multifocal abnormalities 4. Pathology: both structural and metabolic 5. Seizures are refractory 6. Developmental outcome guarded Epilepsy with Myoclonic-Astatic Seizures 1. Onset between the ages of 7 months to 6 years (usually between 2–5 years) 2. Normal developmental background 3. Hereditary predisposition 4. Boys are affected twice as often as girls (unless onset is within the first year) a. Seizures: myoclonic, astatic; myoclonic-astatic, absence or tonic-clonic, frequent status epilepticus 5. EEG: initially normal, but with 4–7 Hz theta/rhythms; evolves into irregular fast spike-or-multiple spike-andwave complexes Epilepsy with Myoclonic Absences 1. Onset usually at 7 years of age 2. Boys more affected than girls 3. EEG: similar to absence seizures 4. Seizures are frequent and less responsive to medication than with childhood absence seizures 5. Mental deterioration and evolution to Lennox–Gastaut occurs Landau–Kleffner Syndrome 1. General features: a. Presents between 3–9 years b. An acquired aphasia associated with seizures c. Seizures may be GTCS, myoclonic or partial d. Word deafness with normal hearing is the seminal feature
SECTION II. Epilepsy
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2. EEG: a. Spike activity over the central temporal regions b. Multifocal spike and slow wave patterns may occur
3) 4) 5) 6) 7)
Absence Status Epilepticus
Clinical features: 1. Sustained impairment of consciousness 2. Patients are confused 3. Partially responsive and able to perform activities of daily living 4. Facial twitching 5. Eye blinking 6. Staring 7. Automatisms 8. EEG: generalized irregular approximately 3 per second spike-and-wave discharges; prolonged generalized bursts of spike-and-wave discharges or irregular slow spikeand-wave discharges 9. Ictal stupor in adolescents with history of childhood absences after seizure free interval 10. Most commonly arms, neck and facial muscles are involved 11. More common in children than adults Electrical Status Epilepticus During Slow Wave Sleep 1. General features: a. Present between 1–12 years of age b. Cognitive regression c. Patient may not have clinical seizures 2. EEG: a. Seizures are commonly nocturnal b. Continuous spike and slow wave during NREM sleep c. Seizures and EEG changes may disappear during the second decade d. Continued cognitive and language deficits
Chapter 3 Progressive Myoclonic Epilepsy 1. General features: a. Primarily a heterogenous group of genetic disorders caused primarily by inborn errors of metabolism b. Major clinical features: 1) Myoclonus 2) Seizures 3) Cognitive decline 4) Progressive neurologic deficits c. Differential diagnosis: 1) Lysosomal storage disease 2) Mitochondrial disorders
8) 9) 10) 11) 12) 13) 14) 15)
Unverricht–Lundborg disease Lafora body disease Hallervorden–Spatz disease Action myoclonus renal failure syndrome Dentatorubral pallidal Luysian Sylvian atrophy (DRPLA) Sialidosis Adult onset polyglucosan body disease Gaucher’s Disease Celiac Disease Neuroaxonal dystrophy Dawson’s encephalopathy Biotin responsive encephalopathy Familial adult myoclonic epilepsy
Myoclonic Syndromes
1. General Features: a. Myoclonic Seizures: 1) Sudden, lightening like contractions of groups of muscles 2) Faster than contractions of muscles noted with clonic seizures 3) Any group of muscles may be affected 4) Patients may fall 5) Myoclonic jerks may occur as a component of an absence seizure or at the onset of a GTCS Early Infantile Myoclonic Encephalopathy (Otohara Syndrome) 1. General features: a. Initial seizures are myoclonic b. Myoclonic seizures prior to 3 months have severe underlying pathology c. No established link with immunization d. Myoclonic seizures are followed by partial seizures, tonic spasms and GTCS e. Psychomotor deterioration 2. EEG: a. Burst suppression b. Neonate presents with burst suppression and evolves to intermittent high amplitude spike and wave complexes West Syndrome 1. Clinical features: a. Infantile spasms b. Arrest of psychomotor development c. Hypsarrhythmia on EEG d. Onset prior to one year (3–7 months) e. Spasms occur in clusters; sudden flexion or extension of the trunk; jack knife pattern (flexion of the head and neck and adduction of the arm) Familial Adult Myoclonic Epilepsy 1. Genetics:
Chapter 3. Progressive Myoclonic Epilepsy
a. Chromosome: 8 q 24; AD b. European family described without linkage to 8 q 24 c. Baltic familial myoclonic epilepsy and familial adult myoclonic epilepsy are on chromosome 8 q 23.3–q 24.1 2. Clinical features of FAME: a. Adult onset of extremity myoclonus b. Infrequent seizures c. Non progressive d. Giant SEP (somatosensory evoked potentials) e. Enhancement of C reflex f. Pre-myoclonus spike g. Onset greater than 30 years of age h. Familial cortical tremor 1) Variant of cortical reflex myoclonus 3. Some Japanese families have: a. FAME; BAFME (Baltic Familial Myodemic Epilepsy); FCT (familial cortical tremor) 4. Lafora body disease a. AR: both sexes equally affected; chromosome 6q b. Clinical features: 1) Seizures 2) Myoclonus a) Affects any area of the body b) Startle sensitive c) Absent during sleep 3) Dysarthria 4) Rigidity 5) Spasticity 6) Dementia follows seizures in two to three years 7) Onset in adolescence or in late childhood; progresses to death between 17–24 years in 90% of patients 8) Generalized tonic-clonic seizures are presenting features; status epilepticus in terminal stage 9) Visual seizures occur in 50% of patients: a) Scotomata c) Occipital CPS b) Simple hallucinations 10) Fluctuating course associated with episodes of cortical pseudo blindness c. EEG: bilaterally synchronous spike and wave complexes noted in association with the myoclonic jerks d. Lafora bodies: 1) PAS positive intracellular inclusions < 3 μm to 30 μm 2) Located in the neuronal perikarya; cerebral cortex, substantia nigra, thalamus and globus pallidus 3) Lafora bodies are found in: heart, skeletal muscle, skin, retina, liver 4) Branched polysaccharide Unverricht–Lundborg Disease (Baltic myoclonus) 1. Genetics: located on chromosome 21q 22.3; AR 2. Mutation in EPM 1 gene a. Encodes cystatin B b. Inhibits cathepsins
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1) Intralysosomal cystine proteases 3. Clinical features: a. Stimulus sensitive; action myoclonus b. Age at onset 8–13; begins insidiously c. Tonic clonic seizures d. Ataxia, dysarthria, decreased swallowing e. Mild dementia f. Exacerbated by phenytoin g. Myoclonus is incapaciting 4. MRI: a. Atrophy of the medulla, pons and cerebellar b. OPCA has V shape of the pons hemispheres 5. Pathology: a. Loss of Purkinje cells, dentate and olivary neurons
Sialidosis
1. 2. 3. 4.
Melioidosis 1 Oligosaccharide sialidosis deficiency Genetics: juvenile Type III; chromosome 10 Clinical features: a. Onset at 6 months b. Mild Hurler’s features (facial dysmorphism) c. Corneal clouding d. Macular cherry red spot e. Mental retardation f. Myoclonic jerks g. Seizures h. Neuropathy
MERRF (Mitochondrial Encephalomyopathy with Ragged Fibers)
1. 2. 3. 4. 5. 6. 7.
Short stature Diabetes mellitus Sensory neural hearing loss Abnormal collection of mitochondria on muscle biopsy Proximal weakness Progressive myoclonic epilepsy Other mitochondrial diseases have myoclonic epilepsy
Neuronal Ceroid Lipofuscinosis
A. Juvenile variant (Spielmeyer–Sjögren Disease) 1. Genetics: AR; chromosome 16p 2. Abnormal lipopigments found in abnormal cytosomes (curvilinear and finger print bodies); abnormalities seen in skin, muscle, peripheral nerve in addition to central nervous system 3. Clinical features: a. Onset 5–10 years of age b. Begins with progressive visual loss
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SECTION II. Epilepsy
c. Pigmentary degeneration of the retina d. Myoclonic and generalized seizures e. Death by end of the second decade B. Adult variant (Kufs disease) 1. Genetics 2. Clinical features: a. Onset in third or fourth decade b. Progressive dementia c. Seizures d. Myoclonus e. Ataxia f. No blindness or retinal degeneration Rare Causes of Progressive Myoclonic Epilepsy: 1. Gaucher’s Disease 2. GMI gangliosidosis 3. Biotin responsive encephalopathy 4. DRPLA-SCA-7 5. Atypical inclusion body disease (Derision’s encephalopathy) 6. Action myoclonus renal failure syndrome 7. Neuroaxonal dystrophy 8. Hallervorden-Spatz Disease 9. Celiac Disease 10. Dutch mt-DNA deficiency (fatal myoclonus epilepsy) 11. HARP
Tonic Seizures
Clinical Features: 1. Brief, usually less than 10 seconds; may last 60 seconds 2. Sudden onset of increased tone in extensor muscles; may be preceded by a myoclonic jerk 3. Patients fall; may be limited to only this manifestation 4. There is impairment of consciousness during the seizure 5. Frequently seen with Lennox–Gastaut Syndrome (mental retardation, mixed seizure disorder, slow spike-and-wave EEG pattern) 6. Apnea due to involvement of the intercostal muscles 7. Long seizures appear to have a clonic component (more frequent at night) 8. Only the axial muscles may be involved
Clonic Seizures
1. Similar to GTCS 2. Rhythmic or semi-rhythmic contractions of a group of muscles 3. Jerks can involve any group of muscles: arm, face > legs Atonic Seizures: 1. Begin in the late infancy; may start in adolescence 2. Sudden loss of muscle tone; no aura 3. Last 1–2 seconds
4. No postictal impairment 5. If trunk is involved the patient falls; if only the neck extensors are involved there is head drop; may be limited to eye blink 6. Longer atonic seizure are associated with loss of consciousness 7. May be seen as component of other seizures 8. Absence seizures often have an atonic component 9. Myoclonic jerk may precede or accompany the seizure 10. Long seizures cause seconds of flaccid paralysis 11. EEG: poly spike and wave or generalized spike and wave are associated with myoclonic jerks Focal Akinetic Seizure: 1. Focal paresis precedes convulsive activity in the affected part 2. Focal paresis may affect one part of the body; convulsive activity may then occur in the affected part 3. Somatosensory sensations may occur before or at the onset of the focal paresis in the same body region 4. Structural lesions have been documented in central parietal regions 5. Patient is motionless with impaired consciousness Epileptic Negative Myoclonus: 1. Action-activated motor activity (jerks) limited to one arm or leg 2. Rarely may be multifocal 3. Patients may demonstrate motor neglect of the affected part 4. Most patients have history of seizures 5. Paroxysmal epileptic activity is seen in areas of the sensorimotor cortex
Chapter 4 Partial Seizures 1. Simple motor partial seizure: a. Motor signs and symptoms depend on the area of the motor cortex activated b. Motor cortex (patterns of spread of the primary motor cortex): 1) Thumb initiates clonic movements followed by twitching of the corner of the mouth and arm; spread is then to the distal leg, the shoulder is often spared 2) Distal leg to proximal leg. The trunk may be spared. Spread is next to the hand, thumb and face 3) Simple partial motor seizure, particularly of the upper extremity may last for days to weeks a) Menshikoff’s syndrome b) Usually follows old vascular lesion c) Very difficult to treat
Chapter 4. Partial Seizures Simple Sensory Partial Seizures
1. Jacksonian march very similar to that noted with motor seizures 2. Face and hand particularly involved (low threshold of neurons to fire; large cortical area) 3. Trunk is involved in a sensory “march” or spread with simple sensory seizure 4. Areas of origin: usually primary homunculus of S1 or posterior parietal sensory area 5 and 7 5. Occasionally sensory seizures may begin in proprioceptive components of the sensory cortex with consequent posturing of the affected extremity; may be initiated by a specific posture 6. Posterior partial sensory seizures may initiate a feeling of tingling in a parietal sensory distribution. Patients may also feel tired 7. SII involvement: causes a sensation of heat that spreads from the feet and envelops the body bilaterally. Most often from spread of a temporal lobe focus
Occipital Lobe Seizures
Seizures emanating from the occipital lobe present a variety of neurological signs and symptoms. In general, forced eye versive movements are a frontal lobe phenomena, but may also occur from seizures of the parietal occipital junction. Oculogyric or oculoclonic eye movements (tonic or clonic contraversive gaze deviation) may occur from occipital seizure foci. Visual symptoms are the most common symptoms of occipital lobe seizures. Area 17 is associated with non-colored flashes of light, teichopsia, scotomata, hemianopia or blindness. Area 18 and 19 association area seizures are associated with moving geometric forms that are colored or patterned (photopsia). If the seizure spreads to the temporal-parietal occipital junction complex visual images may be noted. These consist of visual distortions, micropsia, macropsia, perception abnormalities or visual hallucinations. The later usually are images of past experiences that also may be distorted.
Occipital Lobe Visual Simple Partial Seizure
1. Occipital pole area 17 a. Patients’ experience simple non-colored flashes of light (dots or stars or flashes; in general they do not move across the visual field) 2. Area 18 and 19 visual association cortex: a. Colored (red, green, yellow, blue) geometric figures are experienced b. Figures move across the contralateral visual field 3. Posterior temporal/parietal/occipital junction: a. Specific distortions of the visual object occur
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b. Images are colored c. Associated with other temporal lobe semiologic phenomena 4. Unilateral eye blinking 5. May have cortical blindness 6. Epileptic akinetopsia a. Illusory motion perception b. Occurs in the contralateral field from the focus 7. Epileptic monocular nystagmus
Non-Tumoral Occipital Temporal Epilepsy
1. Seizures from occipital lobes demonstrate heterogeneous patterns of spread a. Spread through inferior longitudinal fasciculus to the temporal lobe This is sufficient spread to activate cortical mediotemporal structures b. Occipital lobe signs and symptoms: 1) Forced eye blinking 2) Blurred vision 3) Flashing lights 4) Ictal blindness 5) Elementary visual hallucination (rare) 2. Signs of occipital seizure spread to temporal lobe: a. Visual component d. Dizziness b. Psychical aura e. Somatosensory aura c. Olfactory aura 3. Seizures with occipital lobe symptoms: a. Approximately 2/3 have temporal auras b. 1/3 have both temporal and frontal auras 4. Periventricular subcortical nodular heterotopias present with temporal-parieto-occipital semiology 5. Focal cortical dysplasia includes polymicrogyria, heterotopias and abnormal lamination. Migrational disorders tend to occur posteriorly. The causes of these disorders if post migrational are: a. Watershed MCA/PCA hypoperfusion b. Prenatal occlusion of the precuneus branch of the PCA (parieto-occipital area) 6. Clinical features of bilateral parasagittal and parietooccipital polymicrogyria induced seizures are: a. Complex partial seizures with minor automatisms b. Patients maintain an average IQ or suffer mild mental retardation 7. Photo sensitive epilepsy with absence and absence status: a. Clinical features: 1) Usually children 2) Early or late onset of benign childhood partial seizures with occipital paroxysms 3) Seizures are elicited by elimination of central vision and fixation 4) Seizures persist as long as the eyes are closed 5) Seizure activity inhibited by patterned vision
SECTION II. Epilepsy
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6) Seizure types: a) Brief absences c) Atypical absence status b) GTCS
Differential Diagnosis between Occipital Seizures versus Migraine Headaches
1. Vomiting may be ictal (right temporal lobe) or part of migraine 2. Hemicranial headache: a. Seizure focus is in the amygdala or hippocampal formation (ipsilateral) b. May also be accompanied by nausea and vomiting (most often migraine) 3. Rapid onset and resolution of symptoms are most often an epileptic discharge 4. Points favoring migraine: a. Prolonged attack b. Severe nausea and vomiting preceded by a visual aura c. Slight impairment of processing rather than complete unresponsiveness
Fixation-Off Sensitive Seizures (FOS) a. Elimination of central vision and fixation induces spikes on EEG 1) Unilateral or bilateral 2) High amplitudes
Division A: Temporal Lobe Epilepsy
The major seizure problem in adults and the source of 75% of intractable epilepsy is complex partial epilepsy of temporal lobe orgin. The spectrum of symptoms is wide and the semiology differs from patient to patient. The symptoms reported may be the only ones remembered and not in the area that initiated the seizure. MRI techniques, PET and SPECT evaluations as well as intraparenchymal recordings now demonstrate significant abnormalities in medial temporal lobe areas and migrational defects that involve the germinal matrix, and focal dysplasia (abnormal lamination) within the cortex itself. Many intractable patients suffer the dual pathology complex of medial hippocampal sclerosis and migrational disorder. Extra temporal foci with spread from the frontal parietal and occipital lobe are a major clinical phenomenon.
Photosensitive Epilepsy (PSE) Genetics of Temporal Lobe Epilepsy
1. 2. 3. 4.
Affects 1 : 4000 seizure patients Most prevalent in adolescence High incidence of family history of epilepsy in PSE General features: a. Stimuli are flashing lights or high contrast patterned stimuli b. Chromatic sensitivity c. Stimulus frequency: 10–30 Hz d. Pattern sensitivity: 0.5 to 6 cycles/degree 1) Chromatic sensitive seizure variant 2) Photoparoxysmal response to rapid color frame changes (blue to red; monochromatic light)
Epilepsy Provoked by Television and Video Games 1. EEG activated by: a. Video screens b. Flickering screen light c. Patterns produced parallel lines that form the image d. Frequency of 25 Hz activate 75% of patients e. Seizure types: 1) Absence 3) Tonic clonic 2) Myoclonic 4) Occipital lobe partial 2. Sensitivity to seizures increases: a. Screen brightness b. Highly contrasted pattern c. Fatigue d. Fever e. Close distance f. Sleep deprivation
Autosomal Dominant Partial Epilepsy with Auditory Features (ADPEAF): 1. Chromosome 10q: gene LG 1 I (leucine rich glioma inactivated protein) 2. Clinical features: a. Onset in the first to third decades b. Not preceded by febrile convulsions c. MRI shows no focal lesions d. Some patients have a receptive aphasic e. Some patients have visual symptoms f. May be developmental abnormality in the affected cortex in 50% of patients 3. LG 1 I gene mutations: a. First described in glial tumors; deletions or rearrangements b. Cause protein truncation; putative loss of function Familial Mesial Temporal Lobe Epilepsy (FMTLE) 1. Clinical features: a. Onset in the second to fifth decade b. No MRI lesions in the temporal lobe or hippocampal formation c. No prior febrile convulsions d. Autonomic and psychic auras; high incidence of déjà vu as an aura FMTLE Associated with Hippocampal Sclerosis: 1. Genetics: a. Some families AD inheritance
Chapter 4. Partial Seizures
2. Hippocampal sclerosis may be caused by: a. Prolonged childhood convulsion b. Encephalitis c. Developmental or migrational defect d. Putative genetic component FMTLE Associated with Febrile Convulsions 1. Genetics: a. One French family-digenic inheritance 1) First to second decade of life onset of seizures 2) Benign course 3) No MRI or temporal lobe lesions b. ADTLE with FS 1) Young age at onset 2) Multiple febrile convulsions 3) No déjà vu, auditory or visual hallucination 4) No hippocampal sclerosis Febrile seizures with medial TLE 1. Genetics: a. Families may have many members with febrile convulsions and a few with TLE 2. Clinical features: a. Association in some patients between prolonged febrile convulsion and HF sclerosis HIMAL 1. Possible familial occurrence 2. Incomplete inversion of the hippocampus 3. Normal size and hippocampal MRI signal 4. Blurred internal structure TLE in the Spectrum of Partial Epilepsy Syndromes 1. Clinical features: a. Familial partial epilepsies: TLE is part of the seizure spectrum A. Specific Syndromes: 1. Familial partial epilepsy with variable foci (FPEVF) a. Onset first to third decade b. Heterogeneous seizure types c. No associated MRI defects or febrile convulsions 2. Genetics of FPEVF a. Possible linkage to 2q b. Two large Canadian families linkage to 22q 11–q12 B. Partial epilepsy with pericentral spikes (PEPS) 1. Clinical features: a. Benign b. Onset first to second decade c. Brazilian family d. Pericentral spikes on EEG e. No MRI or febrile convulsions 2. Genetics: a. Linkage to 4p 15 C. Miscellaneous genes putatively important for TLE: a. IL1B gene b. Subunit opioid gene
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c. Prodynorphin gene 1) Chromosome 20 d. 8q epilepsy e. FAME (familial adult myoclonic epilepsy) f. BAFME (Baltic familial myoclonic epilepsy) g. FCT (familial cortical tremor) h. Epileptic monocular nystagmus General features of TLE 1. May begin at infancy or in old age; most patients have their first seizure in late childhood or early adulthood 2. 75% of patients experience auras of simple partial seizures originating in the temporal lobe 3. Genetic forms: a. Familial b. Chromosome localization as noted above 4. Risk factors for TLE a. Head trauma b. Difficult birth (prolonged delivery, forceps, obstetric complications) c. Genetics d. Family history e. Neuronal migration defects 5. Auras are experienced either independently or as the first phase of a complex partial seizure 6. 50% of patients have unilateral or bilateral secondary generalized tonic; clonic or tonic-clonic seizures 7. Secondary generalization may cause a tonic drop attack; greater than 80% of GTCS are secondarily generalized from TLE Clinical features: 1. Prodrome; an awareness of an impending seizure days in advance. Prodromes consist of: a. Headache d. Personality change b. Irritability e. Depression c. Insomnia 2. Complex partial seizures are either: a. Initiated by an aura b. Start with impairment of consciousness
Auras
An aura: That portion of the CPS that occurs before consciousness is lost (if it is) and is remembered. The aura is an ictal event. General Features of Automatisms: 1. Involuntary motor activity occurring during the period of impaired consciousness 2. Patient is partially or totally amnestic for the behavior 3. May continue or begin in the post ictal period 4. May be a continuation of movements that occurred prior to the seizure (perservative) or may be a new (de novo) movement
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SECTION II. Epilepsy
5. Motor activity is usually fragmentary; rarely are these sequential coordinated movements 6. Automatisms vary from patient to patient, but are stereotyped for an individual patient 7. May occur with absence seizures and in the post ictal phase of a generalized tonic-clonic seizure 8. HF-amygdala complex; rarely meso orbital frontal lobe and ungulate gyrus are the initial site of origin of motor automatisms. Oral buccal automatisms most often originate from the amygdala frontal operculum. Patterns of Clinical Automatisms 1. Oro-buccal lingual: smacking of the lips, chewing, swallowing, choking, eating, spitting abnormal tongue movements and water drinking (amygdala; frontal operculum) 2. Gestural: repetitive movements of the hands and fingers; may be semi purposeful (drawing, playing cards) rubbing the nose (ipsilateral focus) 3. Sexual: masturbation, pelvic thrusting 4. Expressional: facial expressions of fear anxiety, confusion or anger 5. Motor: walking (poriomania), running (cursive); circling with arms raised 6. Speech: crying (dachrymistic), laughing (gelastic); repeating phrases; screaming The Sequence of Motor Automatisms 1. Arrest phenomena: a. Patient stops activity and maintains a posture for a few seconds 2. Autonomic phenomena a. Loss of facial expression associated with pallor 3. Onset of motor phenomena a. Motor automatisms originate most often in the amygdala and amygdala fugal pathways as well as pre-motor and supplementary motor cortex patterns from temporal lobe and frontal lobe Psychic symptoms: 1. Often preceded by alterations in consciousness a. Important in localization b. General rules: 1) Severe anxiety: anterior temporal lobe 2) Complex phenomena (neocortical) lateral temporal lobe 3) Fear, impending doom: medial temporal lobe 2. Complex cognitive emotional states (lateral temporal lobe; right side greater than the left) a. Dream state b. Detachment and strangeness c. Autoscopy: feeling as if you are watching the event d. Time distortion (usually too slow) e. Feelings of unreality f. Forced thinking (continued thinking of a specific thought or phrase) g. Blocking thought
3. Affective symptoms a. Ictal fear; poorly localized, may be associated with abdominal sensation, impending doom, an overwhelming quality (amygdala or medial HF) b. Sadness (common) c. Depression (common) d. Embarrassment (usually medial frontal lobe) e. Joy (rare) f. Ecstasy (rare) g. Crying (dachrymistic): often bilateral temporal lobe foci (mirror focus); may be ictal or post ictal h. Sexual feelings (orgasm right temporal hemisphere) i. Altered body sensation j. Gelastic (laughing): more common with hypothalamic lesions (particularly hamartomas); laughter without mirth, not elaborated correctly; patient may be fearful while laughing 4. Distortion of memory: a. Déjà vu: as if the experience had occurred before: 1) déjà-vu: visual experience 2) Entendu: auditory experience 3) Jamais-vu: prior experience or place is experienced as new or unfamiliar 4) Vivid “flashbacks” of past events 5) Special sensory symptoms 5. General features: a. Alterations of perception 1) Unusual clearness 2) Heightened sensitivity 3) Premature poorly formed hallucinations (primary visual and auditory receptive areas) 4) Complex hallucinations from association areas 6. Fear as a main feature of an epileptic seizure a. Localization of the primary epileptic zone: 1) Right temporal 3) Frontal 2) Bitemporal b. Behavior: 1) Sensation of fear 3) Coordinated behavior 2) Autonomic symptoms c. Neuroanatomical Networks Involved 1) Orbito frontal cortex 2) Anterior cingulate gyrus 3) Temporal limbic system a) Amygdala to the anterior cingulate gyrus d. Clinical features of a panic attack (psychiatry): 1) Sudden spontaneous onset (rarely a trigger) 2) Intense fear and discomfort 3) Impending doom thoughts of dread 4) Feelings of being trapped; losing control 5) Last for a few minutes 6) Full recognition and remembrance of the attack e. Fear as a manifestation of amygdala seizure: 1) Anticipatory anxiety 2) Expression of impending doom 3) Buccal automatism
Chapter 4. Partial Seizures
4) 5) 6) 7)
Autonomic disturbance Complex behavioral automatisms Early in the seizure a call for help; anxiety Incomplete recall for the event
Visceral Auras 1. Olfactory (uncus of the hippocampal gyrus); uncinate fits a. Unpleasant smells; burning rubber, garbage, fecal material, acid; rarely pleasant (usually an exaggeration of the pleasant quality) b. May be produced by stimulation of: 1) Amygdala 2) Olfactory bulb 3) Uncus 4) Posterior orbital frontal cortex c. Olfactory auras may be associated with: 1) Intellectual aura 2) Gustatory, visual and auditory auras 2. Taste (enterorhinal cortex of the temporal lobe) a. Unpleasant: blood, bitter, chemical, rotting, metallic b. Rare pleasant (usually a too sweet taste) 3. Abdominal aura: a. General characteristics: 1) Occurs in 20–60% of patients with TLE 2) Approximately 20% of patients with extra temporal epilepsy 3) Approximately 65% with mesial temporal lobe origin on 35% with neocortical origin 4) Occurs in extratemporal locations: a) 5% perirolandic b) 17–20% parieto occipital c) 3% frontal lobe 5) Occurs primarily from posterior insular cortex; frontal orbital areas connect to anterior insular cortex b. Specific simple sensations: 1) Epigastric rising sensation 2) Feeling of having to defecate 3) “flip flop” of the stomach 4) Automatism follow abdominal auras c. Associated symptoms with abdominal aura 1) Epigastric aura a) Ictal vomiting 2) Subjective fear 3) Oro-alimentary symptoms d. May evolve into clonic seizures 1) Occurs in 2/3 patients with frontal lesions e. Abdominal pain in TLE 1) Pain occurs in 5% of all abdominal auras 2) Pain occurs in 50% of all abdominal auras that originate from the frontal lobe 3) Painful abdominal auras may originate from parietal areas 4. Rare visceral auras: a. Burning, tingling, gnawing, choking, throat sensations
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b. Ictal hunger (right temporal lobe) c. Ictal thirst (amygdala to hypothalamus) d. Severe pain or unusual genital sensations e. Severe vomiting (right temporal focus) f. Goose bumps g. Coldness-shivering (left temporal lobe) h. Expectorations (left temporal lobe) 5. Cardiac and chest aura (anterior insular cortex) a. Heart racing or pounding b. Pain in the central chest (no cardiac radiations) c. Cardiac arrhythmias (atrial or ventricular) 6. Post ictal coughing and nose rubbing a. Ictal activation of central autonomic pathways b. Post ictal coughing 1) Reaction to increased respiratory secretions c. Postictal coughing > postictal nose rubbing d. Post Ictal Coughing 1) Earlier in onset than PIN rubbing 2) PIC just prior to ictal off set 3) PIC > temporal lobe than extra temporal focus 4) Right sided mesial temporal lateralization 5) Ipsilateral to moving hand (postictal nose rubbing) Visual Auras
1. 2. 3. 4. 5. 6.
Blurred vision Micropsia (objects too small) Macropsia (objects too large) Perceptual illusions: objects too far or too close Distorted objects Rare: clear visual hallucinations (evergreen tree in temporal field) 7. Kinesogenic illusions of movement (medial temporal gyrus) Auditory Auras
1. Sound or voices not clearly perceived 2. A1 auditory receiving area aura: clicking, roaring, wind blowing, rumbling sounds 3. Receptive aphasia (left sided areas 22 or 23) 4. Distorted or muffled sounds 5. Sounds too loud or too soft 6. Extremely rare: auditory hallucination (most often a psychiatric or drug withdrawal phenomenon) 7. Macropsia or micropsia Vestibular Auras
1. Non-specific dizziness or light-headedness. One of the most frequent TLE aura’s (probable superior temporal area or intraparietal gyrus) 2. Tornado seizures: severe vertigo, with patient spinning rapidly and falling to the ground (superior temporal lobe or intraparietal gyrus)
SECTION II. Epilepsy
164 Cephalic Auras
1. 2. 3. 4. 5.
Head too big or small Off of the body Ice pick (stabbing) headache (also occurs with migraine) Squeezing compression of the head Unusual position on the neck
Post Ictal Signs and Symptoms of CPS of Temporal Lobe Origin
1. 2. 3. 4. 5.
6. 7. 8. 9. 10.
11.
Gradual transition between the seizure and postictal state Automatisms may continue during post ictal period Deep sleep is unusual Severe fatigue that may last for hours (“drained”) Period of confusion and disorientation following the event (less than one-minute usually, but may last for 30 minutes) Moderate dull headache, occasional vomiting or nausea Post ictal thirst; (common); hunger is rare Postictal hyperhidrosis Aimless wandering (poriomania) Simple partial seizure from the temporal lobe (dizziness, abdominal sensations, déjà vu or jamais vu) last less than 60 seconds and has no postictal symptoms Postictal psychosis
Medial Temporal Lobe Localizing Features: 1. Uncinate auras (abnormal smells and tastes) 2. Impending doom 3. Automatisms (licking of lips, chewing, swallowing) 4. Arrest response (sudden freezing) 5. Searching head movements 6. Contralateral dystonia, body shifting 7. Cough or sigh 8. Amnesia (hippocampal formation) 9. Gustatory a. Nausea c. Borborygmi b. Butterflies Lateral Temporal Lobe Localizing Features: 1. Wernicke’s aphasia; speech arrest left side 2. Psychical auras (right temporal lobe > left) a. Jamais vu b. Déjà vu 1) Auditory experiences (entendu) c. Forced thinking (episodes from past life experience) d. Dreamy state e. Heightened sensations f. Feelings of pleasure or extreme pleasure g. Depression or euphoria h. Epileptic rage i. Detachment j. Unreality
Anterior Temporal Lobe Cortex 1. Panic attacks, anxiety 2. No precipitating cause (precedes the event) 3. Stereotyped 4. Associated with autonomic features: a. Sweating c. Pupillary dilatation b. Hyperventilation Medial temporal lobe syndrome 1. Hippocampal sclerosis: a. MRI findings: 1) Hippocampal atrophy 2) Increased T2 signal 3) Disrupted internal structure of the hippocampal formation 4) Increased size of ipsilateral temporal horn 5) Focal thickening of the fimbria b. Dual pathology: 1) Neuronal loss within the hippocampal formation (HF) 2) Extra hippocampal lesion: a) Migrational defects b) Scar c) Tumor d) Vascular malformation e) Porencephaly f) Hamartoma 3) Occurs in approximately 30% of patients with hippocampal sclerosis 4) 16% of hippocampal sclerosis patients have bilateral abnormalities on MRI in the hippocampal formation 5) Loss of cells primarily CA1 and CA3 in the HF c. Hippocampal sclerosis occurs without hippocampal formation atrophy in 5–10% of patients; normal volume of hippocampal formation d. Younger children less than 12 years with hippocampal formation atrophy 1) Dysplastic lesions and hamartomas more common than astrocytic tumors e. Clinical features of hippocampal sclerosis: 1) Early age at onset of seizures 2) Prolonged febrile convulsions important in etiology; seizure free interval after initial febrile convulsion 3) Material specific memory deficit 4) Executive and attention attributes are intact 5) Deficits in: a) Verbal comprehension b) Perceptual organization c) Verbal memory d) Some visual spatial abilities e) No generalized cognitive impairment f) Impairment of access to an array of cognitive functions rather than restricted pattern of memory loss
Chapter 4. Partial Seizures
6) 7) 8) 9) 10)
Postictal psychosis common Autonomic auras Automatisms (oro-buccal-pharyngeal) Ictal fear Limbic seizures occur in the late afternoon and early evening 2. Amygdala sclerosis: a. 10% evolve into medial temporal lobe seizures b. Amygdala and hippocampal formation involvement: 50% origin of ictal events in MTLE c. Pathology of amygdala sclerosis: 1) Microdysgenesias (microscopic variant of cortical dysphasia) 2) Vascular lesions 3) Cortical dysplasia 4) Abnormal glial cells (large hyperchromatic) 5) Hamartoma (abnormal clusters of neurons and neuroblast cells) 6) Tumor d. Clinical features: 1) Seizure onset later than that of hippocampal sclerosis 2) Amygdala sclerosis on the same side as hippocampal sclerosis in 50–70% of patients 3) More secondary generalization than hippocampal sclerosis 4) In general, same ictal manifestations and auras as those with hippocampal sclerosis 3. Endofolium Sclerosis: a. Neuron loss and gliosis confined to the end folium
Neocortical Temporal Lobe Epilepsy (NCTLE)
A. General features: 1. Older at onset of habitual seizures than medial temporal lobe epilepsy (MTLE) 2. Seizures are shorter than MTLE 3. No seizure free interval once it is initiated B. Clinical manifestations: a. Déjà vu b. Jaime vu c. Depersonalization d. Forced thinking e. Autoscopy f. Automatisms of the contralateral arm; bilateral upper extremity automatisms g. Heightened sensitivity h. Psychical i. Experiential j. Often normal MRI k. Vertigo or tinnitus l. Auditory hallucinations
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Seizure Onset
1. 2. 3. 4. 5.
Motionless stare Upper extremity automatisms (ipsilateral to seizure focus) Dystonic posture of contralateral arm Bilateral upper extremity automatisms Contralateral tonic or clonic activity of the face or extremities; never an early manifestation of seizure
General-Differential features between MTLE and NCTLE 1. MTLE: a. Fear b. Visceral sensations c. High frequency of bitemporal interictal epileptiform abnormality 2. NCTLE a. Psychical b. Experiential c. More frequently contralateral (from the seizure focus or bilateral automatisms than ipsilateral) d. Normal MRI e. Neocortical TLE; well lateralized interictal EEG
Epileptic Forced Thinking
1. Forced thinking definitions: a. Recurrent intrusive thoughts, crowding of thoughts 2. Differential diagnosis is temporal lobe vs frontal lobe origin Differential Diagnosis of Epileptic Forced Thinking: 1. Obsessive thoughts 2. Auditory hallucinations 3. Auditory perservations 4. Temporal lobe limbic illusions (new thoughts not previously experienced) Clinical features of frontal lobe forced thinking 1. Speech arrest a. Seizure of motor language areas (primarily Broca’s) b. Speech arrest or disturbance with intrusive thoughts (urge to shout) 3. Forced thoughts less stereotypic (whatever words or thoughts used by the patient at time of the seizure) 4. Variability of thought 5. Context dependency 6. Experiential imagery characteristic Clinical features of temporal lobe forced thinking 1. Depth electrode stimulation of the amygdala induces: a. Emotional immediacy b. Perceptually vivid features c. Emotional tone in response to remembering 2. Temporal lobe forced thinking
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a. Out of context to environment prior to the seizure (a need to think of letters that begin with “L”; need to think of numbers) 2. Obscene thoughts: a. Patient feels a need to resist or negate the irrational thought b. Obsessive-compulsive status epilepticus 1) Temporal limbic focus c. Temporal limbic seizure focus may spread: 1) Through the uncinate funiculus and cingulum to the frontal lobe 2) Connects the frontal anterodorsal convexities to the temporal lobe
3.
Unusual Manifestations and Localizing Value of Specific Clinical Presentations of CPS
Cardiac Arrhythmia (Anterior Insular Cortex)
1. 2. 3. 4. 5. 6. 7.
Supraventricular tachycardia Sinus tachycardia (L temporal lobe insular cortex) Sinus bradycardia (L temporal lobe/ insular cortex) Sinus arrest AV block Rarely accompanying chest pain SUDEP (sudden unexplained death in epileptic patients)
Aphasia caused by seizure in the fusiform gyrus 1. Fusiform gyrus a. Basal temporal language area; primarily like Wernicke’s; unable to name categories of objects 2. Speech disorders in TLE: a. Paroxysmal dysphasia (Wernicke’s area) b. Speech automatism 3. Paroxysmal dysphasia 4. Wernicke’s area (left side); receptive aphasia 5. Speech automatism (either side) 6. Functional link between left fusiform gyrus and Wernicke’s area Reproductive Dysfunction 1. Left TLE a. Polycystic ovaries 2. Right TLE a. Hypothalamic amenorrhea 3. Decreased pulsatile LH (Luteinizing hormone); locus can be either side Differential Diagnosis of TLE: 1. Facial blankness and staring may resemble absence seizures 2. CPS vs affective psychosis: TLE associated with: a. Geshwind’s Syndrome (CPS personality traits) 1) Schizoid (bilateral temporal lobe involvement) 2) Hyperreligious (three religious conversions)
4.
5.
6.
7.
3) Hypergraphia (lists of every seizure event) 4) Viscous (unable to terminate appropriate question or a personal interaction) b. Rarely TLE manifests: 1) Hallucinations 2) Agitation, anger, fear, irritability and confusion 3) Usually these are of short duration, stereotyped and intermittent 4) Associated with speech arrest, impaired consciousness and autonomic phenomena 5) Patients have insight that symptoms occur incongruously TLE versus episodic dyscontrol syndrome: a. Episodic dyscontrol syndrome: 1) Uncontrolled rage 2) Occurs with provocations 3) Out of character for the patient 4) May have central nervous system deficits 5) May have documented seizures 6) May lose minutes to hours 7) Followed by fatigue and confusions 8) Often amnesia for the event 9) Violence against individuals is common b. CPS: 1) Personally directed violence (very rare) 2) Stereotyped 3) Associated signs and symptoms of seizure activity Migraine with abdominal pain and nausea vs TLE: a. In children with migraine; the abdominal symptoms may be associated with headaches b. TLE, the abdominal auras are followed by impairment of consciousness or other epileptic phenomena TLE versus cardiac arrhythmia: a. Anterior insular cortex CPS may cause chest pain and cardiac arrhythmia that may be difficult to differentiate from cardiac disease b. TLE: 1) Attacks are not associated with usual cardiac precipitants 2) Associated with other epileptic phenomena 3) Impairment of consciousness 4) Post ictal phenomena (fatigue, thirst, headaches) 5) Chest pain not in a cardiac distribution TLE vs syncope (vago vagal) a. Clinical characteristics of vago vagal syncope: 1) Characteristic pallor 2) Precipitating event (for vago vagal; specific sight or stress) 3) Slow pulse (less than 40 beats per minute) 4) Less than 30 seconds in duration; usually lasts less than 10 seconds 5) No confusion or other post event phenomena 6) May have few myoclonic jerks TLE vs vaso depressor syncope: a. Vaso depressor syncope clinical characteristics:
Chapter 4. Partial Seizures
1) Precipitating event (prolonged bed rest; hypertensive medications, upright posture, prolonged parade rest on a hot day) 2) Rapid pulse 3) No confusion 4) May have occasional myoclonic jerks
Special Aspects of TLE
1. Reproductive Dysfunction: a. 50% of women with TLE 1) Have sexual dysfunction 2) Hormonal abnormalities 3) 14–20% have amenorrhea 4) Fertility reduced by 30% b. Men with TLE 1) Approximately 50–70% have sexual dysfunction (lack of libido) 2) Rarely satyriasis occurs c. Associated reproductive conditions reported in TLE 1) Hypogonadotrophic and hypergonadotropic hypogonadism 2) Functional hyperprolactinemia 3) Polycystic ovary disease 4) Anovulatory cycles 2. Prolactin surge after medial temporal lobe seizure: a. Levels peak approximately 20 minutes after the seizure b. Often elevated, but frequently no baseline measurements are available to make this determination accurately c. Amygdala has a direct connection to the VM (ventromedial) nucleus of the hypothalamus 1) Post ictal elevation of hypothalamic releasing and luteining hormone have been noted 2) Post ictal psychosis with CPS 3) Post ictal bradycardia and asystole after CPS 4) Post ictal aphasia (basal temporal area) Interictal personality traits of TLE 1. Diagnostic specificity and validity of specific personality traits in TLE is controversial a. Existence of these traits in patients with other seizure disorders b. Prevalence is variable c. Common in general population 2. Noted interictal traits: a. Catastrophic overemphasis (left temporal lobe) b. Ideational traits (left temporal lobe) c. Overly emotional (right temporal lobe) d. Denial (right temporal lobe) e. Inclusiveness f. Hypersexuality (rare); usually hyposexuality g. Dependence
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h. Obsessive/compulsive behavior i. Hypergraphic j. Hyperreligious k. Oppressiveness l. Hypermorality m. Circumstantiality n. Philosophical interests 3. TLE personality traits and psychopathology: a. Most adult TLE patients are well adjusted and functional b. Personality traits noted primarily with bilateral temporal lobe involvement 4. Dual pathology causative of the personality disorder (ipsi or contralaterally) a. Medial temporal sclerosis with migrational disorder b. Mirror foci (frequent seizures; interictal spiking) c. Trauma (bilateral temporal lobe involvement) d. Surgery on one temporal lobe; remaining temporal lobe dysfunctional e. X-ray (particularly for pituitary tumors) f. Viral involvement (Herpes Simplex encephalitis) 5. Klüver–Bucy Syndrome: a. Hyperorality: all objects are placed in the mouth b. Hypermetamorphopsia: all objects are examined with the same degree of interest and intensity c. Short term memory deficit d. Hypersexuality (attempted intercourse with same sex or inanimate objects) e. Sham rage: trivial provoking events; anger reaches maximum intensity instantly; patient returns to baseline immediately Psychopathology 1. Patients with seizure disorders have a higher incidence of psychiatric disorders than a control population 2. Psychosis resembling paranoid schizophrenia reported in TLE patients a. Better preservation of affect in TLE vs schizophrenia patients b. Less personal isolation than schizophrenic patients 3. Temporal lobectomy may cause: a. New onset of psychosis b. Improvement of instability and aggressiveness 4. Aggressive violent behavior in TLE: a. Non-directed b. Short lived c. Fragmentary d. May be a stereotyped manifestation of some temporal lobe seizures 5. Predictive variables of interictal psychosis in epilepsy a. Earlier age at onset of epilepsy b. Family history of psychosis c. Borderline intelligence d. CPS and GTCS are seizure type
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Amnesia in TLE patients 1. Short term memory loss (dysfunction of medial temporal lobe structures) 2. Defect in confrontational naming 3. Decreased word fluency Temporal Lobe Pathology
Glioma, arteriovenous malformations, cavernous hemangiomas, hematomas or traumatic scars all cause complex partial seizures. The advent of MRI scanning with associated volumetry of medial temporal lobe structures and the hippocampal formation as well as PET, SPECT, and MRI spectroscopy have provided a much better understanding of congenital abnormalities that underlie these conditions. There are a variety of migrational disorders that can be diagnosed by MRI scanning. These are caused by abnormal neuronal migrations of germinal plate neurons from the ventricle to the cortex and disrupted gyration and apoptosis of the neurons that have migrated. Nests of subependymal neurons are noted in the frontal, parietal and temporal white matter, in periventricular heterotopia. This may be seen unilaterally or bilaterally. The walls of the ventricles demonstrate nodules of subependymal neurons that have not migrated. Radial glial fibers from the ventricles to the cortex may be seen in tuberous sclerosis. Migration of these subependymal cells occurs in the 20–22nd week of gestations. A double cortex or thickened band heterotopia may be seen in those patients who have suffered failure of apoptosis and no remodeling of the cortex. The extremes of this condition are schizencephaly and lissencephaly. Failure of architectural remodeling may be seen in focal cortical dysplasia in which the orderly laminar structure of the cortex is disrupted. These focal dysplasias may be further characterized as a laminar heterotopia, simplified gyral pattern and focal microgyri. There are genetic syndromes with X-linked heterotopias and double cortex as well as sporadic genetic forms of abnormal migrational patterns. Agyria, polymicrogyria, macrogyria, and sublobar dysplasias have all been seen with complex partial seizures of temporal lobe origin. Focal cortical dysplasia may demonstrate abnormal giant neurons and balloon cells in a addition to the dysmyelination. The syndrome of medial temporal sclerosis is suspected if the patient has suffered prolonged febrile convulsions as a child. Medial temporal sclerosis may also be seen in conjunction with migrational defects a situation known as dual pathology. Bilateral anatomic abnormalities with a unilateral temporal lobe seizure focus have been seen in 20–40% of patients with medial temporal lobe sclerosis. Mesial temporal sclerosis may extend throughout the temporal lobe and involves both the cortex and white matter. The temporal pole is frequently atrophic ipsilateral to the side of seizure onset in seizure patients.
Bilateral parasagittal, parieto-occipital and episylvian, polymicrogyria as well as hemi megacephaly are other patterns of cortical dysplasia. These migrational defects are frequently associated with contralateral hemiasymmetry of the arms, face and leg. If the face is obviously involved, the process is termed the Parry–Romberg Syndrome. If the seizure disorder is associated with an intrauterine stroke of a vascular territory, severe trauma a porencephalic cyst or arteriovenous malformation, the contralateral hemiatrophy is severe and obvious. Limbic encephalitis not associated with neoplasm is a cause of temporal lobe seizures. Perivascular lymphocytic infiltration is noted. The CSF demonstrates a mild pleocytosis. IgG is demonstrated in 20% of patients and oligoclonal bands in 50%. The differential diagnosis includes Rasmussen’s encephalitis, Hashimoto’s disease, SLE and paraneoplastic limbic encephalitis. Perivascular clustering and cortical neuronal clustering (micro dyseneias) is associated with mossy fiber sprouting into the dentate supragranular layer. Congenital porencephaly may absorb concordant with hippocampal sclerosis. Insular Cortex Seizures
1. General features: a. Hippocampal seizure foci spread to the insular cortex; general afferents from and efferents to: 1) Amygdala 2) Enterorhinal cortex 3) Hippocampus 4) Cingulate cortex 5) Orbito frontal cortex 2. Clinical symptoms: a. Respiratory 1) Modulates the amplitude and frequency of respiratory movements 2) Chest fullness is experienced b. Viscerosomatic 1) Chest constriction ascending to the anterior cervical region; associated with nausea 2) Abdominal constriction and heaviness 3) Intense distressing abdominal pain 4) Throat constriction c. Somatosensory (opposite the side of the focus) 1) Ascending retrosternal sensation of heat 2) Brisk nonpainful heat sensation of the trunk and both upper and lower limbs d. Oroalimentary manifestations 1) Chewing and swallowing 2) Mastication
Division B: Fontal Lobe Seizures
General Clinical Characteristics: Fontal lobe seizures begin abruptly, are often brief, are associated with minimal post ictal confusion, come out of sleep
Chapter 4. Partial Seizures
and may occur in clusters. The clinical features depend on the areas of the frontal lobe that are affected. Seminal features are motor, automatisms, and vocalization. Frontal Lobe Seizures: 1. General Characteristics 2. Genetics: ADNFLE; autosomal dominant nocturnal frontal lobe epilepsy (chromosome 20) 3. Clinical features of localization related frontal lobe seizure: a. Prerolandic cortex (area 6) 1) Speech arrest or impairment 2) Tonic-clonic movement of contralateral face 3) Repetitive swallowing 4) Contralateral flaccidity without movement (suppressor strip of Hines) b. MI (area 4) 1) Jacksonian march; mouth and thumb are affected early; motor neurons here have a wide area of representation and low threshold; often the thumb and corner of the mouth initiate the march 2) Rapid secondary generalization particularly if the focus is in MI or SI 3) Occur during sleep 4) May occur in clusters 5) Inferior second frontal convolution (Broca’s area) cause speech arrest, stammering or stuttering with the seizure 6) Seizures often are brief less than 75 seconds 7) No prolonged ictal state 8) Movements occur with progression of the seizure 9) Bilateral purposeful and non-purposeful movements (motor automatism-bicycle pedaling) 10) High monthly seizure rate 11) Motor arrest 4. Supplementary motor area seizure (SMA): a. SMA area eight of the frontal cortex b. Brief c. May cluster at night d. Preservation of consciousness e. Speech arrest f. Vocalization g. Fencing posture: extended contralateral arm; flexed ipsilateral arm; contraversive head and eye movement h. Versive movement away from the side of ictal onset i. Sudden paratonic posturing of one or more extremities 5. Cingulate cortex: a. Aura; fear and panic b. Emotional outbursts c. Increased sympathetic tone d. Complex motor, gestural, or automatic manifestation with change of mood and affect 6. Orbitofrontal cortex: a. No aura until the seizure spreads into the cingulate or insular cortex
7.
8.
9.
10.
11.
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b. After the spread: 1) Autonomic signs 2) Olfactory hallucinations and illusions 3) Oroalimentary auras 4) Can have persistent vocalization 5) Violent dramatic automatisms 6) Motor and gestural automatisms Dorsolateral prefrontal cortex: a. Tonic posturing of head and upper extremities b. Contraversive head and eye movements c. Clonic facial contractions (rare) d. Speech arrest Frontal eye field (FEF areas 8, 10): a. Head and eye turned side away from the lesion b. Horizontal jerk nystagmus to the contralateral side c. Often impaired consciousness d. Pupillary dilatation of the contralateral eye (early at onset) Paracentral lobule: a. Tonic movement of the ipsilateral foot b. Contralateral leg involvement Opercular areas: a. Ipsilateral clonic facial movements b. Mastication, salivation, swallowing Frontopolar cortex: a. Vocalization b. Hyperventilation c. Truncal flexion d. Complex gesture automatisms e. Sudden awakening after seizure f. Bimanual/bipedal automatisms g. Forced thinking h. Axial clonic jerks (that may cause falling)
Extra Frontal Seizure: 1. Behavioral arrests or automatisms typically precede head deviation Hyperkinetic Frontal Lobe Seizures: 1. Location of seizure focus: a. Orbitofrontal cortex b. Dorsolateral prefrontal cortex c. Frontomesial cortex 2. Clinical features: a. Complex bimanual and bipedal movements b. Kicking, thrashing, clapping, rubbing c. Sexual automatisms d. Autonomic hyperactivity (piloerection, pupillary dilatation, micturition) e. Preserved consciousness f. Usually positive EEG correlate g. Status epilepticus Division C: Parietal Lobe Seizures
Simple partial sensory seizures are usually of parietal lobe origin and often relate to lesions in specific components of the
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sensory homunculus. Abnormal tongue sensations (coldness, stiffness, numbness) are often bilateral. This may also occur with thalamic lesions (VPM). A patient’s awareness of a sensory deficit in 1/2 of the tongue suggests an intraparenchymal brainstem lesion. Fifth nerve lesions from collagen vascular disease such as scleroderma and Sjögren’s disease are usually perceived as numbness. Commonly cervical plexus (posterior roots of C2, C3 – the preauricular nerve) may also cause tongue (unilateral) numbness. Bilateral facial paresthesias and numbness may also emanate from SI. Other positive sensory phenomena emanating from the parietal lobe are the feeling that a body part is being moved or the patient has a desire to move the body part. Nondominant parietal sensory sensations from seizure activity manifest the feeling that a body part is absent. Inferior and lateral parietal lobe seizures may cause feelings of nausea, choking or sinking. Inferior parietal lobe seizures may cause a feeling of the body being tilted or severe disorientation in space or vertigo (intraparietal sulcus). Seizures from this area may also cause epileptic skew deviation (Brodmann’s 19/37/39 and 40) Bilateral heat sensations arising from the feet and sweeping upwards over the body and may emanate from SII (that is at the base of SI). SII seizures may also be associated with poorly localized cold and pain. These sensations may be bilateral, contralateral or ipsilateral to the seizure focus. Dominant parietal lobe seizure activity may cause a receptive or conduction aphasia. Painful contralateral parietal lobe auras have been described. Division D: Febrile Convulsion
Definition: A seizure occurring in infancy and childhood that occurs between three months and five years of age in association with fever, but without evidence of intracranial infection or defined cause. General features: 1. Just one febrile convulsion in the majority of children less than three years of age (18–22 months; boys > girls) 2. Usually generalized clonic-tonic; may be of any type 3. Low incidence of acquired motor or intellectual abnormality following a febrile seizure; low mortality rate 4. Recurrences: a. Approximately 1/3 of children have recurrence; 12– 15% of these children have further recurrences b. Risk factors for a recurrence: 1) Age of onset of first febrile seizure less than 13 months of age 2 : 3 chance of developing recurrence 2) 14–22 months of age, 1 : 2 chance of recurrence 3) Greater than 32 months, 1.5 risk 4) 75% of recurrences within one year; 90% within two years 5. Risk of developing epilepsy after febrile seizure four times the control population 6. Risk for developing epilepsy after a febrile convulsion:
a. b. c. d.
Seizure duration greater than 15 minutes Greater than one seizure in 24 hours Focal features of the seizure Prior neurological deficit before febrile convulsion. Increased risk of epilepsy by age seven is 3x control population e. Not established that children with recurrent febrile seizure have increased risk of epilepsy f. Increased risk of epilepsy if febrile seizures began in infants of 6 months, 5.7% vs 1.5% after the first year g. Family history of febrile convulsions not established as a risk factor for development of epilepsy 7. Genetics: GTCS + febrile convulsions a. Chromosome – gene
Chapter 5 Status Epilepticus Major Motor Status Epilepticus
1. General features: a. 40–80/100,000 patients b. Mortality of 22% c. Occurs in 14% of patients after control of GCTS has been established 2. Repetitive tonic-clonic movements or components that last for seconds to minutes 3. Consciousness is not regained within three minutes prior to the onset of a new seizure 4. Associated features: a. Autonomic changes: 1) Increased heart rate, greater than 120 beats/minute 2) Pupillary changes (dilated) 3) Hyperhidrosis 4) Temperature to 103 degrees Fahrenheit (rarely > 104◦ F) 5. Rare sequelae: a. Cardiac arrest b. Neurogenic pulmonary edema c. Duodenal ulcer (first segment of the duodenum) 6. Serum evaluation: a. Severe acidosis: pH 7.1–7.2 in the serum b. Hyperkalemia > 5 mEq/dl 7. CSF evaluation: a. Up to 100 neutrophils/mm3 b. Acidosis (pH of 6.8) Differential Diagnosis of Adult Major Motor Status Epilepticus
1. Non-compliance with medication 2. Frontal lobe brain tumor
Chapter 5. Status Epilepticus
3. Metabolic abnormalities from organ failure or hypoglycemia 4. Illicit drugs (cocaine, amphetamines) 5. Vascular malformation or infarction 6. Infectious disease: a. Opportunistic organisms (HIV associated) b. Herpes simplex encephalitis c. Meningitis 7. Remote cerebral scar 8. Alcohol related (withdrawal)
Psychomotor or Complex Partial Seizure (temporal lobe) Status Epilepticus
Clinical features: 1. Confused dazed appearance 2. Patient partially responsive to verbal commands 3. De novo or perservative automatisms 4. Myoclonic jerks and eye twitches (intermittent) 5. Patient is ambulatory 6. May last for hours 7. Fugue state: a. Prolonged temporal lobe status epilepticus b. Patient able to perform activities of daily living or more complex tasks such as driving c. Sudden recovery d. Amnestic for the event e. Usually less than 30 minutes; may last for hours
Differential Diagnosis of Adult Complex Partial Status Epilepticus of Temporal Lobe Origin
1. Non-compliance with mediations in a temporal lobe seizure patient 2. Astrocytic tumors of the temporal lobe 3. Medial temporal lobe sclerosis 4. Vascular malformation 5. Severe head trauma 6. Hematoma 7. Migrational disorders: chromosomally linked and sporadic
Focal Motor Statis Epilepticus in an Adult
Differential diagnosis: 1. Stroke or vascular insult (Menshikoff’s syndrome) 2. Arteriovenous malformation 3. Cavernous hemangioma (that has recently bled) 4. Rasmussen’s encephalitis (children and adolescents most often affected) 5. Mitochondrial encephalomyopathy (children and adolescents) 6. Opportunistic infection in a patient with HIV
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Status Epilepticus of the Occipital Cortex (status epilepticus amauroticus)
1. Cortical blindness 2. Unilateral nystagmus
Epilepsia Partialis Continua (EPC)
1. General features: a. Spontaneous focal jerking of a body part b. Duration: days, months, or years c. Aggravated by: 1) Movement 2) Sensory stimuli d. May occur in isolation e. 40% of patients with EPC 1) Cognitive or neurologic decline 2. EPC in children: a. Rasmussen’s encephalitis b. Migrational disorder c. mt-DNA disorders d. Autoantibodies against GluR3 and munc-18 3. EPC in adults: a. Stroke or vascular insult (Menshikoff’s Syndrome) b. Arteriovenous malformation c. Cavernous hemangioma d. Brain tumor (meningioma) e. Mitochondrial encephalomyelopathy (most often children or in adolescents) f. Kuf’s disease late onset form) 1) Type A progressive myoclonic epilepsy 2) Type B: a) Dementia b) Behavior disorder c) Facial dyskinesia d) Absence of generalized epileptiform discharges
Non-Convulsive Status Epilepticus (NCSE)
1. Types a. Generalized NCSE b. Partial NCSE c. Diagnosed by the ictal EEG 2. Generalized NCSE (absence status; “petit mal status”) a. Definition: Multiple seizures or continuous seizure activity on EEG with non-convulsive clinical correlate b. Fluctuating confusion of varying intensity c. Mirror-facial myoclonus d. Cognitive and behavior change e. 50% of patients demonstrate bilateral myoclonus during the ictus f. EEG: symmetric ictal activity g. Precipitating factors of absence status (nonconvulsive status epilepticus) 1) Carbamazepine
SECTION II. Epilepsy
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2) Hyperventilation 3) Inadequate drug levels 4) Infections 5) Noncompliance with medication 6) Benzodiazepine withdrawal 7) Hypoparathyroidism 8) Menses 9) Generalized convulsions 10) Head trauma 11) Alcohol 12) Recent surgery 13) Sleep deprivation 14) Emotional upset 15) Renal failure 16) Pregnancy 17) Methohexital h. Occurs in 8% of comatose patients 3. Partial NCSE: a. Various non-convulsive symptoms with or without confusion b. Continuous or recurrent focal epileptiform EEG pattern 4. Parietal NCSE: a. Symptoms 1) Somatosensory 5) Psychic 2) Visual 6) Cognitive 3) Auditory 7) Affective 4) Vegetative b. No loss of consciousness 5. NCSE of frontal lobe origin a. Prolonged periods of continuous confusion without visible ictal signs b. May have focal lesions in the frontal lobe c. May occur in the middle aged or elderly d. Absence status may occur without overt confusion
Flagrant major motor seizure patterns are the characteristic clinical symptom complex, but any form of seizure may be simulated. Approximately 40–60% of patients with pseudo seizures have documented real seizures. The personality traits and psychopathology noted with complex partial seizures are frequently noted.
Differential Diagnosis of Absence Status
Epileptic Seizure May Progress into Non-Epileptic Conversion Seizures
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Prolonged post ictal encephalopathy Depression Acute or interictal psychosis Factitious disorders Medication overdose Psychotropic drug withdrawal Toxic metabolic encephalopathy Amnesia and automatisms syndrome (from TLE) Transient global amnesia Transient unresponsiveness in the elderly
Patterns of Involvement of Facial Muscles during Epileptic and Non-Epileptic Events
1. Eyes are wide open in greater than 90% of patients during the tonic phase of tonic-clonic seizures 2. Eye closure in any form is uncommon during the ictal phase of an epileptic seizure with motor manifestations 3. Psychogenic seizure have sustained eye closure with active opposition to opening 4. Mouth is open during the tonic phase of a generalized seizure; injury to the tongue and side of the mouth is common (usually side of the tongue is bitten) 5. During seizure: eyes may have upward gaze deviation; empty stare, pupillary dilatation and absence of the corneal reflex 6. Rapid forced blinking with no other facial movementfocus is occipital lobe in origin 7. Focal seizure with tonic contraction of corner of the mouth or zygomaticus muscles (cheek) M1 of the frontal lobe 8. Rhythmic forced contraction of the face occurs with seizures 9. Tongue biting (side of the tongue) contralateral to seizure focus; occurs in the clonic phase of GTCS 10. Cheek biting occurs during automatisms
1. Common for epileptic seizures to become functionally elaborated into a conversion seizure; possibly 30–60% of true seizures have pseudo seizures 2. Precipitating factors: a. Physical and sexual abuse b. Life stressors c. Disability
Features Associated with Pseudoseizures
Chapter 6 Pseudoseizure One of the great diagnostic difficulties of complex partial seizures of temporal or frontal lobe origin is pseudo seizures.
1. 2. 3. 4. 5.
Absence of usual provoking event Abnormal distribution and pattern of movement Pelvic thrusting Thrashing of the arms Forced eye closure that is maintained during examinations
Chapter 7. Genetic Aspects of Seizures
6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Absence of post ictal phenomena Preictal pseudo sleep Gradual onset Induced by suggestion Crying Opisthotonus Asynchronous Emotional triggers Associated with psychiatric diagnosis Side to side head movements
Chapter 7 Genetic Aspects of Seizures
1. Increase in the prevalence of epilepsy in families with epilepsy a. 3–8% in idiopathic epilepsy b. 0.5–15% in symptomatic epilepsy c. Rate in the control population is 0.5% 2. Seizures in close family members a. 3.5 to 29% 3. Twin studies: a. Concordance rates 11% with acquired brain lesions; 70% in those without lesions b. Dizygotic twins: 1) Concordance rate of 3–10% 4. Pedigree analysis: a. Mendelian pattern of metabolic disease with seizures: AR b. Genetic causes of seizures: 1) Absence epilepsy: AD 2) Generalized spike and wave: AD 3) Febrile convulsion: AD 5. Mosaicism a. Presence of more than one distinct cell line in a single individual b. Mutations arise post fertilization c. Somatic mosaicism important in: 1) AD disorders 2) Sex-linked disorders 3) Survival of lethal phenotypes 4) Postzygotic alterations 5) DCX gene on Xq22
X-Linked Metabolic Disorders with Seizures
1. Pyruvate dehydrogenase deficiency 2. Glycerol kinase deficiency 3. OTC (ornithine transcarbamylase deficiency)
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Chromosomally Determined Epilepsies
1. Generalized epilepsy: benign familial neonatal convulsions: a. Genetics: 1) Chromosomes 20q, (EBN-1, KCNQ 2 genes) 2) Code for voltage gated K+ channel 3) Some families map to: a) Chromosome 8q (EBN-2, KCNQ3 gene) (1) Codes for K+ channel gene b. Clinical features: 1) Brief multifocal convulsions 2) Onset first week of life 3) Resolves spontaneously within six weeks 4) Some have febrile convulsions in childhood 5) 10–15% develop epilepsy in adult life 6) Normal neurologic exam 7) Positive family history for febrile convulsions or neonatal seizures 2. Juvenile myoclonic epilepsy (JME) a. Onset in adolescence or early teenage years b. Male equals female incidence c. Interictal generalized bursts of 3.5–6 Hz poly spike and wave on EEG d. Genetics: 1) AD 2) AR 3) Multifactorial 4) Most families have a chromosome 6q defect 5) Some families have a chromosome 15q defect e. Ach receptor (alpha 7 subunit dysfunction) f. Myoclonus on awakening; associated with GCTS and absence seizures 3. Mental retardation epilepsy syndrome, p38 a. X chromosome (TM45F2 gene) b. Generalized seizures c. No regression in mentation or milestones after seizure onset d. Macrocephaly 4. Bilateral periventricular nodular heterotopia in boys with mental retardation and syndactyly a. Clinical features: 5. Idiopathic generalized seizures: a. Chromosome 8 q (EPN2) gene locus b. Also associated with same locus (adjacent to BFNC) benign frontal nocturnal convulsion 1) Febrile convulsions 2) JME 3) Childhood absence epilepsy 4) Asymptomatic generalized spike waves EEG activity c. Idiopathic generalized epilepsy (IGE) 1) Specifically in occurring with JME a) Chromosome 15q (muscarinic Ach receptor alpha 7 subunit gene)
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2) ADNFLE locus (autosomal dominant frontal lobe epilepsy) a) Ach receptor alpha 4 subunit gene b) Chromosome 20q c) Putative IGE locus 6. Progressive Myoclonic Epilepsy (PME) a. Unverricht–Lundberg Disease 1) Baltic myoclonus 2) Major cause of PME in North America 3) Genetics: a) AR b) Chromosome 21 q c) EPM1 gene d) Cysteine-proteinase inhibitor (cystatin B gene) is coded e) Inactivates proteases that leak out of lysosomes f) Dodecanes expansions of the gene b. Point mutation in 14% of patients c. Expansion of a dodecane nucleotide repeat: 1) Normally 2–3 copies 2) Symptomatic patients >60, copies 3) Expansion is 70 nucleotides upstream of a transcription initiation factor (5 flanking promotor) 4) results in decreased RNA for the cysteineproteinase inhibitor 5) Paternally based (repeats more unstable during spermatogenesis) d. Clinical features: 1) Onset between 6–15 years of age; less frequent with age 2) Progressive dementia 3) Ataxia 4) Intention tremor 5) Stimulus sensitive myoclonus 6) Photosensitivity e. Differential Diagnosis of Photosensitivity in Epilepsy 1) Unverricht–Lundborg and Lafora body disease 2) Neuronal ceroid lipofuscinoses 3) MERRF - 4) Sialidosis (cherry red spot epilepsy ±) with occipital lobe seizures Ramsey Hunt Syndrome
1. A form of PME 2. High incidence in Mediterranean region 3. Genetics: a. Possibly mitochondrial b. EPM1 gene Mitochondrial Defects (Seizures and Myoclonus)
1. MERRF 2. Leigh’s disease
3. NARP 4. MNGIE 5. Double mutation (A8296G and Q8363A) a. Transfer RNA for Lys b. VIIIth nerve; cardiomyopathy; myoclonus seizures Progressive Myoclonic Epilepsy of the Lafora Type
1. Genetics: a. AR (consanguinity) b. Chromosome 6q 24 (Lafora) c. Encodes for tyrosine phosphatase 2. Polyglucosan storage disorder 3. Clinical features: a. Onset in late childhood or adolescence b. Myoclonus c. Seizures d. Rapidly progressive dementia Progressive Epilepsy with Mental Retardation
1. Genetics: AR: chromosome 8q 2. “Northern Epilepsy” (Northern Finland) 3. Clinical features: a. Age at onset 5–10 years of age b. Early normal development c. GTCS until adolescence d. Cognitive decline starts later and seizures abate
Genetic Partial Epilepsies
1. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) a. Genetics chromosome 20q 13.2–13.3 alpha 4 subunit (CHRNII) 1) Gene for the RNA nicotinc Ach receptor alpha 4 subunit 2) May be allelic to EBN 1 gene b. Childhood onset: first two decades of life c. Clinical features: 1) Seizures occur during light sleep 2) May occur during daytime nap 3) Occur in clusters of up to 20; typically last 30–40 seconds 4) Interictal EEG is usually normal 5) Gasping; groaning, tonic stiffening, restless, agitation during seizure, changes of positions, vocalizations 2. Ring Chromosome 20 Epilepsy a. Genetics: MCR3 gene on chromosome 20 b. Clinical features: 1) Subtle nocturnal seizures
Chapter 7. Genetic Aspects of Seizures
2) Semiologic variability of seizure pattern: a) NCSE c) Simple and CPS b) GTCS c. Refractory to CBZ 3. Benign centrotemporal (Rolandic) and benign occipital epilepsy a. Genetics: AD: gene and locus not identified b. Possible phenotype variants of the same disease c. Clinical features: 1) Onset 4–10 years of age 2) Seizures stop at age 12–14 d. Possible chromosome micro-deletions; possible chromosome deletions e. Ach R subunit deficits f. Chromosomes: Chromosome 1 (B-2 subunit) coding for B-2 subunit of Ach receptor Chromosome 8 (B3 subunit) coding for B3 subunit of Ach receptor Chromosome 15 (a3, a7, B4 subunit) Chromosome 15q (susceptibility locus) 4. Familial temporal lobe epilepsy (FTLE) a. Genetics: AD 1) Lateral temporal variant a) Partial epilepsy with auditory features (ADTLEAF) b) Chromosome 10 2) Medial temporal variant a) Families linked to chromosome 7 b) Possible reduction of GABA-A subunit
Genetic Syndromes with Epilepsy (Chromosomal)
A. Metabolic 1. Juvenile ceroid lipofuscinosis a. Genetics: AR; chromosomes 16p (infantile and juvenile onset and adult onset patients) b. Over production of autofluorescent lipopigments (ceroid and lipofusion) within the brain, retina and visceral organs c. Clinical features: 1) Onset 4–7 years of age 2) Ocular findings: a) Retinal atrophy b) Optic atrophy c) Granular discoloration of the macula d) Blindness 3) Dementia a) Associated delusions and hallucinations 4) Dysarthria and rigidity develop over time 5) Myoclonic epilepsy begins several years after onset 6) Death within 15 years of onset
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7) Skin biopsy: “Fingerprint bodies” within cytoplasm of epithelial cells 2. Sialidosis juvenile form (Type III) a. Genetics: chromosome 10q b. Deficiency of alpha neuraminidase (sialidoses) c. Clinical features: 1) Type I: congenital; congestive heart failure 2) Type II: infantile form with ataxia mental retardation, myoclonus and seizures 3) Type III: (cherry red spot myoclonus) a) Cherry red spot in the retina (absence of ganglion cells) b) Myoclonus c) Seizures d) Onset is late childhood e) Urine contains oligosaccharides f) Enzyme deficiency can be identified in cultured fibroblasts
Angelman Syndrome
1. Genetics: a. Maternally imprinted micro deletion in chromosome 15q 11–12 1) Non-deleted patients ( 50% of patients (often proximal muscles) B. Laboratory evaluation: 1. CK may be up to 10x normal 2. EMG: a. Positive sharp waves b. Reduced interference pattern c. No persistent MUAP d. Motor NCV are normal SMA IV 1. Onset after age 20; mean onset mid 30’s 2. Slowly progressive 3. Proximal limb weakness with fasciculations 4. Some patients have more aggressive course and are unable to walk by age 20 5. Scoliosis Differential Diagnosis of SMA
The differential diagnosis of SMAIII (Kugelberg Welander disease) includes DMD or BMD. In this instance there are no fasciculations and the CK is usually much higher. Congenital myopathies frequently have ptosis, generalized thinness of muscle, cardiac defects, extraocular muscle palsies and dysmorphisms that readily differentiate them from SMAs. Limb girdle muscular dystrophies have pelvic and shoulder girdle weakness, but stronger muscles with less diminution of reflexes. They also may have specific cardiac, laryngeal, and muscle pattern weakness as well as genetic patterns that make them discernible on clinical grounds. Distal SMA, share pes cavus with CMT, but lack the distal 1/3 of quadriceps wasting (“champagne bottle legs”) and sensory loss. They also have normal SNAPs.
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SECTION III. Anterior Horn Cell Disease that Affects Adult Patients
SMA II and III patients frequently live to adulthood and therefore must be considered in the differential diagnosis of adult motor neuron disease. The CK level maybe markedly elevated in Kugelberg Welander disease (SMA III) up to 10 times normal and are minimally elevated in SMA II and III. EMG reveals persistent motor unit activity most often in SMA I, rarely in SMA II and not in SMA III. Fasciculations are common in SMA II and III. Denervation is seen in all forms of SMA. SMA III and IV show signs of reinnervation. All have normal SNAPs and motor nerve conduction velocities are normal. Those patients with high CK require that inflammatory muscle disease be ruled out. Extraocular muscle and facial involvement exclude SMAs. The differential diagnosis of the “floppy infant” includes a host of central nervous system and congenital myopathies and applies primarily to SMA I Werdnig–Hofmann’s disease that do not reach adulthood.
SMA Variants Linked to Chromosome 5q
Arthrogryposis multiplex congenita A. General considerations: 1. Forms linked to muscle abnormalities, joint, and anterior horn cell disease 2. Anterior horn cell form associated with deletion of the telomeric motor neuron survival gene (SMNt) B. Clinical features: 1. Severe joint deformities 2. Poor muscle tone 3. Poor movement in utero 4. Bilateral congenital hip dislocations
Congenital Axonal Neuropathy
A. General considerations: 1. Homogeneous deletion of SMA gene in the paternal haplotype 2. Mutations in the MP2 gene B. Clinical features: 1. Early onset CMT 1B 2. HSP associated with ataxia, thin corpus callosum, cataracts and axonal neuropathy
Spinal Muscular Atrophies Not Linked to Chromosome 5q
Late Onset Tay Sach Disease A. General considerations: 1. Autosomal recessive 2. Loss of hexosaminidase A; a lysosomal enzyme whose deficiency causes accumulation of GM2 ganglioside in neurons
3. Gene coding for the α or β chain is located on chromosome 15 or 5 respectively; dysfunction of either causes decreased hexosaminidase A 4. Partial deficiency of hexosaminidase causes late onset anterior horn cell disease 5. Various forms of mutations: a. Homozygosity for a single mutation b. Compound heterozygotes with two abnormal alleles on the same chromosome B. Clinical features: 1. Age of onset is the second decade; between 11 to 67 years 2. Dysarthria and truncal ataxia precede appendicular ataxia often the earliest sign 3. Lower motor neuron involvement is prominent 4. Lower extremities > upper extremities 5. Proximal > distal muscle involvement that simulates Kugelberg–Welander disease 6. Recurrent psychosis which may precede or follow the neurologic manifestations 7. Psychosis may be the sole manifestation 8. Rare neurologic features: a. Extrapyramidal tract disease b. Dementia c. Dystonia C. EMG evaluation: 1. Neurogenic; normal motor NCV; normal sensory nerve conduction velocities
Monomelic Muscular Atrophy
A. General considerations: 1. Primarily cervical muscles affected B. Clinical features: 1. Non progressive 2. Asymmetric 3. Usually one upper extremity affected more than the other 4. Rarely the tongue may be affected
Fazio-Londe Disease (see ALS)
A. General considerations: 1. AR B. Clinical features: 1. Limited to the lower cranial nerves 2. Death in 1–5 years
Distal SMA
A. General considerations: 1. Phenotypic CMT
Chapter 1. Spinal Muscular Atrophies Linked to Chromosome 5q11.12–13.3
2. Juvenile or early adult onset with variable rates of progression 3. AD and AR recessive variants B. Clinical features: 1. Distal muscular wasting with pes cavus 2. Proximal musculature is involved with time to a lesser degree 3. No sensory loss
Adult Onset SMA
A. General considerations: 1. AD inheritance B. Clinical features: 1. Proximal limb girdle weakness C. EMG: 1. Normal sensory nerve action potentials
Scapuloperoneal Syndrome
A. General considerations: 1. Both myopathic and neurogenic forms 2. AD inheritance B. Clinical features: 1. Scapuloperoneal distribution of muscle wasting and weakness 2. Variable onset and progression
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a. Wasting of intrinsic hand muscles 4. Exercised induced muscle cramps (neurogenic cramps) 5. Hand tremor may occur prior to weakness (phenotypical of ET) 6. Facial fasciculations (most prominent around the mouth and chin); noted at rest and with contraction 7. Weakness and atrophy of facial muscles and those of mastication; tongue wasting and fasciculation may precede that of other muscles 8. Rare complaints of dysarthria and dysphoria early; they are prominent after 10 years of disease 9. Sensory examination is usually normal 10. Gynecomastia and impotence are present 11. Absent or hypoactive deep tendon reflexes 12. Congenital fractures 13. Some patients with joint contractures C. Laboratory evaluation: 1. Elevated CK (900 to 8000 units/dl) higher than any other AHC disease 2. Muscle biopsy characteristic of denervation D. EMG evaluation: 1. Normal NCSs; CMAP is low from weak and wasted muscle; low amplitude or absent SNAPs 2. Needle EMG demonstrates denervation of extremity muscles; facial and mentalis muscles demonstrate grouped repetitive discharges with activation
Differential Diagnosis of Kennedy’s Disease Fascioscapulohumeral Form of SMA
A. General considerations: 1. Adolescent onset 2. AD inheritance
Non-Immune Lower Motor Syndrome
1. Spinal muscular atrophies (see above) 2. X-Linked Recessive Bulbar Neuronopathy (Kennedy’s disease) Kennedy’s Disease A. General considerations: 1. X-linked recessive inheritance; CAG repeat in the first exon of the androgen receptor gene 2. Phenotypic expression varies within families and does correlate with CAG length; the more repeats the earlier the age of onset 3. Intranuclear androgen receptor protein found in the brainstem and anterior horn cells B. Clinical features: 1. Presents in men in the 3rd to 5th decade 2. Proximal > distal weakness and wasting 3. Distal weakness upper > than lower extremities
The primary differentials are progressive muscular atrophy variants of ALS; facial fasciculations, essential tremor, bulbar involvement make an easy distinction from inflammatory myopathy or any congenital neuropathy. The extremely high CK differentiates it from anterior horn cell disease. Myokymia and neuromyotonia occur spontaneously while mild voluntary contraction produce fasciculations in Kennedy’s disease.
Monomelic Amyotrophy (Hirayama’s Disease)
A. General considerations: 1. World wide distribution; most patients are from Japan and India 2. Putative mechanisms: a. Spinal cord ischemia b. Abnormal neck movement with secondary ischemia c. Traction of the cord due to increased neck flexion d. Abnormal cervical ligaments B. Clinical features: 1. Overwhelmingly a sporadic disease 2. Unilateral weakness and atrophy of intrinsic hand muscles
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SECTION III. Anterior Horn Cell Disease that Affects Adult Patients
3. 4. 5. 6.
Progresses for 1–3 years then stops in 75% of patients Fine tremor of extended fingers in 10% of patients Normal deep tendon reflexes; no upper motor signs Sensation is normal; rarely a rare mild sensory loss over the dorsum of the hand C. Laboratory evaluation: 1. Slightly elevated CK 2. Normal blood chemistries and CSF D. EMG evaluation: 1. Motor NCVs are normal; may have asymmetrical low median and ulnar CMAP amplitudes 2. Preserved SNAPs 3. Signs of denervation in most patients, 20% demonstrate reinnervated units 4. EMG abnormalities may be seen contralaterally (“mirror pattern”) E. MRI evaluation: 1. Cervical and upper thoracic cord atrophy
Differential Diagnosis of Monomelic Amyotrophy
Few diseases resemble one extremity with atrophy that is out of a nerve or root distribution without sensory loss. Syringomyelia invariably has sensory loss (dissociated), inherited or sporadic distal myopathies are not this asymmetric and progress; adult onset SMA is not asymmetrical and is adult onset while this is a disease of young people; spinal cord infarction is not asymmetrical and has specific sulcal artery patterns (most often follows X-RT), asymmetry and lack of sensory loss is not compatible with either posterior medullary (dorsal column) or anterior spinal artery infarction. Tumors progress, are more symmetrical and swell the cord. ALS demonstrates hyperactive reflexes in a wasted extremity. MMN neuropathy is remarkable for little or no atrophy.
Brachial Amyotrophic Diplegia
A. General considerations: 1. Adult onset B. Clinical features: 1. Bilateral proximal arm and shoulder girdle weakness and atrophy 2. Pure LMN weakness; legs are not affected 3. Slower progression than typical ALS 4. Some patients have distal arm involvement 5. Respiratory and bulbar muscles are spared C. EMG evaluation: 1. Denervation of the upper extremities D. Pathology: 1. One autopsied case a. Degeneration of pyramidal tracts and anterior horn cells
Differential Diagnosis of Brachial Amyotrophic Diplegia
Hirayama’s disease or monomelic atrophy is unilateral with strictly arm involvement. Rare adult onset SMAs have lower extremity involvement and are AD. Watershed infarcts (“man in the barrel”) between ACA/MCA territories affect shoulder muscles more than those of the hand and other central features are present such as ideomotor apraxia with hyperactive reflexes. There is no hand wasting. Cervical spondylosis is primarily a C5–C6 disease which is asymmetric and usually is associated with lumbosacral disease and increased knee jerks. Spinal artery infarctions have sensory loss and a different pattern of motor involvement. Post radiation amyotrophy has (obvious history) fasciculations (if the plexus is involved). EMG reveals no evidence of conduction block that are seen with MMN. Progressive Muscular Atrophy
A. General considerations: 1. Considered an ALS variant B. Clinical features: 1. Middle aged patients 2. Slowly progressive asymmetric weakness of upper and lower extremities 3. Fasciculations with wasting 4. Progresses for years 5. No upper motor neuron signs 6. Phenotypically mimics FSHD C. EMG evaluation: 1. Denervation and reinnervation
Chapter 2 Immune Mediated and Genetic Lower Motor Neuron Syndrome (see Neuropathy Section) 1. Multifocal motor neuropathy with conduction block (MMN); less than 50% CMAP is required with specific conduction blocks 2. Differential diagnosis of low titer IgM anti GM1 antibodies (less than 1–400 μg/liter) is: a. GBS b. ALS c. Sensorimotor neuropathy d. CIDP e. MG f. SLE g. Normal patients 3. High titers (greater than 1 to 6400 μg/dl) of GM1 antibodies have 80–90% specificity for clinical disease 4. High titers of IgG anti-GM1 antibodies are found in lower motor nerve syndromes and acute axonal neuropathy secondary to Campylobacter jejuni
Chapter 2. Immune Mediated and Genetic Lower Motor Neuron Syndrome Differential Diagnosis of Immune Mediated Motor Neuropathies
The major clue to this diagnosis is upper extremity asymmetric distal weakness with no sensory loss or upper motor neuron features. The onset may be rather sudden, but progression is insidious. The distal adult SMAs are autosomal dominant and are less asymmetric. Progressive muscular atrophy is proximal rather than distal, monomelic amyotrophia is primarily a disease of Indian and Japanese patients and affects the intrinsic muscles of the hand (more wasting) than immune processes. It is associated with MRI evidence of an atrophic lower cervical and upper thoracic spinal cord. Brachial amyotrophic diplegia affects proximal muscles more than distal and is symmetrical to a large degree. Hereditary sensory motor neuropathy Type II may involve individual upper extremity muscles, but these are usually proximal rather than distal. Distal myopathies that affect the upper extremity can be distinguished by genetic patterns, symmetry of upper extremity involvement, associated features (myotonia) and relative preservation of reflexes. EMG establishes a neurogenic or myopathic process (hexosaminidase A deficiency in the former and glycogen storage disease type 6) in the latter. Muscle biopsy rules out specific forms of congenital myopathy and storage syndromes. Conduction block, significant titers of GM1 antibodies and other signs of demyelination secure the diagnosis of a demyelinating process. Immune neuropathy is differentiated from early ALS on clinical grounds by: 1. Onset prior to age 35 2. An indolent course 3. Absence of significant wasting in the hand (ALS frequently involves the first dorsal interosseus and the 4th and 5th intrinsic hand muscles) 4. Non myotomal pattern of weakness 5. Absence of upper motor signs and no bulbar involvement
Other Immune Mediated Lower Motor Nerve Syndromes
A. General considerations: 1. Many of these patients have high titers of anti-GM1 antibodies B. Clinical features: 1. Most have distal presentation 2. Patients with proximal presentation: a. Later age of onset b. Men > women c. LMN atrophy of extremities that is static for 3–5 years C. Laboratory evaluation: 1. High titers of IgM or IgG or asialo antibodies are present
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Genetic Lower Motor Nerve Syndromes
1. Spinal muscular atrophies (chromosome 5q linked and non-linked) 2. Kennedy’s syndrome (X-linked recessive bulbospinal neuropathy) 3. Monomelic amyotrophy 4. Brachial amyotrophic diplegia 5. Progressive muscular atrophy (ALS variant) 6. Progressive bulbar palsy (ALS variant) 7. Fazio–Londe Disease (ALS variant)
Multiple System Disorders with Anterior Horn Cell Involvement
1. Hereditary spastic paraparesis (HSP) (I-20) complicated and uncomplicated variants 2. Adult hexosaminidase A deficiency 3. Spinocerebellar degeneration: a. OPCA variants b. SCA III (Machado Joseph Disease) 1) AD 2) AR
Adult Polyglucosan Body Disease
A. General considerations: 1. Sporadic and familial cases; high proportion of patients are Ashkenazi Jews 2. In Jewish patients a mutation of the glycogen branching gene is noted but may have more than one basis as non-Jewish patients, have an identical phenotype without the mutation 3. Polyglucosan bodies are also seen in glycogenosis type IV and Lafora body disease a. Noted in astrocytes, subpial and subependymal layer as well as the cerebellum and myelinated nerves; systemically in liver, heart, lung, smooth and skeletal muscle; loss of anterior horn cells B. Clinical features: 1. Onset in the 5th or 6th decade 2. Sensory peripheral neuropathy 3. Abnormal gait 4. Dementia 5. Urinary incontinence 6. Corticospinal tract dysfunction 7. Severity of disease various amongst patients 8. All features are not present in every patient 9. Normal pressure hydrocephalus presentation without other upper or lower motor signs 10. An ALS presentation with only corticospinal and anterior horn cell signs C. EMG evaluation:
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SECTION III. Anterior Horn Cell Disease that Affects Adult Patients
1. Slowing of motor NCVs; low amplitude or absent SNAP’s (sural nerve biopsy demonstrates intra-axonal polyglucosan bodies D. MRI evaluation: 1. Periventricular and subcortical white matter abnormalities on T2 weighted images; no anterior or posterior predilection
Differential Diagnosis of Adult Polyglucosan Body Disease
Primary lateral sclerosis has severe spasticity affecting extremities and cranial nerves. ALS has no sensory loss and in 60% of patients no dementia. There are rarely bladder abnormalities with ALS. Severe demyelinating disease has optic atrophy, an intranuclear ophthalmoplegia and bilateral severe cerebellar ataxia. B12 deficiency has cranial nerve I abnormalities, a frontal lobe affect and active paresthesias in upper and lower extremities. Dorsal column dysfunction predominates the sensory symptoms. Metachromatic leukodystrophy at the age of presentation of APBD has more spasticity and intact u fibers on MRI. ALD is X-linked recessive, has a much earlier onset, and no peripheral neuropathy. Adrenomyeloneuropathy starts in middle age, there is no bladder symptomatology and mentation is much better preserved. The difficult differential diagnosis to make is that of NPH. Prominent features in this entity not noted with APBD are falling backward and gait apraxia. Ventricular enlargement, the temporal horn out of proportion to the lateral ventricles with a mostly intact cortex are distinguishing features. Olivopontocerebellar degeneration, including retinal, dorsal column and brainstem variants have much more ataxia.
b. Anterior horn cell involvement 6. Pick’s disease a. Broca’s aphasia in a patient with otherwise ALZ phenotype 7. HSP a. Spasticity and lower motor neuron features 8. Shy Drager a. Akinetic rigid dementing illness b. Autonomic dysregulation is seminal feature c. Some amyotrophy
Paraneoplastic Motor Neuron Disease
A. General considerations: 1. Occurs with multiple cancers; most often small cell carcinoma of the lung 2. Rarely removal of the tumor stabilizes the MND; most often there is no change 3. Antigenic overlap between tumor cells and motor neurons (molecualr mimicry) 4. MND occurs with other well established paraneoplastic syndromes
Antibodies Associated with MND
1. Anti-Hu with small cell lung cancer; antinuclear neuronal antibody1; ANNA1 2. MND maybe associated with encephalomyelitis; dorsal root ganglionitis and large fiber sensory neuropathy 3. The motor neuron disease may precede the cancer by 4–10 months 4. In general, both removal of the tumor and immune treatment fail to reverse the neurological signs and symptoms
Rare MSA with Anterior Horn Cell Involvement
1. Hallervorden Spatz disease (PANK-2) a. Akinetic rigid syndrome b. “Eye of the tiger” in GPi by MRI 2. Guamanian–Parkinsonian – ALS (Lubag) a. Severe dystonia (particularly of the mouth) b. Lubag (Dystonia 7) c. Dementia d. X-linked 3. Huntington’s disease a. Choreoathetosis of body; choreatic eye movements b. Dementia c. Amyotrophy 4. Creutzfeldt–Jacob a. Classic disease has prominent fasciculations b. Speed of the dementing process plus the myoclonus makes the diagnosis 5. Alzheimer’s variant a. Spastic paraparesis
Hodgkin’s and Non-Hodgkin’s Lymphoma
1. 2. 3. 4. 5.
Subacute painless lower motor neuron syndrome Rare sensory symptoms Anti MA antibodies Variable progression Upper motor neuron symptoms develop over time similar to ALS
ALS Like Syndrome from Multiple Cancers
1. Hodgkin’s lymphoma, breast, uterine, ovarian, non-small cell lung cancer 2. Both upper and lower motor neuron symptoms and signs 3. LMN > UMN manifestations 4. Neurologic symptoms may precede or follow the diagnosis
Chapter 4. Rare Causes of Motor Neuron Disease Primary Lateral Sclerosis Syndrome with Breast Cancer
1. Neurologic manifestations occur prior to the diagnosis 2. Slowly progressive course 3. Upper motor neuron signs are usually first which then evolve into a lower motor neuron syndrome
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b. Tremor c. Spasticity d. Weakness e. Atrophy are often concurrent 7. Death often occurs within three years in some patients
Postradiation Motor Neuron Syndrome Specific Antibodies Identified with Motor Neuron Syndromes
1. Anti-Yo-cerebellar degeneration, primarily Purkinje cell; few patients with MND 2. Anti-Hu-limbic encephalitis, dorsal root ganglionitis, rarely MND 3. M proteins with lymphoproliferative disease 4. GDlb with thyroid adenoma; most often this is correlated with Campylobacter jejuni and CM Fisher syndrome or motor axonopathy 5. Breast cancer patients may have a motor axonopathy and antibodies to nodes of Ranvier; anti-Ri antibodies 6. Testicular-anti Ta antibodies
Chapter 3 Motor Neuron Disease Associated with Physical Agents Electrical Injury
A. General considerations: 1. Causes a delayed upper and lower motor neuron syndrome after both electrical injury or lightening 2. Starts at the site of trauma and then spreads 3. Transient weakness and paraplegia following electrical injury which usually clears after hours to 4 days 4. Permanent sequelae occurs with symptoms starting with years after the accident 5. The pathology is not the same as autopsies of executed criminals B. Clinical features: 1. The source of the current is usually from household circuits, high voltage lines or lightening (usually causes severe burns and cardiac arrest) 2. Electrical current specifically travels down the corticospinal and bladder pathways 3. Weakness and atrophy often begins at the site of injury 4. Weakness spreads in a contralateral pattern 5. Bulbar signs and upper motor neuron weakness and spasticity occur over time 6. Chronic regional pain syndrome (CRPS) frequently occurs with its motor manifestations of: a. Inability to initiate movement
A. General considerations: 1. Delayed occurrence after X-RT 2. Dosages to the cervical spine that cause the syndrome are: approximately 3000 rads; lumbosacral spine 5000–6000 rads 3. Associated with treatment of many different types of tumors B. Clinical features: 1. Occurs months to years after treatment 2. Atrophy of affected muscles with fasciculations 3. No sphincter involvement 4. Normal sensation 5. Lower extremities are preferentially involved 6. Weakness usually stabilizes, but has been described to progress over years 7. A similar process occurs in the lower cranial nerves with head and neck irradiation. The carotid artery is often involved in this situation with a long segment of the artery involved and consequent stroke C. EMG evaluation: 1. Fibrillation potentials are present in the lower extremities 2. Myokymic discharges occur D. Laboratory evaluation: 1. CSF usually normal 2. Protein may be slightly elevated
Differential Diagnosis
The myokymic potentials in the lower extremities and usual lack of involvement of the upper extremities make the diagnosis. Tumor recurrence does occur on this background. This is particularly important with sarcomas of the brachial plexus after X-RT of the breast. The same problem occurs following X-RT involvement for a variety of brachial plexus conditions.
Chapter 4 Rare Causes of Motor Neuron Disease Hyperparathyroidism
A. General considerations:
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SECTION III. Anterior Horn Cell Disease that Affects Adult Patients
1. Several series and isolated case reports associate an ALS picture with hyperparathyroidism 2. Skepticism about the nature of the correlation persists due to lack of EMG correlation of wide spread denervation and failure to halt progression of the disease with removal of the parathyroid glands B. Clinical features: 1. Symmetrical proximal weakness with cramps 2. Hyperactive reflexes and spasticity 3. Inconsistent tongue fibrillations and dysphagia 4. Inconsistent sensory loss 5. Several patients had bladder urgency C. EMG evaluation: 1. Widespread denervation in some patients
Repeated Hypoglycemia
A. General considerations: 1. The syndrome of anterior horn cell disease has occurred in patients with repeated episodes of hypoglycemia B. Clinical considerations: 1. Wasting of extremities 2. Fasciculations
Motor Neuron Disease with HIV/HTLV-I
A. General considerations: 1. HIV frequently causes a vacuolar cervical myelopathy; and severe axonal neuropathy 2. HTLV-I causes a severe chronically progressive cervic/thoracic myelopathy with spasticity and bladder involvement B. Clinical features: 1. A few patients with HIV present with ALS or a primary lateral sclerosis syndrome 2. Most patients have severe lower extremity spasticity and bladder involvement
Postpoliomyelitis Syndrome
A. General considerations: 1. Approximately 500,000 Americans suffer from the diseases 2. Last great epidemic occurred in 1952 3. A few isolated cases have occurred from vaccination; most cases now occur from unvaccinated communities or immigrants B. Clinical features: 1. Further weakening of muscles that had previously been affected 2. Fasciculations in affected muscles
3. Fatigue 4. No upper motor neuron signs 5. Weakness of bulbar and respiratory muscles does occur 6. Patients who have survived polio often have fasciculation for a prolonged period in affected muscles
Drugs Associated with Motor Neuron Disease
Lead A. General considerations: 1. Most often encountered in battery workers, mechanics (car radiator repair) 2. Often associated with systemic signs of anemia, lead lines in gum and bone 3. Renal cortex involvement 4. Basophilic stippling of RBC B. Clinical features: 1. Lower motor involvement of wrist and finger extensors 2. One report of both upper and lower motor neuron involvement C. Rare forms: 1. Dapsone 2. Nitrofurantoin may present with dose dependent reversible lower motor neuron syndrome 3. Guamanian ALS dementia complex has been linked to toxic amino acid ingestion from the cycad nut (Brn methylamine BNXAA). Now not thought to be etiologic
Chapter 5 Amyotrophic Lateral Sclerosis
A. General considerations: 1. Incidence varies from 0.2 to 2.4 per 100,000 people in the world excluding the Western Pacific 2. Prevalence rate is between 0.8 and 7.4 people per 100,000 3. Age is the greatest risk factor with peak mortality between 55 to 75 years of age 4. Peak onset is between 65–70 years of age; earlier onset has greater survival time 5. Male to female ratio is 1.5–2.5 : 1 6. Survival from time of diagnosis a. 50% die within 3 years b. 75% die within 5 years c. 10% live longer than 10 years 7. 85–90% of ALS is sporadic: a. 10–15% of familial ALS have a mutation in the gene for cu/zn superoxide dismutase (SoD1)
Chapter 5. Amyotrophic Lateral Sclerosis
8. Genes for cytoskeletal molecules that may be linked to ALS: a. Neurofilament-Heavy (NF-H) mutation 1) 1% in sporadic ALS 2) 0.3% of familial ALS 9. Possible involvement of the fast conducting corticospinal pathways to a greater degree than polysynaptic pathways 10. Twenty percent of familial forms are manifestations of mutations of the copper/zinc (Cu/ZN) superoxide dismutase 1 (SOD1) gene on chromosome 21 C. Clinical features: 1. May start as atrophy of intrinsic hard muscles in various patterns: a. First dorsal interosseous b. Lateral hand split c. Medial hand benediction sign. The fourth and fifth fingers are involved first as they are with syringomyelia. IN CRPS the fourth and fifth fingers are dystonia 2. Atrophy and fasciculations in a muscle group with increased reflexes 3. Segmental spread: a group of muscles in one extremity that then demonstrate contralateral weakness and atrophy (mirror patterns) 4. Onset in a bulbar distribution (12% of patients) 5. Painless foot drop; clawhand; wrist drop 6. Prominent fasciculations associated with cramps on exercise of the affected muscle 7. Spasticity, hyperreflexia, Babinski signs, retention of cremasteric and abdominal reflexes 8. Fasciculations and fibrillations in a scalloped atrophic tongue 9. A significant number of patients have dementia; other cognitive deficits noted 10. Poor facility of corticospinal type movements
Rare Signs
1. Extraocular movement abnormalities are an exception; may be a decrease of vertical saccades 2. Sphincter dysfunction (occurs late in disease in those on ventilators) 3. Sensory loss (there does appear to be some dorsal column dysfunction) 4. Extrapyramidal signs in 5%; impairment of postural reflexes 5. Autonomic involvement a. Blood pressure, heart rate, GI function
Associated Features
1. Sleep apnea; morning headache
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2. 3. 4. 5. 6.
Sialorrhea Silent and asymptomatic aspiration Disturbance of sleep architecture Decline of voice power with speech Cachexia greater than that expected from decreased nutrition 7. Absence of expected bed sores (possible changes in type III procollagen) 8. Pseudobulbar palsy
ALS Variants
Bulbar Presentation A. General considerations: 1. Growing evidence that ALS is a multisystem degeneration B. Clinical features: 1. Most common in post menopausal women 2. Poor prognosis; in past death occurred in approximately one year 3. Possibly up to 25% of ALS patients present with this onset 4. Spread to the lower cervical upper thoracic myotomes; later to lumbosacral muscles 5. Rarely, it remains bulbar
Primary Lateral Sclerosis
A. General considerations: 1. Does not involve the lower motor neuron B. Clinical features: 1. Age of onset is usually between 50 and 55 years 2. Progresses very slowly 3. May start as spastic paraparesis 4. Severe generalized spasticity, bilateral Hoffman and Babinski signs 5. Pseudobulbar palsy 6. Cognitive impairment is common; overt dementia is rare
Progressive Muscular Atrophy
A. General considerations: 1. Rarest variant of ALS 2. Occurs in approximately 2.5% of patients B. Clinical features: 1. Slowly progressive with better outcome than in classic disease 2. A pure lower motor neuron disease 3. Differential is between this and lower motor onset of SMA
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SECTION III. Anterior Horn Cell Disease that Affects Adult Patients
Flail Arm Syndrome (Bibrachial Diplegia)
A. General considerations: 1. Relatively symmetric proximal and distal wasting of the upper extremities 2. Hyperactive reflexes in both upper and lower extremities 3. Corticospinal tract dysfunction with Babinski signs
3. Excitotoxic cell death from B-N-methylamine BMAA, derived from the cycad nut is not causative 4. ALS form of the complex has declined B. Clinical features: 1. Parkinsonism presents primarily as akinetic rigid variety 2. Dystonia is prominent (“Lubag”); particularly of the mouth 3. ALS in combination with Parkinsonian features; patients may have severe dementia
Mill’s (Hemiplegic Variant)
A. General considerations: 1. Rare; possibly 5% of patients B. Clinical features: 1. Corticospinal and lower motor neuron involvement of one side
Familial ALS
A. General considerations: 1. Approximately 5–10% of ALS patients 2. AD inheritance: a. 20% of patients have mutations in the Cu/Zn SOD1 gene on chromosome 21; all 5 exons are involved b. Gain of function deficit c. Recessively inherited ALS occurs: 1) Apparent single founder for these patients (D90A mutation) 2) Tunisian families with 2q33–35 mutations
Chronic Juvenile ALS
A. General considerations: 1. Chronic juvenile ALS 2. Slow progression 3. Onset approximately 12 years of age B. Clinical features: 1. Earlier onset; approximately 12 years of age 2. Less male predominance 3. Initial manifestations occur in the lower extremities 4. Slow progression C. Pathology: 1. No perikaryal or axonal spheroids 2. Greater involvement of Clarke’s columns
Guam Parkinsonian ALS Dementia Complex
A. General considerations: 1. Endemic areas for this clinical complex are: Western Pacific, Kii peninsula of Japan; West New Guinea 2. No gene has been identified
Differential Diagnosis of ALS
Since ALS and its variants may strike all levels of the neuraxis the differential diagnosis is extremely wide. In reality, the diagnosis is restricted, as there are few illnesses that strike the upper and lower motor neurons simultaneously. The clinician must not miss the illnesses that simulate ALS but are treatable. The most common of these is cervical spondylosis. This is primarily a disease of the motion segments of the spinal segments and occurs in both cervical and lumbar areas concomitantly. It is asymmetrical, biceps jerks are lost, knee jerks are increased ankle reflexes may be asymmetrically decreased. If the ventral roots are severely constricted in the cervical canal fasciculations are noted in the upper extremities. It does not involve the cranial nerves, the neck is in a forward flexed posture and cannot be moved to lateral, anterior and posterior planes. The hands are usually spared, whereas in ALS the first dorsal interosseous is often affected very early. Mentation is normal. The problem arises when the patient has both diseases. Cervical spondylosis does not affect paraspinal muscles. MRI of the cervical spine and back corroborate the diagnosis. The pure motor autoimmune neuropathies may simulate the lower motor form of ALS. The causative antibodies are GMI, MAG, and Gdlb. Serum protein electrophoresis and immune focused electrophoresis often demonstrates an IgM peak (particularly for MAG). Most importantly EMG identifies a conduction block. Wasting is not nearly as prominent as in progressive muscular atrophy (which is most often proximal). Hexosaminidase A deficiency is extremely rare and has prominent psychiatric and cerebellar features. There still is controversy over the link between lymphoma and leukemia with ALS. Clearly, there is a strong association between many malignancies and destruction of various parts of the neuraxis (anti-Hu, anti-Yo, anti-Ri, anti-Ma and antianti TA). A careful evaluation of the bone marrow is in order if there is a suspicion of a lymphoproliferative disorder. Hyperparathyroidism, hyperthyroidism, benign fasciculations, and hyperexcitable syndromes all may produce wide spread fasciculation. A fasciculation must be accompanied by wasting and weakness to be significant. Neurogenic cramps induced by exercise, if in the lower extremity are most often
Chapter 5. Amyotrophic Lateral Sclerosis
due to disc or spondylitic disease in the lumbar roots particularly S1. This rarely occurs in the upper extremity. Neurogenic cramps of the upper extremity suggest the cramp fasciculation syndrome or motor neuron disease. The differentiation can easily be made by EMG. Acid maltase deficiency may give exercise induced cramps with muscle weakness. There is some evidence that anterior horn cell disease may occur in anterior horn cells formerly affected by a polio virus infection. The post polio syndrome is painful and most probably represents accelerated cell death in those anterior horn cells that had compensated for the death of their neighbors. Monomelic ALS seems to affect all muscles of the affected extremity rather than particular muscles of the hand which occurs in ALS (benediction sign of 4th and 5th finger or the lat-
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eral hand). There are frequently EMG findings in unaffected muscles in ALS. Amyotrophy of extremities occurs with multiple system atrophies. The most severe is spinocerebellar atrophy (SCA3) or Machado–Joseph disease. The amyotrophy is never the dominant component of these syndromes. Kennedy’s disease, a bulbar neuronopathy, is X-linked and distinguished by facial fasciculations, genetics and gynecomastia. The CK is usually high and there are diminished SNAPs. The late onset spinal muscular atrophies may overlap with ALS. They usually have symmetric proximal weakness and some are distal with pes cavus.
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Section IV SPINAL CORD DISEASE
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Chapter 1. Introduction
Chapter 1 Introduction
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spinal cord compression. In the lumbar area, roots are involved as the spinal cord ends at T12–L1 (conus medullaris). Differential diagnosis of spinal cord pathology depends on location and pattern of involvement as well as the course of the process.
Spinal Cord Disease
The spinal cord is frequently involved in specific patterns and at characteristic levels that is extremely helpful in differential diagnosis. The lamination of both the dorsal column and the spinal thalamic tracts is such that the patient’s symptoms may not reflect the true level of involvement. This is particularly true with sensory levels. Pain afferents enter the cord and are distributed approximately two segments above and below their level of entry by Lissauer’s tract. Propriospinal fibers connect adjacent spinal dermatomes. The corticospinal tract is arranged so that the fibers innervating the legs are lateral to those of the arm. Bladder fibers are between arm and leg fibers. The spinothalamic fibers are laminated such that sacral fibers are most lateral and leg, trunk and arm fibers are medial and cross at their level of entry. Thus a lateral cord lesion at cervical levels will affect the contralateral sacral and leg sensory fibers prior to arm fibers. The clinical and neuropathological division of the cord is into three spaces: (1) epidural; (2) intraparenchymal and; (3) intradural and extramedullary. Processes that compress the spinal cord cause ataxia, a sensory level, then bilateral motor weakness below the level of the lesion and bladder involvement. If epidural processes are acute, such as metastasis, intradural hematoma or fracture, there will be spinal shock. If this supervenes all sensation, motor function, bowel, and bladder control and reflexes will be lost below the level of the lesion. Long standing intraparenchymal spinal cord disease causes spasticity below the level of the lesion with a neurogenic bladder. There is a segmental sensory loss with normal sensation above and below the lesions. Occasionally, reflexes will be increased above the level of the lesion (Schiff– Sherrington reflex). This is due to disinhibition of excitatory ascending fibers. Cystic intraparenchymal lesions and tumors often cause minimal bladder dysfunction. Epidural compression affects bowel, bladder and then ability to walk, rarely ataxia present initially. Predominantly as the dorsal and ventral spinocerebellar tracts are in the periphery of the cord and they both subserve cerebellar functions of the legs. The patient is ataxic prior to becoming paralyzed. The cuneocerebellar tract conveys proprioception from the upper extremities and is located at cervical levels C1–C4. Propioceptive loss has to be sought by the examiner, although there is frequently a lateral drift of the ipsilateral extremities. Intradural extramedullary lesions are few and comprise meningiomas, neurofibromas, dropped metastasis and enlarged nerve roots from congenital hereditary motor sensory neuropathies. If a neurofibroma or meningioma occurs in the thoracic or cervical area there is often concomitant root and
Specific Patterns of Involvement
1. 2. 3. 4.
Transverse (in fact these are usually longitudinal) Longitudinal hemisection (Brown–Sequard syndrome) Epidural compression Intramedullary (usually inflammatory or tumor and cause a longitudinal lesion on MRI)
The specific diagnostic radiographic features for these patterns are: 1. Transverse myelitis involves more than one segment and expands the spinal cord. If involvement is more ventral a viral etiology is expected. Dorsal column involvement suggest Sjögren’s, B12 deficiency, Tabes dorsalis or toxins. 2. Brown–Sequard: This is a longitudinal division of the cord. The patient suffers ipsilateral proprioceptive, touch and vibratory loss in association with contralateral pain and temperature deficits. There is ipsilateral paralysis below the lesion. The usual etiology is trauma (knife or bullet) or X-RT therapy in which individual sulcal arteries are involved. 3. Intramedullary: The cord is swollen over several segments in an ovoid pattern. Central or asymmetric cysts suggest a syrinx. A post traumatic syrinx occurs above the level of the lesion. Tumors that are associated with intramedullary syrinxes are cystic astrocytomas (frequently an enhancing nodule is seen), hemangioblastomas as well as astrocytomas that occur in the wall of syrinxes. 4. Epidural compression: A saw-toothed or paint brush pattern on myelography is seen with epidural processes. Bony destruction suggests metastatic disease. This is often only at one segment. Disc involvement, with gadolinium enhancement, denotes infection. The anterior and posterior ligament often enhance with gadolinium with infection. Lymphomas often start in the epidural fat. Epidural compression is noted with extra medullary hematopiesis, as well as by fat in patients on steroids. Dural AVMs are epidural and are most common dorsal in the thoracic segments of the cord. Meningitis of all forms may be dorsal and invades the spinal parenchyma through draining veins or exit foramina. Sarcoid often invades the dura at cervical and thoracic levels. Processes that thicken the spinal dura itself are lymphoma, tuberculosis, cryptococcus; rheumatoid arthritis and idiopathic pachymeningitis which simultaneously affect intracranial dura. Carcinomatosis of the meninges characteristically thickens the dura and is seen in the sulci of the cerebellum and cortex. Angioplastic endotheliosis may affect cerebral blood vessels and
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SECTION IV. Spinal Cord Disease
those of the dura. Amyloid may greatly thicken the dura of intracranial and spinal compartments and occasionally forms mass lesions.
Intradural Extramedullary Lesions
The most common of these are Schwannomas that form “dumbbell tumors.” The neuronal exit foramina are expanded and the tumor is seen to compress the spinal cord. Myelography reveals a “cap” sign. Neurofibromas grow through the nerve root, as opposed to Schwannomas which can be separated from the nerve root. Plexiform neurofibromas may involve multiple nerve roots and are characteristic of neurofibromatosis type I (chromosome 17). Hereditary motor sensory neuropathy particularly Dejerine–Sottas disease (HSMN III) greatly enlarge nerve roots and may compress the cord. Meningiomas characteristically are found in the intradural extramedullary space of the thoracic cord in women and are extremely rare in men. A free fragment of a disc may migrate in this space for several cord segments, while arachnoid cysts may fill, in a ball valve fashion, and compress the spinal cord intermittently. Prior to MRI this process was often misdiagnosed as multiple sclerosis. Medulloblastomas, spinal cord, metastases and leukemia frequently seed the spinal cord in the intradural extramedullary space. Spontaneous, traumatic and anticoagulation induced subdural hematomas of the spinal cord also occur here.
Locations
The area of the spinal cord involved is a major clue in the differential diagnosis. The examination is quite specific for each entity. A forward flexed neck with limitation of movement to the lateral planes suggests cervical spondylosis. Degenerative changes in the spine occur at movement segments such as C5–C6, C4–5, while C8–T1 is not affected. All patients above 40 years of age get some degree of cervical spondylosis. The exam will often demonstrate an inverted radial or inverted supinator reflex, increased knee jerks, as well as inability to tandem walk due to lateral pressure on the dorsal and ventral spinocerebellar tracts. A short neck suggests Turner’s syndrome, platybasia, Chiari malformation or abnormalities of C1–C2, basilar invagination or Klippel Feil syndromes. There are five ossification centers of C2, and anomalies and fractures occur in these areas. A long neck is suggestive of the “droopy shoulder syndrome” and brachial plexus traction injuries, but may also be associated with homocystinuria, Marfan’s or Ehlers Danlos syndrome. Lhermitte’s sign is most often associated with demyelinating disease, but also occurs with any lesion that irritates the dorsal columns. Characteristic pathology involving the cervical cord includes HIV infection and B12 myelopathy (both give a vacuolar myelopathy) Sjögren’s syndrome, as well as, spondylosis, disc disease, stenosis, and demyelinating disease. This
is very frequently associated with a dropped sensory level to T4–T6 due to lamination of the sensory systems of the spinal cord. A level here invariably draws an MRI at this level, but most often pathology will be at cervical levels. Hirayama’s disease, abnormal movement of the cervical spinal cord with consequent pathology at C8–T1, and calcification of the posterior longitudinal ligament with cord compression is common in Asian patients. Syrinxes and cavernous hemangiomas are common parenchymal lesions although demyelinating inflammatory lesions are by far the most common. Rarely sarcoid presents with both inflammatory and dural lesions at this level. A ventral AVM of the anterior spinal artery, the “Foix Alajouanine syndrome” lesion, can be found from cervical to thoracic areas.
Thoracic Spinal Cord
Inflammatory lesions at this level are usually demyelinating, but sarcoid may thicken the dura here as well as inflame the cord. Dural AVMs, if spinal, are most common in the dorsal cord. Disc disease is rare, but protrusions here are very dangerous, as the spinal canal is tight (12–24 mm) and the cord is easily compressed. Diabetes, a syrinx and amyloid may destroy propioceptive and pain fibers which produce a “Charcot joint”. This is more common at the shoulder joint, particularly for a syrinx. Metastatic disease with a pathologic fracture and meningioma in women are characteristic. Osteoporosis with anterior vertebral body fracture are most common in elderly women at this level. Ganglioneuromas and chordoma, Weing’s sarcoma are rare tumors of the thoracic cord. An astrocytoma may grow a long distance and destroy anterior horn cells of the thoracic spine asymmetrically giving rise to a “C” form of scoliosis. An “S” shaped scoliosis is congenital (with compensatory curves) and is often asymptomatic. Diastematomyelia, a fibrous band that splits the spinal cord, and reduplication of the cord (two spinal cords with their own dural cover) are rare congenital anomalies. A devastating infection of the thoracic spinal cord is herpes type 6, which leads to necrosis with minimal recovery. West Nile virus, as well as polio, may severely affect this part of the cord, but not to the same degree. Axonal necrosis of the cervical cord with optic neuritis (Devic’s) disease is more common in the cervical cord, but dose occur in the thoracic cord as well. The many forms of hereditary spastic paraparesis affect the thoracic cord severely. In uncomplicated variants, only the spinal cord is affected while complicated variants are also associated with optic, cerebellar, cortical and peripheral nerve deficits.
Lumbar
The lumbar level is most affected with mechanical problems such as disc disease, spinal stenosis, spondylolisthesis and
Chapter 1. Introduction
spondylosis. In general, L5–S1 (the major motion segment) suffers disc disease, while L4–L5 is more frequently the site of spinal stenosis. Synovial cysts of the facet joint is rare, but is often seen in older patients with severe degenerative disease. Facet hypertrophy with tropism (rotation of the inferior facets into the foraminal exit zone) is a common cause of radiculopathy in older patients. In adult populations, meningomyelocele and its variations are rare. A tethered cord, in which the filum terminal is short and the spinal cord is lower than its usual vertebral level at L1, is associated with bladder abnormality, pes cavus and radiculopathy. An abnormally formed lamina or pedicle often is associated with radiculopathy at this level. The lateral recess, particularly at L4–L5 and L5–S1, may be congenitally narrowed with nerve root compression. Lipoma, glioma of the filum terminale, and chordomas are particular to the lumbosacral cord. Lymphomas may occur anywhere in the spine, but tend to envelop the nerve roots of the cauda equina at this level. Sarcomatous degeneration of a lipoma cannot be operated, as it is interdigitated within the nerve roots. Plexiform neurofibromas (NFI) occur in the lumbosacral cord. CMV infections in very ill (CD4+ count of less than 200 mm3 ) HIV patients are characteristic of the lumbosacral cord.
Epiconus
Anatomically, this area is at a spinal level T12–L1 and affects the lower end of the spinal cord segment above the conus medullaris which comprises S1–S5. Lesions here cause involvement of the bowel, bladder and sexual function as well as pain and weakness. A Babinski sign is present. Trauma, congenital defects, such as spinal stenosis in achondroplasia, demyelinating disease or a syrinx may be prominent pathology at this level.
Conus Medullaris
The hallmark of lesions here is the early involvement of bowel, bladder, and sexual function without loss of sensation or weakness. The cauda equina and epiconus are often concomitantly involved. The most common pathologies are trauma, demyelinating disease, vascular malformation, syrinx and, rarely, a tumor. Characteristic of a parenchymal tumor is weakness of the gastrocnemius muscle with spared anterior tibialis and extensor hallucis longus muscle function. Sexual dissociation may also occur whereby a patient may have an erection, but is unable to ejaculate or vice versa.
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Cauda Equina
The cauda equina comprises of the nerve roots that have exited the lumbosacral spinal cord. A cauda equina lesion produces asymmetric severe pain, numbness in the perineal or “saddle distribution” and weakness of the lower extremities. Bladder, bowel and sexual function are affected. The usual pathology of a cauda equina lesion is disc disease, trauma or metastasis.
Spinal Block
In the past, spinal block was most often seen by myelography. The characteristic brush like defect of the contrast column in epidural disease and the meniscus sign of an intradural extramedullary lesion were carefully sought. The block is due to obstruction of the passage of spinal fluid. MRI now allows visualization of water in discs, as well as inflammation and swelling of nerve roots (gadolinium enhancement), while CT allows exquisite detail of the bony exit foramina. The advantage of a myelogram with CT to following is the ability to visualize the relationship of the nerve root both to the pedicle and within its exit foramina. A far lateral disc cannot be visualized with myelography. A spinal block causes a Freund’s reaction in which the protein is very high, while cells and sugar remain normal. A CSF protein of one gram suggests a block as few diseases can raise a protein to this level. The usual protein of an autoimmune process is 80–120 mg%. Deep fungus infections such as blastomycosis may raise the protein to 1 gram/dl, but this is very rare. Most spinal blocks are caused by epidural tumors. Degenerative disc disease is easily seen by desiccation and less signal on T2 weighted MRI images. A lesion in the pedicle or one eroding the end plates of the vertebral body is most often metastatic. A star vertebral fracture may protrude a bone fragment into the spinal canal and cause a spinal block.
Anatomical–Clinical Correlations
1. Dropped sensory levels: a. Thoracic compression causes a dropped sensory level of about two segments. The posterior level is usually slightly higher than the anterior level. b. Cervical cord lesions cause a dropped sensory level of many segments. As noted above, this is due to the lamination primarily of the spinothalamic tract. c. A lateral drift and severe proprioceptive loss suggest dorsal column tract or nuclei involvement. 2. Motor deficits: a. In general, spinal cord lesions cause bilateral motor deficits which may be asymmetrical. X-RT characteristically does this by producing a proliferative end arteritis of a sulcal artery. Another cause of asymmetrical
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3.
4.
5.
6.
7.
8.
SECTION IV. Spinal Cord Disease
motor weakness includes trauma specifically knife or bullet wounds. Most blunt trauma to the cord causes an oblong longitudinal lesion. Bladder involvement may have characteristic features depending on the level of involvement. a. Cervical cord (long standing): 1) Frequency and urgency 2) Loss of urine with a valsalva maneuver. The lesion is often at the ciliary nucleus of Budge at the C8–T1 level and is most often a syrinx. 3) Inability to initiate micturition in the face of urgency. Detrusor dyssynergia is most often seen with demyelinating disease. b. Thoracic cord (long standing): 1) Urgency, frequency, small amounts voided 2) Detrusor dyssynergia. There has to be coordination between contraction of Onuf’s nucleus (S2–S4) and the external sphincter (L5–S1). c. Lumbar cord: 1) Frequency (often irritation of L5–S1 roots) 2) Incomplete emptying of the bladder (30–40 cc residual) stimulates the trigone. Incomplete emptying with large residuals (>300 cc) causes overflow incontinence. Severe infections such as tabes dorsalis and CMV can affect the roots and cause failure of bladder contraction as well as insensibility. Severe neuropathies such as diabetes and toxins are also noted as causes of an overflow bladder. Conus Medullaris: a. Severe inability to contract the detrusor muscle. This does not occur with ALS as Onuf’s nucleus does not degenerate. In many multiple system atrophies, glial inclusions are seen in this nucleus which is occasionally reflected as incontinence. b. Bladder retention with constant overflow incontinence Ataxia of the Legs: a. Often an overlooked complaint with external compression of the spinal cord. b. Caused by pressure on dorsal and ventral spinocerebellar pathways which occupy the lateral components of the spinal cord c. Over shadowed by leg weakness Mass reflex with long standing spasticity: a. Flexion withdrawal (spontaneous or stimulus induced) b. Defecation c. Urination d. Rarely reflex erection and ejaculation e. Usually often spinal cord injury Lhermitte’s sign: a. Dorsal column irritation most often, but not limited to the cervical cord b. Paresthesias may be felt in the arms, legs or straight down the spinal column Sacral sensory sparing:
a. Occurs with central cord lesions: tumors, syrinx, demyelinating disease 9. Thoracic-abdominal signs: a. Beevor’s sign, thoracic umbilical reflex, superficial umbilical reflex; intercostal contraction with breathing-all help to localize a lesion at the thoracic level. Unilateral segmental sweating has been noted with thoracic lesions. Severe segmental dynamic and static allodynia is often associated with HZ that presents without rash (“sine herpeticum”). Rarely tabes dorsalis causes shooting thoracic and abdominal pain as do the neurological causes of porphyria. The most commonly missed thoracic nerve lesion is the intercosticobrachial nerve that is derived from the medial cord of the brachial plexus. The upper component of the nerve innervates the anterior chest wall while the lower component subserves the lateral chest wall and radiates under the breast to the epigastrium.
Cervical Drifts
A lateral drift of the outstretched upper extremities may be seen with cervical cord lesions (decreased proprioception from the cuneocerebellar tract). Severe updrift with ataxia through all components of movement in association with polyminimyoclonus (abnormal finger movements) is characteristic of dorsal column nuclear lesions from Richter’s variant of GBS or DRG large neuropathies.
Babinski Sign
If the sign is elicited by stroking just to the midfoot, the pathology is either very long standing or in the spinal cord. The toe is frequently spontaneously extended. Severe basal ganglia disease may give a dystonic extensor plantar response.
Segmental Atrophy
This sign is most often seen with intramedullary lesions such as a syrinx. The patient may be anesthetic in this area due to destruction of the dorsal horn.
Fasciculations
The more fasciculations noted, the closer the lesion is to the anterior horn cell.
Chapter 2. Congenital Defects of the Spinal Cord Crossed Adductor Reflex
This implies a deficit of spinal cord inhibition. When noted, the patient is suffering from long standing cervical or thoracic cord disease. It may, of course, be seen in any long standing corticospinal tract lesion.
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2) Bony defects secondary to axial mesodermal development without a persistent open neural tube. These are encephaloceles and meningoceles in which there is herniation of the neural tube through a bony defect. In spina bifida occulta and diastematomyelia the defects are entirely skin covered.
The Clavicular Biceps Reflex
Neural Tube Closure Defects
Striking the clavicle and obtaining a hyperactive biceps reflex allows the examiner to note that the lesion must be above C5–C6. (If there is hyperreflexia of the jaw jerk, the process is most likely diffuse and degenerative. A hyperactive jaw jerk means disinhibition of the mid pons). The inverted radial reflex and supinator reflex are characteristic of C5–C6 cervical cord lesions.
Craniorachischisis 1. General Considerations: a. Most severe dysraphism b. Brain and spinal cord are exposed to CSF 2. Clinical Features: a. Necrosis degeneration and angioma-like formation of the cord b. May have preserved optic nerve development
Cape Sensory Loss Myelomeningocele
Decreased sensation of the trapezius ridge, cap of the shoulder and anterior chest wall is strong evidence for a syrinx or other intramedullary lesion.
Dissociated Sensory Loss
Dorsal column modality loss that occurs acutely suggests infarction of the paired posterior medullary arteries. Loss of pain and temperature occurs with ventral cord (anterior spinal artery) or anterior commissure lesions such as a syrinx, intramedullary tumor, demyelinating disease, or compression from a disc.
Chapter 2 Congenital Defects of the Spinal Cord
Dysraphic Disorders (Neural Tube Defects)
General considerations: a. Primary neurulation occurs throughout the brain and spinal cord, to upper sacral levels. It occurs by a process of neural folding. b. Secondary neurulation occurs in the sacral and coccygeal regions by a process that canalizes a solid cord of cells. c. Axial malformations: 1) Failure of neural tube closure that is associated with skeletal modeling defects that occur around a malformed neural tube are anencephaly, meningomyelocele and craniorachischisis
1. General considerations: a. Meninges and spinal cord are herniated through a large vertebral defect 1) Distended meningeal sac filled with CSF and covered by a thin membrane or by skin 2) The spinal cord may be closed or there may be dilatation of the central canal with herniation of the posterior cord b. Myelocoele 1) A flat open spinal cord exposed to CSF 2) The spinal cord at the site of the defect is a flat, discoidal highly vascular mass known as the area medullovasculosa 3) The posterior spinal cord is open at birth 4) The nerve roots end within the vascular mass c. Clinical features: 1) Associated spinal anomalies are: a) Syringomyelia; hydromyelia; diastematomyelia, diplomyelia and double central canal 2) Hydrocephalus is common in association with Chiari Type II malformations 3) Lesions above T12 have a high incidence of other spinal cord malformations; more common in females than males 4) Low lesions have equal sex incidences; but are less severe clinically
Meningocele
1. General considerations: a. A variant of spina bifida cystica
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SECTION IV. Spinal Cord Disease
b. Vertebral defect combined with a cystic lesion of the back c. Usually at the lumbosacral level d. The dura and arachnoid are herniated through the vertebral defect; the spinal cord remains in the canal e. Narrow canal connects the cyst with the vertebral canal 2. Clinical features: a. Associated diastematomyelia, tethered cord and hydromyelia b. Insensibility of lower extremities; bladder; bowel and sexual dysfunction; weakness and wasting of all muscles below the knees; areflexia at the knee and ankle.
Spina Bifida Occulta
1. General considerations: a. Least severe of the neural tube defects b. Closed defect of the embryonic neural bud that undergoes secondary canalization 3. Clinical features: a. Associated sacral agenesis; anomalies of the anorectal and urogenital systems b. Associated spinal cord anomalies are: hydromyelia, diplomyelia (longitudinal splitting or duplication of the cord); tethering e. Defects are low lumbar and sacral f. Associated sacrococcygeal teratoma and lipoma g. Pes cavus and neurogenic bladder occur; other abnormalities of micturition; wasting and sensory loss of the affected roots
Syringomyelia
1. General considerations: a. Lower cervical cord is the most common location; lumbar may cause the most pronounced deficits b. Found in association with Type I Arnold-Chiari malformations in 40% of patients; can be asymmetrical c. Incomplete fusion of the posterior columns or the persistence of the large canal of the embryonic state; may be focal and asymptomatic d. Normal ependymal lining becomes gliotic: e. The syrinx may originate at the base of the posterior horn and extend into the central grey and anterior commissure 2. Clinical features: a. Loss of pain and temperature at the segmental level. A suspended sensory loss: normal sensation above and below the lesion b. Light touch, vibration, position sensibility is relatively spared
c. Amyotrophy of muscles innervated by specifically involved anterior horn cells (cervical cord-intrinsic hand muscles; frequently the 4th and 5th finger extensors; benediction sign) d. Claw hand in late stages (both thenar and hypothenar eminences are involved-“main en Graeffe”) e. Weakness and atrophy is often asymmetric f. Horner’s sign (C8–T1 involvement); destruction of the sympathetic ciliary center of Budge g. Bowel and bladder involvement is late h. Loss of segmental reflexes at the involved level; hyperactive reflexes below this level i. Babinski sign is present with corticospinal tract involvement j. Pain may be severe early in the course of the illness; deep ache or burning quality k. Associated syringobulbia may occur; usually at the junction of the alar and basal palate (level of the vestibular nuclei laterally in the medulla) l. Severe thoracic scoliosis is common m. Rarely there is extension into the centrum semiovale (syringoencephalia) n. Charcot joints occur (shoulder, thoracic spine or hip; rarely at the elbow and wrist) due to lack of proprioception, pain and from repeated trauma o. Autonomic dysfunction of the hands; diffuse swelling and subcutaneous edema (neurogenic edema) p. Associated with Chiari I, small posterior fossa
Lumbar Syrinx
1. Clinical features: a. Atrophy of proximal and distal leg muscles b. Dissociated sensory loss in lumbar and sacral dermatomes c. Loss of deep tendon reflexes d. Bowel and bladder dysfunction; severe if Onuf’s nucleus S2–S4 is involved e. Extensor toe signs
Diplomyelia (Duplication of the Cord)
1. General consideration: a. Two complete spinal cords wrapped in their own dura b. May coexist with diastematomyelia 2. Clinical features: a. Spasticity with a neurogenic bladder
Diastematomyelia
1. General features:
Chapter 2. Congenital Defects of the Spinal Cord
a. A fibrous band that splits the spinal cord; attached from the superior dura to the spinal canal b. More common: thoracic > cervical > lumbar 3. Clinical features: a. Spasticity of the legs b. Bowel and bladder dysfunction c. Loss of lower extremity deep tendon reflexes
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Neurogenic Cyst
1. General considerations: a. Occur in the ventral thoracic cord b. Early developmental defeat 2. Clinical features: a. Compression of the cord with weakness, spasticity and bladder dysfunction
Tethered Cord
1. General considerations: a. Fibrous filum terminale attaches to the sacrum; cord is pulled down; conus medullaris is then below L1 2. Clinical features: a. Often first manifest in middle age b. Women may have lower leg weakness if maintained in the dorsal lithotomy position (childbirth or prolonged vaginal procedures) c. Pes cavus (asymmetric) d. Bladder dysfunction e. Hyperactive reflexes f. Often associated with lipoma of the sacral cord (bright on T1 weighted MRI) Chiari Malformations
1. General considerations: a. Chiari I 1) Cerebellar tonsillar herniation 2) Tonsils are often atrophic, sclerotic and connected by fibrous adhesions to the back of the medulla 3) Cervical roots angled slightly upwards (by myelography) 4) May be asymptomatic 5) Often associated with late onset hydrocephalus and cerebellar ataxia 6) 50% of patients have syringomyelia; 90% of idiopathic syringomyelia patients have a Chiari I malformation 7) Rare familial occurrence of Chiari I and syringomyelia occurs. It is also associated with craniocervical anomalies (platybasia, basilar impression, Klippel–Feil suboccipital dysplasia, and craniosynostosis) 2. Clinical features: a. Signs of a cervical syrinx b. Severe C2 headache with any Valsalva maneuver, but particularly with cough c. Ataxia of upper and lower extremities. Often symptomatic in mid-life; ataxia of gait is the most prominent feature in this instance d. Small slanted posterior fossa, short neck, low set hairline e. Occasional down beat nystagmus exacerbated on lateral gaze
Off Midline Skin Malformations with Underlying Developmental Defects
1. Dimples (dysraphism) 2. Hair patch (AVM, dysraphism) 3. Large hairy mole (malignant melanosis of the dura)
Congenital Bony Defects that Compromise the Spinal Cord or Root Exit Foramina
Developmental Spinal Stenosis 1. General considerations: a. Measurements: 1) Cervical cord C2–C7, 24–26 mm 2) Thoracic cord > than 14 mm 3) Lumbar cord L1–L2 > 24–26 mm 2. Block vertebrae (all achondroplasia patients) 3. Short pedicle syndrome (lumbar) 4. Trefoil configuration of the canal (lumbosacral levels) 5. Lateral recess stenosis (primarily at L5–S1 levels)
Achondroplasia
1. General considerations: a. Block vertebrae at all levels of the spinal cord b. Stenosis at the foramen magnum and lower thoracic levels 2. Clinical features: a. Stenosis of T10–T12, L1–L2 1) Severe pain in an upper lumbar distribution 2) Bowel and bladder dysfunction b. Stenosis of the foramen magnum causes: 1) Automatic breathing deficit (Ondine’s curse); most frequently seen after foramen magnum decompression 2) Spastic quadriparesis
Congenital Abnormalities of the Cervical Vertebrae and Foramen Magnum
A. General considerations: 1. Anatomy of the atlas and axis:
SECTION IV. Spinal Cord Disease
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a. The atlas has a ring like structure, but no vertebral body b. It has synovial articulations with the occipital condyles of the skull and caudally with the odontoid process c. The odontoid process has 3 major ligaments that anchor it to the skull: 1) Posterior cruciate (most important) 2) Two lateral alar ligaments 3) In an adult during flexion the atlas should not move more than 3 mm from the axis. In children the separation is 5 mm d. The tip of the odontoid process should not extend rostrally more than 3 mm above a line from the hard palate to the inner table of the skull at the foramen magnum (Chamberlain’s line). Bull’s and the digastric line are other measurements of this parameter that are rarely used
Occipitalization of the Atlas
A. General consideration: 1. A congenital fusion of the atlas and foramen magnum 2. Neurological symptoms occur when the anterior– posterior diameter of the spinal canal posterior to the dens is less than 19 mm B. Clinical features: 1. Spastic quadriparesis 2. Ataxia of legs greater than arms
Basilar Invagination
A. General considerations: 1. The odontoid process is > 3 mm above Chamberlain’s line 2. The cervical spinal cord is compressed B. Clinical features: 1. Paresthesias of the hands 2. Lhermitte’s sign with neck flexion 3. Sudden medullary compression with cardiac arrhythmia, respiratory arrest and sudden death 4. Symptoms develop in childhood or early adult life 5. The head may be elongated with a decreased vertical diameter 6. Short neck; decreased range of motion to all planes 7. Ataxia; legs > arms 8. Spastic quadriparesis 9. Rarely, papilledema (CSF obstruction); subarachnoid block in many patients 10. Increased CSF protein in 50%
Platybasia
A. General considerations: 1. A flattening of the base of the skull. The normal angle between the planum sphenoidale and the clivus is 135◦ If this angle is increased to >135◦ there is platybasia 2. Possible AD inheritance males > females 3. Associated with other skull base defects: a. Maldevelopment or hypoplasia of the basiocciput b. Partial or complete atlanto-occipital fusion c. Atlantoaxial dislocation d. Stenosis of the foramen magnum 4. Distortion of the pons, medulla, cerebellum; traction on lower cranial nerves 5. Vertebral artery obstruction with head turning B. Clinical features: 1. Vertigo and drop attacks with head turning (obstruction of the vertebral artery) 2. Intermittent hoarseness and swallowing abnormalities due to traction of the lower cranial nerves 3. Spastic quadriparesis; ataxia legs > arms 4. Can be acquired with: a. Paget’s disease b. Osteogenesis imperfecta c. Rickets’ d. Rheumatoid arthritis
Malformations of the Axis and Atlas
A. General considerations: 1. There are five ossification centers in the axis and atlas that may develop abnormally: a. The body and tip of the axis b. The lateral mass of C1 and the central part of the axis c. A fracture through the most rostral ossification center of the odontoid separates the tip from the body and is frequently asymptomatic d. These malformations may occur concomitantly with basilar impression or independently
Dens Atresia
A. General considerations: 1. Part of the odontoid process is fused to the body of C2 2. Anterior dislocation of the axis with cord compression B. Clinical features: 1. Spastic quadriplegia 2. IX, X, XI (spinal accessory component XII involved by traction) 3. Head movement causes pain 4. Mild sensory loss or paresthesias in cervical dermatomes 5. Respiratory involvement
Chapter 3. Vertebral Column Bony Trauma Odontoid Process ossification defects
1. Tip of the odontoid process fracture; usually asymptomatic and occurs with violent head flexion 2. Base of the odontoid fails to ossify; concomitant basilar invagination
Gorlin’s Syndrome
1. Short atlas 2. Odontoid malformations
Congenital Fusion of Cervical Vertebrae
A. General considerations: 1. Congenital fusion of cervical vertebrae is most common at C4–C5 2. Fusion of the upper thoracic and entire cervical spine occurs 3. AD and AR inheritance B. Clinical features: 1. Short neck and low hair line 2. Limitation of neck movement to the lateral planes 3. Spinal stenosis occurs above and below the congenital fusion 4. Associated clinical signs: a. Syringomyelia b. Cardiovascular defects 4% c. Genitourinary anomalies 2% d. Congenital deafness (faulty development of the osseous inner ear) e. Sprengel’s deformity (branchiomeric deformity at C4–C5; elevation and maldevelopment of the shoulder and scapula)
Spina Bifida
A. General considerations: 1. Mild dysraphic defect 2. Asymptomatic unless associated with other congenital deficits: a. Myelomeningocele b. Neurenteric or other cysts c. Lipoma d. Tethered cord
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the usual acquired causes are present such as Paget’s disease, osteogenesis imperfecta (blue sclera) and rheumatoid arthritis (ulnar hand deviation) and rarely rickets, the diagnosis should be suspected. Intermittent lower cranial nerve involvement, particularly hoarseness is common as intermittent brainstem vascular insufficiency with movement of the head to the lateral planes causes vertebral artery occlusion. In a patient with increased reflexes induced by neck flexion, there may excess mobility of the spine at C1–C2. This is often accompanied by paresthesias of the hands. A short neck with low hairline and a shallow posterior fossa should also be sought which is common with osseous cervical congenital malformations. Chiari I malformation are often associated with a cervical syrinx. Hoarseness and ataxia point to this diagnosis as does a severe C2 headache with cough. An acquired thoracic spine scoliosis or kyphoscoliosis point to a reduplication or diastematomyelia of the cord. If the scoliosis is C shaped, there is disruption of paraspinal musculature unilaterally. If there is an S shaped defect, it is a congenital defect with compensation. An astrocytoma may also grow asymmetrically and motor neuron disease and primary muscle disease may affect paraspinal musculature asymmetrically causing a “C” scolioisis. Severe scoliosis and kyphosis are also seen with Emery–Dreifuss muscular dystrophy, fiber type disproportion and limb girdle muscular dystrophy type II B (LGMDIIB). Syrinxes are frequently asymmetric and may extend from the cervical to the sacral cord, producing a C shaped scoliosis. Burns on the hands and arms, as well as suspended sensory loss and segmental atrophy, identify this diagnosis. A tethered cord often is announced in young adults during delivery. A prolonged dorsal lithotomy position during a difficult birth may cause paralysis of the legs. Tufts of hair and strawberry hemangiomas of the skin often have underlying spinal and vertebral body defects. These include spinal bifida, A-V malformations and myelomeningoceles. A tuft of hair off the midline may be the marker of a neurogenic cyst that connects with the intradural space. A patient with a short neck and abnormally raised and malformed shoulder and scapula has Klippel Feil syndrome with Sprengel’s deformity.
Chapter 3 Vertebral Column Bony Trauma Mechanisms of Injury
Differential Diagnosis of Congenital Spine Defects
The general physical examination is most helpful with this differential diagnosis. A patient with a short neck with limited lateral movement suggests basilar impression or platybasia. If
1. Sudden violent flexion (cervical vertebrae): a. Anterior compression fracture of vertebral bodies b. Unilateral or bilateral facet joint dislocation c. Kinking and rupture of the longitudinal and interspinous ligaments
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2.
3.
4. 5.
SECTION IV. Spinal Cord Disease
d. Extrusion of discs has also occurred while holding patients in flexion in preparation for an LP. Severe compression injures: a. Affecting the thoracic lumbar area (ski injuries, falls) b. Burst vertebral bodies (central area of compression with fracture lines radiating outwardly) c. Bone splinters and disc material may extrude into the spinal canal and compress the spinal cord d. Common in elderly osteoporotic women from minimal trauma (opening a window). Usually only local pain with no neurologic deficit (anterior wedge fracture of the thoracic vertebrae) Rotational injury: a. Unilateral pars interarticularis fracture or facet injury b. Rotary facet dislocation. Very difficult to see radiologically. Must be suspected from increased intraspinal distance at that level and persistent focal spine pain (rupture of an interspinal ligament). Jumped facets; the superior facets are displaced anteriorly Hyperextension injury: a. Fracture of the posterior elements with evolving spondylolisthesis at the affected level.
Parenchymatous Cord Trauma
A. General considerations: 1. Incidence 30–40/1,000,000 population 2. Prevalence 900/1,000,000 population 3. 65% of patients are less than 35 years of age 4. Male to female ratio of 3 : 1 5. Second peak occurs between 55–59 years of age 6. Greatest during the summer months and on weekends B. Causes: 1. Motor vehicle accidents a. Single and multiple vehicular accidents b. Motorcycle c. Injuries to pedestrians d. Industrial accidents e. Diving into shallow water f. Sports injuries g. Gunshot wounds h. Stabbing i. Non-industrial falls (elderly patients); cement stairs leading to the basement
Patterns of Spinal Cord Injury Fracture and Dislocations
1. 2. 3. 4. 5. 6. 7. 8.
Jefferson’s fracture (fracture of the atlas) A ring fracture Vertebral body burst fracture Hangman’s fracture (C2–C3 spondylolisthesis) Jumped and locked facet joints Bony canal fracture with cord compression Rotary facet subluxation Odontoid fracture: a. Tip (distal 2–3 mm) b. Base (ossification center) c. Disruption of the cruciate, alar and lateral ligaments 9. Post surgical: a. Severe neck deformity b. Posterior displacement of a bone c. Two level instability d. Overgrowth of a lateral bone graft with stenosis of the canal 10. Rotary injury: atlantooccipital subluxation
Hyperflexion Injury
1. Subluxation 2. Facet joint dislocation 3. Compression of the anterior portion of the vertebral body with fracture and bone fragments that compress the spinal cord
1. 2. 3. 4.
Cord concussion Spinal shock Complete cord transaction (rare) Incomplete cord transaction: a. Brown–Sequard syndrome b. Central cord syndrome c. Anterior cord syndrome d. Posterior cord syndrome 5. Associated injuries: a. Vertebral artery occlusion (cervical cord injury) b. Cauda equina injury c. Conus medullaris injury d. Mixed epiconus, conus and cauda equina lesions 6. Spinal cord concussion: a. Transient neurological symptoms with full recovery in minutes to hours b. Signs develop below the level of injury
Spinal Shock
A. Clinical features: 1. Complete flaccid paralysis below the level of the lesion 2. Anesthesia below the level of the lesion 3. Incontinence of bowel and bladder 4. Areflexia below the level of the lesion 5. Babinski response plantar (muscles are paralyzed); maybe present or intermediate toes are seen (quivering extension/flexion movements); probably equivalent to a Babinski response.
Chapter 3. Vertebral Column Bony Trauma
6. Areflexic hypotonic state changes to hyperreflexia within six weeks (in general) 7. Complete transection of the cord: a. Rare; they are most often caused by a high velocity missile, knife wound or vehicular accident b. Most injuries are bruises that evolve their pathology (ovoid) and extend over time c. Motor, sensory and autonomic dysfunction occurs below the level of the injury d. In chronic patients: 1) Autonomic dysreflexia occurs if not treated with adrenergic blocking drugs. The syndrome consists of: a) Severe hypertension 250–300 mmHg/200 mmHg b) Hyperhidrosis c) Severe headache that is vascular in nature d) Seizures (during the headache phase) e) Intracranial hemorrhage
Brown–Sequard Syndrome
A. General considerations: 1. X-RT to the cord from the treatment of malignancy; usually Hodgkin’s disease, Ewing’s sarcoma, chordoma or non-Hodgkin’s lymphoma. Usual dose is >3000 rads. There is little soft tissue in the neck to absorb radiation. Pathology is a proliferating endarteritis of the sulcal arteries 2. Rarely a knife, bullet or accidental cause has been described. If occurs with demyelinating disease, tumor and tuberculoma. 3. Vertical hemisection of the cord: a. Ipsilateral paralysis below the level of the lesion b. Ipsilateral loss of vibration proprioception, and light touch sensibility (partial) c. Contralateral loss of pain and temperature sensibility d. Bowel, bladder and sexual function is intact e. Ipsilateral segmental loss of sensation or weakness at the appropriate level (destruction of the spinal grey matter at the level of injury)
Central Cord Syndrome
A. General considerations: 1. Usually caused by a hyperextension injury of the neck (fall or automobile accident) 2. Clinical features: a. Hands and arms are more affected than the legs due to lamination of the corticospinal tracts within the cord; brachial plexus traction injury may contribute to the arm weakness.
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b. Sensory loss in the legs and arms is incomplete with sacral sparing. Pressure sensation may be lost in adductor muscles while pin prick and cold can be appreciated (lamination of the spinothalamic tract) c. Acute urinary retention occurs in 50% of patients. Most patients regain bowel, bladder and sexual function d. Visceral pain may be diminished due to its ventral position in the dorsal columns e. Hyperactive reflexes and Babinski sign are present
Anterior Cervical Cord Syndrome
A. General considerations: 1. Acutely ruptured disc with or without fracture 2. Abnormally prolonged and tight neck flexion (children or adults forcibly flexed during an LP) 3. Fracture dislocation of the cervical cord B. Clinical features: 1. Immediate paralysis 2. Loss of pain and temperature sensibility below the lesion 3. Preservation of proprioception and vibration sense below the lesion 4. Urinary retention
Posterior Cord Syndrome
A. General considerations: 1. Differential diagnosis: a. Demyelinating disease b. Sjögren’s syndrome c. B12 deficiency d. Trauma e. Tabes dorsalis (most often a root entry zone lesion) f. Tumor B. Clinical features: 1. Loss of vibration and proprioception. Often may best be determined by placing the tuning fork over the spinous processes. 2. Severe proprioceptive loss in the arms and legs; patients are unable to walk in the dark 3. Updrift of the arms with minimyoclonus of the fingers; a lateral drift occurs bilaterally 4. Dorsal column nuclear involvement causes wild movement of the arms 5. Trauma as a cause may have associated burning pain and paresthesia of the hands 6. Lhermitte’s sign is noted with structured lesions irritating the posterior columns.
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SECTION IV. Spinal Cord Disease
Associated Cervical Cord Traumatic Injuries
A. General considerations: 1. Vertebral artery occlusion from injury in the transcervical canal 2. Dissection may occur at the C2 level B. Clinical features: 1. Rotary nystagmus is ipsilateral > contralateral 2. Involvement of cranial nerves IX, X, XI; XII is involved if the hypoglossal canal is injured at the foramen magnum 3. Pain in the side of the neck; rarely projects specifically to the lateral eyebrow 4. Ipsilateral peripheral or central Horner’s syndrome; peripheral origin is from trauma to the carotid sheath or artery; sympathetics to the eye originate from C8–T1 and wrap around the carotid artery. 5. Ipsilateral Vth nerve involvement; VIth passes through the foramen magnum (upper division VI ) 6. Contralateral loss of pain and temperature below the clavicle 7. Ipsilateral ataxia; leg > arm; patients have lateral pulsion (feeling of being pushed) to the ipsilateral side 8. Nausea and vomiting; hoarseness; infarction of the nucleus ambiguous 9. Prolonged depressed level of consciousness
Epiconus Lesions
A. General considerations: 1. Traumatic; sudden compression injuries of the thoracic spine; falls, ski and motor vehicular accidents 2. Metastatic tumor of the spinal cord 3. Embolic occlusion of the great radicular artery of Adamkiewicz (origin is T10–T12–L1–L2). 4. Aortic surgical procedures; iliac artery or ligature of the ilioinguinal branch that is the origin of the radicular artery of Adamkiewicz 5. T10–T12 is involved primarily B. Clinical features: 1. Bilateral symmetrical leg weakness 2. Sensory level at L1–L2 3. Bowel, bladder and sexual dysfunction 4. Babinski signs are present; the spinal cord ends at the spinal level of S5, but the vertebral level is L1–L2
c. Enlarged nerve roots (congenital peripheral neuropathies) d. Metastatic tumors: colon, lung, breast, lymphoma, prostate are common e. Vertebral fractures with posterior displacement of bone fragments into the spinal canal B. Clinical features: 1. Asymmetric motor and sensory loss 2. Severe pain (usually L5–S1 distribution) 3. Perineal sensory anesthesias (“saddle distribution”) 4. Bowel and bladder dysfunction (obstipation and retention respectively) 5. Areflexic paralysis and sensory loss of the affected roots
Conus Medullaris Lesions
A. General considerations: 1. Differential diagnosis of these lesions is: a. Demyelinating disease in younger patients b. Glioma and chordoma are the primary tumors; metastatic tumors similar to those for the cauda equina c. Syrinx d. Disc fragment e. Lipoma f. Liposarcoma g. Glioma of the filum terminale B. Clinical features: 1. Symmetric if adjacent roots are involved 2. Painless 3. Bowel, bladder and sexual dysfunction are the earliest manifestation 4. Dissociated sexual dysfunction may occur. Patients may have erection without ejaculation or vice versa
Post Traumatic Syringomyelia
A. General considerations: 1. A syrinx appears in a region of spinal cord injury due to phagocytosis of tissue debris; the cavities are surrounded by gliosis and have connective tissue in their walls (not seen in a congenital syrinx) B. Clinical features: 1. A syrinx cavity after injury may extend cephalad into previous uninjured tissue with the expected deficits
Cauda Equina Level Arachnoiditis
A. General considerations: 1. The differential diagnosis for lesions at this level is: a. Disc protrusion b. Spinal stenosis
A. General considerations: 1. Arachnoiditis is a chronic inflammatory response of the spinal arachnoid and pial membrane
Chapter 4. Vascular Anatomy of the Spinal Cord
B. Clinical features: 1. Burning patchy pain over several nerve root distributions 2. Motor power of the roots is relatively well maintained 3. Bladder and bowel may be involved 4. Reflexes are decreased or absent in a patchy distribution C. Pathology 1. The spinal cord and roots are encased by leptomeningeal fibrous tissue and loculated cysts. Rarely, the walls of arteries and veins are thickened (demonstrated by an autopsy series of arachnoiditis patients whose illness was caused by contaminated diluent in an anesthetic solution). D. Imaging evaluation: 1. MRI evaluation reveals clumped nerve roots in the center of the dural sac. Myelography with contrast demonstrates a featureless dural sac.
Chapter 4 Vascular Anatomy of the Spinal Cord
A. General considerations: 1. The arterial blood supply to the spinal cord can be divided into a superior, intermediate and inferior zone B. The superior territory: 1. The cervical cord (C1–T1–T2) receives its blood supply from branches of the vertebral arteries that derive from the subclavian arteries. At the level of the foramen magnum, the vertebral arteries give off medial branches that join to form the anterior spinal artery which lies ventrally in the midline. a. The anterior portion of the anterior spinal artery supplies C1–C4 spinal segments b. Two to four radicular arteries from the vertebral arteries in the transcervical canal or from cervical branches of the subclavian artery contribute to the blood supply of the mid and lower cervical segments. c. C8–T1 is the most vulnerable level of the cervical cord for ischemic injury. C. The intermediate territory (T3–T8): 1. Is supplied by the dorsal radicular artery that travels with the 5th, 6th or 7th thoracic anterior root. D. The Inferior Arterial Territory 1. T8–S5 is supplied by the great radicular artery of Adamkiewicz. a. Usually derives from radicular arteries from T1– L1–L2.
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Intrinsic Vascular Anatomy of the spinal cord
1. Radicular arteries enter at each spinal level: a. They divide and accompany the dorsal and ventral roots b. Ventral root branches join along the midline to form the anterior spinal artery c. Paired posterior spinal arteries form from anastomosis of the dorsal radicular branches d. Circumflex arteries anastomose with the anterior and posterior circulations at the lateral margins of the cord 2. Anterior sulcal arteries a. Arise from the anterior spinal artery and alternately supply: 1) The spinal grey matter 2) The anterior and lateral funiculi 3) Each anterior sulcal artery supplies one segment of the hemi chord 4) The greatest distance between sulcal arteries is in the thoracic cord b. Posterior spinal artery penetrating branches supply: 1) The dorsal columns 2) Upper most Rexed layers of the dorsal horn (I–IV) c. Circumflex anastomotic vessels (the anastomosing plexus of small arteries between the anterior and posterior vessels) supply the superficial white matter
Venous Drainage of the Spinal Cord
1. Radial veins drain the inner cord to form a coronal plexus 2. Deep parenchymal veins drain into central sulcal veins in the median fissure 3. Parenchymal veins drain both sides of the cord 4. Sulcal veins have intrasegmental anastomosis 5. Anterior median spinal vein: a. Drains the sulcal vein b. There may be two veins instead of one 6. Extramedullary venous channels: a. Common on the dorsal cord 7. Eight-twelve anterior radicular veins arise from the anterior to median vein: a. Drain the anterolateral anastomosis from the coronal venous plexus b. The junction of the anterior radicular vein and the coronal venous plexus is at the nerve roots prior to their exit through the dura 8. The lumbar enlargement is drained by the vena radicularis magna 9. Posterior radicular veins are most prominent in the cervical cord 10. Spinal cord venous blood drains into: a. Epidural and paravertebral plexus 1) This is a valveless system b. It extend from the occipital bone to the sacrum
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SECTION IV. Spinal Cord Disease
Causes of Spinal Cord Ischemia
1. Transient ischemic attacks of the cord occur (weakness and numbness that lasts 2–15 minutes) a. Cholesterol emboli b. Fibrocartilaginous emboli 2. Venous occlusion (secondary to severe cervical stenosis or spondylosis) is posited to cause progressive myelopathy 3. Spinal cord infarction: a. Paresis within minutes of the ictus b. Recovery of function is rare if total paralysis lasts for 24 hours 4. Watershed infarction with hypoperfusion is usually overshadowed by cerebral signs and symptoms. The spinal cord is perfused at a much lower pressure than the brain.
Clinical Features of Spinal Cord Ischemia
1. Weakness: a. May be gradual or maximal at onset b. Paraparesis > quadriparesis (midthoracic T4–T6 watershed) 2. Sensory loss: a. Numbness or paresthesias will parallel the weakness; may precede it b. Aching back pain with radicular features is common c. Thoracic band like sensation or abdominal radiations are common d. Some form of sensory loss is invariant e. Suspended sensory loss with sulcal artery occlusions 3. Urinary and bowel dysfunction: a. Urinary retention > than incontinence b. Bowel incontinence later in the course 4. Flaccid paralysis noted early: a. Loss of superficial reflexes (cremasteric and abdominal) b. Areflexia below the lesion is usual: 1) Schiff–Sherrington response may occur above the lesion. Slightly increased reflexes (release of ascending inhibition) above the level of the lesion. 2) Hyperactive reflexes with Babinski’s response may occur if only a few spinal segments are ischemic.
Arterial Syndromes
4) Crural plegia (arm ipsilateral and leg contralateral) 2. Low anterior spinal artery infarction: a. Involvement of the ventral 2/3 of the spinal cord b. Weakness of extremities below the lesion c. Loss of temperature and pain below the lesion d. Bladder involved in 50% of patients e. Intact dorsal column sensory function
Causes of Anterior Spinal Artery Syndrome
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Atherosclerosis of the artery or its feeding vessels Vertebral artery dissection Syphilis (Erb’s spastic paraparesis) Compression from extruded disc or bone fragment Sarcoid (meningeal involvement or vasculitis) Vasculitis (SLE, Wegener’s granulomatosis, collagen vascular disease) Embolus (heart, atrial myxoma, atrial fibrillation); cholesterol emboli Idiopathic pachymeningitis Aortic dissection Giant cell arteritis Takayasu’s disease Bends (nitrogen bubbles) Ischemic atherosclerotic emboli less frequent than asymptomatic emboli Hypoperfusion: a. Lumbosacral > cervical > cervicothoracic Fibrocartilaginous emboli: a. Women > men b. Mid to low thoracic levels
Ischemia of Lower Thoracic Cord and the Lumbar Enlargement by Involvement of the artery of Adamkiewicz
1. 2. 3. 4. 5.
Renal arteriogram Surgical procedures (cross clamping the aorta) Aortic dissection Atherosclerosis Emboli: heart; cholesterol; air; nitrogen bubbles, fibrocartilaginous 6. Aortic dissection
Anterior Spinal Artery Ischemia
1. Origin of the anterior spinal from the vertebral artery a. Atherosclerosis of the vertebral artery b. Medial medullary syndrome 1) Ipsilateral XII nerve paralysis 2) Contralateral proprioceptive and vibratory deficit 3) Contralateral weakness of arm and leg (above the decussation of the pyramidal tract at C2)
Watershed Infarction of T4–T6
A. General considerations: 1. The spinal cord is perfused at a much lower pressure 60–70 mmHg than the brain 2. Infarction of the spinal cord is frequently overshadowed by cerebral signs and symptoms
Chapter 4. Vascular Anatomy of the Spinal Cord
3. Dropped sensory levels to T4–T6 frequently occur from cervical cord disease (lamination of the spinothalamic tract) 4. Internal watershed zones in the spinal cord are the: a. Corticospinal pathways b. Rexed layers V–VI 5. Selective grey matter necrosis does occur 6. Most susceptible region to low flow states is T4–T6 7. Causes of thoracic watershed infarction: a. Systemic hypotension b. Prolonged surgical procedures c. Cardiac arrest d. Anoxia e. Vertebral artery occlusion (primary involvement may be C8–T1) f. Aortic dissection g. Carbon monoxide poisoning
Posterior Spinal Artery Ischemia
A. General considerations: 1. Extremely rare 2. Atherosclerosis 3. Dissection or occlusion of the vertebral arteries B. Clinical features: 1. Severe sensory ataxia (particularly without vision) 2. Loss of vibration and position sense C. Medical Causes of Ischemic Spinal Cord Disease 1. Atherosclerosis 2. Systemic hypotension 3. Collagen vascular disease (PAN, SLE) 4. Thromboangiitis obliterans (Buerger’s Disease) 5. Aortic arch syndrome; coarctation of the aorta 6. Dissection of the aorta (infarction of grey matter; superficial white matter) 7. Neoplastic endarteritis (malignant angioendotheliosis) 8. Infective endarteritis: a. Syphilis c. HIV b. Cryptococcus 9. Fungal invasion of blood vessels: a. Mucormycosis c. Aspergillosis b. Nocardia 10. Illicit drugs: a. Cocaine c. Amphetamine b. Propalolamine 11. Disseminated intravascular coagulation 12. Prothrombotic states 13. Aortic atherosclerosis (feeding vessels; emboli) 14. Aortic aneurysm 15. Aortic surgery (particularly cross clamping > 18 minutes) a. Abdominal aortic aneurysms; cord and cauda equina may be infracted
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16. Ligation of lower thoracic intercostal vessels 17. Nonpenetrating abdominal trauma (torsional occlusion of vessels supplying the cord) 18. X-RT (intraspinal vessels from proliferative endarteritis)
Embolic Disease of the Spinal Cord
1. Atheromatous aortic plaque a. Blue toe syndrome (abdominal aorta) b. Digital arteries of the toes are occluded 2. Cardiac source: a. Atrial fibrillation b. Embolus c. Infective endocarditis (bacteria; fungi) d. Mitral valve prolapse e. Valvular clots f. Atrial myxoma 3. Fibrocartilaginous debris (disc) a. Anterior portion of the cervical cord b. May occlude veins c. Women > men d. Rapidly evolving tetra or paraparesis e. Rarely following trauma f. Anterior spinal artery territory most often affected; mid to low thoracic level 4. Angiography: a. Catheterization for dural AVM 5. Fat: a. Broken bones (long bones) in young patients b. Hip replacement (older patients) c. Diabetic ketoacidosis 6. Tumor cells 7. Nitrogen bubble (Caisson’s disease) 8. Air bubbles a. Diving accidents (scuba) b. Cardiac surgery c. Surgical procedures in sitting position (ENT) 9. Therapeutic renal artery embolization
Venous Infarction of the Spinal Cord
A. General considerations: 1. Venous infarctions without hemorrhage are hard to distinguish from arterial infarction B. Causes of venous infarction of the spinal cord: 1. Extension of thrombophlebitis of pelvic veins 2. Associated with chronic obstructive pulmonary disease 3. Polycythemia vera 4. Associated thrombophlebitis: a. Propagates into cord via venous plexus 5. Subacute necrotizing myelitis:
SECTION IV. Spinal Cord Disease
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6. 7. 8.
9. 10. 11. 12. 13. 14.
a. Associated with spinal cord thrombophlebitis b. No systemic foci c. Association with chronic obstructive pulmonary disease Associated with epidural abscess Endoscopic sclerotherapy (reported for esophageal varices) Coagulopathy: a. Factor V Leiden with protein C resistance b. Anti-thrombin III c. Factor C deficiency d. Factor S deficiency e. Anti-phospholipid syndrome f. Lupus anticoagulant Cancer (prothrombotic states); breast and pancreas Subacute necrotizing myelopathy (paraneoplastic) Birth control pills Pregnancy Disseminated intravascular coagulation (LIC) Dehydration
b) Ischemia of the cord d. Onset of symptoms to diagnosis may be delayed e. Severe weakness in 20% of patients by six months after presentation; 50% by three years f. After onset of leg weakness further disability is rapidly progressive g. Pain may be local or radicular h. Spinal bruit (extremely rare) i. Upper and lower motor neuron weakness
Cobb’s Syndrome
A. General considerations: 1. Cutaneomeningospinal angiomatosis 2. Angiomas on large portions of the trunk 3. Dural angioma with cutaneous angioma in the corresponding dermatome or over many dermatomes B. Clinical features: 1. Spastic paraparesis at the appropriate level 2. Usually at thoracic level
Hemorrhagic Spinal Cord Disease
Angiomas
A. General considerations: 1. Spinal vascular malformations B. Tortuous group of dilated arteries and veins: 1. No intervening capillary network (cavernous hemangioma) a. May involve spinal cord, leptomeninges or both 2. Veins predominance (venous angioma) 3. Arterial predominance (arterial venous malformation) 4. Telangiectasis (capillaries) C. Epidemiology of angiomas: 1. Incidence is not known: a. Occur in 3–11% of spinal cord masses b. Men > women 2 : 1 c. Clinical presentation between 30–70 years of age d. Lower thoracic and lumbar angiomas are the most frequent e. Posterior or posterior lateral intraspinal location 2. Clinical signs and symptoms: a. Onset with pain, weakness and sensory symptoms b. Later bowel and bladder dysfunction c. Cervical lesions produce symptoms earlier d. Onset associated often with: 1) Exercise 2) Trauma 3) Pregnancy 4) Menstruation 5) May bleed during sleep 6) Angiomas may cause: a) Increased local venous pressure
Foix Alajouanine syndrome (Angiodysgenetic Necrotizing Myelopathy)
A. General considerations: 1. Men of middle to late adulthood 2. Clusters or masses of enlarged engorged subarachnoid veins; anterior predominance 3. Lower thoracic and lumbosacral segments are most commonly involved 4. Proliferation of small blood vessels (veins or capillaries) 5. Associated with a dural arteriovenous shunt generally within or near a root sleeve; arterialized venous shunts that drain into the venous system of the cord B. Clinical features: 1. Intermittent and progressive course 2. Asymmetrical clinical findings 3. Pain and sensory loss of the lower limbs 4. Bowel, bladder and sexual dysfunction 5. Spastic and amyotrophic lower extremities
Bannayan–Zonana Syndrome
A. General considerations: 1. AD spinal AVM 2. Most common in Mexican Americans 3. May hemorrhage B. Clinical features: 1. Spastic paraparesis at the appropriate spinal level 2. Associated with intracranial lesions
Chapter 4. Vascular Anatomy of the Spinal Cord
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Klippel–Weber–Trenaunay
Hematomyelia
A. General considerations: 1. AD B. Clinical features: 1. Enlarged extremity with dilated veins and telangiectasias 2. Corresponding AVM at the cervical or lumbosacral level with spastic paraparesis or radiculopathy
A. General considerations: 1. Trauma a. Direct injury to the spine (penetrating and nonpenetrating) b. Hyperextension of the cervical spine 2. Bleeding of a vascular malformation 3. Hemorrhage into a tumor 4. Hemorrhage into a syrinx 5. Coagulopathy 6. Anticoagulation (particularly coumadin) 7. Venous infarction 8. Syphilis B. Clinical features: 1. Presents as spinal shock associated with severe back pain 2. Autonomic instability 3. Gray matter more affected than white matter 4. Spasticity develops below the level of the lesion 5. Atrophy and fasciculations of affected segments occurs with time 6. Babinski’s sign is prominent 7. Sensory level: a. Two segments lower than the lesion (if thoracic) b. Higher in back than front (follows patterns of intercostal nerves) c. Dropped sensory level (T4–T6) following cervical lesions is common (lamination of spinothalamic tract) d. Rare suspended sensory loss (interruption of segmental dorsal horn at the level of injury with preserved long tract sensory function) e. Mass reflex late in the course of the illness
Differential Diagnosis of Spinal Angioma
1. 2. 3. 4. 5. 6. 7. 8.
Multiple sclerosis Neoplasm Herniated disc Spondylolisthesis Intracranial SAH (5% present with neck and back pain) Subacute combined degeneration (B12 deficiency) Transverse myelitis (all causes) Meningovascular syphilis
Spinal Hemorrhage
Differential diagnosis by location: 1. SAH 3. Subdural 2. Intramedullary 4. Epidural
Subarachnoid Hemorrhage in the Spinal Cord
A. General considerations: 1. Spinal SAH < 1% of all SAH 2. Most common cause is rupture of a spinal angioma (10%) B. Clinical features: 1. Acute onset 2. Severe back pain at the level of the hemorrhage 3. Pain quickly becomes diffuse with signs of meningeal irritation 4. Radiculopathy at the site of the lesion 5. If blood diffuses above the foramen magnum: a. Headache b. Cranial neuropathy c. Depressed level of consciousness d. Decreased ankle jerks with increased knee and upper extremity reflexes e. Increased intracranial pressure with papilledema (rare) 6. CSF: a. Hemorrhage (1,000,000 RBCs/mm3 ) b. Within days may have hypoglycorrhachia (severely depressed glucose 75–90% of patients 5. Some angiographic evidence for vascular steal phenomenon as a cause of symptoms 6. Dural arteriovenous fistula at the craniocervical junction: a. MRI evaluation: dilated perimedullary veins around the spinal cord C1–C2 b. High intensity T2 weighted signal in the spinal cord at appropriate levels on T2 weighted images D. Clinical presentations: 1. Present with SAH 2. Progressive myelopathy that may interfere with respiration 3. Intramedullary arteriovenous malformation may occur with lipomyelomeningocele a. MRI: 1) Hypervascular intradural lesion; fatty component extradurally
Intramedullary Spinal Cord Cavernous Malformation (IMSCM)
A. General considerations: 1. Cervical and thoracic cord most common level; rare in the conus medullaris 2. Intramedullary spinal cavernous malformations are associated with cryptic venous malformations 3. May develop tethering of the cord following surgery 4. Episodic, acute or subacute spinal cord dysfunction 5. Appropriately 50% of patients, may have multiple cavernous malformations in the neuraxis B. Clinical features: 1. Myelopathy 2. Radicular pain 3. Conus medullaris syndrome
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Bannayan–Zonana Syndrome
A. General considerations: 1. AD 2. Hamartomatous disorder 3. Macrocephaly 4. Multiple lipomas 5. Male > female 6. Rare extradural spinal hemangiomas occur
Angiographically Occult Vascular Malformations of the Spinal Cord (AOVMS)
1. Cavernous malformations are the most common type of AOVM of the spinal cord 2. Insidious onset with limb asymmetry has been noted 3. Deterioration putatively from repeated hemorrhages around vessels or from intrahumeral thrombosis Differential Diagnosis of AOVMS
1. Primary hemorrhagic tumors of the spinal cord: a. Ependymoma b. Astrocytoma c. Medulloblastoma 2. Hemorrhagic transverse myelitis: a. Lung metastasis (small cell) 3. Paraneoplastic spinal cord hemorrhagic necrosis: a. Small cell lung carcinoma b. Anti-Hu antibody syndrome 1) Occurs at the thoracic level 4. Bleeding diathesis: a. Coagulation defects b. Anticoagulation (coumadin/heparin) c. Platelet disorders d. Leukemia/lymphoma e. Hemorrhagic leukoencephalitis (acuteautoimmune disease) f. Subdural hematoma g. Parenchymatous bleed (trauma) 5. Systemic Conditions Affecting the Spinal Cord a. Whipple’s disease b. Gluten sensitive enteropathy c. Kohlmeier–Degos disease d. Sjögren’s disease e. B12 deficiency 1) Acute following nitrous oxide anesthesia (cobalamin deficiency) 2) High serum B12 level noted with leukemia and lymphoma f. Vitamin E deficiency 1) Dietary 2) Alpha tocopherol transporter defect g. Pure spinal angitis
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SECTION IV. Spinal Cord Disease
Rare Spinal Cord Abnormalities
Werner’s syndrome (Progeria)
A. General considerations: 1. Childhood age of onset 2. Accelerated aging 3. AR B. Clinical features: 1. Balding 2. Atherosclerosis of all circulations 3. Premature graying 4. Osteosclerosis 5. Diabetes mellitus 6. Juvenile cataracts 7. Hypogonadism 8. Rare spastic paraparesis a. Many patients with increased reflexes
Spinal Pseudoathetosis
A. General considerations: 1. Occurs after protracted severe loss of proprioception with acute painful crisis 2. Secondary to: a. Lesions of the dorsal columns or their nuclei b. Lesions of the dorsal root ganglia c. Lesions of the dorsal root entry zone B. Clinical features: 1. Lateral and updrift with polyminimyoclonus 2. Rare flinging of the arms and legs (hemiballism) 3. Severe proprioceptive loss partially compensated 4. Pain may precede the pseudoathetosis C. Differential diagnosis of spinal pseudoathetosis: 1. Tabes dorsalis 2. Spinal trauma (dorsal column destruction) 3. Demyelinating disease 4. Syringomyelia 5. SLE myelitis 6. Friedreich’s ataxia
Stiff Leg Syndrome
A. General considerations: 1. Suspected autoimmune etiology B. Clinical features: 1. Onset in middle age 2. Stiffness and painful spasms of the lower limbs 3. Spasms are spontaneous 4. Reduced by movement 5. Rigidity and abnormal postures of both legs occur 6. No brainstem pyramidal tract or sensory dysfunction C. EMG abnormalities:
1. Repetitive grouped discharge of motor units D. Differential diagnosis of stiff leg syndrome: 1. Stiff man syndrome 2. Idiopathic encephalomyelitis with rigidity 3. Spinal interneuronitis
Venoocclusive Disease
A. General considerations: 1. Associated with spinal cord vascular malformations 2. Associated with acute compressive epidural processes: a. Hematoma b. Epidural abscess Hemorrhagic venous occlusive disease: 1. Back pain at the level of involvement 2. Rapidly progressive (days to weeks) 3. Multiple spinal segments involved Non-hemorrhagic venous occlusive disease: 1. Course is over weeks to months 2. Less pain 3. Fewer spinal segments involved Embolic venous infarction: 1. Fibrocartilaginous 2. Sudden onset 3. Pain at the level of involvement 4. Asymmetric deficit Venous infarction in association with vascular malformations: 1. Subacute neurologic syndrome 2. Foix–Alajouanine syndrome a. Step wise dysfunction due to thrombosis of supplying vessels 3. Intramedullary hypertension due to spinal dural arterial venous fistula Sclerotherapy: 1. Direct penetration of epidural veins 2. Occlusion of the anterior spinal artery 3. Cirrhosis (acquired or congenital) is often the systemic defect a. Related AV shunts b. Inadvertent arterial access following esophageal vein injection
Chapter 5 Spastic Paraparesis
Anatomical Feature of Transverse Myelitis
1. Spinothalamic tract (STT)
Chapter 5. Spastic Paraparesis
a. Lissauer’s tract distributes afferent information two levels above and below the entry level (important in thoracic cord) b. Sacral fibers distributed most laterally in STT; cervical fibers most medially 2. Dorsal column system: a. Leg fibers medially (fasciculus gracilis); arm fibers more laterally (fasciculus cuneatus) b. Sacral fibers outermost most dorsally c. Visceral pain ventrally in both fasciculi 3. Cervical cord involvement frequently causes dropped sensory level to T4–T6 or the abdomen; rarely a discrete far lateral lesion may cause leg or sacral sensory symptoms 4. Associated spinocerebellar or cuneocerebellar (C1–C4) compromised with the sensory abnormalities
Clinical Features of Transverse (Longitudinal Myelopathy Myelitis)
1. Heralded by band like pressure or pain at the segmental level 2. Paresis below the level 3. Bladder affected if both sides of the cord are involved: a. Epidural involvement-earlier and more severe urinary dysfunction than intramedullary lesions b. Cervical Intramedullary lesion: 1) Sudden loss of urine with Valsalva maneuver c. Transverse lesion: 1) Urgency with difficulty in initiation of micturition (lesion between the pontine or cervical bladder micturition centers and the parasympathetic supply to the detrusor muscle (Onuf’s nucleus) Incoordination of ignition of micturition and release of the external sphincter. 4. Conus medullaris level: a. Loss of initiation of micturition and a paralyzed bladder that is insensate to filling pressures
Hereditary Spastic Paraparesis (Strümpell–Lorrain Syndrome)
A. General considerations: Hereditary spastic paraparesis is a clinically and genetically heterogenous disorder with inter and intra familial variation. It is divided into AD, AR, X-linked and syndromic forms. In addition, spastic paraparesis complicates many acquired forms of spinal cord pathologies and is a major component of both demyelinating and dysmyelinating conditions. At present, 18 genetic loci have been reported of which ten are AD, three X-linked and five are autosomal recessive. The pure form is an insidiously progressive spastic paraparesis with a neurogenic bladder and distal vibratory loss in the legs.
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Uncomplicated HSP refers to the pure form in which both the corticospinal and dorsal column systems are involved. Complicated HSP has additional neurological deficits that include optic neuritis, macular and cerebellar degeneration, ichthyosis, seizures, cataracts, cognitive dysfunction, and extrapyramidal signs. B. Genetic features: The average age of onset of symptoms is due to which genetic locus may be involved in uncomplicated HSP; otherwise they present similarly. 1. HSP linked to 2p (SPG4 and SPG13) overlap in time of onset with other early symptomatic forms (SPG10, SPG3 and SGP 12). 2. The average age of onset after age 20 is most typical of SGP8 and SGP 6 3. Approximately 50% of AD uncomplicated HSP are linked to SPG4 4. Approximately 50% of AR HSP is SPG 11 on chromosome 15q13–q15. 5. A rare AR HSP has been mapped to chromosome 16q; the protein product is known as paraplegin. Some kindreds have other neurological deficits such that this mutation leads to a complicated form. 6. Two genes have been identified for an X-linked form of complicated HSP C. Clinical features of uncomplicated HSP: 1. Bilateral lower extremity weakness; anterior tibialis, hamstrings and iliopsoas muscles are most involved 2. Deep tendon reflexes are increased; Babinski signs are prominent (often at rest and by midfoot) the legs are spastic 3. Upper extremity strength, bulk, facility of movement and tone are normal 4. Pes cavus is frequent (if not there other diagnosis should be sought) 5. Gait is abnormal due to limited thigh flexion and dorsiflexion of the feet; circumduction maybe prominent as is increased adductor tone. Hyperlordosis and a short swing phase during gait is prominent. 6. Decreased muscle bulk of the lower extremities 7. Progressive mild loss of proprioception and vibratory sense in the distal lower extremities Autosomal dominant HSP chromosomes SPG4 (Spastin) SPG8 SPG9 SPG10 (kinesin SA) SPG13
pure spinal pure spinal complicated pure spinal pure spinal
2p22 8q23–q24 10q23.3–q24.2 12q13 2q24–34
AD Hereditary Spastic Paraparesis
A. General considerations: 1. Two forms based on age at presentation a. Type 1 < age 35
SECTION IV. Spinal Cord Disease
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b. Type II > age 35 2. Sib-Sib correlation in age of onset is high; onset occurs in the same decade in 2/3 of families 3. Mean age of onset in males and affected offspring is earlier than females 4. Penetrance is variable; inter and intra familial phenotypic variation is normal Clinical features of AD HSP type 1
1. Onset occurs in the first to fourth decade 2. Initial presentation: a. Motor delay c. Leg weakness b. Abnormal gait d. Asymptomatic 3. Upper extremity: a. Weakness < 26% c. Mild ataxia 15% b. Hyperreflexia 45% Lower Extremity Signs and Symptoms of Type 1
1. 2. 3. 4. 5. 6. 7.
Spasticity – 90% Weakness – 55% Distal sensory loss – 20% Urinary symptoms – 15% Pes cavus – 30% Disease duration 20–35 years Wheelchair bound by age 60
Clinical Presentation AD Type II
1. Onset third to seventh decade 2. Initial presentation: a. Abnormal gait 3. Upper extremity signs and symptoms: a. Weakness – 47% c. Ataxia – 20% b. Hyperreflexia – 50% Lower Extremity Signs and Symptoms
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Spasticity – 100% Weakness – 90% Distal sensory loss – 80% Urinary symptoms – 50% Pes caves – 20% Disease duration – 15 to 25 years Loss or depression of ankle reflexes 15% Sexual dysfunction rare and a late occurrence Increased abdominal reflexes early No bowel dysfunction Type II more severe symptoms than Type 1 in general Babinski signs are present Decreased strength of iliopsoas, hamstrings an anterior tibialis muscles
Specific AD Diseases
SPG3 A. General considerations: 1. Chromosome 14q; 10–15% of all AD patients with AD HSP 2. Anticipation occurs B. Clinical features: 1. Pure form 2. Anticipation has been noted SPG 3A A. General considerations: 1. AD a. Atlastin 1 mutation 2. Early onset 3. Disease of African Americans B. Clinical features: 1. Age of onset, 4–14 years 2. Primarily pure spastic gait disorder 3. No spasticity in upper limbs 4. Rare tongue fibrillation, decreased visual acuity 5. Decreased visual acuity Differential point from SPG4: 1. Delayed auditory and visual evoked potentials SPG4 A. General considerations: 1. Chromosome 2p22 a. Spastin gene 2. Most common form of AD spastic paraparesis B. Clinical features: 1. Pure form 3. Urinary symptoms 2. Decreased vibration SPG6 A. General considerations: 1. Chromosome 15q B. Clinical features: 1. Pure form 2. Pes cavus SPG8 A. General considerations: 1. Chromosome 8q B. Clinical features: 1. Pure form SPG9 A. General considerations: 1. Chromosome 10q 23.3–q24.2 B. Clinical features: 1. Cataracts 3. Motor neuropathy 2. Gastrointestinal reflux SPG10 A. General considerations: 1. Chromosome 12q13 2. Kindred described coding for kinesin
Chapter 5. Spastic Paraparesis
a. Possible microtubule binding activity B. Clinical features: 1. Pure form SGP12 A. General considerations: 1. Chromosome 19q13 B. Clinical features: 1. Pure form SGP13 A. General considerations: 1. Chromosome 2q24–34 B. Clinical features: 1. Pure form
Autosomal Recessive HSP
SPG5 A. General considerations: 1. Chromosome 8q B. Clinical features: 1. Pure form 2. Onset first decade; disease duration of 10–30 years 3. Initial sign is a spastic gait 4. Upper extremity weakness (30%) and hyperreflexia – 50% 5. Lower extremity signs and symptoms: a. Spasticity 100% b. Weakness of legs 90% c. Distal sensory loss < 20% d. Urinary symptoms 30% e. Pes cavus 50% f. Sib-sib correlation of time of onset less than AD form of HSP SPG7 A. General considerations: 1. Chromosome 16q; paraplegin gene a. Associated with mitochondrial abnormalities of skeletal muscle b. Nuclear encoded c. Proteolytic and chaperone activities d. Many but not all patients have ragged red fibers and cytochrome oxidase negative fibers B. Clinical features: 1. Pure form 2. Complicated form associated with: a. Dysphagia and dysarthria b. Optic atrophy c. Axonal neuropathy d. Cerebellar and cerebral atrophy e. Evidence of vascular lesions f. Mitochondrial defects on muscle biopsy SPG14
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A. General considerations: 1. Chromosome 3q 28 B. Clinical features: 1. Complicated form associated with: a. Mental retardation b. Distal motor neuropathy
Autosomal Recessive Spastic Paraparesis with a Thin Corpus Callosum
A. General considerations: 1. AR; primarily in Japanese patients; linked primarily to chromosome 15q13–15 B. Clinical features: 1. Mental retardation 2. Spastic paraparesis 3. Symptoms start in second decade 4. Associated sensory loss and urinary incontinence develop with age C. MRI evaluation: 1. Thinned corpus callosum D. Magnetic stimulation demonstrate abnormalities in central motor pathways
Differential Diagnosis of AR HSP with Thin Corpus Callosum
1. Corpus callosum agenesis with peripheral neuropathy (Andermann syndrome) a. Mental and physical retardation b. Seizures c. Sensorimotor polyneuropathy d. Optic atrophy 2. CRASH Syndrome
X-Linked Recessive HSP
SPG1 A. General considerations: 1. LICAM gene (neural cell adhesion molecule) a. Variably expressed in females b. Allelic to MASA cell adhesion syndrome whose clinical features are: 1) Mental retardation 3) Spastic paraplegia 2) Aphasia 4) Adducted thumbs c. Other LICAM gene mutation syndromes B. Clinical features: 1. Thin corpus callosum 4. Spastic paraparesis 2. Mental retardation 5. Hydrocephalus 3. Adducted thumbs C. Complicated form associated with: 1. Hydrocephalus 3. Adducted thumb 2. Aphasia
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SECTION IV. Spinal Cord Disease
SGP2 A. General considerations: 1. Chromosome Xq11.2 2. Proteolipid protein gene (PLP) a. Encodes an intrinsic myelin protein b. Allelic to Pelizaeus–Merzbacher disease B. Clinical features: 1. Early onset severe and slowly progressive phenotypes have been noted in the same families 2. Associated CNS white matter lesions 3. Pure form: a. Onset up to the second decade b. Disease duration 10–25 years c. Initial presentation 1) Spastic gait d. Upper extremity signs and symptoms: 1) Weakness-none 2) Hyperreflexia < 10% e. Lower extremity signs and symptoms 1) Spasticity – 80% 2) Weakness – none 3) Rare distal sensory loss 4) No urinary symptoms 5) No pes cavus
X-Linked Recessive HSP Allelic to Pelizaeus–Merzbacher Disease (PMD)
A. Clinical features: 1. Progressive dementia 2. Nystagmus noted in infancy 3. Choreoathetosis 4. Spasticity 5. Diffuse cerebral hypomyelination by MRI Differential Diagnosis
Complicated hereditary Spastic Paraparesis 1. Spectrum of genetically distinct diseases 2. Spastic paraparesis is associated with other neurological deficits that may be predominant
2. Mast’s Syndrome: a. Dysarthria c. Athetosis b. Dementia d. Spastic paraparesis 3. Troyer’s Syndrome a. Short stature d. Amyotrophy b. Mental retardation e. Spastic paraparesis c. Ataxia 4. Sjögren–Larsson Syndrome a. Ichthyosis c. Spastic paraparesis b. Mental retardation 5. Hellin’s Syndrome a. Mental retardation b. Macular degeneration
AD Complicated Hereditary Spastic Paraparesis
1. Signs associated with spastic paraparesis a. Cerebellar degeneration b. Amyotrophy of the hands c. Peroneal muscular atrophy d. Sensory neuropathy e. Intention tremor f. Extrapyramidal signs g. Muscular dystrophy h. Abnormal skin pigmentation 2. Symptom complexes associated with hereditary spastic paraparesis a. Dystonia, athetosis, dementia, amyotrophy b. Retinal degeneration, dementia, dysarthria, amyotrophy c. Optic atrophy
Associated Neurologic Signs and Symptoms with X-Linked Recessive Complicated Hereditary Spastic Paraplegia
a. Mental retardation and optic atrophy b. Deafness c. Dysarthria, athetosis, amyotrophy
AR Complicated HSP
1. Associated neurological signs a. Cerebellar degeneration b. Sensory neuropathy c. Optic atrophy and dysarthria d. Amyotrophy resembling ALS e. Deranged skin pigmentation Associated neurologic syndromes associated with AR HSP 1. Charlevoix–Saquennay a. Dysarthria d. Spastic paraparesis b. Ataxia e. French Canada c. Distal amyotrophy
Differential Diagnosis of Hereditary Forms of Spastic Paraplegia
Machado–Joseph Disease (SCA3) A. General considerations: 1. Chromosome 14 a. AD 2. CAG repeat disease B. Clinical features: 1. Ataxia 4. Bulging eyes 2. External ophthalmoplegia 5. Amotrophy 3. Spastic paraparesis
Chapter 5. Spastic Paraparesis X-Linked ALD
Werner’s Syndrome
A. General considerations: 1. Disease of CNS white matter and the adrenal cortex: a. ABCD1gene 2. Incidence of 1 in 50,000 people 3. Four major subgroups in affected males: a. Childhood form (severe) b. Adolescent form 1) Onset between 10–21 years c. Adrenomyeloneuropathy (AMN) 1) Onset in the late twenties 2) Sphincter disturbances 3) Distal sensory loss 4) Progressive paraparesis d. Primary adrenal insufficiency 1) Slowly progressive over decades 2) No neurologic abnormalities e. ALD has X-linked inheritance 1) Carrier females have neurological signs and symptoms (usually AMN phenotype) 2) Mean age of onset 38 years; later onset than males 3) Reduced penetrance; milder phenotype in females B. Clinical features: 1. No real distinction clinically between HSP and AMN C. Laboratory features of ALD: 1. Plasma concentrations of very long chain fatty acids are increased in 99% of males; greater than 85% in females D. EMG evaluation: 1. AMN, a subtype of ALD frequently demonstrates decreased nerve conduction velocities
A. General considerations: 1. Chromosome a. AR B. Clinical features: 1. Premature balding 2. Severe atherosclerosis 3. Osteoporosis 4. Hypogonadism
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5. Juvenile cataracts 6. Diabetes mellitus 7. Spastic paraparesis 8. Peripheral neuropathy
Mitochondrial defects A. General considerations: 1. AD B. Clinical features: 1. Spastic paraparesis Familial Paroxysmal Dystonia I (see Movement Disorder Section)
Globoid Cell Leukodystrophy (Krabbe’s Disease)
A. General considerations: 1. AR 2. Deficiency of galactosylceramidase B. Clinical features: 1. Adult onset variant 3. Seizures 2. Optic atrophy 4. Spastic paraparesis C. Laboratory evaluation: 1. Marked slowing of NCV by EMG 2. High CSF protein 3. Multinucleated macrophages or globoid cells in CNS white matter
Metachromatic Leukodystrophy Adrenomyeloneuropathy (AMN)
A. General considerations: 1. Subtype as noted above of X-linked ALD B. Clinical features: 1. Onset after the second decade 2. Progressive spastic paraparesis 3. Prominent sensory loss in the legs 4. Sphincter disturbances 5. Female carries have spastic paraparesis 6. Hypoadrenalism 7. Hypogonadism C. laboratory evaluation: 1. Very long chain fatty acids 2. Choreoathetosis Spasticity Syndrome 3. Planto–Palmar Keratoderma (PPK)
A. General considerations: 1. ARSA gene 2. Lysosomal enzyme arylsulfatase A deficiency B. Clinical features: 1. Late infantile, onset 6 months to 2 years 2. Juvenile, onset 3 to 16 years 3. Adult MLD presentation: a. Behavioral abnormalities (psychosis) b. Spastic paraparesis c. Pathology: 1) Metachromatic inclusions within Schwann cells and macrophages 2) Segmental peripheral nerve demyelination abnormality thin myelin sheaths 4. AB Variant a. Activator protein deficiency b. Normal in vitro activity of arylsulfatase A
SECTION IV. Spinal Cord Disease
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Dentato-Rubral-Pallido-Luysian Atrophy (DRPLA)
A. General considerations: 1. Chromosome 12p; usually 49–88 repeat CAGA nucleotides 2. Homozygosity for an allele carrying intermediate CAG repeat number B. Clinical features: 1. Adult onset > 40 years of age a. Ataxia c. Dementia b. Choreoathetosis 2. Specific patient with paraparesis and: a. Truncal ataxia b. Dysarthria c. 41 CAG repeats d. No dementia, seizure, myoclonus or other involuntary movements
2. 3. 4. 5.
Krabbe’s Disease Hyperlysinemia Pyruvate dehydrogenase deficiency (complex IV mtDNA) Leigh’s Disease (COX deficiency complex III)
Homocarnosinosis
A. General considerations: 1. AR 2. Abnormalities of histidine metabolism 3. Lack carnosinase activity B. Clinical features: 1. Spastic paraparesis 2. Mental retardation 3. Increased homocarnosine in the CSF
Abnormal Vitamin B12 Binding Protein Familial Hyperlysinemia
A. General considerations: 1. AR; AASS gene 2. Deficiency of alpha-amino adipic semialdehyde synthases essential for lysine degradation B. Clinical features: 1. Intellectual impairment 2. Epilepsy 3. Progressive spastic paraparesis C. Laboratory evaluation: 1. Hyperlysinemia 2. Hyperlipinuria
Adult Onset Alexander’s Disease
A. General considerations: 1. AR; mutation affects GFAP 2. Intermediate filament glial fibrillary acidic protein (GIAP) 3. Astrocytic cytoplasmic inclusions called Rosenthal fibers B. Clinical features: 1. Onset third to fifth decade 4. Cerebellar dysfunction 2. Early exacerbations 5. Hyperreflexia 3. Palatal myoclonus 6. Spastic paraparesis
Chapter 6 Enzyme and Metabolic Disorders Affecting the Spinal Cord 1. Metachromatic leukodystrophy
A. General considerations: 1. Abnormal plasma vitamin B12 binding protein 2. High serum B12 level 3. Low CSF S-adenosylmethionine level 4. Low RBC B12 level B. Clinical features: 1. Spasticity of all extremities 2. Subacute combined posterior and corticospinal tract signs and symptoms
Combined System Degeneration (Corticospinal Tract and Posterior Column) after Nitrous Oxide Anesthesia
A. General considerations: 1. Nitrous oxide anesthesia precipitates acute B12 deficiency 2. Cobalamin CO2+ inactivated to CO3+ 3. Methyl cobalamine is a Co-factor for methionine synthetase; failure of conversion of homocysteine to methionine B. Clinical features: 1. Combined posterior and lateral column degeneration 2. Approximately six hours of exposure is required for those that are not B12 deficient prior to exposure; symptoms may appear 2–6 weeks after exposure
B12 Deficiency
A. General considerations: 1. Multiple mechanisms are causative: a. Malabsorption of B12 due to lack of intrinsic factor most commonly b. 5 mcg is needed per day
Chapter 6. Enzyme and Metabolic Disorders Affecting the Spinal Cord
c. Antibodies to gastric parietal cells may accompany all autoimmune diseases d. May occur from tetrahydrobiopterin deficiency and B12 activator deficiency e. The biochemical reactions that depend on B12 are: 1) Folate-dependent reaction that transfers a methyl group from methyltetrahydrofolate to homocysteine that produces methionine 2) Homocysteine to methionine reaction (methionine synthase required; cobalamin is a cofactor). Reduced cofactor activity leads to decreased DNA synthesis f. Spongy degeneration with both myelin and axon destruction are seen in both the central and peripheral nervous system B. Clinical features: 1. Paresthesias with primarily large fiber greater than small fiber neuropathy 2. Dorsal column demyelination with loss of position, light touch and vibration sensitivity 3. Demyelination of subcortical frontal white matter that leads to frontal lobe personality charge 4. Loss of smell 5. Optic neuropathy 6. Cerebellar ataxia 7. Spasticity 8. An extremity that may be wasted with loss of sensation but has hyperactive reflexes 9. Absent reflexes in the ankle with pathological hyperactive reflexes at the knee and in the upper extremities
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11. Babinski sign is present; sparing of superficial reflexes (abdominal; cremasteric) C. Laboratory evaluation: 1. EMG: a. Slow sural nerve conduction velocity; denervation of lower extremity muscles II. Nitrous Oxide (pp. 74) III. Konzo A. General considerations: 1. Occurs in West Africa 2. Cyanide toxicity B. Clinical features: 1. Optic atrophy 2. Spastic paraparesis IV. Ethylene Oxide A. General considerations: 1. Used in gas sterilizations; operating room packs B. Clinical features: 1. Generalized spasticity V. Subacute Myelo-Optic Neuropathy A. General considerations: 1. Caused by ingestion of outdated tetracycline 2. Major epidemics in Japan and Mexico B. Clinical features: 1. Optic neuritis 2. Spasticity from spinal cord involvement
Metabolic Causes of Spinal Cord Dysfunction Selected Toxins Affecting the Spinal Cord
I. Lathyrism A. General considerations: 1. Consumption of the unripe chick pea or grass pea (Lathyrus sativus) 2. Contaminate; used instead of cereals or lentils during periods of great economic stress; need 15–150 mg/day for toxicity 3. Toxin: Beta-N-Oxolamine-L-Alazanine (BOAS) B. Clinical features: 1. Onset during the first four decades 2. Sudden onset of heaviness and leg weakness 3. Subacute onset over months can occur 4. Stiffness in lower extremities – 70% 5. Leg cramps – 50% 6. Paresthesias – 30% 7. Urinary symptoms – 5% 8. Nocturnal erections; ejaculations; urinary urgency may occur 9. Symmetrical spasticity; ankle clonus 10. Mild lower extremity weakness
Hyperparathyroidism
A. General considerations: 1. Occurs with primary and secondary hyperparathyroidisms (usually renal failure) B. Clinical features: 1. Proximal muscle weakness, fatigue and cramps 2. Rarely a fibrillating tongue has been noted 3. Rare urinary frequency 4. Severe hyperreflexia arms greater than legs C. Laboratory evaluation: 1. Erosion of the radial side of the index finger and the acromial head of the clavicle 2. EMG: neurogenic Hyperthyroidism (Davidoff Syndrome)
A. General considerations: 1. Syndrome is seen in the face of severe hyperthyroidism B. Clinical features: 1. Spastic paraparesis 3. Babinski signs are present 2. Ophthalmoplegia
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SECTION IV. Spinal Cord Disease
Portocaval Shunt
A. General considerations: 1. The spinal cord features are usually seen in a setting of severe liver failure 2. Hyperammonia is the rule; neurological features have been seen with normal ammonia levels B. Neurological features: 1. Relapsing intermittent encephalopathy 2. Spastic paraparesis 3. Generalized hyperreflexia C. MRI demonstrates 1. Increased T2 weighted signal in the caudate and putamen
b. Cortical layers III–V that receive thalamic projection c. Purkinje cells of the cerebellum d. Globus pallidus interna cells (GP) e. Cranial nerves of the brainstem (particularly V in children) f. Peripheral nerves B. Clinical features of spinal cord anoxia: 1. Severe rigidity of the extremities 2. Selective death of Renshaw cells (decreased glycine) 3. Loss of inhibitory interneurons of the spinal cord (GABAergic B cells) 4. Clinical spinal cord findings are over shadowed by deficits from other areas of the CNS
Chapter 7
Liver Failure
A. General considerations: 1. Neurological features are seen from hepatic failure from all causes 2. Swelling of Alzheimer type II glia in the brain with increased intracranial pressure 3. MRI findings of increased signal on T2 weighted images (caudate and putamen) B. Neurological features: 1. Clinical stages: a. Acute I: 1) Personality change (active psychosis) 2) Acute increased intracranial pressure 3) Reye’s syndrome (increased ICP, vomiting, low glucose, decortication) b. Subacute stage II: 1) Brainstem involvement 2) Reversible decerebration 3) Spasticity of all extremities 4) Pupils < 1 mm but are reactive to light 5) Babinski signs are present c. Stage III: 1) Coma 2) Fetor hepaticus 3) Failure of Doll’s eye and ice-water calorics C. Laboratory evaluation: 1. Increased serum ammonia may be the best clinical correlation; increased CSF glutamine occurs D. Pathology: 1. Increased prominence of Alzheimer type II glia
Cardiac Arrest and All Forms of Anoxia
A. General considerations: 1. The following structures of the neuraxis are the most vulnerable to lack of oxygen: a. Sumner’s sector V of the hippocampal formation
Autoimmune Causes of Spinal Cord Dysfunction A. General considerations: 1. Maybe ethnically and genetically determined; more common in African American and Asian patients than Caucasians 2. Axonal destruction in the spinal cord greater than demyelination B. Clinical features: 1. Bilateral optic neuritis 2. Affects young patients 3. Severe spastic paraparesis 4. Axonal injury appears early
Multiple Sclerosis
A. General considerations: 1. Spinal cord involvement may be predominant feature in middle aged women; almost always occurs in all forms of MS. The MRI coils to evaluate spinal cord pathology are not as well developed or accurate as those for cerebral imaging B. Clinical features: 1. The process is most often relapsing remitting which slowly evolves into secondary progressive disease; primary progressive and variants occur 2. The spinal lesions are most often occurring at cervical levels which cause a dropped sensory level to T4–T6 rather than at a thoracic level 3. The demyelinating lesions are often longitudinal rather than transverse and occur over several levels 4. Paresthesias of the palms rather than the fingers (the latter more characteristic of nerve or brachial plexus sensory loss)
Chapter 7. Autoimmune Causes of Spinal Cord Dysfunction
5. Lower extremity spasticity 6. Bladder involvement: a. Neurogenic b. Dyssynergy between detrusor contraction and sphincter opening 7. Associated neurological findings: a. Intranuclear ophthalmoplegia b. Afferent pupillary defect c. Bilateral cerebellar ataxia d. Bilateral corticospinal tract dysfunction e. Cognitive decline f. Early loss of superficial abdominal reflexes
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Acute and Chronic Acquired Demyelinating Inflammatory Polyradiculopathy
A. General considerations: 1. The major autoimmune attack is on peripheral myelin 2. GQ1b and other epitopes identified 3. Molecular mimicry is a possible mechanism; overlap between peripheral and central antigens (same epitopes) are responsible for the central manifestations B. Clinical features: 1. Longitudinal myelitis at cervical levels 2. Rarely brainstem and cerebral demyelination occurs
Acute Disseminated Encephalomyelitis
Systemic Lupus Erythematosus
A. General considerations: 1. 75% evolve into multiple sclerosis B. Clinical features: 1. One episode of demyelination 2. May follow a viral illness 3. Brunt of the demyelination is in the brain 4. Age of all lesions is similar 5. Spinal cord involvement is manifest by spasticity, bladder dysfunction and weakness 6. Optic nerve may be involved 7. Adrenocorticoid stimulating hormone may be more effective than intravenous steroids for treatment 8. A great percentage evolve into MS
A. General considerations: 1. Spinal cord involvement occurs in association with arthralgia, skin and visceral involvement 2. Usually systemic markers of activity are high B. Clinical features: 1. Longitudinal myelitis at cervical levels 2. Maybe recurrent 3. Usually a dropped sensory level at T4–T6 4. Corticosplinal tract dysfunction
Acute Hemorrhagic Leukoencephalitis
A. General considerations: 1. Hyperacute demyelination B. Clinical features: 1. One clinical episode 2. Usually affects the left cerebral hemisphere 3. CSF may have up to or greater than 150 RBC cells/mm3 4. Spinal cord maybe affected
Sarcoid
A. General considerations: 1. Lung, cardiac, joint, muscle and nerve involvement B. Clinical features: 1. Dural involvement is common 2. Primarily affects the thoracic cord 3. Compression myelopathy more common than parenchymal vasculitis 4. CSF: a. Sugar 30–40 mg% b. Protein 80–150 mg% c. Lymphocytic cellular response d. Associated cranial nerve and CNS involvement
Post Vaccination Myelitis Stiff Man Syndrome
A. General considerations: 1. Occurs 7–14 days following vaccination 2. Measles and hepatitis B virus are the most common viral vaccinations. Rabies is a rare cause now due to recombinant vaccines. B. Clinical features: 1. More common in children 2. Associated with cerebral periventricular demyelination 3. Longitudinal myelitis occurs most frequently at cervical levels
A. General considerations: 1. Slightly more common in females (50%) 2. Associated with diabetes mellitus, hyper and hypothyroidism, epilepsy in 10% of patients 3. GAD 67-kD isoform appears to be the antigen 4. May be associated with breast cancer; the antigen may be a non-intrinsic membrane protein of 128 kD (amphiphilic) B. Clinical features:
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SECTION IV. Spinal Cord Disease
1. Fluctuating progressive muscle stiffness and painful spasms of the trunk 2. Insidious onset; 4th to 5th decades 3. Axial musculature affected more than appendicular; lower extremities are more affected than the upper 4. Respiratory, facial and bulbar muscles are affected in advanced disease 5. Patients have normal strength and sensation; reflexes maybe increased 6. Lumbar hyperlordosis occurs 7. Hereditary form has been described: a. Stiffness is present at birth; resolves by age 3 and returns in adolescence b. Stiffness precipitated by movement 8. Muscle spasms maybe induced by acoustic, somatosensory or emotional stress C. EMG: 1. Continuous motor unit activity in at least one axial muscle; normal silent period after a painful stimulus
Differential Diagnosis of Autoimmune Diseases Associated with Longitudinal Myelitis
1. Wegener’s granulomatosis (severe sinopulmonary involvement; mononeuritis multiplex) 2. Rheumatoid arthritis (small muscle involvement of the hands, C1–C2 spondylolisthesis with spinal cord compression) 3. Mixed connective tissue disease (elements of polymyositis, scleroderma and SLE). The latter component frequently associated with transverse myelitis. 4. Regional enteritis (usually associated with stroke or cerebral sinus thrombosis loss of clotting factors through the gut causes a prothrombotic state) 5. Ulcerative colitis (most often associated with cerebrovascular accidents, cerebral sinus thrombosis, eye and joint involvement). 6. Relapsing polychondritis (most often associated with disc disease, collapses of the larynx or optic neuritis)
Variants of Stiff Man Syndrome
1. Progressive encephalomyelitis with rigidity a. Rare b. Rapidly progressive (few months) to death 2. Stiff limb syndrome: a. Rigidity and abnormal fixed posturing b. Painful spasms of distal lower extremities c. Sphincter and brainstem involvement in 50% of patients 3. Women with breast cancer a. Antibodies to synaptic vesicle protein amphiphilin I 4. Jerking Stiff Main Syndrome a. Myoclonic jerking is prominent Differential Diagnosis of stiff man syndrome
The symptom complex is rigidity of axial greater than appendicular musculature, action induced spasms and continuous motor unit activity: 1. Isaac’s syndrome 2. Corticobasal ganglionic degeneration 3. Focal spinal cord lesions 4. Tetanus 5. Encephalomyelitis
Sjögren’s Syndrome
A. General considerations: 1. Antibodies to salivary and lacrimal glands; red eyes and serosal surface irritation 2. Peculiar Vth nerve involvement (numb face) B. Clinical features: 1. Primarily posterior column involvement 2. Associated with primary progressive multiple sclerosis
Differential Diagnosis of Arteritic Syndromes Affecting the Spinal Cord
1. Syphilitic proliferative end arteritis a. Occlusion of the vertebral or anterior spinal arteries b. Meningoencephalitis (stage II) c. In association with HIV (all stages appear simultaneously) d. Pachymeningitis cervicalis 2. Anti phospholipid syndrome a. Primary b. In association with SLE 3. Takayasu’s disease a. Vertebral artery and anterior spinal artery occlusions b. Anterior > posterior spinal artery syndromes 4. Isolated angiitis of the spinal cord a. No associated features or laboratory evidence of systemic arteritis 5. Giant cell arteritis a. Rarely can affect all arteries of the internal carotid system b. A component of the aortic arch syndrome (both carotids and vertebral arteries may slowly be occluded) 6. Köhlmeier–Degos Disease a. Characteristic atrophic skin lesions b. Severe retinal arterial spasm c. Spinal cord infarction Paraneoplastic Syndromes
a. anti-Hu antibody (ANNAI) 1) Primarily an antinuclear antibody b. Associated with limbic encephalitis c. Associated primarily with small cell cancer of the lung d. Burning sensory neuropathy and limbic encephalitis e. Longitudinal myelitis
Chapter 8. Infections Affecting the Spinal Cord Vitamin Deficiencies
1. B12 2. Vitamin E deficiency A. General considerations: 1) Dietary (associated with severe diarrhea and malabsorption) 2) Alpha tocopherol transporter deficiency B. Clinical features: 1) Primarily dorsal column dysfunction 2) Associated cerebellar ataxia and large fiber neuropathy
Chapter 8 Infections Affecting the Spinal Cord
A. General considerations: 1. Epidural abscess a. Predisposing factors: 1) Compromised immune system 2) Hematogenous spread from other infections 3) IV drug abuse 4) Prolonged epidural anesthesia B. Clinical features: 1. Severe back or neck pain 2. Intramedullary spread 3. Occasional radicular pain that may precede the myelopathy 4. May present as a Brown–Sequard Syndrome 5. Sudden paralysis from spinal cord infarction C. Laboratory evaluation: 1. Elevated sed rate the most important test; reliable however in only 25–40% of early patient infections. D. MRI evaluation: 1. Increased signal from the disc space on T2 weighted sequences often the first sign of discitis 2. Enhancement of the anterior and posterior longitudinal ligaments; paraspinal muscles and the abscess itself
Gram Negative Infections
1. Occur following post surgical procedures 2. At times one month to six weeks delay from the surgical procedure
Staph Aureus
A. General considerations: 1. Predisposing causes:
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a. IV drug abuse c. HIV b. SBE B. Clinical features: 1. Discitis with severe pain on any movement 2. Several segments are involved 3. Sudden paralysis from infarction of the cord C. MRI evaluation: 1. Disc space enhancement 2. Enhancement along anterior and posterior ligaments
Tuberculosis
A. General considerations: 1. Lumbar spine > thoracic spine in American patients 2. Cervical > thoracic > lumbar infections in Asian patients B. Clinical features: 1. Associated with thoracic Pott’s disease and spinal collapse with spinal cord compression 2. Spinal cord infarction (endarteritis) 3. Cold paravertebral abscess (L1–L4); often minimally painful C. Imaging evaluation: 1. Disc space infection; pus along anterior and posterior ligaments 2. Eburnation of the vertebral end plates
Viral Infections with myelitis
1. Myelitis may follow polio or other enterovirus infections of the anterior horn cells 2. Varicella virus attacks the dorsal root ganglia and nerve roots as well as the adjacent cord (most often thoracic) 3. Parenchymal cord involvement occurs with rabies, HSV, CMV (HIV co infected) HTLV I and II, EBV, simian B virus, and tick borne encephalitis; des encephalitides
Herpes Viruses
A. General considerations: 1. Cause acute infections but also have the capacity for latency 2. Reactivated near the site of the original infection 3. Neurological diseases in humans are caused by the following herpes viruses: a. HHV6 b. Herpes simplex type 1 and 2 c. Varicella virus d. CMV e. EBV f. Simian herpes (“monkey”) B-virus
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SECTION IV. Spinal Cord Disease
Herpes Simplex Type 1
Cytomegaloviruses
A. General considerations: 1. HSV-1 encephalitis is the most common cause of sporadic encephalitis in the US; approximately 10% of encephalitis cases 2. Acquired by respiratory or salivary contact; the cause of oral herpes 3. 30% of HSV-1 encephalitis occurs by spread into the brain from the nasal epithelium B. Clinical features: 1. Encephalitis 2. Myelitis 3. CSF: a. Increased pressure b. Lymphocytic pleocytosis 10–1000 WBC/mm3 c. Glucose is normal or slightly low (30–40 mg%) d. Protein is elevated (usually 60–80 mg%) 4. PCR has sensitivity of 95% 5. Cowdry A intranuclear inclusions
A. General considerations: 1. Common congenital viral infection; possibly up to 2% of the population 2. Deafness or developmental delay 3. Sexual transmission is route of infection in adults B. Clinical features: 1. In immunocompetent adults: a. Aseptic meningitis b. Mononucleosis syndrome c. Asymptomatic d. GBS e. Encephalitis 2. In association with HIV or immunosuppression: a. Retinitis c. Encephalitis b. Lumbosacral radiculitis d. Lumbosacral myelitis C. Laboratory evaluation: 1. Serology or PCR
Varicella Zoster
Epstein–Barr Virus
A. General considerations: 1. Children may suffer: a. Self-limited cerebellar ataxia b. Rare fatal encephalitis c. Post infections encephalomyelitis 1) One in 2500 patients d. Reye’s Syndrome e. Congenital varicella 2. Virus is latent in DRG cells 3. Reactivated by: a. Injury b. Immunosuppression (disease) c. Cancer d. Immunosuppressive drugs e. HIV f. Systemic illness B. Clinical features: 1. Most often T5–T12 are the affected dermatomes 2. Thoracic cord myelitis 3. Lumbosacral ganglia involvement causes bladder dysfunction and ileus 4. Zoster sine herpete: a. Prolonged radicular pain b. No zoster rash c. Detectable VZV DNA in CSF 5. Associated neurologic features include: a. Post herpetic neuralgia: b. Segmental motor atrophy c. Large vessel stroke (most often the MCA) d. Multifocal leukoencephalitis e. Cerebral vasculopathy
A. General considerations: 1. Primary infection is usually infectious mononucleosis; nervous system involvement occurs in less than 1% of patients 2. B-cell transforming virus: a. Associated with CNS and Burkitt’s lymphoma 3. Meningoencephalitis has occurred after bone marrow transplantation B. Clinical features: 1. Transverse myelitis 2. GBS syndrome; small fiber neuropathy; autonomic neuropathy; aseptic meningitis and rarely isolated cranial neuropathy C. Laboratory evaluation: 1. CSF, EBV specific antibodies or PCR
Human Herpesvirus Type 6
A. General considerations: 1. T-lymphotrophic virus 2. Childhood exanthema subitum 3. Opportunistic infection in HIV and other immunocompromised conditions: a. May cause T-cell immunodeficiency B. Clinical features: 1. Ascending necrotizing myelitis of the thoracic cord 2. B-Variant most commonly isolated from immunocompromised patients
Chapter 8. Infections Affecting the Spinal Cord Cercopithecine Herpes Virus 1 (B Virus)
A. General considerations: 1. Carried by old world monkeys 2. Veterinarians and animal handlers at risk; 70% fatality rate 3. Transmitted by animal bit or virus contaminated fomites 4. 70% fatality rate B. Clinical features: 1. Ascending paralysis (longitudinal myelitis) 2. Associated medullary and cortical signs and symptoms occur early
Rabies
A. General considerations: 1. Occurs along the Mexican–American border 2. Reservoirs are: dogs, skunks, bats, raccoons, and fox in the USA 3. Usual transmission is by a bite; rarely aerosol transmission (spelunkers) 4. Incubation period is usually 1–2 months B. Clinical features: 1. Prodrome of headache, fever, paresthesia at the inoculation site 2. Acute neurological phase with severe bulbar and autonomic features which progresses to coma 3. Paralytic or myelitic form: a. Most often from bat bites b. Paresthesias and weakness of the inoculated extremity c. Quadriplegia from spinal cord involvement C. CSF: 1. High titers of neutralizing antibodies in the serum and CSF 2. PCR of CSF is positive
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B. Clinical features: 1. 7–14 day incubation period 2. Prodromal phase of headache and meningeal symptomatology 3. An asymmetric flaccid paralysis occurs; may involve small groups of anterior horn cells (individual finger weakness) 4. Progresses for 3–5 days 5. Dromedary fever, curve maybe seen (two peaks) 6. Transverse myelitis and cerebellitis occur; rare facial weakness 7. Diaphragmatic involvement 8. Severe back pain often occurs 2–3 day C. Laboratory evaluation: 1. CSF: a. Polymorphonuclearcytosis occurs early with a shift to lymphocytosis after 2 days b. Slight elevation of protein (100–300 mg/dl) c. Sugar is normal 2. Virus isolated from CSF, stool, or throat D. Differential diagnosis of viral spinal cord infection: 1. Aseptic meningitis: a. Viruses b. Drug induced chemical meningitis 2. Other viral induced paralysis with cellular CSF: a. CMV b. Carcinomatosis of the meninges 3. Medullary involvement with cellular CSF a. Russian spring and summer encephalitis b. Rabies 4. GBS Syndrome: a. Antecedent rather than concurrent infection b. Cranial nerve VII always involved when quadriparesis supervenes c. CSF cytoalbuminologic dissociation d. Loss of reflexes except triceps (peculiarly often spared)
Coxsackie A and B Polio Virus and Other Enteroviruses
A. General considerations: 1. Enteroviruses are the leading cause of aseptic meningitis that can be identified
Polioviruses
A. General considerations: 1. Infections most common in late summer 2. Transmitted by fecal-oral contact; pharyngeal spread during epidemics 3. Most clinically apparent infection causes aseptic meningitis (8%); paralytic form is 1%
A. General considerations: 1. These viruses account for most cases of viral induced disease in the USA 2. West Nile virus must now be considered in this differential as it is spreading across the USA (first cases outside of LaGuardia airport NYC). B. Clinical features: 1. Aseptic meningitis 2. Encephalitis (rare) 3. Cerebellar ataxia (rare) 4. Paralytic spinal cord disease (rare) 5. CSF a. Poly morphonucleositose 250/mm3 b. Lymphocytic pattern in 2–4 days
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SECTION IV. Spinal Cord Disease
Flavivirus (West Nile)
A. General considerations: 1. Now spreading across the USA 2. Distributed in Asia, Middle East, parts of Europe, former Soviet Union 3. Rash, lymphadenopathy and pharyngitis are premonitory 4. Crows a reservoir (dead crows a clue to its presence) B. Clinical features: 1. Polio-like spinal cord syndrome with myelitis and flaccid paralysis 2. Aseptic meningitis 3. GBS Syndrome 4. Papillitis 5. Radiculitis
Retrovirus Infection
A. General considerations: 1. HIV binds to CD4 receptor 2. Infected macrophages transport the virus into the CNS 3. Vacuolar myelopathy occurs in 25–55% of HIV patients at autopsy 4. CNS a probable reservoir B. Clinical features: 1. Gait dysfunction 2. Spasticity 3. Leg weakness 4. Impaired proprioception and vibration 5. Sphincter dysfunction 6. Evolves over months 7. Associated often with dementia and painful distal symmetrical neuropathy 8. Babinski sign is common 9. Arms are involved late 10. Rare back pain C. Pathology: 1. Vacuolar myelopathy most prominent in the dorsolateral thoracic and cervical cord 2. Vacuolar changes in myelin sheaths with relative sparing of axons
Associated Myelopathies in HIV Patients
1. 2. 3. 4.
Back and radicular pain more prominent More rapid progression than HIV myelopathy CMV affects lumbosacral cord in very ill patients Varicella and Herpes simplex occur concomitantly: a. MRI may show T2-weighted images of a swollen cord 5. Concomitant HTLV1 and infections occur with HIV 6. Epidural abscess is seen with IV drug users
7. B12 deficiency may be a contributing factor to myelopathy in HIV 8. Rare spinal cord involvement occurs with M. tuberculosis and T gondi 9. Epidural metastasis from systemic lymphoma occurs in this setting
HTLV 1 and 2
A. General considerations: 1. Primarily seen in the Caribbean basin, Asia, Indian Ocean 2. May coexist with HIV 3. Sexual transmission B. Clinical features: 1. Longstanding slowly progressive course 2. Cervical > thoracic > lumbar cord involvement 3. Severe spasticity 4. Bladder > bowel and sexual dysfunction
Spirochetes
Syphilis
A. General considerations: 1. Caused by T. pallidum 2. Spread by sexual contact or vertically from mother to child 3. Untreated 1–5% go on to develop tabes dorsalis; usually is seen 15–20 years after the original infection B. Clinical features: 1. Lightening pains (often thoracic or abdominal); dorsal root ganglia involvement 2. Urinary incontinence 3. Sensory ataxia (positive Romberg’s sign) 4. Pupils are abnormal in 90% of patients 5. Argyll Robertson pupils are seen in 50%; other ophthalmological features include: a. Optic atrophy b. Ophthalmoplegia and ptosis c. Uveitis, chorioretinitis and vasculitis 6. Associated disorders: a. Gastric pharyngeal, laryngeal, genitourinary, intestinal, rectal crisis 7. Stamping gait Other Causes of Syphilitic Spinal Cord Involvement
1. Dorsal root entry zone and dorsal roots are sites of pathology a. Hitzig spots (dorsal root posterior rami) cause oval areas of anesthesia on the trunk 2. Pachymeningitis cervicalis: a. Compression of the cord by thickened dura
Chapter 8. Infections Affecting the Spinal Cord
3. Anterior and posterior spinal artery occlusion a. Proliferative endarteritis 4. Laboratory evaluation: a. Oligoclonal bands are present b. IgM and IgG antibodies are seen in the CSF c. PCR > 95% positive
Lyme Disease
A. General considerations: 1. Borrelia burgdorferi 2. Transmitted by the deer tick Ixodes domini, pacificus, ricinus B. Clinical features: 1. Early disease: a. Meningitis c. Bilateral VIIth nerve b. Cranial neuropathy 2. Late disease: a. Encephalomyelitis b. Dementia
Unusual Infections Affecting the Spinal Cord
Actinomycosis
A. General considerations: 1. Caused by a gram positive anaerobic or microaerophilic rod 2. Normal in the mouth and genital flora 3. Most infections are cervical, thoracic, pelvic or abdominal 4. “Lumpy jaw” follows dental procedures or oral mucosa trauma 5. Occurs in immunocompetent patients B. Clinical features: 1. Forms draining sinuses with “sulphur granules” 2. Spinal epidural abscess follows vertebral osteomyelitis a. Primary lung infection
Nocardia Asteroides
A. General considerations: 1. Occurs in immunocompromised patients; dental procedures or inhalation 2. Disseminated disease often invades the CNS 3. Spread from pneumonia with cavity pulmonary lesions B. Clinical features: 1. Concomitant cerebral abscess or meningitis 2. Spinal cord involved by vertebral osteomyelitis
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Hepatitis B Virus
A. General considerations: 1. Associated with fulminant hepatic failure and polyarteritis nodosa 2. Neurological deficits have occurred following hepatitis vaccination B. Clinical features: 1. Transverse cervical or thoracic myelitis 2. Acute cerebral edema 3. Guillain Barré Syndrome 4. Inflammatory neuropathy
Mycoplasma
A. General considerations: 1. M. pneumoniae most often causes pulmonary disease 2. Associated with occlusive cerebral vascular disease, arthralgias, rash, cardiac disease 3. Neurologic features are more common in hospitalized patients: B. Clinical features: 1. Transverse myelitis 4. GBS syndrome 2. Leukoencephalitis 5. Meningoencephalitis 3. Peripheral neuropathy 6. Aseptic meningitis C. Laboratory evaluation: 1. Cold agglutinins 2. Complement fixing antibodies HIV is associated with secondary infective myelopathy 1. Toxoplasmosis 4. CMV 2. Tuberculosis 5. Herpes Simplex 2 3. Syphilis 6. Mycobacterium avium
Chlamydial Diseases
A. General considerations: 1. C. psittaci, C. trachomatis; C. pneumonia are human pathogens 2. Birds to humans by aerosol route B. Clinical features of C. psittaci: 1. Fever, cough, myalgia and hepatomegaly 2. Transverse myelitis 3. Meningoencephalitis 4. Cerebellar ataxia 5. Cranial nerve palsy 6. Seizures C. Laboratory evaluation: 1. CSF: a. >5 lymphocytes b. Normal protein and sugar 2. Diagnosed by serology
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SECTION IV. Spinal Cord Disease
Brucellosis
Spinal Osteomyelitis
A. General considerations: 1. Caused by B. melitensis primarily 2. Multisystem illness with fever joint pain, sacroiliitis and osteomyelitis 3. Transmitted to humans by unpasteurized milk B. Clinical features: 1. Undulant fever pattern occurs in a 2–4 week cycle 2. Lumbosacral radiculitis (L5–S1) is common 3. Meningitis 4. Epidural abscess with myelitis from vertebral, paravertebral or psoas abscess source 5. Meningovascular disease 6. Encephalitis 7. Subdural empyema C. Laboratory evaluation: 1. CSF: a. Lymphocytic pleocytosis b. Low to normal glucose c. Elevated protein d. Positive Brucella agglutination tests
A. General considerations: 1. Predisposing factors: a. Elderly debilitated patients b. Diabetes mellitus c. Rheumatoid arthritis d. Catheter placement (epidural for pain management) e. Surgical procedures 2. Spread: a. Genitourinary tract b. Hematogenous spread 1) Batson’s plexus (perivertebral venous plexus) c. Decubitus ulcer: 1) LP through its periphery may cause inadvertent meningitis d. Phlebitis: 1) Infection spreads to spinal cord by medullary veins e. Endocarditis: 1) Meningeal seeding often occurs early 3. Infections are initiated by: a. Neurosurgical and orthopedic procedures most commonly: 1) Discitis; positive T2 weighted image in the disc space and along the anterior and posterior spinal ligaments
Toxoplasmosis
A. General considerations: 1. Always in an HIV patient with generalized cerebral disease 2. Retinal involvement B. Clinical features: 1. May selectively involve the conus medullaris of the spinal cord 2. CMV involves the lumbosacral roots
Coccidiomycosis
A. General considerations: 1. C. immitis; primarily inhalational route of infection 2. “Valley fever”, dry cough with large joint arthralgia; disseminated infection occurs in 1% of patients 3. Osteoarticular and lytic skull and vertebral lesions 4. Occurs in South Western USA B. Clinical features: 1. Lumbosacral spinal cord and root involvement from contiguous vertebral or sacroiliac osteomyelitis 2. Meningitis occurs within six months of the primary infection; primarily a chronic basilar meningitis C. Laboratory evaluation: 1. CSF: a. Mononuclear or rarely an eosinophilic pleocytosis b. Low glucose c. Elevated protein d. 70% of patients have complement fixing antibody
Most Common Organisms for Vertebral Osteomyelitis
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.
Blood cultures are positive in 50% of patients Staph aureus (50% of infections) Proteus mirabilis Candida albicans Staphylococci epidermidis Citrobacter Klebsiella Escherichia coli Alpha streptococci Salmonella Tuberculosis Brucellosis Salmonella (typhoid and paratyphoid) Blastomycosis
Spinal Epidural Abscess
A. General considerations: 1. Usually they are secondary to systemic infections 2. Alternatively they invade the epidural space from the mediastum, retroperitoneal space 3. Psoas or paraspinal abscess 4. Direct extension from osteomyelitis
Chapter 8. Infections Affecting the Spinal Cord
5. Penetrating trauma 6. LP 7. Epidural catheters 8. Back surgery. B. Clinical features: 1. Early symptoms are localized back pain or radicular pain 2. The thoracic spine accounts for 50–80% cases > lumbar 20% > cervical 10–25% 3. Early symptoms are overshadowed by para or quadriparesis 4. Peripheral white count and sed rate are usually elevated C. MRI evaluation: 1. Particularly helpful if discitis is the source D. Pathology: 1. Peripheral white count and sed rate are elevated 2. Organisms usually can be cultured Differential Diagnosis of Acute Epidural Abscess
1. 2. 3. 4. 5. 6. 7. 8.
Acute epidural hematoma Metastasis Autoimmune transverse myelitis Spinal subdural empyema Primary spinal tumor Arterial venous malformation Embolic disease to the artery of Adamkiewicz Spinal hemangioblastoma
Differential Diagnosis of Chronic Epidural Abscess
Chronic Pachymeningitis of the Spinal Cord
1. Compression: a. Idiopathic pachymeningitis b. Tuberculosis c. Syphilis (pachymeningitis cervicalis) d. Meningeal amyloid
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Lumbar Abscess
1. Flank or psoas abscess a. Extends into iliac fossa, groin, gluteal fold or thigh b. Septic medullary spinal veins: 1) Paraparesis
Pott’s Disease
A. General considerations: 1. Most often thought of as tuberculosis involvement of the spine 2. Less sclerosis in tuberculous spondylosis 3. Tuberculous involvement of the spine is rare in HIV infected patients 4. Most common level is T10 in Americans; in Asians it is cervical and in other ethnic groups it is lumbar (Eskimos) B. Clinical features: 1. Dull aching gnawing pain at the level of involvement 2. Pain is increased by movement 3. Increases during the day; lessens at night 4. Late stages there is a radicular component 5. Low grade fever 6. Anorexia and weight loss 7. Rupture with dissection of pus occurs in 50–85% of patients 8. Paraplegia: a. Epidural compression b. Septic thrombophlebitis of spinal cord draining veins c. Delayed endarteritis d. Bony sequestrum e. Granulation tissue f. Delayed osteoblastic changes
Abscess Formation by Location
Cervical: 1. Retropharyngeal: a. Dysphagia is a primary symptom (streptococcus) 2. Abscess in the neck or supraclavicular fossa: a. Subclavian vein infections from infected lines b. Septic involvement of the vertebral artery 1) Inflammation of the vertebral arteries with stroke 2) May also affect blood supply to the brachial plexus Thoracic Abscess
1. 2. 3. 4. 5.
Rupture into the pleura Dissect along ribs Fluctuant subcutaneous mass Paravertebral mass Ruptures into the epidural space with quadriplegia
Differential Diagnosis of Pott’s Disease
Bacterial Agents
1. Staphylococcus aureus: a. Often seen in IV drug abuser b. Metastatic to bone marrow which is highly vascular and a major source of growth factors c. Thoracic > cervical cord Streptococcus
1. Retropharyngeal abscess (from tonsil) also known as Vincent’s angina 2. Severe dysphagia
SECTION IV. Spinal Cord Disease
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Gram Negative Bacteria
1. 2. 3. 4.
May affect any cord level E. coli Pseudomonas Liver failure a predisposing cause; absence of Kupffer cells
Salmonella
1. Most often seen in sickle cell (SS) patients 2. Concomitant large joint involvement 3. Thoracic > lumbosacral level Fungal Disease
1. Blastomycosis a. S.E. United States b. Characteristic skin lesions (raised advancing border) c. Thoracic cord most often involved (paravertebral mass from lung abscess) Actinomycosis
1. Lung involvement with paravertebral mass 2. In the normal flora of the mouth 3. Thoracic level of involvement Cryptococcus
1. Lung abscess (found in soil, inhaled) 2. Thoracic cord level Coccidiomycosis
1. Lumbosacral involvement (sacroiliac and sacral joint osteomyelitis) 2. Contiguous spread to spinal levels Differential Diagnosis of Pott’s Disease
1. Most common tumors are metastatic: a. 5% of all cancers are metastatic to the spine 2. Multiple myeloma with bone destruction 3. Ankylosing spondylitis (cervical and thoracic): a. Myelopathy is precipitated by trauma 4. Osteoporosis (thoracic spine with anterior wedge fracture) 5. Eosinophilic granuloma (skull, humerus and thoracic spine): a. Rare vertebral collapse with spinal cord compression 6. Osteoid osteoma (usually the pedicle is involved) 7. Hemangioma (thoracic vertebral)
Chapter 9 Tumors of the Spinal Cord A. General considerations:
1. Patterns of involvement a. Epidural c. Intraparenchymal b. Intradural extramedullary
Epidural
A. General considerations: 1. The overwhelming majority of tumors that are epidural are metastatic. Multiple myeloma and chordoma are the primary spine tumors that invade this space. 2. Epidural spinal cord compression occurs in approximately 5% of cancer patients 3. 50% of all epidural metastatic lesions are from the lung or breast. Others are: a. Prostate c. Lymphoma b. Melanoma d. GI tract 4. Tumors reach the epidural space by: a. Hematogenous spread b. Through Batson’s venous plexus (perivertebral) c. Through nerve root exit foramina (lymphoma in particular) 5. 70% involve the thoracic cord; 10% the cervical cord and 20% the lumbosacral cord. Lung and breast metastasize to the thoracic spine; colon, prostate and ovarian tumors to the lumbosacral spine and melanoma to unusual areas of the spine (in addition to digits, heart surface and intestinal wall). B. Clinical features: 1. Unrelenting boring back pain; made worse with recumbency (differential point from disc disease) 2. Exacerbated at night 3. Persists with bed rest 4. Gait ataxia prior to weakness (compression of the dorsal and ventral spinocerebellar tracts) 5. Weakness may precede sensory symptoms 6. Bowel and bladder dysfunction rarely the earliest symptoms 7. Sensory complaints are often painful 8. Rapid progression suggests: a. Lung c. Melanoma b. Renal cell C. Laboratory evaluation: 1. CSF: a. Malignant cell determination is directly related to the volume of fluid studied b. Glucose of 30–40 mg% c. Protein 80–150 mg% d. If the protein is 800 mg to 1000 mg% is a spinal block (Freund’s reaction) D. Imaging evaluation: 1. Pedicle involvement; erosion of the end plates and central vertebral body lesions noted on plain film suggest metastatic disease
Chapter 9. Tumors of the Spinal Cord
2. Bone involvement is cancer; disc involvement is infection 3. MRI evaluation of metastatic disease to the vertebrae: a. Multiple areas of T1 weighted low density areas in the vertebra b. Pathologic fractures c. Osteoblastic bone changes; 1) Myeloma; prostate; Hodgkin’s, rarely breast cancer d. Does not invade the disc space e. Density or enhancement in the CSF space between cerebellar folia suggests associated carcinomatosis of the meninges
Division A: Primary Tumors of the Vertebral Column with Secondary Epidural Compression
A. General considerations: 1. Tumors of the vertebral column are often malignant 2. Multiple myeloma is the major malignant bone tumor of adults: a. Peak incidence is sixth–eighth decades b. A higher incidence in African-Americans than Caucasians c. Extradural compression occurs in 10% of patients d. Plasmacytoma: 1) Evolves into multiple myeloma within 10 years 2) Male to female ratio is 3 : 1 3) Associated with neuropathy 3. Chordoma: a. Arises form notochordal remnants b. Clivus and sacrococcygeal in location c. Peak incidence is 5th through 7th decade d. Hematogenous metastasis occur in approximately 1/3 of patients
Intradural Extramedullary Tumors
Differential diagnosis includes: 1. Neurofibroma 2. Schwannoma 3. Meningioma 4. Dropped metastasis from medulloblastoma and pinealoma (from cells circulating in spinal fluid) 5. Leptomeningeal metastasis 6. Congenital neuropathy with enlarged nerve roots (HSMN III)
Nerve Sheath Tumors
A. General considerations:
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1. Neurofibroma is a mixture of Schwann cells, fibroblastic and collagen fibers that grow through and cannot be separated from the nerve 2. Schwannoma is composed of Schwann cells that cause an enlargement of the involved nerve root 3. They are evenly distributed along the neuraxis 4. Occur equally in men and women 5. Onset is usually between 30–60 years of age (average is 43 years) 6. Two thirds are intradural; they often are intradural and extradural (dumbbell) B. Clinical features of Neurofibroma: 1. Specific painful radicular syndrome 2. Skin stigmata of NFI (chromosome 17) 3. Slow spinal cord compression (intradural component) a. Weakness and spasticity below the level of the lesion b. Sensory loss at two segments below the lesion if in the thoracic cord; dropped sensory level of many segments if the lateral cervical cord is compressed c. Clear Babinski sign is present d. Usually only mild bladder involvement C. Imaging features: 1. Dumbbell tumor; widens the neural exit foramina; intra and extradural component 2. Scalloped vertebral body (long standing pressure) 3. Meniscus sign on myelography 4. Heterogeneity of Schwannoma, more homogeneity of neurofibroma on T2 weighted MRI images; enhancement is often a sign of cystic degeneration
Meningioma
A. General considerations: 1. Arise from arachnoid cap cells 2. Greater than 90% are intradural; rare in the thoracic cord of men; peak incidence is between 40–70 years of age 3. Approximately 80% are in women and 80% are in the thoracic cord; pain (ependymomas have pain) 2. Malignant astrocytomas may have leptomeningeal spread (similar to the extra phytic spread of cerebral gliomas) C. Imaging evaluation: 1. Approximately 40% have an associated syrinx 2. Usually enhance with gadolinium in a heterogeneous pattern 3. Asymmetrically expand the cord 4. In the presence of NF-2 they may be multiple Pilocytic Astrocytoma
A. General considerations: 1. May occur simultaneously or at different sites in the CNS (usually with NF-1) 2. Grow long distances throughout the brainstem with minimal dysfunction 3. No progression to malignant astrocytoma 4. Primary tumor of children and adolescents
5. Rare in the spinal cord B. Clinical features: 1. Depends on the level of involvement in the cord C. Imaging evaluation: 1. MRI: a. Fusiform thickening of the cord 2. PET: a. High rate of glucose utilization
Ependymoma
A. General considerations: 1. Approximately 55% involve the cervical spinal cord or arise from the filum terminale 2. Male to female ratio is 2 : 1 3. Mean age of onset is 40 years of age 4. Most common neuroepithelial tumor of the spinal cord B. Clinical features: 1. Most common sites are: cervical > cervicothoracic > lumbosacral > cauda equina 2. Back pain is the most common complaint 3. Dysesthesia without sensory loss Myxopapillary Ependymoma
A. General considerations: 1. Age of onset 36 years (6–82 years); males > females 1.7 : 1 2. Compresses and envelops the cauda equina 3. Occasionally invades the nerve roots 4. Pain and numbness occur in a radicular pattern in the legs; the tumor is in the filum or conus medullaris; these are usually histologically separate from neural tissue. B. Clinical features: 1. Asymmetric loss of lower extremity reflexes with radicular pain 2. Large tumors may invade adjacent bone 3. Post operative complications are: dysesthesias and loss of proprioception C. Imaging evaluation: 1. Homogeneous enhancement by MRI; sharply defined rostral and caudal borders 2. Approximately 30% have associated cysts 3. Pseudocapsule; intense enhancement D. Subcutaneous Sacrococcygeal Myxopapillary Ependymoma 1. Develop in the skin and subcutaneous tissue of the sacrococcygeal area 2. Often misdiagnosed as pilonidal cysts 3. May cause distant metastasis 4. Approximately 20% have local recurrence
Chapter 9. Tumors of the Spinal Cord Intramedullary Metastasis
A. General considerations: 1. Approximately 5% of spinal tumors in cancer patients 2. Lung > breast > lymphoma > colorectal > head and neck > renal 3. Origin is arterial blood 4. Approximately 50% of spinal metastasis have concomitant brain metastasis 5. Conus medullaris is the most common site of metastases 6. Approximately 10% are multilevel 7. Occurs in up to 8% of patients with non Hodgkin’s lymphoma; 70% of patients with Leukemia 8. Most common solid tumors causing infiltration of the arachnoid and pia mater (leptomeninges) are: a. Breast cancer c. Melanoma b. Lung carcinoma d. Gastrointestinal cancers 9. Risk factors for leptomeningeal spread of nonHodgkin’s lymphoma are: a. Bone marrow and testicular involvement b. Extranodal spread c. Epidural metastasis d. Lymphoblastic histology e. Burkitt’s syndrome 10. General rule: a. Primary lymphomas are parenchymal with leptomeningeal spread b. Systemic lymphomas are meningeal with secondary parenchymal spread B. Clinical features: 1. Rapid progression of clinical signs 2. Ataxia, weakness, sensory level, urinary incontinence and pain 3. Weakness is asymmetrical
Benign Spinal Tumors (Embryonal)
A. General considerations: 1. These tumors comprise female 1.6/1 2. Origin is most frequently the roof of the IVth ventricle (superior medullary velum) 3. Metastasize to the spinal cord via CSF pathways
Intravascular Malignant Lymphomatosis
A. General considerations: 1. Rare fatal disease 2. Multicentric proliferation of intravascular malignant mononuclear cells 3. Systemic involvement: a. Heart c. Skin b. Kidneys d. Lymph nodes 4. Primary cerebral or spinal intravascular lymphomatosis is rare; a good clue is the triad of dementia, small strokes and meningeal signs B. Clinical features: 1. A disease of middle age and elderly patients (61 years is median; 12–87 years) 2. 34% of patients have myelopathy 3. Occludes and infarcts spinal vessels; dementia and meningeal signs are associated C. Laboratory evaluation: 1. Increased sed rate 2. Elevated serum lactic dehydrogenase 3. CSF reveals lymphocytic pleocytosis D. MRI evaluation: 1. Rare meningeal involvement demonstrated
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SECTION IV. Spinal Cord Disease
A. General considerations: 1. Most tumors develop in the temporal lobe 2. 20–50% arise in the spinal cord: a. Any site may be the origin including the conus medullaris b. Usual sites: 1) Cervicothoracic cord > thoracolumbar > multiple spinal cord segments B. Clinical features: 1. Dependent on spinal cord location 2. Onset at age 20 (1–80 years) 3. Slight male preponderance at all sites 1 : 2 4. Not associated with phakomatosis or heritable disease, but with migrational defects 5. 6% of patients develop malignant anaplastic ganglioglioma
lumbosacral cord is the region of most benign tumors, that often have associated skin manifestations. A malignant subcutaneous myxopapillary ependymoma may grow into lumbar subcutaneous tissue. Ependymomas present with pain more frequently than paresthesias. Radicular complaints and weakness suggest a myxopapillary tumor. Asymmetric reflexes in the lower extremities support the diagnosis. As a general rule epidural tumors are painful and present with symmetrical weakness and bladder dysfunction. Ataxia due to cervical cord lesions is commonly overshadowed by weakness. Obstipation may occur prior to bladder dysfunction. In medullary cervical tumors one may be precipitate micturition with a valsalva maneuver. Most patients with intraparenchymal tumors have difficulty with recumbency that causes them to sit up in a chair to sleep. Astrocytomas, hemangioblastomas and ependymomas may have an associated syrinx. A combination of cerebral strokes, dementia and meningeal signs should suggest cerebral angiolymphomatosis.
Gangliocytoma
Malignant Bone Tumors Involving the Spinal Cord
A. General considerations: 1. Increased number of abnormal neurons 2. Site of origin is cerebrum and cervicothoracic spinal cord B. Clinical features: 1. Clinically symptomatic by age 30 (20–60 years of age) 2. Slowly evolving long tract signs 3. Recurrence of the tumor is restricted to its original site
Chordoma
Ganglioma
A. General considerations: 1. Ganglion cell differentiation occurs in 50% of patients 2. Age of onset is around 13 years (described into the 8th decade) 3. Rare tumor of the spinal cord and cauda equina
A. General considerations: 1. Mean age at diagnosis is 48 years (8–83 years); mean age for sacrococcygeal ependymoma is 56 years 2. Male predominance of 2 : 1 3. Arises from vestiges of the embryonal notochord 4. Sacrococcygeal > sphenooccipital > greater than the vertebral column 5. Vertebral chordoma: a. Lumbar > cervical > thoracic b. Bulk of the tumor is usually anterior to the vertebral body B. Clinical features: 1. Pain 4. Mass over the coccyx 2. Rectal dysfunction 5. Sciatic pain 3. Urinary incontinence C. Clinical features of vertebral body chordoma: 1. Pain 3. Lower extremity weakness 2. Bladder dysfunction D. Differential Diagnosis 1. Metastatic carcinoma (particularly colorectal or prostate) 2. Chondroid tumors 3. Chondrosarcoma
Differential Diagnosis of Spinal Cord Tumors
Multiple Myelomatosis (Disseminated plasma cell tumors)
Meningiomas occur in the thoracic cord of women. They are extremely rare in men in this distribution. A common mistake in the past was making the diagnosis of metastatic disease in a breast cancer patient that had a thoracic meningioma. The
A. General considerations: 1. Skull and vertebral columns most often affected 2. Predilection for bones of the thoracic cage (clavicle, ribs, vertebrae)
Central Neurocytoma
A. General considerations: 1. Most often they are supratentorial around the lateral or III ventricle 2. Tumors occur in the cervical spinal cord
Central Neuroblastoma
Chapter 9. Tumors of the Spinal Cord
B. Clinical features: 1. Vertebral body invasion with collapse and subsequent spinal cord compression 2. Necrotizing progressive myelopathy 3. Leptomeningeal spread may occur 4. Plasmacytomas and plasma cell myeloma are associated with HIV infection
5. 6. 7. 8. 9. 10.
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Hemangioblastoma Hemangioma Central neurocytoma Dermoid Teratoma Hibernoma (vestigial remnants of brown adipose tissue)
Ganglioneuroma Chondrosarcoma
A. General considerations: 1. Occur in the first and second decades in the same areas as chordomas 2. May occur after excision; late metastases noted 3. Arise from the petroclival suture 4. Rarely arises from the nasopharynx, vomer and sphenoethmoidal region B. Clinical features: 1. Rare in the spinal cord; features of extradural compression C. Imaging evaluation: 1. CT and MRI demonstrate an erosive destructive lesion of the skull base that may involve the brainstem and cervical cord 2. May calcify Ewing’s Sarcoma
A. General considerations: 1. Primarily a tumor of adolescence 2. Involves the cervical spinal cord B. Clinical features: 1. Extradural compression C. Imaging evaluation: 1. Onion peel periosteal reaction Osteogenic Sarcoma
A. General considerations: 1. 10% occur in the third decade; osteosarcoma in the fifth and sixth decades are due to transformation from a benign condition B. Clinical features: 1. May affect any vertebrae 2. Extradural clinical features 3. Destructive moth eaten lesion; speculated periosteal reaction (sunburst appearance)
Division B: Differential Diagnosis of Benign Spinal Cord Tumors
1. 2. 3. 4.
Meningioma (see intradural extramedullary tumor) Neurofibroma (see intradural extramedullary tumor) Schwannoma (see peripheral nerve sheath tumor) Ganglioneuroma
A. General considerations: 1. Circumscribed ganglionic cell tumor a. 56–70% of tumors are located within the posterior mediastinum or retroperitoneum in association with the sympathetic neuraxis b. 20–30% involve the adrenal gland c. May arise anywhere along the paramidline d. Onset second to third decade (later onset if arise in unusual positions) e. Female predominance 1.3–3.5 B. Clinical features: 1. Compress the spinal cord (intradural extramedullary component) 2. Grow through the intervertebral foramina 3. Dumbbell shaped tumor 4. Rare active hormone secretion (vasointestinal peptide VIP; catecholamines; testosterone may also be secreted) 5. Ganglioneuromatosis occurs concomitantly with NFI; gastrointestinal tract may have diffuse ganglioneurofibromatosis 6. Associated with: a. MEN type 2B syndrome b. Familial neural crest tumors c. Cowden’s syndrome d. Juvenile polyposis C. Imaging evaluation: 1. CT-calcification 20–30% 2. Thoracic tumors are associated with rib deformities 3. Paraspinal lesions; dumbbell shaped tumors
Hemangioblastoma (Capillary Hemangioblastoma)
A. General considerations: 1. Benign; highly vascular often cystic 2. Single or multiple 3. Seen often in associated with Van Hippel–Lindau’s disease 4. Peak incidence between 35–45 years of age 5. Male predominance 2 : 1 6. Site of origin: a. Posterior fossa (94%) b. Spinal cord (3%) c. Supratentorial (3%) d. Very rare at the cervicomedullary junction
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SECTION IV. Spinal Cord Disease
7. Capillary hemangioblastoma occur with: a. Gliomas c. AV malformations b. Subependymomas B. Clinical features: 1. Spinal cord hemorrhage 2. Slow progression of long tract signs C. Pathology: 1. Formed by blood vessels: a. Lined by single layer of epithelium b. Cysts occur with tumors in the spinal cord Lipoma
A. General considerations: 1. Probable aberrant differentiation of the tail bud (multipotential cells) 2. Low lumbar sacral origin 3. Histology: a. Simple lipoma b. Complex forms: ectodermal, mesodermal or endodermal origin B. Clinical features: 1. Radicular pain and motor loss 2. Congenital lumbosacral lipomas with tethered cord symptomatology a. Conus medullaris lipoma b. Lipomyeloschisis 3. Tethered cord intradural lipoma: a. Cervical to lumbar cord in location b. Dysesthetic pain (non-radicular) c. Mixed with nerve roots Dermoid Cysts
A. General considerations: 1. Lumbosacral site; extra or intramedullary a. Dermoid cysts connect to dermal sinuses that may penetrate the dura b. Dermis, hair follicles, sebaceous and sweat glands are present; bone and cartilage is rare c. Slow growing benign lesion; rare malignant transformation to squamous cell cancer B. Clinical features: 1. Pyogenic infection (if extends through the dura) with unusual organisms 2. Rupture of the cyst into CSF pathways that causes severe granulomatous meningitis 3. Associated midline skin dimple or pit: a. Below the inguinal crease; they end blindly and never extend intraspinally b. Dimples above the inguinal fold may connect intradurally c. Dermal sinuses may lead to spinal cord tethering 4. Pes cavus may be associated 5. Asymmetry of motor and sensory loss 6. Bladder dysfunction
Epidermoid
A. General considerations: 1. Extremely rare in the spinal cord: a. May extend into the cervical cord from the cerebellopontine angle b. Intramedullary cysts have been described 2. Epidermoid cysts originate from the ectoderm 3. Benign; slowly growing; encapsulated; whitish capsule (pearly tumor) 4. Usually associated with dysraphism B. Clinical features: 1. Sites: a. Intramedullary b. Intradural 2. Re-tethering of the cord after repair of lipomyelomeningocele (delayed >10 years) 3. Associated with LP early in neonatal life 4. Intradural extramedullary types: a. Bone or skin malformation (spina bifida or dermal sinus) b. Pathogenic from LP (epidermal cells pushed in by the needle) c. Lumbar pain d. Urinary dysfunction 5. Thoracic intradural epidermoid: a. Sudden paraplegia
Spinal Teratoma
A. General considerations: 1. Site of origin: a. Sacrococcygeal area 2. Associated with: a. Dysraphic states b. Diastematomyelia c. Lipomyelomeningocele B. Clinical features: 1. Urinary retention 2. Weakness of the legs 3. May be seen at different level than an associated malformation 4. Scoliosis 5. Rarely may be extradural and compress the cord having extended through intervertebral foramen
Metastatic Spinal Cord Tumors
A. General considerations: 1. Destroy the vertebra: a. Mid vertebral body destruction b. Pedicles and posterior elements are affected c. Effects the cord by epidural compression from the intervertebral canal
Chapter 9. Tumors of the Spinal Cord
d. Does not involve the disc space e. Pathologic fractures are common B. Clinical features: 1. Boring nocturnal pain 2. May have radicular component 3. Ataxia prior to weakness; usually overshadowed by the weakness 4. Early bladder involvement 5. Obstipation may be noted prior to bladder symptoms 6. Dropped sensory levels (particularly from the cervical cord) 7. Parenchymal metastases: a. Blood borne to the spinal cord b. Lung c. Malignant melanoma d. Less bladder and bowel involvement e. Sacral sparing (if Intramedullary) f. Local atrophy at the affected level 8. Rare involvement of sympathetic thoracic ganglion with segmental hyperhidrosis; usually from lung tumors C. Specific tumor metastatic patterns: 1. Lung: a. Multiple metastatic sites b. Most common in males c. Blood borne to center of the cord d. Hemorrhagic Intramedullary necrosis e. Direct extension (Pancoast); sulcal tumor from apex of the lung f. Almost always concomitant cerebral metastases D. GI tract: 1. May destroy the sacrum 2. Colorectal cancer E. Prostate: 1. Local lumbosacral invasion 2. Osteoblastic and osteoclastic components 3. Spinal cord and radicular components T10–L1 to L3 roots as opposed to L4–S1 roots from mechanical cause 4. Slowly progressive 5. Has been described in the petrous apex of the posterior fossa F. Renal cell: 1. Radicular component 2. Usually only one cerebral metastasis G. Leukemia 1. Marble vertebra (dense on spine film; marrow change on MRI) 2. Involvement of nerve roots and spinal compression 3. 70% have leptomeningeal spread H. Lymphoma: 1. May infiltrate vertebral body (dense vertebrae) 2. Envelops the lumbosacral dura and cauda equina 3. Cord compression and nerve root involvement 4. Leptomeningeal spread I. Drop metastasis: 1. Medulloblastoma 2. Ependymoma
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J. Differential Diagnosis of intrinsic vertebral body bone disease (with spinal cord compression) 1. Paget’s disease 2. Fibrous dysplasia of bone (Albright’s disease) 3. Brown bone cyst 4. Articular bone cyst 5. Osteosarcoma 6. Ewing’s sarcoma (12% vertebral body) 7. Chondrosarcoma 8. Osteosclerotic myeloma (POEM’s syndrome) 9. Multiple myeloma 10. Osteoid osteoma 11. Hemangioma of bone 12. Eosinophilic granuloma 13. Osteochondroma 14. Osteoporosis 15. Hyperparathyroidism 16. Ankylosing spondylitis 17. Vitamin deficiency 18. Osteomalacia (syndromes) 19. Vertebral collapse (prolonged IV heparin) 20. Chordoma
Osteosarcoma
A. General considerations: 1. Young patients 2. Long bones preferred sites; distal femur most common B. Clinical features: 1. Rare in vertebral body thoracic levels b. With spinal cord compression 3–5 vertebrae are involved B. Clinical features: 1. Slow progression (6–12 months) 2. Sensory loss and weakness early; then spasticity, bowel and bladder involvement 3. Lumbar involvement usually single vertebrae: a. Radiculopathy (single) c. Polyradiculopathy b. Neurogenic claudication 4. Cervical: a. Extremely rare b. Quadriplegia reported
Osteoclastic Monostatic Myeloma
A. General considerations: 1. One vertebral body involved 2. May be any bone in the body or any vertebral level 3. Motor sensory neuropathy B. Clinical features: 1. POEMS syndrome: a. Polyneuropathy d. Myeloma b. Organomegaly e. Skin lesions c. Endocrinopathy
Eosinophilic Granuloma
A. General considerations: 1. Young patients (10–20 years of age) 2. Involvement of proximal humerus, skull and thoracic spine
A. General considerations: 1. Long bones are involved 2. Most often asymptomatic B. Clinical features: 1. Associated with syndromes that may affect the spinal cord a. Bannayan–Zonana syndrome (AVMs of the cord) b. Gardner’s syndrome
Paget’s Disease
A. General considerations: 1. Increased bone resorption followed by increased bone formation 2. Long bones of lower extremities, pelvic bones, skull, upper extremity bones, ribs, scapulae, vertebrae; one vertebrae (ivory vertebrae) are affected 3. Slowly progressive B. Clinical features: 1. Malignant (sarcomatous transformation) a. Occurs in pagetic bone of skull or spine b. female 4. Pattern of involvement is: a. 60–70% kyphoscoliosis; 17% kyphosis; 15% scoliosis (pure) 5. Slowly progressive thoracic myelopathy B. Clinical features: 1. Pain locally at area of spinal deformity 2. Acute precipitation by trauma (rare) 3. Bladder relatively spared 4. Spasticity with paraparesis 5. Radiculopathy
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SECTION IV. Spinal Cord Disease
Thoracic Spine Kyphoscoliosis
A. General considerations: 1. Earlier causes tbc and poliomyelitis 2. Myelomeningocele common cause at present: a. Associated anomalies: 1) Hemivertebrae 2) Absence of ribs 3) Diastematomyelia 4) Klippel–Feil deformity 5) Sprengel’s deformity 6) Arnold Chiari malformation b. Kyphoscoliosis occurs in patients with hydrocephalus that is unrelated to congenital spine defects c. Acquired kyphoscoliosis of the thoracic spine is from: 1) Infection of vertebral body, lamina, pedicles 2) After laminectomy for tumor 3) Syringomyelia 3. Complications of therapy: a. Halo femoral or halo pelvic traction 1) Cranial nerve palsies involving VI, IX, X, XI (cervical kyphoscoliosis) 2) Brachial plexus traction injury 3) Horner’s syndrome 4) Myelopathy with motor and sensory deficits b. Harrington rod placement: 1) Paraplegia 2) Anterior spinal cord syndrome 3) Urinary tract dysfunction c. Postlaminectomy kyphosis: 1) Follows spinal operations for: trauma, tumor, myelomeningocele
Vitamin D Deficiency:
A. General considerations: 1. Dilantin use 3. Multiple bone fracture 2. Kidney disease B. Clinical features: 1. Severe bone pain affecting the pelvic girdle 2. Associated proximal muscle weakness pelvic girdle > shoulder girdle I.V. Heparin Therapy
A. General considerations: 1. Thoracic vertebrae deformity (fish mouth) B. Clinical features: 1. Pain locally 2. Heparin use greater than two weeks 3. Rare vertebral body collapse
Differential Diagnosis of Intrinsic Disc Disease with Spinal Cord Involvement
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Extruded disc (centrally) Free fragment disc (may migrate) Relapsing polychondritis Ochronosis (homogentisic aciduria) Collagen gene defects (COLA 1–5) Ehlers Danlos syndrome (type IV) Marfan’s syndrome Tbc SBE (staph aureus) Gram negative infection following surgery Charcot joint (disc destruction) a. Syphilis c. Amyloid b. Diabetes mellitus d. Syrinx 12. Trauma (exacerbates pre existing disc dysfunction; does not cause degenerative disc disease) 13. Fungal infection: a. Nocardia b. Cryptococcus c. Blastomycosis d. Coccidioidomycosis (not uncommon from contiguous sacroiliac infection)
Disc Disease
A. General considerations: 1. Central disc protrusion may compress the spinal cord acutely or chronically at cervical, thoracic, and high lumbar levels 2. Most dangerous area is thoracic due to the small diameter of the spinal canal at this level 3. A disc fragment may erode through the posterior longitudinal ligament and compress the cord; it may migrate rostrally and caudally 4. Radicular symptoms may be noted with lateral or contralateral disc protrusion (loss of bilateral foraminal integrity) there may or may not be associated cord compression 5. Initial thoracic disc protrusion symptoms: a. Patients legs collapse during heavy lifting b. Severe thoracic radicular pain 6. Central cervical disc rupture most common at C5–C6; C6–C7 (greatest flexion and extension movement segments) B. Clinical features: 1. Incomplete spinal cord injury 2. Brown Sequard syndrome 3. Anterior spinal artery syndrome 4. May cause pseudo peripheral nerve sensory loss of the lower extremities (stocking like)
Chapter 9. Tumors of the Spinal Cord Relapsing Polychondritis
A. General considerations: 1. Autoimmune disease of cartilage 2. Associated cartilage involvement of trachea, pinna and nose 3. Cause of relapsing meningitis 4. Cause of optic neuritis B. Clinical features: 1. Affects disc at any level with cord compression
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6. Involvement of the pre and post vertebral fascia is common; may extend over several segments 7. Usually only one disc level is involved 8. Arteries that supply the disc are end arteries 9. Paravertebral muscle involvement: a. Common in the iliopsoas (cold abscess) at the L1– L3 levels in American patients with tuberculosis b. Asian patients tend to have more cervical involvement Clinical Characteristics of Specific Infections of the Disc Space
Ochronosis
A. General considerations: 1. Defect of homogentisic acid metabolism 2. Affects thoracic discs 3. Dark urine B. Clinical features: 1. Rare clinical symptoms C. Imaging evaluation: 1. Calcification of thoracic discs (“rugger Jersey”) 2. Calcified ear lobes
Charcot Joints and Disc Destruction of the Thoracic Spine
A. General considerations: 1. Loss of pain and proprioceptive input to the joint 2. Occurs with: a. Diabetes mellitus c. Syphilis (tabes dorsalis) b. Amyloidosis d. Thoracic or cervical syrinx B. Clinical features: 1. Proprioceptive loss at the affected level 2. Abnormal motion segment; vertebral body collapse 3. Cord compression, radicular motor or sensory loss C. Collagen defects all have disc capsule defects with extrusion of the nucleus pulposus 1. Marfan’s disease 2. COLA 1–5 gene defects 3. Ehlers Danlos (type IV) 4. Osteogenesis imperfecta
Infections of the Disc Space
A. General considerations: 1. Exquisite pain with movement or vibrating the bed 2. Frequent radicular component 3. High sedimentation rate 4. Local pain at the level of involvement 5. Eburnated end plates of the vertebral bodies are characteristic of tuberculosis
1. Staphylococcus aureus: a. Common with IV drug abuse and in HIV infected patients b. Rapid symptomatology c. Can be at any spinal level but most often at thoracic levels d. Concomitant with SBE 2. Gram negative infections: a. Post disc surgery b. Pseudomonas; E coli; enterococcus are the most common c. Organisms may have delayed onset; 2–3 weeks after post surgical procedure; rarely 6–8 weeks after surgery 3. Nocardia: a. Noted in patients with lung abscess b. May have cervical predilection c. Associated with immunosuppressed patients 4. Cryptococcus a. Low cervical and thoracic disc spaces b. Lung origin c. HIV and immunocompromised patients d. Associated meningitis and cranial nerve II involvement 5. Coccidiomycosis a. Lumbosacral disc spaces; origin of infection is contiguous bone osteomyelitis b. Associated arteritis c. South West USA (San Joaquin valley fever) 6. Actinomycosis a. Thoracic and low cervical disc spaces b. Concomitant lung infection c. Draining sinuses with sulfur granules
Division C: Concomitant Spinal Cord Compression from Pathology of Ligaments/Arachnoid Cysts and Dural Processes
1. Posterior longitudinal ligament calcification (cervical); Japanese patients primarily 2. Ankylosing spondylitis (anterior and posterior longitudinal ligament calcification) 3. Acromegaly (generalized swelling of all soft tissue)
SECTION IV. Spinal Cord Disease
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4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
14.
Mucopolysaccharidoses (Shie’s disease) Idiopathic hypertrophic pachymeningitis Syphilitic cervical pachymeningitis Familial amyloid polyneuropathy – type I (meningeal involvement) Sarcoid dural infiltration Lymphomatous dural infiltration Tuberculous dural infiltration Low CSF pressure states (dural enhancement after LP); no pressure on the spinal cord Rheumatoid dural proliferation Ligamentous laxity syndromes: a. Mongolism (C1–C2) b. Ehlers Danlos type IV c. Marfan’s disease d. Homocystinuria e. Rheumatoid arthritis (pannus formation; destruction and erosion of atlanto axial ligaments at C1–C2) f. Spinal arachnoid cysts Hirayama’s Disease a. Abnormal laxiff of ligaments and movement at C8–T1
Ossification of the Posterior Longitudinal Ligament
A. General considerations: 1. Occurs in the cervical spine 2. Extends only two segments or the entire cervical spine; upper and midportion of the spine involved > lower segments 3. Occurs in patients > 40 years of age 4. Males > females 5. Most frequent in Japanese patients B. Clinical features: 1. Myelopathy > radiculopathy; both may occur concomitantly 2. Posterior cervical pain may be an isolated complaint 3. Usually a slowly progressive myelopathy 4. Trauma may precipitate acute cord compression in a congenitally narrow canal 5. Radiculopathy with segmental pain; weakness and sensory loss is frequent 6. Most frequently involved roots are C7, C8 and T1 7. May compress one half of the spinal cord
Acromegaly
A. General considerations: 1. Enlargement of all ligaments 2. Associated soft tissue hypertrophy 3. Cardiac and joint involvement B. Clinical features: 1. Carpal and tarsal tunnel syndromes are the frequent presenting complaints 2. Spinal cord compression with myelopathy (all levels)
Mucopolysaccharidoses
A. General considerations: 1. Cataracts; dysmorphisms (type V Scheie’s) 2. Scheie patients may have normal intelligence B. Clinical features: 1. Carpal and tarsal tunnel syndromes are frequent presenting complaints 2. Spinal cord compression with myelopathy may occur at all levels
Idiopathic Hypertrophic Pachymeningitis
A. General considerations: 1. Affects dura throughout the CNS 2. Cerebral and cranial nerve dura are involved (cranial nerve compressive palsies occur) B. Clinical features: 1. Slowly progressive myelopathy concomitant with cerebral and cranial nerve involvement C. Imaging evaluation: 1. Meninges thickened 2. Most often enhance with gadolinium D. Differential diagnosis: 1. Sarcoid 2. Lymphoma 3. Rheumatoid dural involvement 4. Syphilis (pachymeningitis cervicalis)
Sarcoid
A. General considerations: 1. Midthoracic dural involvement 2. May involve dura throughout the CNS B. Clinical features: 1. Concomitant cranial nerve, pituitary, chiasmatic and parenchymal involvement 2. May present with concomitant sensorimotor or GBS syndrome C. CSF: 1. Glucose 30–40 mg% 3. Lymphocytes 5–30 mm3 2. Protein 100–150 mg% D. Imaging evaluation: 1. Dural enhancement with gadolinium 2. Lesions occur in the posterior pituitary, hypothalamus and all areas of the parenchyma
Ligamentous Laxity Syndrome
A. General considerations: 1. Atlanto-axial hypermobility
Chapter 10. Vascular Disease of the Spinal Cord
a. Odontoid to axis should separate no more than 3 mm on flexion in an adult b. Cruciate ligament (behind odontoid); alar ligament (tip of the odontoid to rim of foramen magnum); lateral ligaments (odontoid to lateral masses of C1) are loose c. Atlanto axial subluxation > subaxial subluxation d. Differential diagnosis of lax ligaments: 1) Mongolism 2) Ehlers Danlos type IV 3) Marfan’s 4) Rheumatoid arthritis 5) COLA 1–5 gene defects B. Clinical features: 1. Paresthesias of the hands 2. Minimal trauma may cause quadriparesis (most common in spondylolisthesis of rheumatoid arthritis) 3. Neck flexion may cause drop attacks and increased reflexes
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B. Clinical features: 1. Clinical signs of congenital neuropathy 2. Cauda equina compression 3. Radiculopathy 4. Widening of the spinal canal 5. Association with nerve root cysts 6. Rupture with chronic low pressure headache C. Imaging evaluation: 1. MRI demonstrates thickened roots compressing the spinal cord Differential diagnosis of dural ectasia: 1. Neurofibromatosis type I 2. Marfan’s syndrome 3. Ehlers Danlos type IV 4. Collagen gene defects (I–V) 5. Ankylosing spondylitis
Chapter 10 Vascular Disease of the Spinal Cord
Unusual Causes of Spinal Cord Compression
A. General considerations: 1. Cord compressed at thoracic level a. Associated with: 1) Severe obesity 2) Chronic steroid treatment B. Clinical features: 1. Usually slowly progressive paraparesis C. Imaging evaluation: 1. Calcification of fat in Paget’s disease 2. Increased fat on T1 weighted images Extramedullary hematopoiesis A. General considerations: 1. Bone marrow failure 2. Hemolytic anemia 3. Male > female 4. Postpolycythemic myeloid metaplasia 5. Thalassemia 6. Sickle cell disease 7. Hereditary spherocytosis B. Clinical features: 1. Clinical level is usually midthoracic 2. Slowly progressive myelopathy C. Imaging evaluation: 1. Abnormal marrow signal over the vertebral column (loss of marrow fat)
Enlarged Nerve Root
A. General considerations: 1. HSMN I, III, V are most common
A. General considerations: 1. Vascular anatomy a. A single artery spinal originates from both vertebral arteries, merges and courses from the foramen magnum to the filamen terminale in the ventral midline. It supplies the ventral horns and white matter of the lower 2/3 of the spinal cord. b. The sulcal arteries arise in turn such that a small segment of the major artery may supply alternate halves of the cord. If occluded over a long enough segment both sides of the cord will be infarcted. X-RT therapy frequently causes a proliferative endarteritis which may occlude only one sulcal artery that causes a consequent Brown–Sequard syndrome. Compression of the ventral cord may infarct both sides of the spinal cord. c. The ventral pattern of vascular supply to the spinal cord is similar to that of the basilar artery with midline perforators and short and long circumferential arteries. The lateral circumferential arteries give rise to perforating arteries that supply the corticospinal pathways, the ventral white matter and tips of the anterior horn. d. The sulcal arteries supply the ventral gray. e. A posterior spinal artery arises from each vertebral artery to supply the dorsal 1/3 of the spinal cord. This consists of the dorsal columns and most of the dorsal horn (to Rexed layer V). f. The spinal cord is perfused at a very low pressure 90/50 mmHg. Many spinal cord vascular events are obscured by major deficits induced by infarction of the cerebral vasculature at equivalent perfusion pressures.
SECTION IV. Spinal Cord Disease
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g. The major watershed infarction of the spinal cord often occurs through the pyramidal tract. h. Thyrocervical and costocervical branches of the subclavian artery perfuse the cervical enlargement i. The thoracic spinal cord is perfused primarily by intercostal arteries from the aorta and radicular deep cervical arteries. The watershed of the thoracic cord is usually at T2–T4 or T2–T6. The lumbosacral cord is fed by the great radicular artery of Adamkiewicz. It enters the cord from the left side and originates from the ilioinguinal artery derived from the aorta. It usually is found from T9–T12, but may enter the cord at L2. On arteriography it is easily recognized by its hair pin appearance. The sacral cord and cauda equina are nourished by vasovasorum from the hypogastric and obturator arteries whose origin is the aorta. These anatomical considerations of aortic origin are important as younger patients suffer infarction of the cord from various arterial procedures. j. The posterior cord vascular plexus whose origin is the paired posterior spinal arteries from the vertebral arteries are fed by radicular arteries at each level. k. Segmental arteries that supply paraspinous processes may anastomose with vasovasorum of the nerve roots and are often the source of spinal arteriovenous malformations.
Venous Drainage of the Spinal Cord
A. General considerations: 1. This drainage is most important as compression of the spinal cord by facet and ligament hypertrophy as well as traction (spondylolisthesis) may compromise venous drainage and raise cord pressure. This mechanism has been posited for the common myelopathy associated with severe cervical spondylosis. Once initiated, surgical decompression does not reverse any deficits, but may halt neurological deterioration. 2. Radicular veins at reach level drain into paravertebral and the intravertebral plexus and ultimately the pelvic veins. Thus severe pelvic thrombophlebitis may give rise to venous infarction. The posterior venous drainage is into a large midline vein.
Rare Features of Spinal Cord Vascular Disease
1. Transient ischemic attacks a. Posterior columns are spared; vibration is intact b. Putative source is aortic plaque emboli 2. Vertebral body ischemia may occur concomitantly with spinal cord infarction from aortic emboli
3. Pseudomotor neuron disease: a. Selective ischemia of the sulcal arteries that perfuse the ventral horns with pyramidal tract involvement b. Process may be subacute and progressive
Division A: Arterial Syndromes
A. General considerations: 1. Origin of the anterior spinal is from the vertebral artery a. Atherosclerosis of the vertebral artery and orifice of ASA B. Clinical features: 1. Medial medullary syndrome: a. Ipsilateral XII nerve paralysis b. Contralateral proprioceptive and vibratory deficit c. Contralateral weakness of arm and leg (above the decussation of the pyramidal tract at C2) d. Crural plegia (arm ipsilateral and leg contralateral) may occur 2. Low anterior spinal artery infarction: a. Involvement of the ventral 2/3 of the spinal cord b. Weakness of extremities below the lesion c. Loss of temperature and pain below the lesion d. Bladder involved in 50% of patients (often recovers) e. Intact dorsal column sensory function C. Differential Diagnosis of Anterior Spinal Artery Syndrome 1. Atherosclerosis of the artery or its feeding vessels 2. Vertebral artery dissection 3. Syphilis (Erb’s spastic paraparesis) and tuberculosis (proliferative endarteritis) 4. Compression from extruded disc or bone fragment 5. Sarcoid (meningeal involvement or vasculitis) 6. Vasculitis (SLE, Wegener’s granulomatosis, collagen vascular disease) 7. Emboli: (from the heart, atrial myxoma; atrial fibrillation); cholesterol emboli, SBE 8. Idiopathic pachymeningitis 9. Aortic dissection 10. Giant cell arteritis 11. Takayasu’s disease 12. Bends (nitrogen bubbles) 13. Hypoperfusion a. Lumbosacral > cervical > cervicothoracic areas affected Fibrocartilaginous emboli A. General considerations: 1. Women > men 2. Mid to low thoracic levels 3. Cartilaginous material from intervertebral discs blocks spinal arteries and veins 4. Primarily in cervical levels in young women 5. Risk factors appear to be pregnancy, the puerperium, oral contraceptives, neck movement of minor trauma
Chapter 10. Vascular Disease of the Spinal Cord
B. Clinical features: 1. First symptom is neck, upper back or radicular pain 2. Asymmetric weakness that may evolve to quadriparesis 3. Dissociated sensory loss in a cape distribution 4. May occur in the conus medullaris 5. Usually is an ischemic infarct, but maybe hemorrhagic 6. Imaging studies usually do not show herniated discs that compress the cord or nerve roots 7. Ischemic rather than a hemorrhagic infarction
Ischemia of the Lower Thoracic Cord and the Lumbar Enlargement
A. General considerations: 1. The spinal cord is perfused at a much lower pressure 60–70 mm Hg than the brain 2. Infarction of the spinal cord is frequently overshadowed by cerebral signs and symptoms that occurred during an incident of anoxia and hypotension 3. Dropped sensory levels to T4–T6 frequently occur from cervical cord disease (lamination of the spinothalamic tract) 4. Internal watershed zones in the spinal cord are: a. Corticospinal pathways b. Rexed layers V–VI 5. Selective grey matter necrosis does occur 6. Most susceptible region to low flow states is T4 B. Clinical settings in which spinal cord ischemia occurs: 1. Renal arteriogram 2. Surgical procedures (cross clamping the aorta) 3. Aortic dissection 4. Atherosclerosis 5. Emboli: heart; cholesterol; air; nitrogen bubbles, fibrocartilaginous 6. Aortic dissection Differential Diagnosis of Causes of Thoracic Watershed Infarction: 1. Systemic hypotension 2. Prolonged surgical procedures 3. Cardiac arrest 4. Anoxia 5. Vertebral artery occlusion (primary involvement may be C8–T1) 6. Aortic dissection 7. Carbon monoxide poisoning
Ischemia of the Lower Cervical Cord
A. General considerations: 1. Extremely rare 2. Atherosclerosis 3. Dissection or occlusion of the vertebral arteries
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B. Clinical features: 1. Severe sensory ataxia (particularly without vision) 2. Loss of vibration and position sense 3. Rarely severely gyrating arms 4. Lateral drift with “finger playing hands” Aortic Disease as a Cause of Spinal Cord Ischemia
A. General considerations: 1. Surgical procedures of the aorta are a common cause of spinal cord ischemia 2. Most dangerous procedures are repair of thoracic and abdominal aneurysms a. 3–5 hour procedures b. Concomitant spondylosis that may compromise radicular arteries and the vasovasorum of the nerve roots 3. Compromised radicular artery supply to the anterior spinal artery 4. Emboli occur during cross clamping of the aorta 5. Dissections of the aorta occlude radicular arteries B. Clinical features: 1. Thoracic cord infarction following surgery: a. Spinal shock occurs with paralysis, hypotonia and loss of bowel and bladder function with the demarcation of a thoracic sensory level b. One month to six weeks later the lower extremities become spastic and wasted
Lumbar Cord Infarction Following Aneurysm Surgery
1. Hypotonia 2. Loss of bowel, bladder and sexual function (conus medullaris) 3. Leg flexion may occur 4. Paralysis may occur from ischemia to the nerve roots 5. Primarily “saddle” or perineal sensory loss; variable sensory loss to all modalities may occur up to the T11–T12 dermatomes. Differential Diagnosis of Aortic Artery Disease with Spinal Cord Infarction
1. Unruptured aneurysms 2. Dissection 3. Embolic occlusion of the aorta (usually the artery of Adamkiewicz is involved) 4. Takayasu’s arteritis (may present with isolated pulmonary or aortic vasculitic segments) 5. Cholesterol emboli syndrome: a. Isolated digital toe artery occlusion (“purple toe” syndrome) 6. Atrial myxoma 7. Fat emboli 8. During severe hyperglycemia (fat) 9. Coarctation of the aorta
SECTION IV. Spinal Cord Disease
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Medical Causes of Ischemic Spinal Cord Disease
1. 2. 3. 4. 5. 6. 7. 8.
9.
10.
11. 12. 13. 14. 15.
16. 17. 18. 19.
Atherosclerosis Systemic hypotension Collagen vascular disease (PAN, SLE) Thromboangiitis obliterans (Buerger’s Disease) Aortic arch syndrome (gradual occlusion of both carotid and vertebral arteries) Dissection of the aorta (infarction of grey matter; superficial white matter) Neoplastic endarteritis (malignant angioendotheliosis) Infective endarteritis: a. Syphilis d. TBC b. Cryptococcus e. Lyme borreliosis c. HIV Fungal invasion of blood vessels a. Mucormycosis c. Aspergillosis b. Nocardia Illicit drugs: a. Cocaine c. Amphetamine b. Propalolamine Disseminated intravascular coagulation Prothrombotic states Aortic atherosclerosis (supplying vessels; emboli) Aortic aneurysm Aortic surgery (particularly cross clamping > 18 minutes) a. Abdominal aortic aneurysms; cord and cauda equina may be infracted Ligation of lower thoracic intercostal vessels Nonpenetrating abdominal trauma (torsional occlusion of vessels supplying the cord) X-RT (intraspinal vessels are occluded from peripheral endarteritis) Adhesive arachnoiditis
Embolic Disease of the Spinal Cord
1. Atheromatous aortic plaque a. Blue toe syndrome (cholesterol emboli) 2. Cardiac source: a. Atrial fibrillation b. Red clot c. Infective endocarditis (bacteria; fungi) d. Mitral valve prolapse e. Valvular clots f. Atrial myxoma 3. Fibrocartilaginous debris (disc) 4. Angiography a. Catheterization for dural AVM 5. Fat: a. Broken bones (long bones) in young people b. Hip replacement (older patients)
c. Diabetic ketoacidosis 6. Tumor cells 7. Nitrogen bubble (Caisson’s disease) 8. Air bubbles: a. Diving accidents b. Cardiac surgery c. Surgical procedures in a sitting position (ENT and neurosurgery) 9. Therapeutic renal artery embolization
Division B: Venous Infarction of the Spinal Cord
A. General considerations: 1. Venous infarctions without hemorrhage are hard to diagnose; the underlying medical condition is most helpful 2. Extension of Thrombophlebitis of pelvic veins: a. Usually occurs in long standing bed ridden patients b. Associated leg vein thrombosis c. Propagates into the cord through the venous plexus 3. Associated with chronic obstructive pulmonary disease 4. Polycythemia vera 5. Subacute necrotizing myelitis: a. Associated with spinal cord thrombophlebitis b. No systemic foci c. Association with chronic obstructive pulmonary disease 6. Associated with epidural abscess 7. Endoscopic sclerotherapy (reported for esophageal varices) a. Cervical spinal cord 8. Coagulopathy: a. Factor V Leiden with protein C resistance b. Anti-thrombin III c. Factor C deficiency d. Factor S deficiency e. Anti-phospholipid syndrome f. Lupus anticoagulant 9. Cancer (prothrombotic states); breast and pancreas are the most common 10. Subacute necrotizing myelopathy (paraneoplastic); small cell lung carcinoma 11. Birth control pills 12. Pregnancy 13. DIC 14. Dehydration 15. Possible mechanism of progressive cervical myelopathy
Division C: Hemorrhagic Spinal Cord Disease
A. General considerations:
Chapter 10. Vascular Disease of the Spinal Cord
1. Hemorrhages of the spinal cord occur in specific locations: a. Epidural space b. Intradural and extramedullary space c. Intraparenchymally 2. Hematomyelia a. Hematomyelia is bleeding into the spinal cord parenchyma b. Area of involvement is often the central gray of the cervical cord c. Vascular malformations may present with ischemia rather than hemorrhage; may have both ischemic and hemorrhagic symptomatology 3. Specific categories of spinal malformations that may bleed: a. Angioma 1) Tortuous groups of dilated arteries and veins b. Venous angioma 1) Veins predominant in the malformation c. Arterial predominance 1) Arteriovenous malformation d. Telangiectasia 1) Composed of capillaries
Functional Division of Malformations
Type I Dural Malformations
A. General considerations: 1. The blood supply is derived from arteries located in the dural sleeves of nerve roots 2. The nidus of these arteriovenous malformations is from dural branches of radicular arteries 3. Drainage of the malformation is through enlarged dorsal spinal cord veins 4. The dural arteries do not supply the spinal cord; there may be more than one arterial feeder 5. Low-flow lesion by angiography that has no concomitant arterial or venous aneurysms 6. Cervical fistulas: a. Often are located at the cervicomedullary junction b. May cause SAH B. Clinical features: 1. Progressive paraparesis or worsening radiculopathy 2. Acute exacerbations with bladder involvement 3. Back pain occurs often in the mid back or in a radicular pattern 4. Symptoms and signs may worsen with exercise. Prior to MRI these patients were often thought to suffer MS 5. Paralysis may occur from prolonged venous hypertension or venous thrombosis C. Imaging evaluation: 1. Increased T2 weighted signal with edema is noted in the cord by MRI
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2. Dorsal myelography is being supplanted by radicular artery selective angiography; dorsal serpiginous veins are often seen by magnetic resonance angiography
Spinal and Paraspinal Dural Fistula
A. General considerations: 1. Primary locations are the spine or paraspinal structures 2. Drainage is into the epidural venous system B. Clinical features: 1. Compressive myelopathy from enlarged veins 2. Venous hypertension with progressive myelopathy C. Imaging evaluation: 1. MRI demonstrates a positive T2 weighted signal with an intramedullary lesion, tortuous epidural veins, and dilatation of perimedullary veins
Intradural Type II Arteriovenous Malformations
A. General considerations: 1. Intramedullary or parenchymal in most instances; some may have an intradural extramedullary component 2. Categories of intradural malformation: a. Glomus malformation: 1) Well localized nidus of abnormal arteries and veins intramedullary b. Juvenile malformation: 1) May involve the entire cord 2) Fed by segmental arteries c. Arteriovenous fistulas: 1) Derived from blood vessels that supply the cord d. Cavernous angiomas: 1) Similar to cavernous hemangiomas of the brain 2) Associated syrinx may be present B. Clinical features: 1. Present in young patients, female 3. High flow lesions that may hemorrhage occur in a significant percentage of patients 4. Distributed throughout the spinal cord with a cervical predominance 5. Associated with spinal and extraspinal aneurysms and AVMs of the neuraxis C. Imaging evaluation: 1. MRI demonstrates a nidus of juvenile, glomus and intradural AVM on T2 weighted images 2. Enlarged cord with dilated serpiginous veins 3. Hemosiderin ring around the lesion represents a prior bleed. Increased T2 weighted image within the malformation represents a 4–7 day old bleed and methemoglobin (a “popcorn” lesion)
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SECTION IV. Spinal Cord Disease
Subarachnoid Hemorrhage in the Spinal Cord
A. General considerations: 1. Spinal SAH < 1% of all SAH 2. Most common cause is rupture of a spinal AVM; other causes are: a. Coarctation of the aorta b. Rupture of a spinal artery c. Aneurysm of a spinal artery d. Polyarteritis nodosa e. Lumbar puncture f. Spinal tumors g. Blood dyscrasias h. Anticoagulation B. Clinical features: 1. Acute onset 2. Severe back pain at the level of the hemorrhage 3. Pain quickly becomes diffuse with signs of meningeal irritation 4. Radiculopathy at the site of the lesion or down the legs 5. If blood diffuses above the foramen magnum: a. Headache b. Cranial neuropathy c. Depressed level of consciousness d. Decreased ankle jerks with increased knee and upper extremity reflexes e. Increased intracranial pressure with papilledema (rare) C. Laboratory evaluation: 1. CSF: a. Hemorrhage greater than 1,000,000 RBCs/mm3 ) b. Within days may have hypoglycorrhachia (severely depressed glucose < 20 mg%)
Hematomyelia
A. General considerations: 1. Trauma a. Direct injury to the spine (penetrating and nonpenetrating) b. Hyperextension of the cervical spine 2. Bleeding of a vascular malformation 3. Hemorrhage into a tumor 4. Hemorrhage into a syrinx 5. Coagulopathy 6. Anticoagulation (particularly coumadin) 7. Venous infarction 8. Syphilis B. Clinical features: 1. Presents as spinal shock, back pain, sensory loss, paralysis and areflexia 2. Autonomic instability 3. Gray matter more affected than white matter; weakness of the arms
4. Spasticity develops below the level of the lesion 5. Atrophy and fasciculations of affected segments occur with time 6. Babinski’s sign is prominent 7. Sensory level: a. Two segments lower than the lesion (if thoracic) b. Higher in the back than front (follows patterns of intercostal nerves) c. Dropped sensory level (T4–T6) following cervical lesions is common (lamination of the spinothalamic tract) d. Rare suspended sensory loss (interruption of segmental dorsal horn at the level of injury with preserved long tract sensory function) 8. Mass reflex late in the course of the illness
Spinal Epidural and Subdural Hemorrhage
A. General considerations: 1. Epidural hemorrhage > frequency than subdural hemorrhage, 4 : 1 2. Spinal epidural hemorrhage: a. Peak occurrence during childhood and the fifth to sixth decade b. Cervical lesions more common in childhood; thoracic and lumbar lesions in adults c. Frequently occur with trivial trauma or exertion B. Clinical features: 1. Similar for both subdural and epidural hematoma 2. Severe back pain at the level of the bleed 3. Myelopathy (compressive) 4. Cauda equina syndrome 5. Radicular pain (involved segment) 6. Progresses over hours to days 7. Acute transverse myelitis (presentation of epidural hematoma) 8. Bowel, bladder and sexual dysfunction 9. Rare Brown–Sequard pattern C. Imaging evaluation: 1. MRI: a. T1 weighted images: 1) Signal intensity of the epidural hematoma is primarily isointense to the spinal cord 2) T2 weighted images of epidural hemorrhage: a) Heterogenous hyperintensity as compared to the cord b) Focal hypointensity (acute blood; deoxyhemoglobin) 3) Capping of epidural fat 4) Direct continuity with adjacent osseous structures 5) Compression of epidural fat, subarachnoid space and spinal cord 6) Posterolateral location
Chapter 10. Vascular Disease of the Spinal Cord
7) Spontaneous spinal epidural hematomas located in the ventral space: a) Premembranous hematoma b) Posterior longitudinal ligament hematoma D. Differential diagnosis of spinal epidural hemorrhage: 1. Epidural anesthesia 2. Lumbar puncture (particularly in anticoagulated patient 3. Blood dyscrasias 4. Anticoagulation 5. Neoplasm 6. Vascular malformations 7. Thrombocytopenia 8. Following heparinization after lumbar surgery 9. Portal hypertension 10. Following exercise and valsalva maneuvers
Specific Spinal Cord Malformations
Differential diagnosis 1. Hemangioblastoma (Von Hippel–Lindau syndrome) 2. Arteriovenous malformation (glomus, juvenile, paravertebral) 3. Dural arteriovenous fistula (Type I) 4. Intramedullary spinal cord cavernous malformations and type II lesions 5. Bannayan–Zonana syndrome 6. Occult vascular malformations 7. Foix Alajouanine syndrome 8. Cobb’s syndrome
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d. Increased levels of vascular endothelial neurotrophic factor B. Clinical features: 1. 80% in cerebellum 2. 20% in spinal cord 3. 35% of patients with hemangiomas have VHL disease; 60% of those patients who are symptomatic are less than 30 years of age 4. Spinal hemangioblastoma: a. Related to VHL more often than those found in infratentorial locations 5. VHL at diagnosis are younger than sporadic cases 6. VHL patients develop endolymphatic sac tumors (tinnitus or deafness as clinical manifestations) 7. Spinal hemangioblastoma: a. Often associated with cerebellar hemangioblastoma b. May be multiple c. May be extramedullary and on spinal roots in location d. Renal cell carcinoma may metastasize to the hemangioblastoma
Arteriovenous Malformations (Type I and Type II)
A. General considerations: 1. Males > females 2. Thoracolumbar location (dorsal) 3. Associated with: a. Cobb’s syndrome b. Wyburn Mason syndrome c. Kartagener’s syndrome
Hemangioblastoma Spinal Dural Arteriovenous Malformations (Type I)
A. General considerations: 1. May arise in isolation 2. Major manifestation of Von Hipple–Lindau disease (VHL) a. Prevalence 1/36,000 population
Von Hippel Lindau Disease (VHL)
A. General considerations: 1. AD: chromosome 3p25–3p26 deletions or mutations 2. Associated central nervous system hemangioblastomas: a. Cerebellum b. Retinal 3. Associated systemic manifestations: a. Renal cysts b. Renal carcinoma c. Pheochromocytoma (specific alleles of VHL disease)
A. General considerations: 1. Most frequent spinal arteriovenous malformation 2. Posterior and posterolateral dorsal cord most common location B. Clinical features: 1. Diagnosis established after months of intermittent symptoms 2. Progressive myelopathy 3. Cauda quina and conus medullaris dysfunction 4. Low back pain (pseudo radicular pain) 5. Lower extremity weakness 6. Sphincter disturbance a. Early involvement of micturition b. Late involvement with disc disease 7. Combined upper and lower motor neuron signs 8. Symptoms may vary with posture, menses and exercise C. Imaging evaluation of dural arteriovenous fistula (DAVF) Type I 1. MRI:
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SECTION IV. Spinal Cord Disease
a. Enlarged spinal perimedullary veins; occasionally also seen with intracranial fistulas b. Intramedullary high intensity signal changes on T2 weighted images; high intensity lesions decrease within 1–4 months after treatment c. Angiographic evaluation: 1) Anterior spinal vein draining a SDAVF 2) Distortion of the hairpin turn of the artery of Adamkiewicz 3) Some angiographic evidence for vascular steal phenomenon as a cause of symptoms D. Laboratory evaluation: 1. CSF is abnormal in >75–90% of patients Dural Arteriovenous Fistula at the Craniocervical Junction
1. Clinical presentation of craniocervical junction AVM: a. Present with SAH b. Progressive myelopathy that may interfere with respiration
Cavernous Angioma
A. General considerations: 1. Incidence is not known a. Occur with 3–11% of spinal cord tumors b. Women slightly greater incidence than men c. Clinical presentation between 30–70 years of age d. Cervical > lower thoracic > conus medullaris are the most frequent location e. Posterior or posterior lateral intraspinal location f. Cervical lesions produce symptoms earlier g. May develop tethering of the cord following surgery h. Approximately 50% may have multiple cavernous malformations in the neuraxis i. Associated with cryptic venous malformations B. Clinical features:
1. Onset with pain, weakness and sensory symptoms 2. Later bowel and bladder dysfunction 3. Onset associated with: a. Exercise b. Trauma c. Pregnancy d. Menstruation e. May bleed during sleep f. Cavernous angiomas may cause: 1) Increased local venous pressure 2) Decreased arterial flow by pressure on the anterior spinal artery of the ventral fissure 3) Ischemia of the cord d. Onset of symptoms to diagnosis may be delayed e. Severe weakness in 20% of patients by six months after presentation; 50% by three years f. After onset of leg weakness further disability is rapidly progressive g. Pain may be local or radicular h. Spinal bruit (extremely rare) i. Upper and lower motor neuron weakness j. Conus medullaris syndrome (rare) C. Imaging evaluation (MRI): 1. Heterogenous well circumscribed lesion 2. Hemosiderin external ring (prior bleed) 3. Central area of increased T2-weighted image (7–10 day old blood) D. Differential Diagnosis of Cavernous angioma 1. Multiple sclerosis 2. Neoplasm 3. Herniated disc 4. Spondylolisthesis 5. Intracranial SAH (5% present with neck and back pain) 6. Subacute combined degeneration 7. Longitudinal myelitis; inflammatory; collagen vascular disease 8. Meningovascular syphilis
Section V CRANIAL NERVES
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Chapter 1. Cranial Nerve I
Chapter 1
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Meningioma of the Olfactory Groove (Foster–Kennedy Syndrome)
Cranial Nerve I
Anatomy
A. General features: 1. Olfactory nerve penetrates the cribriform plate of the ethmoid bone to synapse on the olfactory bulb 2. Axons of mitral and tufted cells form the olfactory tract 3. Olfactory tract divides into a median and lateral olfactory stria 4. Lateral striae project to ipsilateral piriform lobe of temporal cortex (primary olfactory cortex) 5. Projections to amygdala, septal nuclei and the hypothalamus 6. Anosmia: a. Representation of smell in the piriform cortex is bilateral therefore no loss from cortical lesions b. Unilateral loss of smell is caused by lesion of the olfactory bulb, tract or striae 7. Parasomnia: perversion of smell 8. Cacosmia: unpleasant odors
A. General Features: 1. Mucocele of the frontal sinus 2. Subfrontal subdural hematoma 3. Ipsilateral anosmia 4. Ipsilateral optic atrophy 5. Contralateral papilledema B. Differential Diagnosis: 1. Mucocele 2. SDH (subdural hematoma) 3. Esthesioblastoma: a. Tumor of the olfactory epithelium b. Frontal lobe behavior syndrome c. CSF leak through the nostril d. Seizure presentation
Pseudo Foster–Kennedy Syndromes
1. Papilledema of the spared eye in a patient with prior optic atrophy in contralateral eye
Syndromic Anosmia Differential Diagnosis of Anosmia
1. Trauma: a. Fractures of cribriform plate of the ethmoid bone b. Closed head injury without fracture (tear of olfactory filaments): 1) Impairment of recognition 2) Preserved olfactory detection 3) Lesion of the orbitofrontal or temporal lobe 4) Basilar skull fracture c. Disturbance of complex olfactory function 1) Detection preserved > discrimination ability: a) Korsakoff’s syndrome b) Thalamic lesion c) Prefrontal lesion d) Alzheimer’s disease e) Parkinson’s disease f) Huntington’s disease g) Neurodegenerative disease 2. Tumor: a. Olfactory groove meningioma b. Esthesioblastoma (tumor of the olfactory epithelium) c. Glioma of the frontal lobe d. Osteoma of sphenoid or frontal bone e. Pituitary adenoma with frontal suprasellar extension f. Carcinomatosis of the meninges
1. Walker–Warburg Syndrome 2. Kallmann’s (ovarian dysgenesis) 3. Hecker’s Type I and II (post viral); Type I taste and smell lost; Type II posterior pharyngeal taste preserved 4. Machado-Joseph (SCA Type III) 5. Foster–Kennedy Syndrome
Miscellaneous
1. 2. 3. 4.
Abscess of the frontal lobe Mucocele of the frontal sinus Post viral infection (Hecker’s variant) Siderosis (Fe++ deposition on the nerve from recurrent cerebral bleeding; AVMs and cavernous hemangioma)
Systemic Disease
1. B12 deficiency 2. Paraneoplastic disease
Parosmia and Cacosmia
1. Head injury 2. Psychiatric disease
SECTION V. Cranial Nerves
264 Olfactory Hallucination
1. Primary olfactory cortical injury (piriform lobe of temporal cortex) 2. Direct interruption of the olfactory pathway 3. Unilateral paroxysmal olfactory hallucination (paroxysmal dysosmia), possible irritation of the olfactory bulb or nerve 4. Complex partial seizures 5. Hyperosmia occurs with migraine and hyperemesis gravidarum 6. Hyposmia and parosmia (dysosmia) a. Associated with hypogeusia (diminished and perverted taste)
Chapter 2 Cranial Nerve II
Anatomy of the Retina
A. General Features: 1. Retinal pigment epithelium is the origin of rods and cones; internal to the choroid 2. Rods and cones then project to bipolar and amacrine cells; these project to ganglion cells; further projection to lateral geniculate body or superior colliculus 3. Rhodopsin pigment (glycoprotein) of the rods; reacts to wave lengths from 400–800 mm; 100 million rods; more numerous in the fundus 4. Seven million cones; react differentially to wave lengths of light; fovea in the center of macula; 0.35 mm area of greatest visual discrimination 5. 1.2 million ganglion cells of the inner retina: a. Smaller receptive fields in the posterior pole b. Ganglion cells concentrated in posterior pole c. One to one connection with ganglion cells d. Periphery of globe: extensive overlapping of receptive fields subserving ganglion cells e. Relative sparing of peripheral vision with ganglion cell disease f. Ganglion cells specialized for spatial discrimination project to the lateral geniculate body (LGD); those specialized for movement and fixation reflexes synapse on the SC (superior colliculus) g. Ganglion cells closer to the disc send axons through the entire nerve fiber layer h. Papillomacular bundle temporal side of the disc that course from the macula straight to the nerve head; superior macular fibers arch superiorly and then descend to the disc; the reverse occurs for inferior temporal fibers
i. Neurons subserving a macular strip centered in the fovea project bilaterally B. Clinical presentation: 1. Normal visual acuity and contrast sensitivity if macula is spared 2. Color perception: blue affected greater than red with photoreceptor lesions 3. Visual field deficit: a. Central (optic nerve; tip of the occipital lobe) b. Cecocentral (between fixation and blind spot); toxins, e.g. alcohol c. Arcuate (glaucoma) d. Sectorial ring with nasal step (glaucoma) e. Altitudinal (optic nerve, chiasm, occipital lobe) 4. Micropsia (CPS) 5. Normal pupillary light reflex (cortical lesions)
Optic Nerve and Optic Chiasm
A. General Features: 1. Intraocular position: a. Optic nerve head 1 mm b. Fourteen small vessels across the disc c. Lamina cribrosa seen (within the cup) d. Slight nasal blurring (normal) e. Blood supply: watershed between central retinal artery (ophthalmic) and posterior ciliary arteries (external carotid) 2. Intraorbital portion: a. 25 mm length b. Surrounded by fat in the cone between the extraocular muscles c. Apex of the cone is open to optic foramen and the superior orbital fissure d. Ophthalmic artery, ciliary nerves and ganglia, nerves to extraocular muscles are in close proximity to the optic nerve 3. Intracanalicular segment: a. 9 mm length in the optic canal b. Ophthalmic artery and sympathetic fibers of the carotid plexus travel with the optic nerve 4. Intracranial portion: a. 4–16 mm (depending whether the chiasm is pre or post fixed in relation to the pituitary) b. Optic nerve is above the carotid artery; above the sphenoid sinus; superior to the optic nerve A, segment of ACA, ACOA is superior to the optic nerve (anterior communicating artery) and chiasm c. In 5% of individuals the chiasm overlies the anterior margin of the sella (prefixed) 12% it lies over the diaphragm a sella; 79% it is above the dorsum sellae; 4% it is post-fixed and lies behind the dorsum sellae
Chapter 2. Cranial Nerve II
d. Inferior nasal fibers cross inferiorly in the chiasm and extend into the contralateral optic nerve (Willebrand’s knee) to project laterally in the optic tract. Superior nasal retina fibers are medial in the optic tract e. Nasal and temporal macula project crossed and uncrossed fibers f. Macula fibers occupy the dorsal optic tract g. Lateral geniculate body (LGD): I, IV, VI receive fibers from the contralateral eye; II, III, V – ipsilateral eye; macular region is represented centrally
The Optic Radiations
A. General Features: 1. Upper bundle: a. Origin is medial part of LGD; superior retina b. Deep parietal white matter; projects to superior lip of calcine fissure 2. Central bundle: medial part of LGD; subserve the macula; projects to posterior calcarine fissure of both upper and lower lips a. Lower bundle: 1) Lateral part of nucleus; lower retina 2) Meyer’s loop; 5 cm behind tip of the temporal lobe; to lower lip of calcarine fissure b. Anterior radiations: 1) Macular fibers run medially 2) Meyer’s loop: fibers from contralateral eye medial to ipsilateral fibers
Vascular Supply of the Visual Pathways
A. General Features: 1. Retina supplied by the central retinal artery (CRA) that branches from the ophthalmic artery 5–15 mm in the optic canal: a. CRA pierces the nerve and divides into superior and inferior branch at the optic disc b. Macula may be supplied by the cilioretinal artery that branches into superior or inferior divisions c. Ophthalmic artery gives off several posterior ciliary arteries: they supply the optic disc, outer layers of retina and choroid d. In a small percentage of patients the macula and papillomacular bundle is supplied by the cilioretinal artery that derives from the posterior ciliary arteries; may spare central vision after CRA occlusion e. Posterior ciliary artery is involved by vasculitis; CRA ischemia is from microthrombi or emboli, migraine and hypercoagulable f. CRA and posterior ciliary artery occlusion cause attitudinal VF deficit
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Optic Nerve Vascular Supply
A. General Features: 1. Proximal: ophthalmic artery, near the chiasm is supplied by the carotid and ACA 2. AcoA supplies the dorsum of the chiasm 3. Inferior chiasm supplied by: a. Carotid c. PCA b. PCOM 4. Optic tract supplied by: a. PCOM c. Anterior choroidal artery b. PCA 5. Lateral geniculate (LGD) a. Anterior choroidal artery (laterally) b. Lateral posterior choroidal artery (medially) 6. Optic radiations: a. Upper portion: MCA b. Lower portion: PCA c. Occipital pole anastomosis: 1) Angular or posterior temporal arteries (MCA branches) 2) Calcarine branch PCA
Visual Acuity
A. General Features: 1. Visual discrimination of fine details of high contrast 2. Macular function or its projections 3. Impaired by: a. Changes in the shape of the globe b. Refractory characteristics of the vitreous c. Compressive and noncompressive lesions of the optic nerve; often prior to detectable field deficit d. Medial chiasmal lesion decrease acuity bilaterally e. Lateral chiasmatic lesions decrease acuity in the ipsilateral eye f. Visual acuity remains intact if the crossing or noncrossing foveal fibers are intact g. Retrochiasmatic bilateral lesions decrease visual acuity equally in both eyes
Contrast Sensitivity
A. General Features: 1. Detects dysfunction of the macula, optic nerve and chiasm 2. Impaired contrast sensitivity detects more subtle defects than visual acuity
Color Perception
A. General Features:
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SECTION V. Cranial Nerves
1. Decreased in areas of VF deficit 2. Desaturation for red in lesions of visual pathways 3. Retinal photoreceptor damage affects the perception of blue 4. Detects macular dysfunction (these projections affected in optic nerve and chiasm lesions) 5. Color vision loss usually parallels VA loss; optic neuritis color loss > VA deficits; in optic neuritis, chromatic sensitivity loss > luminance sensitivity 6. Impairment of color perception occurs with posterior VA defects 7. Bilateral lesions of the inferomedial occipital lobe; color blindness with normal visual acuity
1. 2. 3. 4.
Evident with double simultaneous stimuli Often seen with incomplete homonymous defect During recovery of dense VF deficit Involvement of parieto-occipital or frontal cortical lesions R > L
Dissociation of Kinetic and static VF Response to Stimuli
A. General Features: 1. Riddoch’s phenomenon 2. Occipital lobe > optic tract > chiasm 3. Moving objects seen in otherwise dense static VF defect; possible extrastriate visual pathways are involved
Visual Field Defects Visual Field Defects
A. General Features: 1. Macular lesion cause central defects 2. Retinal lesions causes inverted (superior lesion causes inferior deficit; lateral retinal lesion causes medial visual deficit) 3. Cecocentral defect: a. Affects the macula b. Papillomacular bundle c. Peripheral defects in the nasal field are often from the retina or optic nerve d. Small deep retinal lesions cause discrete deficits in appropriate part of the VF e. Defects from lesions of nasal retinal fibers (temporal field lateral to blind spot) are sectoric. The nasal retinal fibers are straight rather than accurate f. Retinal lesions that affect the superficial fiber layer cause fan-shaped arcuate defects with its tip pointing to the lesion and its base toward the nasal meridian. These defects are dependent on the fact that superficial layers of the nerve fiber bundle subserve peripheral vision g. Ring VF defect; preserved central and peripheral vision to the defect: 1) Unilateral pericentral scotomata is macular 2) Retinitis pigmentosa (large peripheral ring scotoma) 3) Paracentral and arcuate scotomata suggest glaucoma 4) Fusion of superior and inferior arcuate defect cause ring scotomata 5) Horizontal step of ring shaped scotomata (mismatch of superior or inferior arcuate defect) suggests glaucoma rather than visual pathway lesion
Visual Inattention
A. General Features:
1. Monocular defect: a. Retina (associated with ophthalmologic defects) b. Optic nerve c. Early stage of chiasmatic defect (temporal portion of the central field of the ipsilateral eye) d. Lesions of the most anterior portion of the calcarine cortex; crescent defect of the contralateral eye. Usually the reverse occurs with posterior calcarine cortex lesions in which the temporal crescent is spared e. Monocular altitudinal defect: 1) Frequent macular sparing associated (macula bilaterally innervated) 2) CRA disease; macula also frequently supplied by cilioretinal arteries 3) Differential diagnosis: a) Choroidal coloboma b) Choroiditis c) Glaucoma d) Retinal detachment e) Optic nerve hypoplasia f) Ischemic optic neuropathy g) Optic neuritis h) Drusen i) Optic nerve trauma j) Sarcoid k) Hematoma l) Chronic papilledema 4) Bilateral altitudinal defects: a) Most commonly occipital lobe vascular disease b) Head trauma c) Rarely: bilateral ischemic retinal or optic nerve disease 5) Bilateral ring defect: a) Bilateral occipital disease (1) Associated with vertical step defect b) Retinal disease (rare) 6) Bitemporal hemianopia:
Chapter 2. Cranial Nerve II
a) Chiasmatic disease b) Defect respects the midline c) Differential diagnosis: (1) Chromophobe adenoma (2) Pituitary apoplexy (hemorrhage) (3) Craniopharyngioma (4) Meningioma (sella) (5) Dilated suprachiasmatic recess from increased intracranial pressure (6) Rathke’s pouch cyst (7) Pituitary cancer or metastasis (8) Cushing’s Syndrome (9) Prolactinoma (10) Multiple sclerosis (11) Glioma of the chiasma (12) Sarcoid d) Junctional scotomata (kissing scotomata): (1) Compression of the ipsilateral optic nerve with extension of 2–3 mm into anterior chiasm (a) Ipsilateral optic nerve defect (b) Contralateral superior lateral defect e) Homonymous hemianopsia: (1) Congruent: posterior lesion of the optic radiations (2) Incongruent: lesion of the optic tract (3) Congruency: the lesion in one field is superimposable on the lesion of the other field (4) Anterior choroidal artery stroke: (a) Sparing of a horizontal sector (b) Incongruous defect of upper and lower quadrants (c) Quadruple sectoranopia (d) Lateral (LGD) lesion (e) Infarction of the hilum and anterolateral part of LGD (lateral geniculate nucleus) f) Superior homonymous quadrantic defect: (1) Large lesion of the inferior bank of the calcarine fissure. Small lesions cause scotomata. (2) Temporal loop of the optic radiations (Van Willebrand’s knee) (3) Deep parietal lesions affect the dorsal component of the optic radiations to produce an inferior quadrantic defect (4) Quadrantic defects most often are due to optic radiation lesions g) General points: (1) Macular sparing with occipital lobe lesions; dual blood supply; large macular representation (2) Bilateral homonymous cortical lesions: (a) Tip of the basilar pathology affecting both PCA arteries (b) Seriatim lesions
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(c) Anoxic insult (d) Cardiac surgery (emboli and watershed infarction) (e) Complication of cerebral angiography (f) Migraine (g) Embolus to top of the basilar (h) Tentorial herniation (PCA occluded) (i) Anton’s syndrome occurs if complete: 1. Denial of blindness (confabulation) 2. Normal pupillary light reaction 3. May have small peripheral visual field spared; able to avoid large objects 4. Early euphoria (3) Lesions of anterior optic pathways: (a) Difficulty in reading (b) Dimness of vision (c) Attitudinal defects: downward shade or looking over the horizon (4) Vertical hemianopsia: (a) Bumping into objects in the blind field (5) Metamorphopsia and micropsia: (a) Distortion of objects; decreased size of objects (b) Most often retinal disease; may be from complex partial seizure (occipital or posterior temporal lobe) (c) Displacement of retinal cells 1. Micropsia separation of photoreceptors by edema (d) Distorted perception noted with migraine (e) Optic neuritis: 1. Movement phosphenes 2. Flashes of light with eye movement in the dark 3. Spontaneous discharge of demyelinated Mechanosensitivity fibers (f) Chiasmatic lesions: 1. Respect the midline vertical meridian 2. Lose central vision with convergence; the temporal VF defects merge 3. Image displacement (in face of normal extraocular muscles) (a) Small ocular muscle imbalance compensated by binocular fixation with full fields; with VF deficit become manifest with Bitemporal defect (b) Horizontal or vertical deviation of the images from either eye (c) Hemifield slide phenomenon
Ophthalmoscopic Observations
1. Optic atrophy:
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a. Sharp disc margins b. Loss of the lamina cribrosa c. Decreased cup disc margin ratio d. Sharpness of disc margin (particularly temporally) e. Decreased visual acuity f. Loss of disc capillaries ( exophthalmos d. Optic nerve affected by compression 2. Chloroma: a. Associated with myelogenous leukemia and lymphatic leukemia b. Green mass c. Base of the skull; predilection for the orbit d. Bilateral tumors e. Hemorrhage into the lids and orbit is common 3. Malignant Melanoma: a. Primary malignant melanoma is rare (choroid pigment epithelium) b. Recurrence after enucleation c. Brownish mass d. Extrusion of an implant or poor retention of a prosthesis from tumor growth 4. Rhabdomyosarcoma: a. Exophthalmos a presenting sign b. Eye displaced out and down > forward; mass upper nasal orbit c. Progresses rapidly without pain d. Ptosis 1/3 of patients e. 10% nose bleed and pain around the orbit f. Frequent conjunctival chemosis and congestion g. Venous congestion; retinal striae; rare disc edema 5. Retinoblastoma: a. Almost always childhood illness b. 25% are bilateral c. Initiated intraocularly; grows along the optic nerve d. May grow through the sclera to form an orbital mass e. Endophytum type: 1) Inner retinal layers 2) Pink color (blood vessels) 3) Grows into vitreous cavity f. Exophytum type: 1) Outer retinal layers g. May grow through central optic pathways h. Necrosis and calcification in the orbit i. May present with leukocoria (white pupil)
Differential Diagnosis of Leukocoria
a. b. c. d. e. f. g.
Glioma Retrocentral fibroplasias Persistent hyperplastic vitreous Nematode endophthalmitis Massive retinal fibrosis Retinoblastoma Metastatic retinitis
h. Retinal dysplasia i. Coat’s disease: 1) Disease of young men 2) Late 20’s 3) Unilateral 4) Massive macular exudative retinitis
Tumors Affecting the II Cranial Nerve and/or the Orbit
1. Meningioma of Schwalbe (optic nerve sheath; perioptic meningioma) 2. Sphenoid wing meningioma 3. Lymphoma 4. Rhabdomyosarcoma 5. Leukemia (particularly CLL) 6. Chloroma 7. Optic nerve glioma (neurofibromatosis 1; chromosome 17) 8. Ganglioneuroma 9. Hemangioma of the orbit 10. Hypereosinophilia (involving II directly) 11. Carcinomatosis of the meninges (lung > breast > GI tract > melanoma) 12. Metastasis (breast, lung, melanoma) 13. Dermoid 14. Epidermoid
Tumor of the Orbit
A. General Features: 1. Optic disc swelling with orbital lesions: a. Proptosis may be minimal or absent b. Graves orbitopathy c. Optic glioma d. Carotid cavernous fistula e. Perioptic meningioma: 1) Slowly progressive visual loss 2) Ptosis with disc swelling 3) Papillary retinal ciliary venous shunts 2. Funduscopic changes induced by retrobulbar mass lesions: a. Compression of the posterior wall 1) Choroid retinal striae b. Compression of the equator of the globe 1) Diffuse retinal flattening c. Dilatation and tortuosity of veins as a consequence of high pressure 3. Orbital cysts: a. Congenital: 1) Dermoid 4) Meningocele 2) Teratoid 5) Encephalocele 3) Ischemia
Chapter 2. Cranial Nerve II
4.
5.
6.
7. 8. 9. 10.
b. Acquired: 1) Implantation 2) Serous 3) Parasitic (hydatid or cystercercosus) Epidermoid: a. Present at puberty b. Upper and outer quadrant of the orbit; near lacrimal gland; deep in the orbit Dermoid: a. Cysts may have multiple diverticulae b. Choroidal involvement c. Most common location on the globe is the limbus; upper outer quadrant d. Associated with coloboma of the lid and aniridia e. Inflammatory reactions may appear around cysts that have perforated f. Deep dermoids compress the optic nerve g. Primary cholesteatoma of the orbit cannot be differentiated from a dermoid except histologically h. Dermoids may span the orbit and cranial vault Orbital bone cysts: a. Cysts contain channels with thin or thick septa b. Orbital roof in location c. Blood may be present in the cyst Cystic orbital teratoma Congenital cystic eyeball Orbital encephalocele Meningocele
Vascular Masses of the Orbit
1. Orbital lymphangioma: a. Seen on the lids and in orbits b. Resemble cavernous hemangioma (spaces contain lymph) c. Benign, slowly progressive tumor d. Involve the lymph and vascular system e. Usually present in children f. Approximately 50% have involvement of lids, conjunctiva, face and palate g. Hemorrhage into tumor occurs frequently h. Plateau of growth by adulthood 2. Hemangioma: a. Frequently encountered orbital tumor (23% of all orbital tumors) b. Cavernous hemangiomas: 1) Epithelium lined spaces 2) Long and encapsulated c. Racemose form: 1) Completely formed blood vessels; veins predominant 2) Isolated masses of blood vessels 3) May pulsate 4) A-V aneurysms in the retina
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d. Tumors occur within the muscle cone e. Proptosis; straight forward without deviation f. Engorgement of retinal vessels, disc edema, loss of vision g. Ocular pulsation may develop; occasional ocular bruit noted h. Intermittent exophthalmos 3. Hemangioleiomyoma: a. Composed of thick walled vessels b. Contain smooth muscle c. Encapsulated tumor 4. Hemangioendothelioma: a. Originates from endothelial cells b. Contain anastomosing vascular channels c. May be malignant; may metastasize d. May occur in the soft tissue of the body 5. Hemangiopericytoma: a. Proliferating cell is the pericyte; potentially malignant b. May invade the bone and erode into the cranial cavity
Lacrimal Gland Tumor
1. Mixed tumor: a. Benign or malignant b. 50% of the epithelial tumors of the lacrimal gland c. Myxomatous stroma and epithelial elements d. Benign mixed tumors: 1) Most common type of epithelial tumor of the lacrimal gland 2) Encapsulated 3) May recur and invade bone 2. Adenoid cystic carcinoma: a. Lacrimal gland > frequency than salivary gland b. 50% of epithelial tumors of the lacrimal gland are carcinomas (adenocystic most common) c. Adult tumor d. Presents as a lump in the upper outer orbit e. Exophthalmos slight or late f. May have early disc edema g. Decreased vision due to optic nerve pressure h. May invade bone and cause pain
Sarcoma of the Orbit
1. Specific type: a. Rhabdomyosarcoma d. Myxosarcoma b. Osteosarcoma e. Fibrosarcoma c. Chondrosarcoma 2. Primary, metastatic or involve the orbit by extension 3. Rare tumors; 2% of those presenting with proptosis 4. Leiomyosarcoma: a. Usually arise in the uterus, GI or genitourinary tract
SECTION V. Cranial Nerves
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5.
6.
7. 8.
9.
10.
11.
12.
b. Originates from smooth muscle of blood vessels c. Grow rapidly and metastasizes Fibrosarcoma: a. Rare in the orbit b. Extend locally rather than metastasize Chondrosarcoma: a. Arises from bone soft tissue b. Orbital tumors arise from bone c. Affect orbit by extension (greater wing of sphenoid) Osteosarcoma: a. Associated with fibrous dysplasia Liposarcoma: a. 20% of malignant tumors of soft tissue b. Extremely rare in the orbit Malignant granular cell myoblastoma: a. Average age of onset 20–30 years b. Metastases or reoccurrences occur after many years c. May have bone formation in the tumor Primary orbital melanoma: a. Majority of orbital melanotic tumors are extension of choroidal melanoma b. Possible association with nevus of ota (benign melanosis of the skin innervated with orbital melanoma) c. Glioma of the retina has been described Post irradiation orbital tumor: a. Sarcoma following X-RT for retinoblastoma b. Develops many years following therapy (4–25 years) c. Fibrosarcoma, carcinoma, mesenchymal tumors are d. First evidence of tumor is in the area treated e. Mass is frequently at the orbital margin Metastatic tumors: a. Posterior choroid predilection b. Left side involved > right; more direct course of the carotid artery c. Twenty short posterior ciliary arteries; seven anterior ciliary arteries and two long posterior ciliary arteries. Metastasis more likely to go to short posterior ciliary arteries d. Breast carcinoma to the uveal tract > orbit e. Prostate metastases to orbit > uvea f. Neuroblastoma 13% may occur after 20 years of age
Intraocular Metastatic Tumor
A. General Features: 1. Occur < primary malignant intraocular tumors 2. Tumor emboli metastasize to uveal tract 3. Infectious emboli go to retina (smaller than metastatic tissue) course in the CRA circulation 4. Uveal metastases females > males 5. 25% of patients metastasis are bilateral 6. Breast carcinoma >50% of uveal cases 7. Lung metastasis: higher incidence of iris and ciliary body location
8. GI tract approximately 7% of Intraocular metastasis 9. Rare primary tumors: thyroid, liver, ovary, parotid glands, testicle, pancreas, kidney, uterus and bladder metastasize to the orbit Majority of uveal metastases: a. Choroid; temporal to the disc and near the macular b. May extend to involve the iris and ciliary body B. Clinical symptoms: 1. Choroidal metastasis: visual impairment with rapidly progressive course (involvement of macula); retinal detachment with central scotomata 2. Rarely painful 3. Retinal elevation with an indistinct margin 4. Extraocular extension is rare; involvement of the retina is rare except by detachment 5. Anterior uveal metastasis: a. May be no visual loss b. Single or multiple metastases c. Discreet nodule in the iris or ciliary body 6. Metastatic tumor of the retina: a. Metastasis to the retina is rare b. In a setting of wide spread metastases c. Painless loss of vision 7. Orbital metastatic tumor: a. Metastatic orbital tumors are less common than tumors that extend form the para nasal sinus or nasopharynx b. Cause of unilateral proptosis (30%) c. Female > male (breast cancer); 5–6th decade; L > R side d. Breast > lung > prostate > uterus e. Develops within few years of diagnosis of the primary f. Clinical symptoms: 1) Diplopia first 2) Pain around the eye 3) Proptosis 4) Decreased vision, pain, extreme proptosis are late manifestations 8. Metastasis to adnexa a. Rare 9. Metastases to the optic nerve: a. Extremely rare b. May involve the nerve or the nerve sheath c. Progressive loss of vision
Orbital Complications of Sinus Disease
1. Frontal sinusitis: a. Mucocele: 1) Orbital mass 3) Naso orbital hyperostosis 2) Exophthalmos b. Encysted empyema: 1) Upper inner angel of the orbit
Chapter 2. Cranial Nerve II
2) Swelling and ptosis of the lids c. Orbital osteoperiostitis d. Diffuse orbital suppuration and abscess 2. Maxillary sinusitis: a. Osteoperiostitis b. Optic nerve involvement c. Lacrimal apparatus destruction d. Iritis, iridocyclitis, neuroretinitis 3. Ethmoidal sinusitis: a. Mucocele (young patients) c. Osteoperiostitis b. Suppuration 4. Sphenoidal sinusitis: a. Cavernous sinus thrombosis b. Orbital abscess c. Optic neuritis d. Ocular nerve palsy; VIth most frequent
Miscellaneous Orbital Pathologies Affecting CNII
1. Thyroid ophthalmopathy: a. Preceded by exophthalmos (no ocular deviation) b. Orbital edema c. Inflammation and fibrosisof the muscles d. Insertions of the muscles not involved e. Inferior rectus, more severely affected > medial recti > superior recti > oblique muscles f. Vertical diplopia from asymmetric involvement of the inferior or superior recti is common early presentation g. Abduction may cause extorsion of the globe (due to inferior oblique myositis) h. Orbital congestion i. Upper lid retraction (Dalrymple’s sign) j. Lid lag on down gaze (Von Graefe’s sign) k. Infrequent blinking (Stellwag’s sign) l. Convergent weakness (Moebius sign) m. Optic nerve compression with scotomata (severe orbital congestion by swollen muscles at the orbital apex) 2. Paget’s disease (overgrowth of bone in the optic canal) with optic nerve compression 3. Fibrous dysplasia of bone (compression of the optic canal) 4. Osteopetrosis
Traumatic Optic Nerve Injury
1. Orbital and facial fracture: a. Penetrating orbital lesions b. Blunt trauma to the eye: 1) Putative contusion of retrobulbar axons 2) Hemorrhage of nerve or nerve sheaths c. Loss of vision during orbital surgery: 1) Post operative orbital hemorrhage 2) Direct nerve injury 3) Repair of orbital floor fracture 4) After rhinoplasty 5) Blepharoplasty (orbital hemorrhage) 6) Neurosurgical procedures (face down); malposition of the head rest tamponades of globe; retinal choroidal infarction d. Optic nerve tethered to bone: 1) Areas of injury: a) Orbital opening of the canal b) Canal 12 mm c) Intracranial entrance of the canal compressed 2) Anterior frontal impact (rapid deceleration): a) Falls, windshield trauma, frontal head trauma b) Instantaneous severe visual loss
Radiation Injury of the Optic Nerve
1. Usually secondary to X-RT of pituitary tumor or paranasal sinus 2. Radionecrosis: a. Proliferative endarteritis (endothelial cells) b. Fibrinoid vessel necrosis c. Necrosis of retrolaminar nerve substance d. Delayed visual loss with optic atrophy
Thermal Burns
1. Thermal burns of the body: a. Delayed optic neuropathy b. Bilateral involvement c. Infants, children, young adults d. Early visual loss due to diffuse cerebral edema or hypoxia
Miscellaneous Conditions Affecting CNII
1. Increased intracranial pressure: a. Suprachiasmatic recess compresses the chiasm (transient visual obscurations) b. Venous congestion of cavernous sinus with secondary orbital venous congestion 2. Idiopathic pachymeningitis (in association with other cranial nerve involvement) 3. Paraneoplastic involvement
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Nutritional and Toxic Optic Nerve Disease
1. General clinical symptoms: a. Insidious and slowly progressive b. Affects central fields c. Decreased acuity d. Dyschromatopsia e. Central scotomata
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SECTION V. Cranial Nerves
2. Differential diagnosis: a. Atypical central field loss with glaucoma b. Macular cone dystrophy c. Primary hereditary optic atrophy 3. Vitamin deficiency: a. Thiamine b. B12 (pernicious anemia) c. Cuban optic neuropathy 1) Multiple vitamin deficiencies d. Nigerian civil war (optic neuropathy, nerve deafness and sensory ataxia; cassava roots and leaf diet; putative cyanide primarily in the roots) 4. Drugs/Toxins: a. Ethambutol (green cones affected) b. Chloromycetin (seen in children with cystic fibrosis) c. Streptomycin d. Isoniazid e. Chlorpropamide f. Digitalis g. Chloroquine (macular lesion) h. Placidyl i. Antabuse j. Heavy metals k. Methanol (optic nerve destruction; bloody papilledema) l. Halogenated hydroxy quinolones: subacute; myelooptic neuropathy (SMON) m. Toluene (glue sniffing) n. D-penicillamine o. Intracarotid BCNU (glioma treatment) p. Amiodarone q. Hexachlorophene r. 5-fluorouracil 5. Tobacco-alcohol amblyopia: a. Probable dietary deficiency of B-complex vitamins and protein b. Elderly patients c. Some patients have concomitant B12 deficiency d. Thiamine therapeutic e. Bilateral symmetric centrocecal scotomata (between blind spot and fixation point) f. No nerve fiber defect is discernable g. V.A. 20/200 is typical h. Defect may extend across the vertical meridian i. Vertical median respected in chiasmatic defects, rarely hemorrhages are seen on or off the disc (splinter variety); disc swelling (rare) 6. Methanol: a. Disc edema (may be hemorrhagic) b. Associated encephalopathy c. T2 MRI lesions in the BG (striatum) d. Poor recovery 7. Jamaican optic neuropathy: a. Young adults; may be seen in all Caribbean islands b. Rapidly progressive
c. Bilateral optic atrophy d. Vision reduced to 20/200; dense central scotomata are noted e. Patients may be well nourished and non intoxicated
Toxic Optic Neuropathy
1. General Clinical Features: a. Subacute onset b. Slowly progressive c. Positive visual evoked potentials d. Discrimination in contrast sensitivity (decreased) e. Centrocentral or bitemporal VF deficit (chiasmatic involvement)
Masses of the Optic Disc
1. Pseudopapilledema: a. Anomalous elevation of the disc b. Hylan bodies (drusen) c. Gliotic dysplasia 2. Fibrillary astrocytoma (NF type) 3. Glial remnants of the hyaloid vasculature (their membranes or gray nodules attached to the disc) 4. Capillary and cavernous hemangioma 5. Racemose malformation (Wyborn Mason Disease) 6. Melanocytoma 7. Sarcoid granuloma 8. Leukemic infiltrate 9. Metastatic carcinoma
Clinical Features of Acquired Optic Nerve Disease
1. Monocular defect is usual 2. Bilateral defect: a. Hereditary diseases b. Toxic nutritional diseases c. Rarely Devic’s disease 3. Defects of central VF function: a. Decreased visual acuity b. Decreased brightness c. Hue desaturation d. Afferent pupillary response 4. Visual field defects: a. Central scotomata b. Arcuate nerve fiber defects c. Altitudinal defects are most often vascular d. Glaucoma, ischemia, drusen produce nasal defects 5. Head and eye pain rare; retrobulbar neuritis is the exception 6. Abrupt loss of monocular vision in the elderly is ischemic infarction of the disc; early disc swelling
Chapter 2. Cranial Nerve II
275
7. Slowly progressive monocular visual loss (months) suggests tumor compression (meningioma of Schwalbe) 8. Insidious bilateral asymmetric centrocecal scotomata suggest toxic or nutritional intrinsic optic nerve disease 9. Heredofamilial disease is bilateral and often associated with other neurological signs 10. Prechiasmal optic neuropathy: a. Inflammatory or vascular disease 11. Chiasmatic disease: a. Tumor (glioma; adenoma; craniopharyngioma) b. Aneurysm (carotid, A-com) c. Cysts (Rathke’s pouch remnants)
6. ION insufficiency in may be due to posterior ciliary arteries: a. Infarction of retinal nerve fiber bundles in the disc (anterior to the nerve fiber bundle) 7. Contralateral eye involvement 30–40% of patients 8. Simultaneous bilateral disc infarction does not occur 9. Higher incidence of DM and HCVD patients < 45 years of age 10. Abrupt visual loss in the elderly without disc swelling may occur with: a. Carcinomatosis of the meninges b. Basal brain tumor
Differential Diagnosis of Optic Neuritis
Giant Cell Arteritis
1. Autoimmune: a. MS d. Post viral infection b. ADEM e. Devic’s c. AIDP/CIDP (rare) 2. Specific viral infection: a. Measles d. Viral encephalitis b. Mumps e. HZ c. Chickenpox f. HIV 3. Contiguous inflammation: a. Orbit c. Meningeal b. Sinuses 4. Deep fungal infection: a. Mucormycosis c. Cryptococcosis b. Aspergillus 5. Syphilis 6. Sarcoid 7. Intraocular inflammation a. Serous retinopathy b. Neuroretinitis
1. General features: a. Onset in 70–80 year old patients b. Retrobulbar infarction occurs c. Premonitory visual symptoms d. Posturally sensitive visual loss e. Female preponderance 3 : 1 f. Prevalence rate 60–69; 33/100,000 people g. Worse visual loss than nonarteritic ION h. May have CRA occlusion i. Bilateral or rapidly segmental ION typical (usually days to weeks) 2. Associated eye signs: a. Hyperemia of conjunctiva and episcleral vessels b. Mild corneal edema c. Decreased Intraocular pressure d. Iris rubeosis e. Progressive cataract f. Chorioretinal pigmentary changes (weeks after visual loss) 3. Systemic signs and symptoms: a. Weakness b. Weight loss c. Myalgia of proximal muscles; no demonstrable weakness d. Fever e. Above features constitute polymyalgia rheumatica f. Sedimentation rate: 1) 80–100 mm/minute 2) Rare patient with normal sed rate 3) 35 to 40 mm (Westergren units) upper limit of ESR in elderly patients g. Burning headache; sensitive hair
Ischemic Optic Neuropathy (ION)
1. Infarction of the disc: a. Sudden loss of vision in the elderly b. Most common cause of disc swelling after 50 2. Involves prelaminar portion of the nerve 3. Rarely associated with retrobulbar location from arteritis 4. VF deficit: a. Maybe maximum at onset b. May progress for days to weeks c. Recurrences in same eye are rare d. No premonitory warning e. No recovery 5. Swollen disc: a. Flame hemorrhages noted in edematous sector b. Pain is rare c. Presymptomatic phase of disc swelling in contralateral eye (rare)
Rare Causes of Ischaemic Optic Neuropathy
1. Cataract surgery: a. 4–15 months post operatively b. Sudden visual loss
SECTION V. Cranial Nerves
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2.
3.
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5. 6. 7. 8. 9. 10. 11.
c. Disc infarction occurred with both retrobulbar or general anesthesia d. Second eye frequently involved (if operated) ION of the young: a. Acute disc edema and visual loss b. Cluster headache and migraine: 1) Unilateral or bilateral disc infarction (rare) 2) Sequential (rare) c. Possible autoimmune vasculitis Ischemic disc swelling: a. Marked or recurrent blood loss (G.I. tract) b. Delayed for days to weeks c. Rarely seen with by-pass surgery Uremic optic neuropathy: a. Bilateral visual loss b. Disc swelling c. Severe renal disease; uremic state d. Complicating features include: 1) Increased CSF pressure 2) Consecutive ION 3) Possible reaction to hemodialysis procedure Carotid artery disease Atrial fibrillation (emboli to posterior ciliary arteries) Coronary by-pass surgery Cardiac catheterization Eclampsia Acute intermittent porphyria PXE (platelet hypercoagulability)
Heredodegenerative Optic Nerve Disease
1. Recessive (simple): a. Severe visual impairment b. Severe disc atrophy c. Attenuation of arteries d. Electro retinopathy normal 2. Recessive (complicated): a. Behr’s Syndrome: 1) Optic atrophy 3) Spasticity 2) Mild mental retardation 4) Ataxia b. Onset by nine years of age c. Temporal disc pallor d. Strabismus 2/3 of patients e. Atrophy of optic nerves, tracts, lateral geniculate bodies; visual radiations and cortex 3. Recessive optic atrophy and juvenile diabetes: a. Childhood onset of optic atrophy b. Visual loss 20/200 c. Disc pallor related to degree of diabetic retinopathy d. Sensorineural hearing loss e. Diabetes insipidus f. Ptosis g. Ataxia h. Nystagmus
i. Seizures j. Mental retardation k. Abnormal ERG l. Increased CSF protein m. Short stature
Autosomal Dominant Optic Atrophy
A. General Features: 1. AD inheritance 2. Onset 4–8 years of age (insidious) 3. VA from 20/30 to 20/70; asymmetry of arteries 4. Disc pathology: a. Temporal pallor b. Temporal sectoral excavation c. Thinning of the papillomacular layer 5. Centrocecal enlargement of the blind spot a. Mid zonal temporal depression 6. Full peripheral fields to white targets 7. Acquired blue yellow dyschromatopsia 8. Inverted peripheral fields to color
Specific Diseases
1. AD optic atrophy with hearing loss 2. Leber’s hereditary optic atrophy A. General Features: 1. Mitochondrial genetics 2. Sudden loss of central vision 3. Onset second to 3rd decade 4. Male gender predominant 5. Peripapillary microangiopathy with arteriovenous shunting 6. Skeletal muscle defects 7. Cardiac muscle (pre-excitation syndrome) 8. Dystonia (striatal degeneration) 9. Cerebellar signs 10. Pyramidal system dysfunction B. Visual symptoms: 1. Loss of vision is rapid; VA 20/200 2. Acute phase: disc swelling occurs 3. Large dense central scotomata at fixation 4. Some patients regain vision
Dominant Pseudo Glaucoma
A. General Features: 1. Deeply excavated optic disc 2. Slowly progressive glaucomatous VF deficit 3. Normal intraocular pressure 4. Normal outflow 5. Visual symptoms start at 20 to 35 years of age
Chapter 2. Cranial Nerve II
3) 4) 5) 6) 7)
Differential Diagnosis of the Swollen Disc
1. Congenital: a. Anomalous disc: 1) Tilted 2) Elevated b. Hyalin bodies (drusen) c. Gliotic dysplasia 1) Embryonic vascular remnants 2. Intrinsic ocular disease: a. Uveitis c. Vein occlusion b. Hypotony 3. Inflammatory: a. Papillitis c. Papillaphlebitis b. Neuroretinitis 4. Infiltrative: a. Lymphoma c. Reticuloendothelial disease b. Leukemia 5. Systemic disease: a. Anemia (Fe deficiency; B12) b. Hypoxemia c. Hypertension d. Acute blood loss e. Uremia 6. Disc tumors: a. Hemangioma c. Metastatic b. Glioma 7. Vascular disease: a. Ischemic optic neuropathy b. Arteritic (giant cell) c. Arteritis associated with collagen vascular disease d. Juvenile diabetes e. Proliferative retinopathies f. Orbital tumors: 1) Perioptic meningioma 3) Sheath “cysts” 2) Glioma 4) Retrobulbar masses 8. Graves Disease 9. Elevated Intracranial Pressure: a. Mass lesion b. Pseudotumor cerebri 10. Hypertension 11. Papilledema secondary to increased intracranial pressure: a. Increased nerve sheath pressure b. Optic nerve fibers: 1) Compressed by increased CSF pressure in subarachnoid space 2) Intraorbital part of optic nerve is affected 3) Water and protein diffuse into prelaminar region of the disc c. Later events: 1) Venous obstruction 3) Vascular telangiectasia 2) Nerve fiber hypoxia d. Rare causes of papilledema with possible differential mechanisms: 1) Cyanotic congenital heart disease 2) Decreased arterial oxygen saturation
12.
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Polycythemia vera Systemic hypertension Sleep apnea Syringomyelia without hydrocephalus Spinal cord tumors (increased CF protein; blocked absorption) 8) AIDP/CIDP (increased protein; blocked absorption; cytotoxic) 9) Diagnosed CSF deficits; (post meningitis) Basic mechanisms of papilledema: a. Intracranial mass lesion (pressure and venous outflow obstruction) b. Increased CSF production (choroid plexus papilloma) c. Decreased CSF absorption (obstruction of Pacchionian granulations) d. Obstructive hydrocephalus e. Increased cerebral blood volume (AVM) f. Venous outflow obstruction: 1) Atresia of venous sinuses 2) Obstruction of sinuses (inflammatory; clotting abnormalities) g. Neck surgery h. Jugular vein compression i. Thoracic increased pressure Chronic Unilateral Papilledema: a. Nerve sheath tumor b. Intraorbital mass c. Occasionally seen with true increased intracranial pressure d. Previous optic atrophy of contralateral side (pseudo Foster–Kennedy syndrome) e. Congenital nerve sheath anomaly Clinical manifestations: a. Infants (open sutures); elderly patients (cortical atrophy) do not get papilledema b. Usually days to weeks to develop; develops within hours with: 1) Severe head trauma (loss of autoregulation) 2) SAH (possibly second hemorrhage; acute obstruction of CSF absorption) 3) Greater than 60–80 ml intracranial hemorrhage c. No visual acuity loss d. Enlargement of blind spot e. Normal pupillary light response f. Visual fields intact Late papilledema: a. Irregular peripheral VF constriction b. Nerve fiber bundle defect c. Transient visual obscuration: 1) Momentary dimming of vision 2) One eye at a time 3) Lasts a few seconds (less than 10–15 seconds) 4) Occurs with postural change or spontaneously 5) Clears completely
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SECTION V. Cranial Nerves
6) Pressure on the globe may reproduce the obscuration 7) Transient fluctuation of optic disc perfusion d. Late VF loss has tendency to involve the nasal quadrants; constriction of the fields bilaterally (late sign) 16. Evaluation of papilledema: a. Blurring of nerve fiber layer: nasal earlier than superior > inferior > temporal b. Veins engorged, dusky and tortuous c. Spontaneous pulsations cease: 1) Seen in 80% of patients 2) Cease at 200 ± 25 mm H2 O d. Splinter hemorrhages in nerve fiber layer, also occur in: 1) Drusen 3) Elderly 2) Glaucoma e. Nerve fiber layer infracts: cotton wool spots f. Disc hyperemia (dilatation of the superficial capillary bed on the disc); disc is progressively obliterated g. Retinal folds (Patin’s lines); circumferential retinal micro-folds; may extend to the macula h. Rare concomitants of extreme papilledema: 1) Choroidal folds 2) Ischemic infarction of the disc 3) Infarction of the central retinal artery 4) Visual loss following placement of a ventricular shunt
Differential Diagnosis of Pseudo Tumor Cerebri
Pseudotumor Cerebri
Time Course of Optic Neuritis
A. General Features: 1. Definition a. Raised intracranial pressure b. Papilledema c. No clinical or radiographic structural lesion noted d. Normal CSF (exception is increased pressure) 2. Allowable neurological signs and symptoms: a. Increased blind spot b. VI nerve palsy (generalized intracranial pressure; nerve trapped in Dorello’s canal under the petroclinoid ligament) c. Tinnitus (may be pulsatile) d. Visual obscuration (pressure on the chiasm from the suprachiasmatic recess) e. Severe headache B. Clinical Features: a. Female preponderance (teens through fifth decade) b. Men approximately 20% c. VF defects: 1) Increased blind spot 2) Arcuate nerve bundle defects (within central 30 degrees) 3) Defects nasally (along the horizontal meridian)
1. Congenital defects: a. Aqueductal stenosis: 1) Forked aqueduct 2) Small multichannel variant 3) Congenitally small aqueduct (less than 3 mm) b. Syringomyelia c. Chronic sepsis (obliteration of the Pacinian granulations) 2. Drugs: a. Amiodarone f. Birth control pills b. Tetracycline g. Lithium c. Nalidixic acid h. Hypervitaminosis A d. Tetracycline i. Hypervitaminosis D e. Steroid withdrawal 3. Venous thrombosis: a. Venous anomalies of sinuses b. Hypercoagulable state (sinus thrombosis) 4. Hypothyroidism 5. Pernicious anemia 6. Iron deficiency anemia 7. Addison’s disease 8. SLE 9. Polycythemia vera 10. Hypothalamic pituitary dysfunction a. Stein–Leventhal syndrome
1. Impairment of vision (central scotomata): a. Progresses for hours or days b. Maximum loss at one week 2. Episode involves one eye: a. Viral illness may involve both eyes in children b. Devic’s disease (may involve both eyes) 3. Eye pain: a. Globe, orbit or forehead; periorbital b. Eye movement exacerbates pain (retrobulbar neuritis) 4. Visual field loss: a. Scotomata 1) Central 2) Centrocecal 3) Altitudinal and nerve fiber defects 4) General field constriction (rare) 5. Decreased: a. Color sense (hue desaturation) b. Acuity c. Contrast sensitivity d. Depth perception e. Decreased visual function with heat 6. Visual function: a. Improves within 1–2 weeks b. May steadily improve over months
Chapter 2. Cranial Nerve II
c. Rarely vision may not improve to functional levels 7. Children more likely to have bilateral involvement 8. Slow or poor recovery associated with more extensive lesions 9. Disc edema is more often associated with anterior lesions; can occur with intracanalicular lesion 10. Retinal perivenous sheathing (Rucker’s periphlebitis retinae) more likely to develop in MS 11. Uveitis (pars planitis) may be associated with MS, sarcoid and Behçet’s disease
Atypical Optic Neuritis
1. SLE: a. Disc swelling and retrobulbar form b. Possible small vessel ischemia 2. Sjögren’s syndrome 3. Ulcerative colitis 4. Para infectious: a. Specific agents: 1) Chicken pox 4) EBV 2) Mumps 5) AIDP 3) HZ 6) CIDP b. Clinical manifestations: 1) Visual loss is bilateral 2) Not direct viral involvement; putative immunologic cascade 3) Ten days to 14 days after infection 4) Good prognosis
Infections of the Optic Nerve
1. Syphilis: a. Neuroretinitis b. Papillitis c. Perineuritis: 1) Manifestations of second stage disease 2) Reoccurrence (particularly AIDS patients) 3) Slowly progressive atrophy (stage III) 4) Retrobulbar neuritis (rare) 2. Neuroretinitis in secondary syphilis: a. Clouding of the central retina b. Hemorrhages c. Migration of the pigment epithelium (retinitis pigmentosa; localizes around blood vessels) d. Vitreous cellular debris e. Disc swelling f. Vasculitis 3. Optic neuritis with HIV: a. Associated infections: 1) Syphilitic optic perineuritis 2) CMV neuroretinitis; papillitis
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3) Hepatitis B b. HIV: 1) Bilateral optic neuritis c. Lyme’s disease d. Toxoplasmosis (inflammatory papillitis) e. Toxocara canes (inflammatory papillitis)
Slowly Progressive Optic Neuropathy
1. Unilateral and bilateral visual field loss occurs in MS: central or centrocecal scotomata 2. Sarcoidosis: a. Disc granuloma b. Optic nerve granula c. Sheath infiltration
The Optic Chiasm
A. General Features: 1. Anatomy: a. The chiasm is in the suprasellar cistern b. Floor of the suprachiasmatic recess c. Eight to 13 mm above the plane of the clinoid processes d. Intracranial nerve: 1) 45% inclined above the horizontal 2) 17 ± 2.5 mm in length e. Lateral chiasm adjacent to the supraclinoid carotid artery f. Anterior cerebral arteries are dorsal to the optic nerves B. Clinical Feature of Chiasmatic Disease: 1. Insidious progressive visual field loss 2. Asymmetrical 3. Tumors or aneurysms may cause fluctuations of vision 4. Nonparetic diplopia 5. Clumsiness with maneuvers that require depth perception 6. Diminished fusional capacity (non-fixed nasal fields): a. Vertical and horizontal slippage: 1) Doubling of images 2) Gaps in a visual image 3) Steps in the perception of horizontal lines 7. Extinction of objects beyond the fixation point 8. Extraocular palsies with VF defect is associated with disease of the cavernous sinus 9. Optic nerve atrophy (frequent) 10. Vertical meridian is respected in chiasmatic defects
Rare Manifestations of Chiasmatic a VF Defect
1. Bilateral atrophy and central scotomata
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2. Posterior chiasm angle defect: a. Homonymous hemianopia b. Depression of the inferior temporal VF near fixation d. Decreased visual acuity e. Optic atrophy
A Pseudo Chiasmatic VF Defect
1. The vertical meridian (isopter defect “8–12”) is involved in true chiasmatic defects 2. Bilateral intrinsic eccentric central or centrocecal scotomata (intrinsic optic nerve or retinal disease) 3. Nasal sector retinal disease (bilateral retinitis pigmentosa) 4. Greatly enlarged blind spots from severe longstanding papilledema (Rare in the CT/MRI age) 5. Congenitally tilted discs (inferior crescents; nasal fundus ectopia)
Congenital Defects
1. Maldevelopment of the optic vesicles: a. Unilateral or bilateral anophthalmos b. Microphthalmic cysts 2. Nerve hypoplasia: a. Occurs in isolation b. Occurs with ocular and forebrain malformations c. Partial aplasia; micropapilla 3. Bilateral optic nerve hypoplasia: a. Decreased visual acuity b. Nystagmus c. Associated with forebrain or developmental defects 4. VF deficits with optic nerve hypoplasia: a. Smaller the disc in general > decreased vision b. Decreased acuity c. Temporal wedge and hemianopsia d. Inferior altitudinal defect e. Constriction of the VF 5. Septo-optic dysplasia (De Mosier syndrome): a. Short stature e. GH, ADH deficiency b. Nystagmus f. Small pituitary c. Disc hypoplasia g. Mental retardation d. Holoprosencephaly 6. Dysplastic disc development: a. Congenital tumor (hypoplastic truncated, irregularly oval) b. Enlarged disc with optic glioma
2. Faulty closure of the embryonic ventral fissure of the optic stalk and cup 3. Enlarged disc that is excavated 4. Retained glial and vascular remnants 5. Posterior displaced disc within excavated peripapillary coloboma 6. Excavated disc adjacent to retinochoroidal coloboma 7. Pits within the nerve head 8. Rare AD inheritance of coloboma: most are sporadic inheritance
Association of Disc Malformation and Forebrain Anomalies
1. Basal encephalocele: a. Pulsating exophthalmos (spheno-orbital encephalocele) b. Hypertelorism with pulsatile nasopharyngeal mass c. Frontonasal mass (fronto-ethmoidal encephalocele) 2. Coloboma of the disc with hypertelorism or midface abnormality: a. Highly associated with basal encephalocele 3. Bilateral disc coloboma: a. Bilateral retrobulbar arachnoid cyst b. Dandy–Walker malformation 4. Unilateral coloboma: a. Carotid occlusion b. Moya–Moya Syndrome with dolichoectasia c. Absent carotid artery 5. Pits of the disc: a. Intrapapillary pearly grey dimples or slits b. Contain glial elements c. Located within scleral rim of disc margin d. Single; temporal location > central > inferior, superior or nasal quadrant w. Temporal pits associated with serous detachment of the macula 6. Dysversion (tilted disc) and associated crescents of the optic disc: a. Inferior crescent most frequent (inferior conus; Fuchs coloboma) b. Adjacent retinal sector disorganization of the choroid and pigment epithelium c. Inferior crescents associated with: 1) Myopia 3) Decreased visual acuity 2) Astigmatism 4) Decreased foveal reflex 7. Disc abnormalities are associated with: a. Hypertelorism c. Apert’s syndrome b. Crouzon syndrome
Coloboma Neoplasms Affecting the Optic Chiasm
1. Congenital malformation that enlarges or distorts the nerve head circumference
1. Adenoma of the pituitary:
Chapter 2. Cranial Nerve II
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5.
a. Most common presentation 4–7th decade; uncommon in patients younger than 20 b. Non secretory adenoma: 1) Larger than secretory tumors 2) Present 50–60 years of age 3) Males greater than females Visual field deficits: a. Superior bitemporal hemianopsia b. Hemianopic scotoma near fixational area adjacent to the vertical meridian c. Asymmetric d. Eye with greater deficit may demonstrate loss of visual acuity e. Posterior adenomas involving the optic tract: 1) Incongruous hemianopsia 2) Decreased central vision (ipsilateral eye) 3) Optic atrophy occurs 4) Rarely: Bjerrum arcuate scotomas (blind spot to nasal field; or terminate at the vertical meridian) Prolactinoma: a. Most common pituitary tumor b. Female > males most microadenomas ( posterior fossa 21% > parasellar region 18% B. Clinical Features (when symptomatic): 1. Headache (50%) 2. Blurred vision (40%) 3. Seizures (40%) 4. Diplopia (15%) 5. Associated optic nerve sheath cysts (disc swelling)
Chapter 2. Cranial Nerve II Metastatic Disease of Optic Nerves and Chiasm
1. 2. 3. 4.
Rapid unilateral or bilateral visual loss Usually without disc swelling Hematogenous spread; spread through CSF spaces Associated with rapid sequential multiple cranial nerve palsies 5. Malignant lymphoma grows through the perivascular spaces; may have segmental demyelination 6. Chronic lymphocytic leukemia (involves chiasm) 7. Metastases to pituitary gland that secondary affect the chiasm as rare; may be associated with diabetes insipidus: a. Seeding of posterior greater than anterior lobe b. Diplopia may be associated
Sphenoidal Mucoceles
1. Mucocele of posterior ethmoid and sphenoid paranasal sinus: a. Clinical features: 1) Chronic headache 2) Varying ophthalmoplegia (involvement of the orbital apex) 3) Visual loss and VF defects 4) Involvement of chiasm (rare)
Trauma
1. Visual loss after closed head trauma: a. Neurapraxia, contusion or laceration of the optic nerve b. Immediate visual loss 2. Chiasmatic traumatic syndromes: a. Much less common than optic nerve deficits 3. Visual field deficits: a. Complete monocular blindness with contralateral temporal deficits (junctional type) b. Bitemporal arcuate scotomata c. Transient diabetes insipidus d. Anosmia: defects of II, IV, VII, VIII e. CSF rhinorrhea; otorrhea f. Carotid-cavernous fistula g. Carotid pseudo aneurysm h. Meningitis 4. Mechanisms of chiasmatic injury: a. Sagittal tearing (sphenoidal fracture) b. Thrombosis or shearing of carotid artery blood supply to the chiasm c. Contusion or hemorrhage of the chiasm itself
Complications of X-RT
A. General Features:
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1. Radiation necrosis occurs approximately 8–13 months after treatment 2. Radionecrosis of anterior visual system B. Clinical presentation: 1. Rapidly progressive visual loss in one eye 2. Decreased vision of second eye follows at short interval 3. Relentless progression to severe deficit 4. Visual field deficits: a. Central scotoma or nerve fiber bundle defects b. Chiasmatic defect c. Optic tract defect 5. Chiasmatic defects associated with pituitary X-RT 6. Optic atrophy occurs two to three months after visual loss 7. Doses clearly associated with radionecrosis (5000 cGY); complications may occur with daily fractional doses of 200 to 220 cGY/treatment 8. Proliferative endarteritis of small blood vessels with secondary anoxia
Hydrocephalus
A. General Features: 1. Pressure of the anterior aspect of the III ventricle (suprachiasmatic recess) on the chiasm (neurapraxia) B. Clinical presentation: 1. Bitemporal VF deficit 2. Progressive optic atrophy from pressure against bones of the sella or carotid artery
Pregnancy
1. Increase of supra sella meningioma growth during the 2nd and 3rd trimester 2. Optic neuritis more common after delivery 3. Lymphocytic adenohypophysitis: a. Occurs in a close time interval with pregnancy b. Diffuse lymphocytic infiltration of the pituitary gland c. Pituitary immune mediated d. Exclusive to women
Empty Sella Syndrome
A. General Features: 1. Extension of the subarachnoid space through the diaphragma sella 2. Defects in the diaphragma sella that are greater than 5 mm occur in 40% of patients 3. Normal volume of sella 4. Associations of empty sella: a. Spontaneous b. Arachnoidal cysts
SECTION V. Cranial Nerves
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c. Infarction of the pituitary gland d. Pseudotumor cerebri e. Pituitary surgery f. X-RT g. Pituitary apoplexy B. Clinical presentation: 1. Chiasmal herniation into the sella 2. Visual defects from adhesions of the optic nerves and chiasm (traction injury; diplopia and micropsia are rare complaints) 3. More frequent in obese women 4. 20–70 years of age (mean of 50 years) 5. Headache (usually frontal or bitemporal) 6. Occasional pituitary dysfunction (growth hormone, thyroid or luteinizing hormone; prolactin secretion) 7. Occasional CSF rhinorrhea 8. Blurring of vision, diplopia, micropsia a rare visual complaint
Miscellaneous Chiasmatic Process
1. 2. 3. 4.
Devic’s disease (MS) EBV infection Ethylchloranil (placid) Opticochiasmatic arachnoiditis: a. Associated with meningovascular syphilis b. Polyarteritis c. Cystic adhesive fibrous arachnoidal thickening with lymphocytes 5. Infectious meningitis: a. Chiasmatic arachnoid inflammation (silent infection) b. Cryptococcosis, pseudomonas aeruginosa, staphylococcus, streptococcus pneumonia; tuberculous meningitis; HIV, CMV of the optic nerve and chiasm; necrotizing angitis 6. Sarcoidosis: a. Involves posterior hypothalamus b. Pituitary c. Optic nerve sheaths d. Chiasm involvement e. Chiasmatic visual field loss
Chapter 3 Cranial Nerve III A. Anatomical Features: 1. Ipsilateral and contralateral innervation of the superior rectus 2. Dorsal neurons of lateral nucleus (inferior rectus) intermediate neurons of lateral nucleus (inferior oblique) Ventral neurons of lateral nucleus (medial rectus)
3. Central caudal nucleus-levator muscles of both eyes 4. Edinger–Westphal nucleus-dorsal rostral portion of the oculomotor complex: a. Anteromedian nucleus and EW: preganglionic parasympathetic b. Post ganglion sympathetic fibers reach the eye by the short ciliary nerves c. 3–3.5% of ocular parasympathetic axons supply the iris sphincter; greater than 90% supply the ciliary muscle and medicate accommodations d. Pressure sensitive axons for pupillary contraction occupy form medial margins of IIIrd nerve; may be spread equally throughout the nerve; fibers for accommodation may be with pupillomotor fibers e. Fascicular; cavernous; orbital portion (through) the S.O.F. and the annulus of Zinn f. IIIrd separate into two divisions either within the anterior cavernous sinus or the orbit: 1) Superior division: SR, levator of the lids 2) Inferior division: MR; IR; IO; parasympathetic fibers (with the branch to the IO) g. Blood supply: 1) Small arteries from the posterior cerebral and basilar arteries 2) Artery of the inferior cavernous sinus (branch of meningohypophyseal trunk) 3) Recurrent branched from ophthalmic artery to orbital portions of the nerve B. IIIrd nerve nuclear complex: 1. Ipsilateral and contralateral innervation of the superior rectus 2. Dorsal neurons of the lateral nucleus innervate the inferior rectus; intermediate neurons of the lateral nucleus (inferior oblique) ventral neurons of the lateral nucleus (medial rectus) 3. Central caudal nucleus innervates the levator muscles of both eye lids 4. Edinger–Westphal nucleus overlies the dorsal rostral portion of the oculomotor complex: a. Anteromedian nucleus and EW: preganglionic parasympathetic axons to the ciliary ganglion b. Post ganglionic sympathetic fibers reach the eye by the short ciliary nerves c. 3–3.5% of ocular parasympathetic axons supply the iris sphincter; >90% supply the ciliary muscle and mediate accommodation d. Pressure sensitive axons for pupillary contraction occupy dorsomedial margin of the IIIrd nerve alternatively they may spread equally throughout the nerve; fibers for abomination course with pupillomotor fibers e. Fascicular; cavernous; orbital portion (through the S.O.F. and the annulus of Zinn) syndromes occur clinically
Chapter 3. Cranial Nerve III
f. IIIrd separates into two divisions either within the anterior cavernous sinus or the orbit: 1) Superior division: SR, levator of the lid 2) Inferior division: MR; IR; I.O: parasympathetic fibers (with the branch to I.O.) g. Blood supply to the IIIrd nerve: 1) Small arteries form the posterior cerebral and basilar arteries (IIIrd nerve complex) 2) Artery of the inferior cavernous sinus (branch of meningohypophyseal trunk) 3) Recurrent branches from ophthalmic artery to orbital portions of the nerve
Vascular IIIrd Nerve Syndromes
1. Nuclear IIIrd nerve syndrome: a. Intrapeduncular branch of the PI division of the PCA (often involved) b. Bilateral ptosis c. Bilateral pupillary dilatation d. Bilateral superior rectus palsy e. Rarely a partial syndrome occurs 2. Fascicular IIIrd nerve/intraparenchymal lesions: a. Weber’s syndrome: ipsilateral IIIrd (may or may not be pupil sparing) crossed hemiparesis; awake patient b. Benedict’s syndrome: ipsilateral IIIrd nerve with contralateral movement disorder c. Claude’s membrane: ipsilateral IIIrd contralateral nerve with cerebellar outflow d. Subdural Hematoma: ipsilateral IIIrd nerve; involved pupil; spastic hemiparesis; headache with lethargy 3. Cavernous IIIrd nerve lesion: a. Involved with IV, VI and first division of V1 b. Superior division involved anteriorly in the sinus (superior rectus and levator palpebrae) 4. Orbital IIIrd nerve lesion: a. Involved with IV, VI and first division of V b. Superior division: SR and levator palpebrae c. Inferior division: pupillary involvement; medial rectus, inferior rectus, and inferior oblique d. Intermediolateral limb of the external carotid (ILL) is the blood supply 5. Nuclear III and IV nerve (Masugi’s syndrome): a. Posterior lateral choroidal artery from the terminal PCA (P4) b. Simultaneous nuclear IIIrd and IVth nerve paralysis c. Crossed hemisensory deficit d. Rare mild internal capsule type motor deficit 6. Hematoma of the midbrain: a. Lethargy to obtundation (periaqueductal grey) b. Failure of vertical gaze c. Large 3–4 or 4–5 mm pupils; sluggishly reactive d. Quadriparesis (if pressure on the cerebral peduncles) e. Nystagmus retractorius
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f. Rare: convergent nystagmus g. Hydrocephalus 7. Vascular Malformation of the midbrain: a. Cavernous hemangioma b. Capillary telangiectasia (rare: usually pons or cortex) c. Arteriovenous malformation: 1) Different clinical manifestations due to size, recurrent bleeding, and exact location 2) Arterial venous malformations in association with Wyburn–Mason and Von Hippel Lindau malformations 3) Cavernous hemangiomas rebleed repeatedly (specific MRI appearance: hemosiderin ring and increased signal intensity on T1 weighted image (old blood) 4) Capillary telangiectasia (asymptomatic and rare) 8. IIIrd nerve involvement from emboli or infarction secondary to “top of the basilar syndrome”
Aneurysmal Involvement of the Third Nerve
1. Pain behind the eye 2. Pupil involved early (vulnerability of location of pupillomotor fibers; dorsomedial part of the nerve, 3–4 micron small pressure sensitive fibers; may be spared: a. P-COM (third nerve affected alone) b. Carotid artery (third with contralateral face, arm and leg involvement) c. Between the posterior cerebral and superior cerebellar artery (usually IIIrd nerve alone) d. Giant aneurysm at the top of the basilar artery (IIIrd nerve involved in the interpeduncular fossa; hydrocephalus and contralateral spastic hemiparesis) e. Cercoid posterior cerebral artery (elongated; tortuous) f. Retroorbital pain more severe and prolonged than in diabetic neuropathy g. Intracavernous aneurysm may erode into the sphenoid sinus and present with a profuse nose bleed; usually gradual VIth nerve weakness and V1 facial pain
Ischemia of the Intracavernous Internal Carotid Artery
1. Inferolateral trunk of the ECA (external carotid artery): a. Superior or tentorial branch b. Anteromedial branch 2. The anterolateral branch of the ILT (inferolateral trunk of the ECA) anastomosis with the distal portion of the internal maxillary artery and the posterior branch anastomosis with the accessory and middle meningeal arteries 3. The IIIrd and IVth nerves are supplied by the superior or tentorial branch of the ILT 4. Cranial nerves III, IV, VI supplied by the anteromedial branch
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5. The vascularization of the IIIrd nerve depends on the specific territory of the ILT; the nerve is supplied predominantly by the superior or tentorial components or the anteromedial branch 6. Clinical presentation of ischemia of the IIIrd nerve from external carotid artery disease: a. Isolated IIIrd nerve b. IIIrd nerve associated with Vth nerve c. IIIrd nerve associated with Vth, IVth, and VIth nerve d. IIIrd and IVth involved together 7. Blood supply of the IIIrd nerve: a. Region of the posterior perforated substance, artery from the basilar, causes isolated IIIrd b. Supracavernous region; artery of the tentorium; IIIrd, IVth nerve c. Intracavernous; ILT of the ECA; IIIrd, IVth VIth and Vth and VIth; rarely IInd and VIIth d. Ischemia affects the central portion of the nerve
Congenital Defects
1. Congential absence of IIIrd nerve nuclei in association with absence of other cranial nerves 2. Congential abnormalities of innervation; fascicles of IIIrd nerve may innervate Vith nerve 3. In association with Möbius syndrome. (Facial diplegia and ptosis.)
Trauma
1. Head trauma: occasionally III and IV nerve are injured simultaneously 2. IIIrd trapped: a. Between the posterior cerebral and the superior cerebellar arteries b. At the tentorial edge c. Damaged in the cavernous sinus d. Disrupted orbital wall e. Compression by the uncus of the hippocampal genus; tentorial edge or under the posterior cerebral artery by herniation from edema or mass lesions 3. Aberrant regeneration: a. Classic misdirection syndrome; engagement of the IIIrd nerve induces pathological lid retraction; no up or down movement of the globe (simultaneous innervation of the superior or inferior rectus muscles); adduction of the eye and pupillary constriction are intact b. Fully developed misdirection syndrome; minimal retraction of the globe, slight enophthalmos, droop of the upper lid on abduction
Neoplasm
1. Accounts for approximately 20–25% of IIIrd nerve paralysis 2. Midbrain tumors involving intraparenchymal portion of IIIrd: glioma, medulloblastoma, hemangiomas, metastatic lesions 3. Parinaud’s syndrome: a. Paralysis of upward and downward gaze b. Dissociated vertical and horizontal gaze with opticokinetic nystagmus c. Pupillary abnormalities (large, poorly reactive; 3–4 mm dissociated light and accommodation pupillary response) d. Bilateral hearing loss e. Failure of convergence f. Nystagmus retractorius 4. Tumors of the quadrigeminal plate (gliomas) do not produce motility disorders until they extend beyond the tectal plate 5. Mild head trauma: may precipitate IIIrd nerve palsy from parasellar or clival tumor (to be ruled out if there is no fracture or the palsy lasts longer than 1–2 months) 6. Pituitary adenoma: a. May spread into cavernous sinus; compression of the nerve against the dura at the entrance of the sinus b. Pituitary apoplexy (associated with headache, sudden loss of vision, cranial nerve palsy) may have unilateral or bilateral IIIrd nerve palsy; CT and MRI demonstrate more benign clinical picture of pituitary apoplexy than formerly taught c. Intermittent signs and symptoms may be present with pituitary tumors 7. Nasopharyngeal tumors: a. May affect IIIrd nerve in the cavernous sinus b. Origin at the fossa of Rosenmüller; extend into the middle fossa through the foramen lacerum or ovale c. Squamous cell CA, lymphoepithelioma and lymphosarcoma may present similarly 8. Sphenoid sinus tumor: a. May produce cavernous sinus syndrome
Tumors of the IIIrd Nerve (Intrinsic)
1. Schwannoma 3. Fibroblastic tumors 2. Neurofibroma
Metastatic Tumors
1. Intracranial metastasis constitute about 30% of neoplasm that affect the IIIrd nerve 2. Nasopharynx most frequent metastatic tumor 3. Breast, thyroid, lung and lymphoid tumors
Chapter 3. Cranial Nerve III
4. Most frequently affects the nerve by direct invasion 5. 10–25% of late stage lymphoma invade the CNS; affects the nerve by involvement of the meninges and direct extension
Orbital Tumors
1. Metastatic: a. Breast, lung, melanoma of the choroid, lacrimal gland, lymphosarcoma, lymphoma leukemia, hypereosinophilia syndrome b. Intraorbital mass 1) Hemangioblastoma (conus) 3) Pseudotumor 2) Dermoid 4) Meningioma
Pupillary Involvement of the IIIrd Nerve
1. Internal carotid disease: a. Fibromuscular dysplasia, dissection, carotodynia, ischemia (atherosclerosis or arteritis) all may cause sympathic paresis. The internal carotid artery vasovasorum feed the internal branch of the sympathetic innervation to the eye b. Complete Horner’s syndrome: 1) Myosis 2) Ptosis (sympathetic innervation of the tarsal muscles of the upper and lower lid); the upper lid droops while the lower lid rises) 3) Decreased sweating of the face (if the common carotid bifurcations and or external branches are affected) 4) Apparent enophthalmos; decreased innervation of Mueller’s muscle behind the globe c. Iris ischemia with large pupils in carotid disease (10% of patients) d. Argyll Robertson pupil: 1) Secondary to syphilis; pretectal lesions 2) Six components: a) Small (1 mm) b) Irregular c) Does not respond to light d) No response to ciliospinal reflex e) Does not respond to mydriatics f) Responds to accommodation e. Behr’s pupil: 1) Dilated 2) Ipsilateral to optic tract lesions f. Holmes–Adie pupil: 1) Responds sluggishly to light and accommodation 2) May be unilateral 3) More common in young women 4) Associated with absent ankle jerks; occasionally loss of knee reflexes
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5) Part of generalized small fiber neuropathy g. Wernicke’s pupil: 1) Slit lamp directed at retina that subserves VF deficit from stroke; slower contraction of the pupil h. Elliptical pupil (cat’s eye): 1) Pretectal lesion 2) Usually seen after severe head trauma i. Oval pupil: 1) Diabetes 2) Herniation with compression of the IIIrd nerve 3) Syphilis j. Light near dissociation: 1) Diabetes 2) Amyloid 3) Syphilis 4) Rarely pressure on the nuclear complex or pretectal area k. Anisocoria: 1) 25% of the population 2) Equally reactive to light and convergence
Muscle Disease Affecting the IIIrd Nerve
1. Oculopharyngeal dystrophy: a. Middle to older patients b. Bilateral ptosis (may be severe) c. French Canadian ancestry d. Rimmed vacuoles on muscle biopsy 2. Myotonic dystrophy: a. Severe ptosis b. AD; chromosome 17 c. Multisystem disease: flat glucose tolerance curve, cardiac arrhythmia, high FSH/LH; small testicles; frontal bossing; 50% decreased intelligence 3. Mitochondrial diseases: a. Kearns–Sayre: complete ophthalmoplegia; heart block; hearing loss; diabetic glucose tolerance curve b. Progressive external ophthalmoplegia with ptosis; associated myopathy and symmetrical neuropathy c. Late onset mitochondrial myopathy; ptosis; short stature; VIIIth nerve involvement 4. Myotubular myopathy; primarily bilateral ptosis with minimal proximal muscle weakness 5. Thyroid muscle disease (Hoffman’s syndrome): a. Inferior rectus muscle may enlarge first b. All muscles are thickened and enlarged c. Elevated long acting thyroid stimulating hormone d. Sclerae and the tendinous insertion of muscle are not involved (they are in pseudo tumor of the orbit)
Neuromuscular Junction Disease
1. Acquired myasthenia gravis:
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2. 3.
4.
5.
6.
SECTION V. Cranial Nerves
a. Asymmetric ptosis and IIIrd nerve involvement b. The pupil is not clinically involved c. May be associated with pseudo intranuclear ophthalmoplegia d. Rapid nystagmus Congenital nystagmus Tetanus: a. IIIrd nerve with pupillary involvement b. Systemic muscular involvement c. Opisthotonus Botulinum toxin: a. Nausea and vomiting c. Bilateral dilated pupils b. Bilateral ptosis Snake bite (Elapidae species) a. Nausea, vomiting, and vertigo b. Ptosis c. Diplopia; IIIrd nerve and other cranial nerve involvement Lambert–Eaton syndrome: a. Asymmetrical ptosis b. IIIrd nerve and other cranial nerve involvement c. Impaired strength with exercise
Collagen Vascular Disease/Arteritis
In general the arteritic process affects the vascular supply to the nerve which affects the central rather than the peripheral part of the nerve. The pupillomotor fibers are on the peripheral dorsomedial part of the nerve. 1. SLE: affects the IIIrd and VIth nerve most commonly 2. Wegener’s granulomatosis: affects the Vth nerve as well as the IIIrd and VIth most commonly 3. Tolosa–Hunt: (severely painful ophthalmoplegia): a. All eye muscles may be involved in the affected eye; III, IV, and VI b. V, II and periarterial sympathetic fibers may be involved c. Persists for days to weeks; remission and exacerbations are common d. Nonspecific granulomatous involvement in the cavernous sinus e. Steroid responsive 4. Periarteritis nodosa: IIIrd nerve involvement rare; usually mononeuritis multiplex 5. Hypereosinophilic syndromes (>20,000 eosinophile/mm3 ) 6. Granulomatous angiitis
Infections
A. Viral Infection: 1. St. Louis, Eastern and Western Equine encephalitis; IIIrd nerve involvement is rare
2. Polio and Von Economo IIIrd nerve palsy was occasionally reported 3. Most viral illness: the IIIrd nerve palsy occurs 2–3 weeks after the febrile illness 4. IIIrd nerve palsy may occur with: HZ, EBV, pertussis, measles, influenza and HIV 5. HZ-ophthalmoplegia III > IV nerve; recovery occurs B. Bacterial Infection: 1. Acute bacterial meningitis III and VIth nerve frequently involved; transient and clears with recovery; perineural inflammation may extend into the nerve substance (most commonly seen with meningococcus, pneumococcus and haemophilus influenzae) 2. IIIrd nerve involved in syphilitic basilar meningitis (pupillomotor and medical rectus muscle fibers are most vulnerable) 3. Lyme disease: IIIrd nerve may be an initial manifestation 4. Tuberculosis: tuberculous meningitis may affect the IIIrd nerve; pupillomotor fibers are vulnerable C. Fungal infections: 1. Mucormycosis (genus Rhizopus): a. Occurs in severely immunocompromised patients; cancer, diabetic ketoacidosis, HIV, uremia b. Underlying sinus infection c. May concomitantly involve the venous sinuses with consequent infarction d. Black palate syndrome (lateral and jugular sinus infarction) 2. Cryptococcosis: a. Accompanies HIV infection b. Usually cranial nerve II involved greater than III c. Indolent with headache and dementia D. Systemic disease: 1. Diabetes mellitus: a. Painful or painless ophthalmoplegia; pain retroorbital or at times with peduncular lesions there is no pain b. Pupil sparing c. Recovery without “misdirection” 2. Cranial amyloid: a. Primary uveal veil (vitreous) b. Associated with meningeal involvement c. Light near dissociation 3. Hypertrophic pachymeningitis: a. Exuberant overgrowth of the meninges that traps cranial nerves b. Differential diagnosis includes: sarcoid, lymphoma, tuberculosis c. Patients afebrile, do not appear ill, IIIrd nerve involved d. Pupil sparing 4. Carcinomatosis of the meninges: a. MRI reveals that it often is associated with minimal features; enhancement of cerebellar folia; base of the skull
Chapter 4. Cranial Nerve IV
b. III relatively commonly involved 5. Wernicke-Korsakoff’s Syndrome: a. Cranial nerve II and VI frequently involved bilaterally b. Associated with thiamine deficiency c. Encephalopathy, ataxia and neuropathy associated d. Ophthalmoparesis less common in black patients 6. Sarcoid: a. Meningeal involvement of IIIrd nerve
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4. Posterior lateral choroidal branch of PCA (p4) C. Vascular lesions (parenchymal): 1. Nuclear IV as part of a superior cerebellar artery stroke 2. Masugi’s syndrome in which the IIIrd and IVth nerve are infarcted simultaneously; superior cerebellar artery; ipsilateral ataxia and contralateral loss of pain and temperature sensation below the clavicle 3. May be involved in isolation; posterolateral choroidal artery from p4; associated pulvinar involvement
Immune Mediated Congenital Defects
Multiple sclerosis: 1. IIIrd nerve relatively uncommonly involved directly; extremely commonly involved as component of intranuclear ophthalmoplegia Miller Fisher variant of GBS: 1. GD1b or GQ1b epitopes 2. Ophthalmoparesis, areflexia, ataxia are concomitant neurological findings Descending GBS: 1. III, VI, and VIII nerves are involved concomitantly 2. Pharyngeal innervated cranial nerves involved (cervicalbrachial pattern) CIDP: 1. Rarely associated IIIrd nerve palsy Trauma: 1. Orbital fracture injuring either the superior or inferior division of the nerve 2. Injured during uncal herniation or anterior temporal lobe lobectomy
1. Unilateral or bilateral absence of IV in association with absence of III, VI and other brainstem nuclei
Trauma
1. 5% of cranial nerve palsies that follow severe head trauma afflict the IVth nerve 2. Approximately 15% of all ocular palsies have traumatic origin; most compression or contusion injuries heal within 2–5 weeks 3. Approximately 30% of IV nerve palsy are traumatic; brainstem is compressed against the lateral edge of the tentorium may damage both IVth nerves 4. Orbital fractures may damage the IVth nerve 5. Surgery involving the tentorium; anterior temporal lobectomy; top of basilar artery aneurysm surgery 6. Post traumatic intracavernous aneurysm
Chapter 4 Cranial Nerve IV A. Anatomy 1. Nucleus is below that of the IIIrd nerve at the level of the inferior colliculus 2. Supplies the contralateral superior oblique muscle 3. Longest intracranial course; emerges from the dorsal surface of the midbrain below the inferior colliculus and curses below the tentorium; enters the cavernous sinus below the IIIrd nerve, enters the orbit through the superior orbital fissure outside of the annulus of Zinn B. Blood supply: 1. Anastomosis of ascending and descending branches of nutrient subpial arteries 2. Superior cerebellar artery branches supply the IVth nerve nuclei 3. Superior division of the intermediolateral trunk of the external carotid artery supplies the nerve in the superior orbital fissure
External Carotid Artery Ischemia
1. Involving the ILL of the external carotid artery or its superior branch (during course of embolization of vascular lesions or tumor) 2. Diabetic induced infarction 3. Arteritis
Systemic Disease
1. Cavernous sinus infection and tumor (simultaneous involvement of III, VI, VI) 2. Superior orbital fissure syndrome (tumor of the orbit or infection) 3. Collagen vascular disease with infarction 4. Diabetes 5. Wegener’s and necrotizing arteritides
SECTION V. Cranial Nerves
290 Neuromuscular Junction Disease
1. 2. 3. 4. 5.
Congenital and acquired MG Tetanus Botulinum poisoning Neurotoxic snake venom Lambert–Eaton syndrome
Ocular Muscle Disease
1. PEO 3. Thyroid ophthalmopathy 2. Kearns-Sayre Syndrome 4. Orbital pseudotumor Superior Oblique Myokymia
1. Rapid spontaneous firing of the superior oblique muscle 2. Congential superior oblique palsy
2. Sensation: spares the angel of the jaw (C2); innervates scalp to the bregma; tragus of the ear; anterior wall of external auditory meatus; anterior part of the tympanic membrane; dura of the anterior and middle fossa; may decrease taste on ipsilateral tongue or palate (may need somatic as well as special sensation for full taste) 3. Mental nerve; buccal nerve; auricular temporal nerve; great auricular nerve 4. Main sensory nucleus; (light touch); the spinal tract and nucleus; (pain and temperature) 5. Mesencephalic nucleus takes origin from the rostral tip of the main sensory nucleus to the superior colliculus; subserves proprioception of muscles of mastication and the mechanoreceptors of the peridental membrane 6. Motor root: innervates muscles of mastication the tensor tympani and tensor veli palatini
Neoplasms
Trauma
1. Tumors that invade the cavernous sinus: pituitary adenoma, meningioma, lymphoma 2. Nasopharyngeal cancer 3. Isolated neurinoma or Schwannoma 4. Carcinoma of the sphenoid sinus
1. Dental treatment 2. Pressure on the mental nerve from dentures (bone resorption) 3. Surgical trauma 4. Head and facial trauma 5. Skull base fracture; trigeminal abducent nerve synkinesis may occur with lesions at the petrous apex
Infections
1. 2. 3. 4. 5. 6. 7. 8.
Herpes zoster (rare); less common than III EBV; St. Louis, Eastern and Western equine viral infection Syphilis Lyme’s HIV Purulent bacterial infections (meningeal involvement) Rare involvement with polio Mucormycosis
Immune Mediated
1. Miller Fisher Syndrome 4. MS (rare) 2. CIDP 5. Sarcoid (rare) 3. Descending GBS
Migraine Variants
1. Facial paresthesias and numbness are common with both common and classic migraine 2. Lower face migraine affecting V2 and V3 3. Paroxysmal hemifacial pain; multiple attacks of severe pain primarily in V2 division daily; responsive to indomethacin 4. Classic cluster migraine with severe orbital and retroorbital V1 pain 5. Raeder’s paratrigeminal neuralgia pain in V1 distribution with associated photophobia, phonophobia and nausea. Type I with ptosis and miosis; type II with no cranial nerve abnormality. 6. SUNCT: sudden unilateral neuropathic pain in V1 with conjunctival injection and tearing
Chapter 5 Cranial Nerve V A. Anatomy: 1. Innervates: head, mouth, nasal cavity, motor and proprioceptive innervation of the muscles of mastication
Tumors
1. Trigeminal neurinoma: a. 0.2% of intracranial tumors; 14–67 years of age; most often occur in middle age; incidence equal in both sexes
Chapter 5. Cranial Nerve V
2.
3. 4. 5. 6. 7. 8. 9. 10. 11.
12. 13. 14. 15. 16.
17. 18.
b. Arise in the distal portion of the nerve; probable Schwann cell origin; at the region of the ganglion; rarely may extend through the foramen rotundum or ovale. c. 2.5 cm by time of diagnosis; may undergo malignant transformation d. Numbness or paraesthesias in the distribution of the nerve; trigeminal neuralgia or painful paresthesias less common e. Erode the medial part of the floor of the middle fossa; erosion of apex of the petrous bone Meningoma: a. More often arise in Meckel’s cave than trigeminal neurinoma b. Spread en plaque along the floor of the middle fossa; along the trigeminal nerve root into the middle fossa c. Meningioma affects V3 more often than trigeminal neuroma Gangliocytoma (rare primary malignant tumor of the ganglion) Epidermoids primary or secondary Chondroma Chondromyxoma Sarcoma Lymphoma Fibrous xanthoma (fibrous histiocytoma) Hemangioblastoma Malignant Schwannoma (from the trigeminal ganglion or its divisions): a. Numbness or paresthesia in distribution of the nerve or its branches in 2/3 of patients b. Painful burning and paresthesias 1/3 of patients c. May erode into the cavernous sinus; V1 , IVth, IIIrd nerve involvement with consequent proptosis and visual loss Nasopharyngeal cancer (fossa of Rosenmüller is its origin) Maxillary sinus cancer Neural spread of squamous cell cancer of the face Prostate cancer spread to Meckel’s cave (spread via Batson’s plexus; paravertebral veins) Cholesterol granulomatosis; benign; striking MRI findings (positive T2 weighted images; apex of the petrous bone) Salivary gland adenoma Submaxillary gland cylindroma
Congential Trigeminal Anesthesia
1. May be isolated and is usually bilateral; may present with corneal ulceration 2. May be associated with ectodermal or mesenchymal structural defects:
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a. Goldenhar syndrome: oculoauricular vertebral dysplasia 1) Abnormalities of the first and second branchial arches, vertebrae and eyes. These include: preauricular tags, malformed pinnae, epibulbar dermoids b. Associated with Möebius syndrome: congenital facial diplegia and horizontal gaze Vascular Lesions
1. Wallenberg’s syndrome (medial branch of PICA or vertebral artery occlusion) 2. Pontine ischemia (short circumferential arteries) 3. Aberrant branch of AICA that abuts the Vth nerve 4. AVM of the ganglion 5. Ischemia of the inferolateral trunk of the external carotid artery; usually involved with VII or with nerves of the superior orbital fissure 6. Internal carotid artery aneurysm (compresses the trigeminal ganglion and concomitantly the IIIrd nerve) 7. Cavernous sinus aneurysm: a. Affects primarily middle aged women b. VIth nerve involved first followed by severe pain in V1 and V2 c. Often bilateral d. Pain is predominant symptom Systemic Disease
1. Hypothyroidism (may present with severe facial pain: V1 , V2 divisions) 2. Sarcoid (rare) 3. Wegener’s granulomatosis (often V2 ) 4. Scleroderma (Vth nerve involvement may be presenting symptom) 5. SLE 6. Sjögren’s disease 7. Periarteritis nodosa 8. Mixed collagen vascular disease Idiopathic Trigeminal Neuropathy
1. After exclusion of all known entities that affect the Vth nerve 2. Motor function rarely affected 3. 10% of trigeminal lesions 4. Numbness most often V2 , V3 , spreads to adjacent divisions in days to weeks; recovery over weeks to months 5. Sensation of numbness, swelling, coldness and tingling 6. Inflammatory process of the ganglion (pathologically) 7. Reported with arteritis: rheumatoid arteritis, Sjögren’s, MCTD, most commonly associated with scleroderma 8. Taste affected over the anterior 2/3 of the tongue (affected in some patients) 9. Trigeminal trophic syndrome (very rare)
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SECTION V. Cranial Nerves
Trigeminal Neuralgia
Infection
A. General Features: 1. Young patients: a. Multiple sclerosis b. Vascular loop compressing the entry zone c. Spinocerebellar degeneration 2. Older patients: a. Idiopathic b. Vascular loop originates 1) Superior cerebellar artery > AICA > basilar artery B. Clinical Presentation: 1. Lancinating severe pain 2. Less than 15 seconds in duration 3. Most often unilateral; V3 division > V2 division thalamus/IC > corona radiata) 7. AICA infarction (infarcts peripheral branches of the nerve outside of the brainstem (internal auditory and subarcuate arteries) 8. Basilar artery aneurysm (fusiform with blockage of perforators and short circumferential arteries) 9. AICA aneurysm (spasm) 10. Aberrant artery of AICA (nerve compression in CPA) 11. Dolichoectasia of vertebral and basilar artery 12. Millard–Gubler syndrome (short circumferential arteries) 13. Foville syndrome (short circumferential arteries)
Collagen Vascular Disease/Arteritis
1. 2. 3. 4. 5. 6.
SLE Periarteritis nodosa Sarcoid (vasculitic form) Giant cell arteritis Wegener’s granulomatosis Mixed collagen vascular disease
Immune Mediated
1. 2. 3. 4. 5. 6. 7.
MS (direct involvement; myokymia) ADEM AIDP CIDP Post immunization Bell’s palsy Necrotizing leukoencephalopathy (associated with increased serum IgM) 8. PML (leukoencephalopathy – rare in pons)
Systemic Disease
1. 2. 3. 4. 5. 6.
Diabetes Hypertension Amyloidosis Whipple’s disease Sarcoid Heerfordt’s syndrome (bilateral VII nerve and uveitis with sarcoid) 7. Idiopathic hypertrophic pachymeningitis
Infections
1. Herpes zoster (Ramsey-Hunt syndrome): a. Acute facial paralysis; grouped vesicles in and behind the ear
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SECTION V. Cranial Nerves
b. Less than 1% of acute Bell’s palsy 2. Herpes simplex (HS) 3. Few patients with new infection or reactivation of CMV, adenovirus, EBV; more common in association with HIV 4. Otitis media: a. 0.5 to 1% complicated by facial paralysis 5. Leprosy 6. Syphilis 7. Osteomyelitis 8. Bacterial meningitis 9. Tuberculous meningitis 10. Fungal meningitis 11. Lyme disease (Bannwarth syndrome) 12. Polio 13. Trichinosis 14. Cysticercosis 15. Abscess of pons
Tumors Affecting the VII Nerve
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Pontine glioma Pilocystic astrocytoma Metastatic disease (solid tumors) Carcinomatosis of the meninges Intracranial metastases from pinealoma Melanoma metastasizes to the nerve Lymphoma Leukemia Parotid tumor (mixed parotid gland tumor) Adenocarcinoma of the salivary gland
Toxin/Physical Agents
1. Ethylene glycol (in moon shine aka “smoke”) 2. X-RT; frequent myokymia; direct nerve damage
Congenital Disease
1. 2. 3. 4. 5.
Trauma at time of birth 1/2000 deliveries Congenitally narrow facial canal Alexander’s disease (AD/AR) Hemifacial spasm (narrow posterior fossa) New born neuropathic facial paralysis: a. Intrapartum compression b. Intrauterine posture c. Forceps trauma e. Nuclear aplasia 6. Möbius syndrome (facial diplegia with VI nerve palsy): a. Cardiofacial syndrome (lower lip weakness with cardiac anomalies) b. Valetta–Van Lowe syndrome (associated) c. Facial paralysis incomplete in 2/3 of patients; frontalis and orbicularis oculi > perioral muscles d. Associated anomalies; ptosis; anterior lingual atrophy, pectoral muscle defects, clubfoot, mental retardation, arm malformations
Traumatic Facial Paralysis
1. Closed head injury: a. Acute facial paralysis: 1) Longitudinal (parallel to the long axis of the petrous pyramid) 2) Transverse fracture of petrous pyramid 3) Temporal bone fracture demonstrated in almost all cases of traumatic fracture b. Delayed onset facial paralysis: 1) Bleeding from the ear and evidence of temporal bone fracture prognostic for a delayed VII nerve paralysis c. Surgical trauma (ear surgery primarily) 1) VII nerve paralysis may be immediate or delayed
Differential Diagnosis of Bilateral VII Nerve Palsy Melkersson–Rosenthal Syndrome
1. 2. 3. 4.
Recurrent facial palsy with facial edema Lingua plicata (scrotal tongue) Facial weakness begins prior to age 16 Edema effects upper lip most frequently; persistence of swelling with time; permanent state of lip and facial enlargement 5. Cheilitis granulomatosa (small granulomas found in diffusely edematous interstitial tissue) Hereditary Facial Paralysis
1. Some families have a juvenile onset 2. Recurrent facial palsy 3. May be in association with other cranial nerve palsies
A. Syndromic: 1. Wernicke–Korsakoff (concomitant IIIrd and VIth) 2. Melkersson-Rosenthal (scrotal tongue) 3. Möbius (concomitant VIth nerve) 4. Steven–Johnson’s syndrome (severe mucous membrane involvement) 5. Familial Finnish amyloidoses (abnormal sagging facies) 6. Kennedy’s syndrome (with fasciculation)
Infections
1. Lyme’s 2. HIV 3. Ebstein–Barr
Chapter 8. Cranial Nerve VIII
4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Herpes Simplex Poliomyelitis HZ Mycoplasma pneumonia Leprosy Trichinosis Tuberculosis Cryptococcus Syphilis Rhombencephalitis (HS; rare other viruses)
Immune Mediated
1. MS 2. CIDP 3. AIDP (classic) 4. ADEM
5. CM Fisher (variant) 6. Bilateral Bell’s palsy 7. Graft versus host disease
Tumor
1. 2. 3. 4. 5. 6.
Carcinomatosis of the meninges Leukemia (CLL) Nasopharyngeal cancer Pontine glioma Fibrillary astrocytoma Prepontine meningioma (meningioma en-plaque)
Systemic Disease
1. 2. 3. 4. 5.
Sarcoid (Heerfordt’s syndrome) Diabetes (bilateral Bell’s) Collagen vascular disease Pontine hemorrhage Head trauma
Chapter 8 Cranial Nerve VIII
A. Anatomy (General) 1. Auditory nerve: a. Afferents of the cochlea 2. Vestibular nerve 3. Afferents from the saccular and utricular macula a. Sense linear acceleration 4. Cristae of the semicircular canals: a. Sense angular acceleration
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Anatomy and Physiology of the Auditory Pathways
1. Hair cells of the organ of Corti (first order neurons) stimulated by sound: a. Cochlear apex senses low tones; hair cells at the base; base high tones: b. Spiral ganglion of the cochlear nerve c. Comprise the cell bodies of the first order neurons 2. Rosenthal’s canal 3. Afferents of the spiral ganglion neurons contact inner (majority) and outer hair cells of the cochlea 4. Activation of hair cells depolarizes the spiral ganglia neurons whose efferents synapse in the ventral cochlear nucleus (cochlear nerve) 5. Cochlear nerve projects and synapses with: a. Dorsal cochlear nucleus b. Anteroventral and posteroventral nuclei of the cochlear complex c. Dorsal components of the complex process afferents from “high frequency” basal cells; ventral neurons process afferent from the “low-frequency” apical cells d. Dorsal and ventral cochlear nuclei project to the contralateral brainstem nucleus of lateral lemniscus e. Dorsal acoustic striae: 1) Intermediate acoustic stria (dorsal part of the ventral cochlear nucleus) 2) Ventral acoustic stria (part of trapezoid body) f. Lateral lemniscus projects to the inferior colliculus and medial geniculate nucleus g. Ventral cochlear nucleus synapses with the superior olivary nucleus: reticular formation and the nucleus of the trapezoid body h. Medial geniculate body (afferents from the inferior colliculus): 1) Low frequency fibers-synapse on the apical lateral areas 2) High frequency afferent fibers synapse in the medial portion of the nucleus i. MGB (geniculotemporal fibers) project to lamina IV of the primary auditory cortex (area 41) and association areas 42. High tones terminate medially and low tones laterally. 1) Core system for audition: a) Central nucleus of the inferior colliculus b) Components of the medial geniculate c) Primary auditory cortex d) Direct auditory pathway e) Tonotopic organization 2) Alternative auditory projection system: a) Pericentral region of the inferior colliculus (IC) b) Non laminated MGB neurons c) Area 42 (secondary auditory cortex) d) Less tonotopic organization
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SECTION V. Cranial Nerves
Anatomy of the Vestibular System
1. Monitors angular and linear accelerations of the head 2. Accelerations are transduced into action potentials in the membranous labyrinth (utricle, saccules and, semicircular canals) 3. Linear acceleration registered by: a. Macules of the utriculus and sacculus 4. Angular acceleration registered by: a. Cristae in the ampullae of the semicircular canals 5. Horizontal head movements: stimulates the utricle linearly; tilting activates the sacculus 6. Activation of cristae or macules discharges neurons in the vestibular ganglion of scarpi whose afferent fibers are the vestibular nerve: a. Anterior, horizontal semicircular canals (SCC) and the utricle comprise the superior portion of the vestibular nerve b. Posterior SCC and sacculus comprise the inferior portion of the nerve c. Afferents to the vestibular nerve: 1) Superior nucleus (Bechterew) SCC 2) Lateral nucleus (Dieter) macules (utriculus and sacculus); comprises the vestibular spinal tract 3) Medial nucleus (Schwalbe) SCC 4) Inferior (Roller) macula (utriculus and sacculus) d. Vestibular efferents: 1) MLF; superior nucleus is ipsilateral; other nuclei efferents are contralateral 2) Medial vestibular tract: a) Excitation or inhibition of the cervical and upper thoracic levels of the contralateral spinal cord 3) Lateral vestibulospinal tract: a) LVN; ipsilateral spinal cord; cervical cord afferents project to the posteroventral part of the nucleus; lumbosacral to the dorsocaudal areas of the nucleus b) Excitatory projections to extensor trunk muscles; antigravity axial muscles; afferents from the utriculus “anti-gravity detection” 4) Cerebellum receives afferents from: a) Inferior and medial nuclei b) Ipsilateral floccular nodular lobe (receives LVN projections) c) Uvula; fastigial nucleus (receives LVN projections 5) Reticular formation receives afferents from VN and projects to: a) Lateral reticular nucleus b) Nucleus reticularis pontis caudalis
Topography of Clinical Symptoms
1. Decreased perception of tones or speech:
a. Lesion central to the oval window 2. Cochlear deficit (sensory); perception of sound 3. Cochlear nerve or nuclei or central pathways; perception of sound 4. Sensorineural loss: a. Greater difficulty with high pitched sounds b. Loss of speech discrimination > pure tone deafness c. Tinnitus (varies in pitch and intensity): 1) Paroxysmal or continuous 2) More frequent with external middle ear disease than central lesions 5. Low roaring-cochlear hydrops (Ménière’s) 6. High pitched; presbycusis; VIII nerve tumor 7. Pulsatile tinnitus: a. Glomus jugulare tumor b. Intracranial or cervical aneurysm c. Increased intracranial pressure (unilateral tinnitus) d. Middle ear congenital defects e. Arteriovenous malformation
Miscellaneous Causes of Tinnitus
1. Gaze evoked tinnitus (after removal of tumors of CPA); presents with saccadic movements pursuit or vestibular induced movements 2. TMJ disease 3. Labyrinthitis 4. Brainstem lesions 5. High cardiac output 6. Palatal myoclonus (clicking in association with the myoclonic jerks)
Localization of Lesions Causing Sensorineural Deafness
A. Cerebral lesions (41, 42, 22): 1. No complete deafness even with bilateral lesions of the cortex 2. Unilateral lesion: a. Subtle hearing impairment with unilateral lesion b. Difficulty locating sounds c. Predominantly posterior temporal lesions or bilateral temporal lesions; pure word deafness (inability to comprehend spoken language) with normal auditory acuity; reading, writing, naming and comprehension of non language sounds are intact d. Bilateral lesions of the auditor cortex: 1) Cortical deafness 2) Generalized auditory agnosia 3) Selective auditory agnosia 4) Pure word deafness 5) Amusia 6) Depressed temporal analysis of sound
Chapter 8. Cranial Nerve VIII Irritative Lesion of the Temporal Cortex
1. Simple auditory hallucinations (tinnitus) > complex hallucinations (voice or music) 2. Areas 42 and 22 cause more hallucinations than 41 3. Temporal lobe seizures have both acoustic and vertiginous auras (dizziness one of the commonest TLE auras)
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8. Decreased corneal reflex (if anterior to the IAC) 9. Hydrocephalus B. Anterior extension of the tumor: 1. V (facial pain, decreased corneal reflex) 2. VIth nerve weakness C. Posterior inferior extension: 1. IX dysphagia, absent pharyngeal reflex 2. X hoarseness 3. XI trapezius, sternocleidomastoid muscle weakness
Brainstem Lesion
1. Lesions above cochlear nucleus there is no clinical hearing loss 2. Bilateral hearing loss: a. Trapezoid body (stroke or hemorrhage) b. Pons (stroke or hemorrhage) c. Midbrain tegmentum (hemorrhage, tumor) d. Pineal and midbrain tumor: 1) Central stem deafness of Brunner (pressure on the isthmus acusticus); bilateral e. Lower midbrain or rostral pontine tegmentum lesions cause: 1) Auditory hallucinations (release type) 2) Clear sensorium 3) Hearing loss f. Brainstem auditory hallucinosis with lower pontine tegmental hemorrhage
Peripheral Nerve Lesions
1. Cochlear lesion: a. Deafness c. High frequency hearing loss b. Tinnitus 2. Causes: a. Basal skull fracture b. Syphilis/bacterial infection c. Streptomycin/neomycin/gentamicin d. AICA aneurysm e. CPA tumors
Acoustic Neurinoma
A. General features: 1. Origin: vestibular portion of VIIIth nerve in the IAC 2. Unilateral high pitched tinnitus 3. Progressive sensorineural hearing loss 4. Early loss of speech discrimination 5. Less than 10% have sudden deafness 6. Vertigo, dizziness, ipsilateral unsteadiness (vestibular nerve involvement) 7. V, VI, VII (weakness, loss of taste anterior 2/3 of tongue, Hitselberger sign (numbness of external auditory canal)
Vertigo
Peripheral Causes: 1. Short duration 2. Severe, paroxysmal 3. Tinnitus 4. Hearing loss (may be associated) 5. Nystagmus (horizontal/rotary; contralateral; decreased by visual fixation) 6. Romberg (fall to the affected side); subjective environmental twirl, past pointing-to the side of the lesion; fast component of nystagmus to the opposite side B. Canal paresis (total loss of horizontal SCC): 1. Ipsilateral head rotation cause compensatory refixation saccades C. Bilateral vestibular paresis: 1. Head movement-dependent oscillopsia (movement of the visual environment only with head movement) D. Positional vertigo (induced by head position): 1. Benign positional vertigo: a. Degeneration of the macula of the otolith; obstruction of endolymph floor b. Lesions of the PSCC (otoconia from degenerating utricular macula attach to the cupula of the posterior SCC) c. Differential diagnosis of cupulolithiasis: 1) Trauma 2) Infection (Hs) 3) Labyrinthine fistula 4) Ischemia 5) Demyelinating disease 6) Posterior fossa tumor 7) Arnold–Chiari malformation 2. Benign positional vertigo (BPPV): a. Induced nystagmus: 1) Latency 2–15 seconds 2) Fatigue (lasts less than 10 seconds) 3) Torsional nystagmus 4) No associated cochlear or central symptoms 5) Vertigo (less than 60 seconds) 6) Upright position: rebound nystagmus to the opposite side 7) Lying in lateral position may cause protracted nystagmus
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SECTION V. Cranial Nerves
8) May have long course (years); one exacerbation after initial remission 9) Habituates (lesions with continued repositioning) 3. Central vertigo: a. Short latency b. No fatigue c. No habituation d. Vertigo absent or mild (less than 60 seconds) e. Nystagmus: 1) Direction changing greater than fixed 2) Induced by several head positions f. Associated CNS signs 4. Maturational vertigo: a. Induced on rising; turning over in bed prior to rising b. Disorders in which vertigo and nystagmus are prominent
Differential Diagnosis of Peripheral Vestibulopathy
Vestibular neuronitis: 1. Acute severe vertigo; associated with nausea and vomiting 2. Absent calorics on the affected side 3. Self limited; lasts 7–10 days 4. No cochlear symptoms or other neurologic signs 5. Unrelated to head position 6. May reoccur Acute Labyrinthitis
1. 2. 3. 4.
Vertigo, nausea and vomiting Tinnitus Hearing loss Follows: bacterial or viral labyrinthitis; aminoglycosides; loop diuretics
Variants of Ménière’s
1. Cochlear Ménière’s: a. Vertigo is absent 2. Vestibular Ménière’s: a. Severe vertigo b. Hearing loss and tinnitus are later features 3. Tumarkins otolithic catastrophe: a. Severe episodic vertigo b. Loss of muscle tone; patient falls to the ground c. No loss of consciousness 4. Medical conditions with severe episodic vertigo: a. Congential syphilis (bilateral disease) b. Viral and bacterial labyrinthitis c. Hyperlipidemia d. Diabetes mellitus e. Labyrinthine otosclerosis f. Hypothyroidism g. Ramsay Hunt (HZ of geniculate ganglion): 1) Vesicular eruption of the external auditory meatus 2) Peripheral facial paralysis 3) Vertigo 4) Hearing loss h. Chronic ear infection i. Putative autoimmune etiology j. Cardiac insufficiency: 1) Cardiac arrhythmia: a) Tachyarrhythmia with decreased stroke volume (1) Presyncopal feeling (2) Visual loss (closing in from the side) (3) Fading out of hearing (4) “Light headed” or dizzy b) Congestive heart failure c) Aortic stenosis d) Carotid sinus hypersensitivity
Hematologic Disease
Aberrant Branch of AICA Compresses the VIIIth Nerve
1. Constant positional vertigo 2. Severe nausea 3. Tinnitus Ménière’s Disease
1. 2. 3. 4. 5. 6. 7. 8. 9.
Episodic severe vertigo Fluctuating sensorineural hearing loss Fullness or pressure sensation in the ear Bilateral in 30–40% of patients Endolymphatic hydrops; increased volume of endolymph Roaring tinnitus Attacks: minutes to hours Between attacks: dysequilibrium noted in some patients Hearing loss low tones ( A) 3. Lateral branch infarction may just have vertigo and dizziness (PICA) 4. Labyrinthine stroke: a. Occlusion of the internal auditory artery (origin is AICA) 1) Superior vestibular artery: vertigo, nausea and vomiting 2) Common cochlear artery: deafness 5. Bickerstaff’s migraine: a. Vertebrobasilar ischemia b. Tingling of the hands c. Dizziness, dysarthria, ataxia d. Short loss of consciousness 6. Subclavian steal syndrome: a. Severe stenosis of the subclavian artery prior to the origin of the vertebral artery b. Dizziness, dysarthria, diplopia c. Occurs during continued overhead use of the right arm d. Rarely symptomatic 7. Cerebellar infarction or hemorrhage 8. BPV may occur secondary to labyrinthine ischemia 9. Dolichoectasia of the vertebral, basilar and AICA arteries 10. AICA or PICA aneurysm with distal emboli or vasospasm
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Vertigo from Head or Cervical Trauma
1. Inner ear concussion 2. Fracture of the temporal bone with labyrinthine or VIII nerve damage 3. Uncovertebral joint (cervical spine) or cervical plexus injury (unequal afferent information to the vestibular nuclei)
Syndromic Deafness (Selected)
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
Ménière’s disease Susac’s disease Wolfram (DIDMOAD) Norrie’s Romano ward LEOPARD Albinism deafness syndrome Voigt–Koyanagi–Harada Pendred Usher Alstrom Roger (TRMA) Otodental Brachia-oto-renal CHARGE Large Vestibular aqueduct Vohwinkel SAPHO Wolf–Hirschhorn Jervell Lange Nielsen Perrault Treacher–Collins Waardenburg DiGeorge Wildervanck Fountain Bing–Nell
Ménière’s (discussed above) Disease
Susac’s Syndrome: 1. Retinal vascular lesion 2. Sensorineural hearing loss
3. Stroke
Wolfram Syndrome (DIDMOAD); Familial or Sporadic
1. 2. 3. 4. 5. 6.
Diabetes insipidus Optic atrophy Deafness Urinary tract (anomalies) Abnormalities of endocrine glands MRI: a. Absence of high signal in the posterior pituitary
SECTION V. Cranial Nerves
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b. c. d. e. f.
Shrinkage of optic nerves, chiasm, tracts Atrophy of hypothalamus Atrophy brainstem and cerebellum Atrophy of the cortex High signal in SN (substantia nigra)
Norrie’s Syndrome (Atrophia Oculi Congenita)
1. 2. 3. 4. 5. 6.
X-linked recessive Bilateral deafness at birth (20–25% of blind males) Phthisis bulbi Dementia or psychosis in 25% Pseudotumor of the retina Lens, corneal opacities
Usher’s Syndrome
1. 2. 3. 4.
5.
6.
7. 8.
AR 3.4/100,000 Congential bilateral sensorineural hearing loss Progressive visual loss from retinitis pigmentosa Type 1 (USH1); 14q; 11q; 10q, 21q: 1. Congenital deafness 2. Absent vestibular function Type II (USH2); 1q: 1. Moderate-to-severe hearing loss (congenital) 2. Normal vestibular function Type III (USH3); 3q: 1. Progressive loss 2. Normal vestibular function Myo7A gene (encodes myosin VII A); USH1B USH2A phenotype (laminin is encoded)
Differential Diagnosis
1. 2. 3. 4. 5. 6. 7.
Retinoblastoma Retrolental fibroplasia Toxoplasmosis Falciform detachment of the retina Juvenile retinoschisis Sex linked microphthalmia Sex linked cataract and congenital retinal detachment
Alström’s Syndrome
1. 2. 3. 4. 5. 6. 7.
AR; French Canadians; North Africans Retinal pigment degeneration Neurogenic deafness Infantile obesity Hyperlipidemia Non-insulin dependent diabetes mellitus Chromosome 2p12–13
Romano–Ward Syndrome
1. AD 3. Sudden death from tachyarrhythmia 2. Long – QT 4. HERG gene
Leopard Syndrome
1. 2. 3. 4.
Lentigines Ocular hypertelorism Mental and growth retardation Deaf mutism
Roger (Thiamine Responsive Megaloblastic Anemia; TRMA) Syndrome
1. 2. 3. 4. 5. 6.
AR; chromosome 1q23.2–1q23.3 Megaloblastic anemia Diabetes mellitus Sensorineural deafness Responds to megadoses of thiamine SLC19AZ gene on 1q23.2–23.3 encodes thiamine transporter 1 (THTR-1)
Albinism with Deafness
Otodental Syndrome
Voigt–Koyanagi–Harada 1. White forelock 4. Uveitis 2. Dementia 5. Recurrent meningitis 3. Cerebellar degeneration 6. VIII nerve involvement
1. AD 2. Bulbous canines; globe shaped posterior teeth; agenesis of maxillary premolars 3. High frequency sensorineural hearing loss 4. Abnormalities of deciduous and permanent dentition
Pendred Syndrome Branchio-Otic-Renal Syndrome (BOR)
1. 2. 3. 4.
AR; 7.5–10/100,000; 7q 22–31 Goitre (thyroid dysfunction variable) Sensorineural hearing loss Malformation of inner ear
1. AD; BOR gene at chromosome 8q13 2. Preauricular pits branchial fistulas 3. Renal anomalies
Chapter 8. Cranial Nerve VIII
4. Hearing loss 5. Some families: branchial anomalies, preauricular pits, and hearing loss; no renal anomalies; some families branchial and renal anomalies with no hearing impairment
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Perrault Syndrome
1. Ovarian dysgenesis 2. Deafness
Treatcher–Collins (Mandibulofacial Dysostosis) CHARGE Syndrome
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Coloboma (79%) Heart malformations (85%) Choanal atresia (57%) Growth-mental retardation (100%) Genital anomalies (34%) Ear anomalies (91%) Deafness (62%) Semicircular canal hypoplasia Cranial nerve palsy Facial anomalies Neonatal brainstem deficits Polytopic development field defect involving the neural tube and neural crest cells
Wildervanck Syndrome:
1. Variant of Klippel–Fiel 3. Deaf mutism 2. Retraction of eye ball
Wartenberg Syndrome
1. 2. 3. 4. 5. 6. 7.
AD Lateral displacement of medial canthus Approximation of eye brows White forelock Heterochromia aurides Absence of organ of Corti Atrophy of spiral ganglion
Large Vestibular Aqueduct Syndrome
1. Progressive sensorineural hearing loss
Alport Syndrome
Cogan’s Syndrome
1. Congenital renal disease 2. Marked stria atrophy; mild secondary neural degeneration
1. Ocular inflammation 2. Vestibulo-auditory dysfunction 3. Vasculitis (includes abdominal and mesenteric arteries)
Vohwinkel Syndrome
1. 2. 3. 4. 5. 6.
Mutilating keratoderma Papular and honeycomb keratoderma Constriction of digits (autoamputation) Starfish acral keratoses Sensorineural deafness Mutation in connexin 26 (CX26 gene); encodes portions of intercellular gap junctions 7. Nonconservative mutation of D66H in CX 26
Cockayne Syndrome
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Retinitis pigmentosa Sensorineural deafness Cerebellar ataxia Peripheral neuropathy Microcephaly; dwarfism Kyphosis Flexion deformity Loss of subcutaneous fat Photosensitivity to UV (ultra violet) light Anhidrosis
Hallgren Syndrome SAPHO Syndrome
1. 2. 3. 4. 5. 6.
Synovitis Acne Palmoplantar pustulosis Hyperostosis Osteitis Diffuse sclerosing osteomyelitis of the mandible; inflammatory spread from the TMJ to the cochlea (sudden deafness)
1. Retinitis pigmentosa (RP) 3. Ataxia 2. Profound congenital deafness 4. Mental retardation
Laurence–Moon Biedl Syndrome
1. RP 4. Obesity 2. Sensorineural hearing loss 5. Polydactyly 3. Mental retardation 6. Hypogonadism
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SECTION V. Cranial Nerves
Refsum’s Disease
1. Intermittent neuropathy 4. Ichthyosis 2. Cataracts 5. Short stature 3. Phytanic acid elevation 6. Increased CSF protein
Retinitis and hearing Loss
1. OPCA 2. Juvenile and adult onset lipidoses
Optic Atrophy, Hearing Loss and Peripheral Neuropathy
1. Friedreich’s ataxia (uncommon)
Hearing Loss and Optic Atrophy
1. Sylvester syndrome (AD): a. Optic atrophy, ataxia, progressive hearing loss 2. Nyssen Van Bogaert syndrome: a. Opticocochleodentate degeneration 3. Rosenberg-Chutorian syndrome: a. Optic atrophy, polyneuropathy, sensorineural hearing loss
Rare Associations of Hearing Loss
1. 2. 3. 4.
Spinal muscular atrophy Fascio scapular humoral dystrophy Roussy–Levy syndrome Myotonic dystrophy
Brown-Vialetto-Van Laere Syndrome
1. 2. 3. 4.
Pontobulbar palsy with deafness Familial Bilateral nerve deafness Motor components of VII; IX–XII; rarely III, V, VI involved 5. Severe loss of axons of the auditory and vestibular nerves
Non-Syndromic Hereditary Hearing Loss
1. Mitochondrial genetic disease: a. MELAS b. Mitochondrial 3243t RNA A (leu) A to G mutation 1) Pigmentary retinal dystrophy 2) Defective retinal pigment epithelial 3) Cells of rod and cone photoreceptors are deficient 4) A3243G 0.5 to 2% of diabetics
5) Deafness c. MERFF d. PEO e. Kerne–Sayre syndrome 2. Identified Genes/Chromosomal Loci/Genetic Associations: a. CX26 (mutated 50% of all recessive deafness) b. Myosin 7A – usher type 1B (identified with syndromic/nonsyndromic hearing loss) c. X-Linked deafness type 3-POU3FH gene d. DFNA6 chromosome 4p 16.3 (progressive low frequency hearing loss) e. Mitochondrial 12S r RNA deficit f. Enlarged vestibular aqueduct; nonsyndromic hearing loss; same 7q 31 locus as Pendred syndrome g. X-Linked cochlear degeneration h. Autosomal dominant cerebellar atrophy-type I i. Familial spastic paraparesis (complicated) j. Autosomal dominant recurrent VIII nerve deafness k. Familial vestibulopathy l. Familial amyloidosis type IV m. Late onset peroxisomal deficiency n. X-Linked deafness o. CADASIL p. AD osteogenesis imperfecta q. Hereditary sensory autonomic neuropathy r. X-Linked motor-sensory neuropathy type II s. Trisomies of D and E 3. Tumors Affecting the VIII Nerve: a. Carcinomatosis of the meninges b. Leukemia c. Lymphoma d. Acoustic Schwannoma (NFI or sporadic) e. Meningioma f. Epidermoid (primary and secondary) g. Metastasis h. Exophytic glioma i. Pinealoma (dysgerminoma; pineocytoma) j. Ependymoma k. Malignant melanoma (metastatic) l. Neurofibromatosis (type II; bilateral acoustic neuroma) m. Intravascular malignant lymphoma 4. Infections: a. Tuberculosis b. Cryptococcus c. Aspergillosis d. Deep fungal infection e. HIV f. CMV g. Purulent bacterial meningitis h. EBV i. Vestibular neuronitis j. Cysticercosis k. Histoplasmosis
Chapter 8. Cranial Nerve VIII
l. Coccidioidomycosis 5. Drugs/Toxins/Physical Agents: a. Cis-platinum b. Aminoglycosides c. Superficial siderosis d. Furosemide diuretics (loop diuretics) e. Zidovudine f. Dideoxyadenosine g. Streptomycin h. Interferon gamma 1 i. Depakote j. X-RT k. Increased ICP l. Midbrain trauma m. Trauma skull n. Alcohol o. Lead p. Mercury 6. Bone Disease: a. Paget’s disease b. Fibrous dysplasia (Albright’s syndrome) c. Synchondrosis of the skull d. Osteogenesis imperfecta e. Congenitally small IAC 7. Vestibular Disease: a. Vascular (see above) b. Bing–Neel (hyperviscosity syndromes) c. Hypothyroidism d. Syphilis e. Autoimmune (putative); AIDP; CIDP f. Drug (cis-platinum; streptomycin) g. Cupulolithiasis (displaced otoconia) h. Trauma (petrous and skull fractures) i. Perilymphatic fistula j. Vestibular hemorrhage (trauma) k. Hypertrophic VII nerve compression of the VIIIth nerve (IA Meatus) 8. Defects in development: a. Aplasia: 1) Complete absence of the otic capsule and VIIIth nerve; thalidomide ingestion 2) Incomplete development of the bony and membranous labyrinth; dysgenesis of the spiral ganglion 3) Membranous cochleosaccular dysplasia of the VIIIth nerve in the porous acoustics; 20% of patients 9. Trauma: a. Blunt trauma: 1) Transverse or longitudinal fracture (relations to the long axis of petrous bone) 2) Longitudinal fractures: a) More common than transverse b) Usually no VIIIth nerve damage 3) Transverse fracture: a) Anteroposterior trauma
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b) Roof of the internal auditory meatus in fractured c) Total deafness and severe vertigo; 40–50% of patients; concomitant VIIth nerve paralysis 4) Blunt head trauma with temporal bone fracture: a. Concussion of the inner ear b. Concomitant secondary neural degeneration 5) VIIIth nerve injury from commercial and sports diving 10. Infection: a. Blood borne infection: 1) Reaches the inner ear by invasion of the endolymphatic system 2) Meningoencephalitis: a) Invasion along the nerves and vessels of the internal auditory meatus 3) Streptococcus pneumonia, meningococcus and haemophilus influenzae: a) Direct invasion of the labyrinth with subtotal destruction of sensory and neural elements b) Total vestibular destruction may cause oscillopsia if any vestibular function remains; central compensation occurs with no vestibular symptoms but profound hearing loss 4) Syphilitic labyrinthitis: a) Most common cause of hearing loss in syphilitic patient 5) Borrelia burgdorferi (Lyme’s): a) Cochlear and vestibular involvement 6) Petrositis (chronic middle ear infection): a) Gradenigo’s syndrome: otitis media, VI as it crosses the petrous bone; pain behind the ipsilateral eye (V nerve ganglia in Meckel’s cave). Vertigo and hearing loss due to erosion of the bony labyrinth or the VIIIth nerve in its bony canal. 7) Pseudomonas aeruginosa (malignant external otitis): a) Debilitated; severe diabetic or renal failure patients b) Invades the junction of the cartilaginous and osseous portion of the external auditory canal to invade adjacent bones
Viral Infection
1. Viruses may damage the cochlea greater than the VIIIth nerve 2. Also, meningoencephalitis directly invades along the nerves and blood vessels (Herpes Zoster and mumps) a. Ramsay Hunt: 1) Deep burning ear pain 2) Several days after onset: vesicular eruption of the external auditory canal and cochlea
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SECTION V. Cranial Nerves
3) Concomitantly or 1–2 days following vesicular rash, hearing loss and vertigo occurs; may involve the VIIIth nerve directly 3. Infection of Scarpa’s ganglia demonstrated with HS, rubella and reovirus 4. Vestibular neuronitis: a. Affects patients who are: 1) 30–60 years of age 2) Sudden vertigo involving one ear that lasts for 1–3 weeks 3) Nystagmus is opposite the involved ear 4) No hearing loss; no associated neurologic signs 5) Recovery in many months; may recur 6) Superior and ampullary branches of the vestibular nerve are involved; normal cochlea
Disorders of the Temporal Bone
1. Otosclerosis: a. Disease of the bony labyrinth b. Immobilization of the stapes c. Compression by otosclerotic foci of cochlear neural elements 2. Paget’s disease: a. Hearing loss is usually bilateral b. Sensorineural deficit; may have conductive deficit c. Vestibular symptoms usually progressive, but may be episodic 3. Fibrous dysplasia: a. Compression of the VIIIth nerve 4. Osteopetrosis: a. VIIth and VIIIth nerve compression may be early symptoms b. Conductive defect: 1) Narrowing of the external auditory meatus 2) Encroachment of bones of the middle ear on the ossicles c. Sensorineural deficit (compression of the cochlear nerve in the IAC) 5. Recessive osteosclerosis (Van Buchem syndrome or hyperostosis corticalis generalisata): a. Hyperostosis; skull, ribs, clavicle, long bones and pelvis b. VII and VIII nerve palsy in 50% of patients c. Encroachment of bone in the neural foramina 6. Hyperostosis cranialis interna: a. Hyperostosis and osteosclerosis of the calvaria and base of the skull (only) b. AD inheritance c. Recurrent VII nerve palsy, decreased vision, hearing and vestibular function d. Cranial nerve foraminal encroachment
Chapter 9 Cranial Nerve IX
Anatomy
1. Emerges dorsal to the inferior olive in close relation to X and XI (spinal accessory nerve; distal or within the jugular foramen nerves widen to form the superior and inferior petrous ganglion) 2. Upper neck: IXth is between the ICA and jugular vein (anterior to Xth nerve) 3. Innervates: stylopharyngeus (elevates the pharynx; occasionally innervates the superior constrictor (rather than vagus). Innervates the cricopharyngeus muscle (external pharyngeal sphincter) 4. Parasympathetic fibers: origin inferior salivary nucleus (near superior pole of X); leaves the nerve at the petrous ganglion; travels with the tympanic nerve (petrous bone) and superficial petrosal nerve to the otic ganglion. Post ganglionic fibers travel with the auriculotemporal branch of V to innervate the parotid gland 5. Sensory fibers: afferents from posterior 1/3 of tongue, tonsils, nasopharynx, inferior surface of soft palate, uvula, eustachian tube, tympanic cavity; small area in front of the tragus and small part of anterior wall of external auditory meatus 6. Taste: posterior: 1/3 of the tongue; cell bodies are in the petrous ganglion, terminate in the nucleus tractus solitarius 7. Carotid sinus nerve: a. Afferents of chemoreceptors of carotid body b. Baroreceptors of carotid sinus wall c. Project to the nucleus of the tractus solitarius
Clinical Aspects of IX Nerve Lesions
1. Involved with vagus nerve: a. Taste involved posterior 1/3 of tongue b. Decreased gag reflex c. Decreased salivary secretion from the parotid gland d. Transient hypertension after bilateral surgical section e. Bonner syndrome (intramedullary involvement): 1) VIII, IX, X involvement 2) Vertigo dysphagia, dysarthria 3) Contralateral hemiplegia 4) IX nerve involvement 5) Syringobulbia, stroke, tumor, inflammatory f. Paroxysmal lacrimation (Bogorad syndrome): 1) Abnormal lacrimation, normal production of saliva 2) Following middle ear surgery; the lesser superficial petrosal nerve to the parotid is damaged
Chapter 9. Cranial Nerve IX
3) Aberrant innervation from the parasympathetic fibers (from otic ganglion) now innervate the lacrimal gland; also seen in Bell’s palsy with lesions proximal to geniculate ganglion (preganglionic fibers to lacrimal, nasal, palate, pharyngeal, submandibular and sublingual glands travel conjointly) 4) Sphenopalatine ganglion-postganglionic parasympathic supply to the lacrimal gland
Glossopharyngeal Neuralgia
1. Idiopathic or secondary to structural lesion 2. Males and females have equal incidence; onset 40–60 years of age 3. Stabbing unilateral pain 4. Pain radiates to the base of the tongue; faucial (tonsils); may radiate into X sensory area; in or behind the external auditory meatus; beneath the angle of the jaw 5. Trigeminal and glossopharyngeal neuralgia may occur concurrently 6. Hacking cough may accompany the paroxysms of pain 7. Triggers: swallowing, talking, pressure on the tragus or auricle, sneezing, coughing, moving the head 8. Associated: salivation, flushing, sweating, tinnitus, lacrimation, tachycardia, hypertension and vertigo; rare seizures or cardiac asystole (cardio depressor nerve) 9. Bradycardia and syncope: afferent impulses to brainstem vasomotor center that excite X; pacemaker prevents bradycardia but not a fall in blood pressure; therefore syncope still occurs. 10. Pain occurs 2–3× per year; lasts a few minutes or occurs over several days 11. Differential diagnosis: a. Occlusion of the ICA b. Elongation of stylomastoid process c. Tumors of the posterior fossa (25%) d. Tortuosity of PICA (pressure on the nerve) e. Local infection f. Neck trauma
Carotid Sinus Hypersensitivity
1. General features: a. Syncope with head and neck movement b. Tight collar c. Stretching the neck d. Response to carotid massage: 1) Decrease of heart rate of 50% 2) Asystole greater than three seconds 3) A fall in blood pressure of 50 mmHg e. Cardioinhibitory form: decrease of heart rate f. Mixed form: heart rate is maintained in the face of decreased blood pressure g. Vasodepressor form; hypotension alone
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Differential Diagnosis of IX Nerve Syncope
1. 2. 3. 4. 5. 6. 7. 8. 9.
Digoxin B-adrenergic blockers Biliary disease (high bilirubin depresses SA and AV node) Elderly patients (atherosclerosis) Takayasu’s disease Carotid body tumor (chromaffin) Tumor infiltration around the sinus Post carotid endarterectomy Elicitation of cardiodepressor reflex: ventricular fibrillation has occurred; R > L side
Vascular Disease
1. Wallenberg’s syndrome (PICA) 2. Cavernous hemangioma, AVM, telangiectasia, hemorrhage 3. Aberrant vertebral artery or PICA with nerve compression 4. Bonner’s syndrome
Tumors of the IXth Nerve
1. 2. 3. 4. 5. 6.
Glomus jugulare Schwannoma Meningioma Chordoma Metastatic disease Jugular foramen syndrome (Vernet) IX, X, XI are affected
Peripheral Nerve/Neuromuscular Junction
1. 2. 3. 4.
Diphtheria AIDP CIDP Meningeal involvement (infection, tumor, pachymeningitis) 5. Tabes dorsalis (carotid and baroreceptor dysfunction) 6. Hencken’s syndrome: loss of taste posterior 1/3 of the tongue and pharynx 7. Lesions within the retropharyngeal or retroparotid space: a. Nasopharyngeal cancer b. Abscesses c. Adenopathy d. Aneurysms e. Trauma (birth injury) f. Surgical procedures (head and neck carcinoma) g. Carotid endarterectomy h. Pure glossopharyngeal syndrome: 1) Minimal dysphagia 2) Depressed gag reflex 3) Ipsilateral palatal weakness
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4) Loss of taste of the posterior 1/3 of the tongue 5) IX sensory distribution loss i. Associated syndromes: 1) Collet–Sicard: IX, X, XI, XII 2) Villaret’s: IX, X, XI, XII sympathetic chain, occasionally VI j. Basilar skull fracture k. Bogorad syndrome: crocodile tears from aberrant regeneration of lesser superficial petrosal nerve
Chapter 10 Cranial Nerve X
1. Anatomy: a. Dural sheath with XI in the jugular foramen (pars venosum) b. Inferior to jugular foramen (or within it): 1) Jugular ganglia (general somatic afferent) 2) Nodose ganglia (special and general visceral afferents) c. Between the two ganglia: 1) Auricular ramus (Nerve of Arnold) branches to innervate the concha of the external ear 2) Meningeal ramus: posterior fossa dura 3) Pharyngeal ramus: forms the pharyngeal plexus with IX; innervates the muscles of the pharynx and soft palate (except stylopharyngeus IX) and tensor veli palatine (V) 4) Superior laryngeal nerve arises from the vagus near the nodose ganglia: a) External motor branch: cricothyroid muscle b) Internal ramus: sensory fibers to the larynx 5) Neck: carotid sheath with internal carotid artery and internal jugular vein: a) Cardiac rami: to the cardiac plexus b) Recurrent laryngeal nerve: (1) Right side ascends in the tracheoesophageal sulcus (2) Left recurrent laryngeal: beneath the aortic arch to tracheoesophageal sulcus (3) Recurrent laryngeal nerves divide into anterior and posterior rami which supply all muscles to the larynx except cricothyroid 6) Dorsal motor nucleus of the vagus: motor nerves; preganglionic parasympathetic fibers to pharynx, trachea, bronchi, lungs, heart, stomach, small intestine, ascending and transverse colon, liver and pancreas 7) Nucleus ambiguous: all striated musculature of soft palate, pharynx and larynx (except stylopharyngeus IX; tensor veli palatini V
8) Nodose ganglia: taste from epiglottis, hard and soft palate, pharynx, and projects to the nucleus tractus solitarius (NTS) 9) General visceral sensation: oropharynx larynx, lining of thorax and abdominal viscera; cells of origin in the nodose ganglia and project to NTS 10) Exteroceptive sensation from concha: vagus to jugular ganglion to descending tract of V 11) Ipsilateral vocal cord in cadaveric position with Xth nerve lesion (between abduction and adduction)
Lesions of X
1. Supranuclear lesion: a. Cortical representation is at the foot of the precentral gyrus b. Solitary unilateral palatal weakness with lesion in the corona radiata with no associated limb weakness c. Bilateral upper motor lesions result in pseudo bulbar palsy 2. Pseudo-bulbar palsy: a. Emotional incontinence b. Increased gag reflex (rarely decreased) c. Dysphagia d. Pathologic laughter and crying e. Spastic tongue f. Explosive spastic dysarthria g. Gag reflex: may be associated with retching and vomiting h. Associated extremity spasticity 3. Medullary lesions: a. Wallenberg’s b. Syringobulbia c. Motor neuron disease d. Inflammatory disease (demyelinating) e. Primary and metastatic tumors 4. Rostral part of N ambiguous injured: a. Palatal pharyngeal paralysis of Avellis b. Larynx spared 5. Posterior fossa lesions affecting X: a. Glomus jugulare tumor c. Meningioma b. Metastatic disease d. Chordoma 6. Miscellaneous: a. Carcinomatosis of the meninges b. Idiopathic pachymeningitis c. Leukemia/lymphoma d. Sarcoidosis e. AIDP f. Trauma g. EBV h. CMT-4C
Chapter 10. Cranial Nerve X Syndromes
1. 2. 3. 4. 5.
6.
7.
8.
9.
Jugular foramen: (Vernet) IX, X, XI Schmidt: X, XI (venous component) Hughlings’ Jackson: X, XI, XII Collet–Sicard: IX, X, XI, XII Vagal nerve lesions (trunk): a. Neck or thorax b. Ipsilateral vocal cord paralysis; unilateral laryngeal anesthesia c. Differential diagnosis: 1) Tumor (lung most common) 2) Aneurysm internal carotid artery 3) Trauma 4) Enlarged lymph node Superior laryngeal nerve: a. Primarily a sensory branch; cricothyroid muscle weakness with minimal hoarseness and hypophonia b. Surgery, trauma, tumor Recurrent laryngeal nerve: a. Left damage > right (longer nerve) b. Unilateral paralysis: 1) Transient hoarseness 2) Flaccid dysphonia: harshness and breathiness, decreased volume, mid inhalation stridor 3) Palate pharyngeal function normal 4) Diplophonia: two pitch levels produced by unequal frequency of vibration between the two vocal cords 5) Semon’s law: a) Abductor muscles of larynx affected first with peripheral nerve injury c. Differential diagnosis: 1) 25% cause unknown 2) Aneurysms of aortic arch or subclavian artery 3) Enlarged tracheobronchial lymph nodes 4) Mediastinal tumor 5) Thyroidectomy 6) Cancer extending behind the carotid sheath at C6 level: combination of recurrent laryngeal, phrenic, vagal, preganglionic sympathetic (Rowland-Payne Syndrome) Bilateral recurrent laryngeal nerve: a. Thyroidectomy b. Carcinoma of thyroid c. Carcinoma of esophagus d. AIDP (descending form) e. Bilateral abductor paralysis (cord lies midline or near midline): 1) Approximation of the vocal cords 2) Weak voice that is clear 3) Inspiratory stridor 4) Dyspnea on exertion Bilateral lesions affecting the superior laryngeal nerve: a. Damage above the nodose ganglion b. Associated palatal and pharyngeal paralysis
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c. Vocal cords in the cadaveric position d. Phonation severely compromised e. Vocal pitch cannot be changed
Vagal Autonomic Functional Deficits
A. Esophageal, gastric and intestinal motility: 1. Esophageal motility: a. With denervation hypersensitivity to cholinomimetic drugs; primary action at the smooth muscle in the lower third of the esophagus b. Achalasia: cholinergic medicines cause uncoordinated and painful contraction of the esophagus 2. Gastric mobility: a. Gastroparesis (diabetes, amyloid) b. Hyperactivity (gastrojejunostomy and pyloroplasty; increased gastric emptying may cause early dumping syndrome (postprandial weakness, light headedness, flushing, sweating, palpitations, tachycardia); later dumping syndrome (insulin release with sugar ingestion; reactive hypoglycemia; diarrhea may be associated) 3. Intestinal motility: a. Measured by evaluation of myenteric migrating complexes (MMC’s) b. Absent MMC: neuropathy or intestinal muscle impairment 4. Pancreatic polypeptide release (depends on the vagus): a. Increased levels with hypoglycemia b. Measure of abdominal vagal activity c. Autonomic failure with vagal denervation (diminished levels of pancreatic polypeptides with hypoglycemia occur) d. Vagovagal syncope increases pancreatic peptide levels
Vagal Efferent Dysfunction
A. Cardiac: 1. Neural control of heart rate is primarily vagal 2. Blocked vagus: heart rate 100–110 beats per minute 3. Diminished cardiac vagal tone: a. Multiple system atrophy; degeneration of the vagal nuclei b. Primary autonomic failure; peripheral vagal nerve degeneration c. Diabetic autonomic failure; heart rate is initially high and then falls 4. Chronic autonomic failure: a. Decreased HR response to hyperventilation b. Similar response in polyneuropathies and autonomic failure secondary to alcohol 5. Vagal dysfunction earlier than sympathetic loss:
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SECTION V. Cranial Nerves
a. Alcoholism b. Non-alcoholic liver disease c. Cardiac transplantees’ d. Ocular hypertension e. Severe obesity B. Impaired vagal innervation of the GI tract: 1. Primary autonomic failure: a. Decreased gastric emptying b. Impaired pancreatic polypeptide response to hypoglycemia 2. Diabetic neuropathy: a. Peripheral vagal degeneration b. Gastric dilation with reduced peristalsis and delayed emptying c. Nocturnal watery diarrhea 3. Gastrointestinal atrophy with botulism 4. Pure cholinergic dysautonomia (putative immune basis) 5. Destruction of intrinsic gut plexuses: a. Achalasia (esophageal sphincter degenerates and fails to relax) b. Chagas disease (cellular immune response: antiparasympathetic neuronal IgG) C. Vagal nerve hyperactivity: 1. Emotional syncope (vagovagal): a. Sight or thought of specific stimulus b. Brachycardia c. Loss of consciousness 2. Oculocardiac reflex 3. Vagal reflexes augmented by drugs and anesthetics 4. Glossopharyngeal neuralgia (some sensory radiations into X territory) 5. Swallow syncope (Charcot’s) 6. Carotid sinus hypersensitivity 7. Plural aspiration 8. Increased vagal activity with high cervical cord lesions: a. Hypoxia b. Pulmonary emboli c. Acidemia d. Decreased cardiac sympathetic tone (cord lesion) e. Paralysis of respiration (decreased activation of the pulmonary stretch reflex which inhibits the vagus) f. Tracheal intubation in quadriplegics g. Volatile substance abuse (enhances vagal activity) h. Hyperactive diving reflex
c. May occur with: neck operations, thoracotomy or T2 sympathetectomy d. Gustatory piloerection may be associated with sweating; aberrant innervation of the sympathetic ganglia e. Gustatory sweating in diabetics in the territory of the superior cervical ganglia
Vagal Afferent Dysfunction
1. Cough Reflex: a. Supplies sensation to the mucous membrane of the larynx and the tracheobronchial tree b. Afferent limb of the cough reflex c. Bilateral lesions cause aspiration d. Stimulation of trachea and larynx in tetanus causes severe hypertension (sympathetic overactivity; hypotension and bradycardia in tetraplegics) 2. Superior laryngeal neuralgia: a. Paroxysmal lancinating pain b. Radiation from the side of the thyroid cartilage to the angle of the jaw; occasionally to the ear c. Trigger: pressure over the skin that overlies the thyrohyoid membrane 3. Pulmonary Vagal Afferents: a. Pulmonary stretch receptors increase activity with inspiration b. Receptors in the chest wall for stretch are more active than pulmonary afferents c. Vagal lung irritant receptors: respond to irritants, over or underinflation, emboli or congestion (neuropeptide P mediated) 4. Cardiac Receptors: a. Activation of cardiac vagal afferents in the ventricle substance P (SP) mechanoreceptors: induce bradycardia, hypotension and syncope b. Stimulated by forceful contraction: 1) Aortic stenosis 2) Tilt table 3) Coronary arteriography (bradycardia and hypotension)
Vascular Lesions Affecting the Xth Nerve Aberrant Regeneration of IX and X
1. Gustatory sweating: a. Excessive sweating during eating b. Damage to lesser superficial petrosal nerve (aberrant postganglionic sympathetic nerves in auriculotemporal distribution; Frey’s syndrome)
1. Wallenberg’s syndrome (N ambiguous) 2. Hemorrhage: hypertension (rare females 3rd decade of life Perhaps 20% of Xth nerve lesions Left side more frequently affected than the right Unilateral recurrent laryngeal nerve palsy: a. Twice as common as that seen in combination with superior laryngeal nerve b. DM c. Idiopathic d. Infection
Chapter 11 Cranial Nerve XI 1. Anatomy: a. Purely motor nerve b. Cranial portion: caudal part of N. ambiguus; spinal portion: (accessory nucleus C1–C5) of the ventral horn: 1) C1–C2 innervates the ipsilateral SCM muscle 2) C3–C4 innervates the ipsilateral trapezius c. Cranial part of nerve (N. ambiguus) supplies the pharynx and larynx; the internal ramus d. External ramus: innervates SCM and trapezius; receives branches from C2, C3, C4 (anterior roots) e. Corticobulbar fibers to the trapezius are primarily crossed; to the SCM muscle ipsilateral termination; possible that there is a decussation to the opposite pons and then a decussation back to terminate on the side of origin (ipsilateral hemisphere), the second decussation occurs at C1 of the cord
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SECTION V. Cranial Nerves
f. Sternal head of SCM may receive bilateral cortical innervation (ipsi > contralateral) and double decussation (pons/cervical cord); clavicular head (tilts the head ipsilaterally) g. Corticobulbar innervation to the SCM is located dorsally in the brainstem tegmentum; fibers to the trapezius are located in the ventral brainstem 2. Trapezius muscle: a. Retracts the head b. Raises the abducted arm above the horizontal 3. Bilateral SCM weakness; weakness of neck flexors; head falls backward 4. Unilateral trapezius weakness (accessory nerve lesion); upper trapezius fibers (lower fibers supplied by cervical plexus): a. There is a lower shoulder on the affected side b. The scapula is displaced down and laterally c. Paresis of shoulder elevation and retraction; cannot raise the arm above horizontal after it has been abducted (supraspinatus and deltoid) d. Bilateral trapezius weakness; weakness of neck extension Anatomical Syndromes of XI
1. Weakness of the SCM or trapezius: a. Lesions of accessory nerve distal to its bifurcation 2. SCM and trapezius weakness same side: a. Contralateral brainstem lesion b. Ipsilateral high cervical cord lesion (interrupts second decussation from the pons) c. Proximal accessory nerve lesion 3. SCM weakness with spared trapezius: a. Lesion of dorsal brainstem tegmentum (SCM represented dorsally in the tegmentum) b. Lesion of upper cervical accessory roots (lower cervical roots innervates the trapezius)
Lesions Within the Neck
1. 2. 3. 4. 5. 6. 7. 8. 9.
10. 11.
Posterior triangle surgery (lymph node biopsy) Internal jugular vein catheterization Blunt trauma to the shoulder Radiation therapy Dislocation of the shoulder X-RT (myokymia; hypertrophy) Brachial plexus traction injury with associated cervical plexus injury Partial hanging (suicide attempt) Posterior triangle injury (primarily occurs with lymph node biopsy for lymphoma; causes isolated trapezius weakness Aberrant vessel (cervical dystonia); pressure on the nerve Cervical cord trauma
Differential Diagnosis of Neck Extensor Weakness
1. 2. 3. 4. 5. 6. 7.
MG Motor neuron disease (MND); dropped head Polymyositis Dermatomyositis Inclusion body myositis FSH dystrophy Congenital absence SCM (flexor weakness)
Tumors
1. 2. 3. 4. 5. 6. 7.
Meningioma Schwannoma Chordoma (at jugular foramen) Glomus jugulare Base of the skull metastases Cervical syrinx with astrocytoma Hemangioblastoma with cervical syrinx
Nuclear Lesions of XI
1. Atrophy and fasciculations of affected SCM and trapezius muscles 2. Intraparenchymal tumor (astrocytoma, metastases) 3. AVM or cavernous hemangioma 4. Syringobulbia Peripheral Lesion (within Skull and Foramen Magnum)
1. Syndromic associations: a. Vernet’s (jugular foramen); tumor, fracture, infection b. Schmidt’s X, XI c. Collet-Sicard IX, X, XI, XII (retroparotid or retropharyngeal space) d. Garcin: all cranial nerve on one side (tumor); following chemotherapy; diabetes
Chapter 12 Cranial Nerve XII Anatomy
1. Nucleus extends from the caudal medulla to the pontomedullary junction 2. Two discrete nerve bundles intracranially; unite after emergence through the hypoglossal canal 3. Passes over the internal and external carotid artery; lies beneath the digastric, stylohyoid and mylohyoid muscles 4. Muscular or lingual branches supply the intrinsic tongue muscles and the hypoglossus, styloglossus, genioglossus, geniohyoid (extrinsic muscles)
Chapter 12. Cranial Nerve XII
5. Descending hypoglossal ramus: forms the ansa hypoglossi in the neck: a. Fibers from C1–C3 cervical roots (associated) b. Innervate infrahyoid muscles: sternohyoid, omohyoid, sternothyroid, thyrohyoid and geniohyoid 6. Corticobulbar fiber controlling the genioglossus are crossed; other tongue muscle bilateral supranuclear control 7. Lateral movements of non protruded tongue are performed by intrinsic muscles therefore patient cannot turn tip of the tongue to affected side.
4. 5. 6. 7. 8. 9. 10.
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Squamous cell (base of the tongue) Metastatic (bronchial, thyroid, esophageal) Lymphoma (Hodgkin/non-Hodgkin) Leukemia Schwannoma Meningioma (foramen magnum) Occipital condylar syndrome: a. Metastasis to posterior occipital condyle b. Ipsilateral XIIth nerve involvement c. Mediastinal tumor
Anterior Horn Cell/NMJ/Nerve Involving the XII Nerve Vascular Disease Affecting XII
1. Medial medullary syndrome (Dejerine’s): a. Infarction of the vertebral or anterior spinal artery b. Ipsilateral XII paresis (atrophy and fasciculations) c. Contralateral hemiplegia d. Contralateral loss of lemniscal sensation (proprioception and vibration) e. May occur bilaterally (quadriplegia with facial sparing), bilateral lower motor neuron tongue paralysis, loss of lemniscal sensation of all extremities f. Tongue may occasionally be spared in anterior spinal artery syndrome 2. Rare XII nerve involvement with ectasia from hypertension, AVM, cavernous hemangioma or telangiectasia 3. Carotid artery dissection with pseudoaneurysm and compression 4. Dolichoectasia of the vertebral artery in the medulla
1. 2. 3. 4. 5. 6. 7. 8. 9.
MND MG Eaton–Lambert Diphtheria AIDP CIDP EBV (infectious, mononucleosis) X-RT Machado–Joseph Disease (SCA); facial lingual fasciculations
Intraparenchymal Lesions Involving the XII Nerve
1. Syrinx (syringobulbia) 3. Demyelinating disease (rare) 2. Tumor
Abnormal Tongue Movements Trauma
1. Fracture through the hypoglossal canal or foramen magnum 2. Head injury (blunt) 3. Penetrating head and neck wounds (knife, bullet, ensuing carotid fistula and pseudoaneurysm with nerve involvement) 4. Dental operative procedures; extractions 5. Subluxation of odontoid process (rheumatoid arthritis, connective tissue disease, tear of the alar and cruciate ligaments) 6. Surgical trauma (particularly carotid endarterectomy) 7. Numb tongue-neck syndrome (cervical plexus; intrinsic proprioceptive fibers in the nerve)
Tumors Involving the XII Nerve
1. Retroparotid tumors 2. Retropharyngeal tumors 3. Salivary gland (adenocarcinoma; mixed)
1. 2. 3. 4. 5.
Oral buccal lingual dyskinesia Athetosis Palatal myoclonus Trombone tongue (choreiform movements; syphilis) Galloping tongue: a. Episodic b. Rhythmic c. Involuntary d. May spread to head and neck e. Three per second waves f. Starts posteriorly in the midline g. Focal tongue contraction h. Putative pontine lesion 6. Continuous lingual myoclonus after head injury
Glossodynia
1. Burning pain of tongue and oral mucosa 2. Middle aged and elderly patients 3. B vitamin deficiency (putative)
SECTION V. Cranial Nerves
316 Macroglossia
1. Cerebral gigantism 4. Acromegaly 2. Syndromic 5. Hypothyroidism 3. Primary amyloidosis 6. Mucopolysaccharidosis
Chapter 13 Multiple Cranial Neuropathy 1. Neuromuscular Junction Disease: a. MG d. Botulism (toxin) b. c. Tetanus 2. Autoimmune cranial neuropathies: a. AIDP b. CIDP c. Bell’s palsy (putative) d. CM Fisher variant (Gd1b; GQ1b epitopes) e. Descending AIDP (Munsat’s variant; cervical-pharyngeal variant) f. Acute oropharyngeal GBS (GT1a epitope) 3. Tumor: a. Carcinomatosis of the meninges b. Leukemia c. Lymphoma (Hodgkin/non-Hodgkin) d. Garcin’s syndrome (base of the skull metastatic) e. Nasopharyngeal cancer f. Adenocystic carcinoma of the salivary gland g. Cylindroma of the parotid gland h. Chromophobe adenoma (pituitary apoplexy) i. Glomus jugulare or tympanicum j. Melanoma (metastatic to cranial nerves) k. Pinealoma (CSF pathways to cranial nerves) l. Cerebellopontine angle mass or tumor (compression) m. Retroparotid or retropharyngeal tumors (IX, X, XI, XII) n. Mucoepidermoid cancers
4. Vascular disease (peripheral supply): a. Intraparenchymal (syndrome) b. Inferolateral branch of the external carotid (III, IV, VI) c. Ascending pharyngeal artery – IX, X, XI (arch of the aorta) d. Internal maxillary artery – V, VII (branches) e. Carotid dissection in the neck – IX, X, XII f. Isolateral angiitis of the external carotid 5. Chemotherapy: a. Internal carotid artery cis platinum (III–VI) b. External carotid artery cis platinum (VII, XII) c. Gracin’s syndrome (with diabetes, cancer in conjunction with chemotherapy; all cranial nerves are one side) d. Vincristine/vinblastine-sympathetic and parasympathetic supply of the cranial nerves 6. Infectious Disease: a. Myobacterium pneumonia b. Rochalimaea henselae (cat scratch fever) c. Tuberculosis d. Deep fungi (histoplasmosis, cryptococcus, microcytosis, Coccidiomycosis) e. Cysticercosis f. Chagas disease (trypanosoma cruzi) g. Syphilis h. Lyme’s disease (Borrelia burgdorferi) i. Pseudomonas aerogenesis (malignant extend otitis) 7. Bone disease (foraminal exit compression): a. Paget’s b. Osteogenesis imperfecta c. Hyperostosis osteosclerosis of the calvarium d. South African sclerostenosis e. Congenitally small posterior fossa and internal auditory canal f. Fibrous dysplasia 8. Systemic disease: a. Familial primary amyloidosis b. Tolosa Hunt syndrome (cavernous sinus); III, IV, VI c. Diabetes mellitus
Section VI RADICULOPATHY
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Chapter 1. Introduction
Chapter 1 Introduction A. General features: 1. Contents of the neural foramina are the spinal nerve roots, recurrent meningeal nerves and radicular blood vessels. The anatomical boundaries are the pedicles inferiorly and superiorly, anteriorly the intervertebral disc and vertebral body and posteriorly by the facet joint. The superior and inferior facet of the joints are lined by synovium. The dorsal root ganglia (DRG) may compress roots at higher levels as they can be more intraspinal. 2. The blood supply to a spinal nerve root derives from the corresponding radicular artery. At the root entry zone, blood vessels lie on the surface of rootlets and in interradicular spaces capillary density is high in the ventral root entry zone. 3. Facet joints are innervated by branches of the posterior primary ramus of the spinal nerve root 4. The posterior longitudinal ligament which overlies the disk has nociceptive innervation 5. Disc contents illicit an inflammatory response in surrounding tissue that induces the production of IL-1, IL6 and tumor necrosis factor α(alpha) TNFα. The later has been shown to directly depolarize nociceptive C-fiber and A-delta afferents. 6. The outer annulus of a disc may have nociceptive innervation and may be able to refer pain. 7. Dorsal ganglia have a less tight blood nerve barrier than the roots or axons Radicular pain is elicited from depolarization of A-delta afferents (1-4u). It is characterized as lancinating and is well localized. It may be followed by a deep aching pain with a burning quality which is mediated by 1μ C-fibers. Sympathetic discharge elicited by somatic sympathetic reflexes may amplify and drive this pain in chronic conditions. The usual radicular pain radiates within a specific dermatome. It may be appreciated in only one part of the anatomical confines of the dermatome. Thus an L5 root may be felt just or predominately in the lateral thigh or great toe and not the lower back. The pain is usually increased by mechanical maneuvers that increase intraspinal pressure or stretch the nerve root. The nervi nervorum of the nerve sheath, is sensitized so that a mechanical rather than tissue destructive stimulus will depolarize the nociceptors of the nerve sheath and the radicle itself (basis for the straight leg raising test and other provocative stretch maneuvers). There is segregation of spinal root afferents at the dorsal root entry zone (DREZ). Medial dorsal root fibers carry proprioception vibration and light touch. Lateral dorsal root fibers (closest to the dorsolateral extrusion area of the discs) carry lancinating pain (A-delta fiber mediated), cold (A-delta
319
fiber), temperature and burning pain (C-fiber). Lesions affecting the dorsal root entry zone are in general painful. Lesions peripheral to the DRG in the neuronal exit foramina cause numbness. Lesions of the medial branch of the posterior primary division are associated with numbness and paraesthesias 1½ inches laterally from the spinous process. Meningeal branches innervate the dura at that level. These are the recurrent branches of Spurling. The L5 branch is particularly relevant as it refers sensations to the top of the thigh (often mistaken for L1, L2, L3 patterns). Ventral root lesions causes segmental weakness. If axons are severed, there will be associated atrophy and fasciculation. Early with compressive or irritative lesions, reflexes may be enhanced. This has been posited to be caused by differential susceptibility of inhibitory afferents in the ventral root. In the lower extremity the examiner must always be aware of higher compressive or intrinsic spinal cord lesions that may disinhibit the corticospinal tract and increase reflexes below the lesion level.
Dorsal Root Entry Zone
1. Medial dorsal root fibers carry proprioception, vibration, light touch and tap 2. Lateral dorsal root fibers carry lancinating pain (A-delta), cold (A-delta; 1-4 u), temperature (heat; C-fibers) 3. Clinically: a. Lesions affecting the dorsal root entry zone (DREZ) are painful b. Lesions peripheral to the DRG cause numbness 4. Lesions of the medial branch of the posterior primary division; numbness, paresthesias and pain 1.5 inches from spinal process laterally 5. Meningeal branches (dural innervation of the meninges) a. Recurrent nerves of Spurling occur at each level b. Particularly relevant at L5 (referred sensation to the top of the thigh)
Ventral Root Lesions
1. 2. 3. 4.
Dermatomal or segmental weakness Atrophy Fasciculation of involved muscle groups Absent or depressed segmental reflexes: a. Early with compressive or irritative lesion; the reflexes may be enhanced; then it is lost with further pathology (pressure or destruction) b. Reflexes may be increased with spinal cord disinhibition (B12; compressive higher lesions such as spinal stenosis) c. There are putative inhibitory afferents in the ventral horn
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SECTION VI. RADICULOPATHY
Spinal Nerves and Roots
A. Anatomy of a Spinal nerve 1. Posterior primary rami of a spinal nerve: a. Supplies the skin of the dorsal trunk b. Innervates the longitudinal muscles of the axial skeleton 2. Anterior primary rami: a. Motor innervation of the limbs b. Non-axial skeletal muscles c. Skin of the lateral and anterior trunk and neck (lateral cutaneous and anterior cutaneous branches) d. Communicate with the sympathetic ganglion by way of white and grey rami communicantes 3. Dorsal root irritative lesions: a. Radicular pain b. A-delta fibers c. Lancinating, sharp, well localized d. Abrupt in onset e. Radiates to a specific dermatome f. Increased by mechanical maneuvers that increase intra spinal pressure or stretch the nerve (if it is sensitized it is mechanosensitivity; fires to a mechanical rather than a nociceptive stimulus) g. Pain may be the first symptom of a sensory radiculopathy; often intermixed with deep ache or paresthesia 4. Destructive dorsal root lesion: a. Hypesthesia of a core region supplied by that root b. Overlap of adjacent roots; therefore, little sensory loss c. Multiple root involvement; area of analgesia larger than anesthesia d. CRPS I/II; the area of involvement does not respect the affected dermatome; it is extraterritorial e. Loss of motor function in involved myotome; atrophy f. Reflex loss in involved myotome is usual; the following exceptions occur: 1) Early lesions may increase reflex (loss of inhibition) 2) GBS (triceps spared) 3) Acute intermittent porphyrias (ALP and variegate porphyrin-ankle jerks spared) 4) B12 deficiency: may have hyperactive reflexes in face of peripheral muscle atrophy
Mechanical Degenerative Root Disease
A. Differential Diagnosis of Benign Processes 1. Herniated nucleus pulposus 2. Cervical and lumbar spondylosis 3. Spondylolysis (defect of pars interarticularis) 4. Spondylolisthesis (malalignment of vertebrae)
5. Osteophytes within the foraminal exit foramina 6. Lateral recess syndrome L5 (the longest exit foramina) 7. Degenerative facet disease with tropism (rotation of the inferior facet into the exit foramina) 8. Spinal stenosis (degenerative) 9. Synovial cyst of the facet joint
Chapter 2 Disc Disease Cervical Disc
A. General features: 1. A bulging disc extends beyond the margin of the end plate of the vertebral body but the annulus fibrosis is intact 2. A disc extrusion is an extension of the nucleus pulposus through the annulus; usually remains anterior to the posterior longitudinal ligament (rarely it extends through it). 3. A sequestered fragment is completely separated from the nucleus pulposus. This segment may migrate up or down the spinal cord. 4. Cervical spine roots exit horizontally from the cord to the neural foramina and entrap the root corresponding to the vertebral body directly below it. 5. The ventral and dorsal roots join distal to the DRG and form a spinal nerve; the dorsal ramus supplies the paraspinal muscles and is the cutaneous innervation of 1½–2 inches lateral to the spinous process; the ventral rami form the cervical and lumbar plexus 6. Posterolateral disc herniation often compresses the root that will exit one level below. The root at the level of the herniation has already exited. A far lateral disc may trap the root at the specific level. The exiting nerve root is lateral to the descending root. A posterior or large HNP may compress the cauda equina and compress many descending nerve roots. 7. Disc disease occurs at motion segments: 1) C4–C5; C5–C6; C6–C7 at cervical levels 2) L4–L5; L5–S1 at lumbar levels 8. Disc herniation may cause bilateral symptoms. The foraminal exit may be compressed (superiorly) as the disc desiccates, extends and does not maintain its normal height. The side with direct nerve root compression is affected to a much greater degree B. Clinical Presentation: 1. The pain emanates from the neck and radiates primarily to the spine and the shoulder. C4–C5 disease radiates to the cap of the shoulder. C5–C6 to the shoulder and biceps. C6–C7 to the spine medially and lateral forearm [C6 and posterior (triceps area, C7)]. Radia-
Chapter 2. Disc Disease
2.
3.
4.
5.
6.
7.
tion of cervical disc to the hand is rare (C6 thumb and index finger; C7 third finger; extremely rarely C8. Median nerve compression involves all fingers clinically. It should split the fourth finger (median nerve side medially). Ulnar nerve lesions at the cubital tunnel radiates pain to the last ½4th and complete 5th finger. The ulnar nerve has only a small innervation area; one inch above the wrist and the last two 4th/5th fingers. The lateral cord of the brachial plexus radiates pain to the thumb, index, and radial part of the third finger. Posterior interosseous nerve from the posterior cord and middle trunk of the brachial plexus is a pure motor nerve. The medial forearm radiations are primarily from the medial cord. Limitation of neck movement due to pain is common with disc disease; Spurling’s maneuver (extending and rotating the neck to the side of the lesion and then pressing it downward) may irritate the involved root. Neck extension induces posterior disc bulging and lateral flexions and rotation narrows the ipsilateral neural foramina. A position of comfort is for a patient with cervical radiculopathy to place the arm over the head which decompresses the nerve root sleeve. Thus maneuver severely exacerbates brachial plexus pain by stretching sensitized nerve roots. Valsalva maneuvers exacerbate the pain of disc disease by causing further protrusion. The C5 root radiates to the neck and cap of the shoulder; weakness is seen in shoulder abduction, external rotation, elbow flexion and forearm supination. There is depression of the biceps and brachioradialis reflex. The C6 root radiates pain to the neck, shoulder, lateral forearm and rarely the thumb and index finger. Strength is diminished similarly to C5 involvement but, there is added pronation weakness of the arm. The C7 radiates to neck, triceps, medial spine and rarely the long finger. Weakness is noted in elbow and wrist extension, forearm pronation and wrist flexion. The triceps reflex is depressed. The C8 root is rarely affected by disc disease as it is not a movement segment. Pain and paresthesias are noted in the medial forearm and fourth and fifth fingers. Weakness occurs in the muscles of the thenar eminence, most prominently thumb flexion. There is concomitant weakness of finger and wrist extension (ulnar side) distal finger flexion and minimal dorsal and volar interossei function. The finger flexion reflex is lost. The T1 root is rarely injured by disc disease as it is also not a motion segment. There is medial arm (usually T2) and forearm pain. Finger abduction and adduction and muscles of the hypothenar eminence are most severely involved. Rarely there is anterior chest wall pain. This is most often a reflection of sensitization of the intercostico-brachial nerve that derives from the medial cord of the brachial plexus. There is no reflex abnormality that can be elicited.
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If the ventral roots are primarily involved in root disease there is atrophy and wasting of the affected myotome to a greater degree than sensory loss. This is more characteristic of bony defects such as cervical spondylosis and osteophytes of the foramina. Fasciculations may be induced by movement or percussion of the affected myotome (rare) with severe ventral root compressions.
Clinical Features of Lumbar Disc Disease
1. L5–S1 greater than L4–L5 segments are the motion segments and are primarily involved. The L5 disc may be subject to the greatest intradiscal pressure with sitting and standing. L1–L3 root involvement suggests medical illness. 2. Compression of the affected interspace may be painful; there may be slight decrease of sensation in a 1½ inch cutaneous area from the spine laterally (cutaneous territory of the dorsal rami). 3. Mechanical stretch maneuvers are positive. The straight leg raising maneuver with concomitant Lasègue’s sign (extension of the ankle with the leg extended) elicits pain. The patient may have referred pain to all aspects of the sciatic distribution, but usually it is proximal in the posterior thigh and back. It may radiate pain to the great toe (L5) or the little toe (S1). Pain may be more prominent when the leg is lowered. Raising the normal leg may refer pain to the affected leg. 4. Tinel’s signs are positive over the nerve that carries the specific root; the sciatic nerve (L4–S2) is most frequently involved with disc disease. Tinel’s signs (mechanical pressure over the nerve elicits pain) are positive at the sciatic notch, in the posterior popliteal fossa and at the interspinous process at the affected level. 5. There is muscle tenderness of the muscles that are innervated by the specifically sensitized root. The disc compression more proximally has sensitized the deep poly modal C-fiber and A-delta nociceptors such that mechanical pressure rather than tissue destructive stimuli will depolarize them. 6. Pain radiations of L5-(usual): a. Interspace at L4–L5; L5 S1 b. Buttock c. Lateral thigh d. Posterior popliteal fossa e. Top of the foot f. Great toe Additional radiations of L5: a. Hip b. Top of the thigh: 1) Somatic referred pain from the innervation of the anterior disc capsule 2) Dura at L5; the innervation of the recurrent nerve of Spurling at that level
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SECTION VI. RADICULOPATHY
c. Scrotum d. Rarely the anterior lower abdominal wall 7. Painful radiation of S1: Usual: a. Interspace of L5–S1 in the back b. Buttock c. Posterior thigh; laterally S1; medially S2 d. Posterior popliteal fossa e. Heel and sole of the foot f. Little toe and lateral lower leg g. Calf Unusual pain radiations of S1: h. Groin i. Tip of the penis (rare) j. Ipsilateral vagina (rare) k. Anus (argument; some feel there is S5) 8. Pain radiations of L4: a. Inside the lower leg (saphenous nerve distribution) b. Band around the ankle Severe L4–L5; L5–S1 disc disease: c. Increased frequency of urination d. Slight decrease of bladder emptying (S1 root) e. Pain increased during menstruation (convergent innervation from the uterus, fallopian tubes and ovary to L5, S1. DRG (somatic-visceral convergence) 9. Exacerbating factors for the pain: a. Flexion and extension posture; sitting; driving a car b. Valsalva maneuvers c. Sleep (veins that overlie the root compress the sensitized root; patients awakens with back pain at 4–5 AM. Inability to lie down suggests intraparenchymal spinal cord tumor (patients sleep upright in a chair). Awakening slightly earlier at night suggests a subarachnoid cyst compressing the spinal cord d. Leg feels as if it will suddenly “give away” and will not support the body weight. Relieving Factors for L4–S1 Disc Disease
1. Rest; supine posture with flexed knees 2. Heat over the affected interspace 3. Some patients improve with exercise (heat may decrease conduction in sensitized nerve roots) Motor Weakness of L4–S1 radiculopathy of Disc Disease (Differential Diagnosis)
1. L4: weakness of the quadriceps, tibialis anterior and hip adductors; depressed knee jerk. Need to r/o lumbosacral plexopathy and femoral neuropathy. 2. L5: weakness of the anterior tibialis; extensor hallices longus; weakness of ankle inversion (absent in peroneal palsy). Weakness of the gluteus minimus and medius localizes the lesion proximal to the sciatic nerve, but L5 could still be a component of lumbosacral plexopathy.
3. S1: weakness is primarily of the gastrocnemius and soleus muscles > hamstrings and glutei. Gluteus maximus weakness localizes the lesions prior to the sciatic nerve. Deficient ankle jerk. Need to rule out lumbosacral plexopathy, tibial and sciatic neuropathy. 4. Lower sacral radiculopathy: a. Usually S2–S5 are involved concomitantly; often from central disc herniations b. Pain and sensory loss in the perineal area; usually asymmetric; “saddle anesthesia” c. Urinary and fecal incontinence d. Decreased sensation of the S1–S5 dermatomes in an unequal distribution e. Weakness of gluteal muscles with S1–S2 involvement; toe flexor weakness with S3 involvement; atrophy of EDB with S1–S2 lesions; soleus and gastrocnemius are weak if S1 is compressed f. Reduced or absent anal sphincter tone, decreased bulbocavernosus and anal wink reflexes with S1–S5 involvement.
High Lumbar Root
In general, the L1–L3 are not affected by disc disease as they are not motion segments. They are involved in diabetic plexopathy, ilioinguinal and genitofemoral nerve injury from surgical procedures (hernia, catheterization of the femoral artery), intra abdominal surgical procedures; lymphoma, retroperitoneal hematoma and autoimmune processes. L1 Root: Pain and paresthesias in the inguinal area; slight weakness of the iliopsoas (hip flexion). L2 Root: Anterolateral thigh pain and weakness of the iliopsoas muscle; differential diagnosis includes high lumbar plexopathy, neuralgia paraesthetica or femoral neuropathy. In general, femoral neuropathy is associated with quadriceps weakness and a decreased knee jerk. L3 Radiculopathy: Pain in the anterior thigh to the knee; iliopsoas and quadriceps weakness; a plexus lesion usually involves the hip adductor muscles (L3 root) and the obturator nerve. There is a depressed knee jerk. The distribution overlaps the projected pain from the recurrent nerve of the Spurling at L5 (dural radiation at this level). Diabetic amyotrophy (most often a lumbosacral plexopathy) frequently involves this root).
Cervical and Lumbar Spondylosis
A. General features of cervical spondylosis 1. Involves the disc, the uncovertebral and facet joints. 2. Age related changes occur in the annulus fibrosus and disc proteoglycan composition with desiccation and narrowing of the intervertebral space.
Chapter 2. Disc Disease
3. The marrow of the vertebral body undergoes fibrovascular changes and fatty replacement. This is often most evident at the end plates of the vertebra (eburnation). 4. Osteophyte formation occurs at the margins of the vertebral bodies and in the foramina. Osteophyte formation also occurs at the uncinate joint. 5. Facet joint degeneration occurs with widening of the synovial space and internal rotation into the foraminal exit canal. 6. Bony changes predominate at upper cervical levels and disc degeneration at C5–C6; C6–C7 the major motion segments. 7. At upper cervical levels (C4–C5 and C5–C6) the DRG’s may contribute to foraminal exit stenosis as they may be intraspinal. General Clinical Characteristics of Cervical Spondylosis
A. Clinical Presentation (cervical spondylosis) 1. Mechanical signs: a. Forward flexed neck (spondylitic posture) with restricted movement to all planes b. Proximal > distal weakness in the upper extremities; a C5–C6, C6–C7 disease c. Weakness and atrophy of deltoid cap, supraspinatus and rhomboids > biceps d. Trapezius ridge prominent; pain (C4–C6) C8–T1 innervated muscles are generally spared e. C5–C6 sensory loss rare; primarily a motor illness; fasciculations, reflex depression of C5–C6, C7 may be hyperactive f. Decreased biceps with increased triceps and finger flexion reflex. The inverted radial reflex is often present. There is concomitant spinal compression at C4–C5. Neural foraminal exit osteophyte. g. Poor tandem gait; compression of the dorsal and ventral spinocerebellar tracts which are lateral in the spinal cord. This occurs late in the course of the disease. h. Neurogenic bladder B. General Clinical Characteristics of Lumbar Spondylosis 1. Combination of degenerative disc disease (desiccation of the disc; hard disc) with foraminal exit arthritic changes (osteophytes) 2. Weakness, sensory loss, atrophy and decreased reflexes in the involved myotomes and dermatomes 3. Mechanical signs are prominent (positive straight leg raising test) 4. Almost always associated with lumbar spondylosis 5. May have increased KJ and AJ which are due to associated cervical stenosis Lumbar Spondylolysis
1. Fracture through or maldevelopment of the pars interarticularis of the posterior vertebral elements (usually at L4– L5; L5–S1)
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2. Asymptomatic unless there is spondylolisthesis (malalignment) 3. Jumping down or minimal trauma frequently displaces or breaks the malformed pars interarticularis 4. Minimal non-radiating back pain initially
Lumbar Spondylolisthesis
1. Spondylolysis from pars interarticularis disease initiates the process 2. Retrograde or antegrade movement of the superior vertebrae over the inferior one (or the reverse); lumbar pain radiating into sciatic nerve distributions 3. Congenital flat pelvis with typical stance (pelvis shifted forward) 4. Bilateral radicular pain exacerbated by standing or particular postures (high heeled shoes) 5. Often occurs in childhood and progresses through the teenage years 6. Dramatically positive mechanical signs; flexion and extension posture exacerbates the pain 7. Weakness and wasting of the affected myotome with associated reflex loss
Cervical Spondylolisthesis
1. Occurs frequently following trauma and may be in association with “jumped” (overriding facet joints) 2. Usual levels are C4–C5; C5–C6; C6–C7’s unusual to have process at higher cervical levels but it does occur 3. Severe pain in the neck with guarding and restriction of movement 4. Often there is bilateral a increase of reflexes at the appropriate level due to pain; if the root is compromised there is asymmetric loss of the specific segmental reflex
Cervical Stenosis
A. General features: 1. The confines of the cervical spinal canal are: a. Laminae and ligamentum flavum posterolaterally b. Pedicles anterolaterally c. Discs and vertebral bodies anteriorly 2. The dimensions of the cervical spinal canal at C1–C3 (16–30 mm); C4–C7 (14–23 mm) 3. Extension reduces the canal 2–3 mm B. Pathology of cervical canal stenosis: 1. Congenitally small canal 2. Disc herniation with concomitant facet and uncovertebral joint osteoarthritic overgrowth 3. Hypertrophy of the posterior longitudinal ligament; particularly common in Japanese patients
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SECTION VI. RADICULOPATHY
C. Clinical Presentation: 1. Occurs concomitantly with lumbar stenosis 2. Preserved muscle mass, hyperactive reflexes, poor balance (lateral compression of the DSCT and VSCT) 3. Neurogenic bladder 4. Hyperactive reflexes and Babinski signs 5. Concomitant root involvement from spondylosis may give myotomal atrophy and muscle weakness f. Venous congestion contributes to myelomalacia with spinal cord signs and symptoms
Lumbar Spinal Stenosis
A. General features: 1. A combination of desiccated disc disease with central bulge, facet and ligament hypertrophy that cause trefoil canal compression 2. L4–L5 > L5–S1 level-most frequent levels that are stenosed 3. Congenitally small canal; acquired stenosis occurs one level above a surgical fusion 4. Claudication may be caused by a combination of venous congestion and occlusion of the vaso vasorum. Radicular arteries are patent. B. Clinical Presentations: 1. Neurogenic claudication 2. Often bilateral radicular pain 3. Unable to move immediately after arising; patients stand at the side of the bed for a minute 4. Characteristic “simian” stance; spine forward flexed arms forward 5. Very positive straight leg raising signs; paraspinal muscle rigidity 6. Strength of muscles preserved; minimal atrophy of involved muscle g. Reflexes increased in upper and lower extremities as cervical stenosis frequently accompanies that at lumbar levels; may be absent if there is accompanying spondylosis h. Poor tandem gait (cervical stenosis) i. Positive Babinski’s (if concomitant cervical stenosis)
Associated Processes:
Facet Hypertrophy
1. Uncovertebral joints at C4–C5; C5–C6 and C6–C7 in the cervical spine 2. L4–L5; L5–S1 at lumbar levels 3. Pain is constant at the affected levels; often burning in quality 4. Present during movement and at rest 5. Atrophy, sensory loss and weakness at the affected level
Lateral Recess Syndrome
1. Exit foramina stenosis at L5 is narrowed (3-4 mm from the cord) 2. Pain, atrophy, weakness, reflex depression at the affected level Synovial Cyst of the Facet Joint
1. Usually at L4–L5; L5–S1 may irritate the nerve root as it exits 2. Often midline back pain 3. May occur concomitantly with degenerative osteoarthritis at the same level 4. May present with radicular symptoms at the involved level Posterolateral Disc Herniation
1. Interspace level and location of the disc protrusion determine the root that is affected 2. Posterolateral protrusion at L4–L5 may compromise the L5 root prior to its exit at the L5–S1 foramen Far Lateral Disc Herniation
1. Compromises the root leaving the exit foramina at that level Central Disc Herniation
1. 2. 3. 4. 5.
May affect roots bilaterally Bilateral pain Bowel and bladder paralysis if at sacral levels Perineal anesthesia (saddle anesthesia); S1–S5 roots Anterior tibialis, extensor hallucis longus, everter and intrinsic foot weakness 6. Cauda equina syndrome (often acute) 7. Medial disc protrusions compress roots that will exit at a lower level; may also compress exiting root at that level
Cauda Equina Syndrome
A. General Features: 1. More than two contiguous nerve roots are involved 2. Bilateral lumbar or sacral radiculopathies B. Clinical Presentation: Midline variant: 1. Compression of nerve roots of the central cauda equina 2. Acute or gradual onset 3. Acute onset: a. Disc herniation (L4–L5 most common); sacral roots are positioned most medially and therefore are involved first b. Severe pain; usually asymmetric sacral root involvement c. Perineal (“saddle anesthesia”)
Chapter 3. Cervical Root Disease
d. Bladder and bowel incontinence e. Leg weakness; primarily L5–S2 innervated muscles f. Progressive Neurogenic Claudication: a. Back, thigh and leg pain with walking (often 2–3 blocks) b. Relieved by rest in 2–3 minutes; neurogenic cramps of the calf c. Rarely pain is induced only with standing without exercise d. Walking through pain induces weakness and paraesthesias in lumbosacral roots e. Sitting or raising one leg and bending at the waist are relieving maneuvers f. Neurologic examination is that of lumbar spinal stenosis
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b. Platybasia of the skull c. Basilar impression with C2–C3 impingement d. Arnold Chiari malformation with traction on posterior roots of C2 and C3 with severe pain; specific cough or Valsalva headache causes C2 traction headache 2. Klippel Feil Defect: a. Congenital fusion of C4–C5 > C5–C6 (C3–C4 rare) b. Severe pain at this root level c. Spinal stenosis at or one level above the fusion d. Associated with Spangle’s deformity: 1) Myometric abnormality of C4–C5 2) Shoulder muscles and scapula poorly developed; shoulder elevated 3. Syringomyelia a. Atrophy at the level of the involved root b. Associated AC type II malformation
Thoracic Disc T1 Congenital Anomalies of the Thoracic Outlet
1. Rare; usually T8–T11 2. Midline back pain; 50% have radiculopathy at the affected level 3. Dangerous due to small canal at these levels (if acute HNP) 4. Early leg weakness, bowel and bladder involvement with cord compression 5. Symptoms are frequently chronic 6. Bilateral Babinski’s signs with cord compression 7. Valsalva maneuver and pressure on the shoulders (extrusion of disc and compression of the spinal cord) increases radicular pain and myelopathy 8. Lateral protrusion causes intercostal radicular pain 9. C8–T1 disc may affect ipsilateral sympathetics to cause Horner’s syndrome 10. Medical causes of thoracic discs: a. Diabetes mellitus b. Syphilis (denervated disc capsule; paretic joint) c. Amyloid (painless joint; small fiber loss) d. Ochronosis (homogentisic aciduria); calcified discs; “Rugger Jersey” disc 11. Usually requires severe trauma or heavy lifting 12. Early leg weakness, bowel and bladder involvement
Chapter 3 Cervical Root Disease Congenital Root Diseases
1. C1–C3 roots: a. Abnormal ossification of the odontoid process or the lateral masses of the atlas
1. The major components of the thoracic outlet: a. Sternocostovertebral space: 1) Most proximal part of the thoracic outlet tunnel 2) Anatomy: a) Anteriorly (sternum) c) Laterally (first rib) b) Posteriorly (spine) 3) Subclavian artery, subclavian vein C4–T1 roots of the plexus traverse the space 4) Nerve roots have exited the spine and have not formed trunks 5) Associated structures: a) Apex of the lung and pleura b) Sympathetic trunk c) Jugular vein d) Lymphatics of the neck 6) May rarely be congenitally narrowed 7) Usual pathology in the sternocostovertebral space a) Thyroid mass b) Thymus enlargement c) Parathyroid mass d) Lymph nodes e) Lung mass f) Pancoast tumor (squamous or adeno Ca of lung) b. Scalene triangle: 1) Anatomy a) Anterior scalene muscle anteriorly b) Middle scalene muscle posteriorly c) First rib forms the base 2) Anterior scalene muscle: a) Origins are the transverse processes of C3–C6 b) Insertion on the scalene tubercle of the first rib varies; tubercle insertion is between the subclavian artery and vein and pleural dome
SECTION VI. RADICULOPATHY
326
3)
4)
5)
6) 7)
c) Variants of insertion: (1) Behind the artery (2) Between the artery and brachial plexus (3) Entire base of the scalene triangle (traps the neurovascular bundle) (4) Anterior insertion may merge with insertion of middle scalene muscle (20% of patients) (5) C5 and C6 roots may transverse the anterior scalene muscle rather than descend between the anterior and middle scalene muscles Middle scalene muscles: a) Origin is the transverse processes of C2–C7 b) Insertion-Chassaignac’s retro arterial tubercle of the first rib c) May insert on the fibrous septum of the pleural dome; lateral fibers insert on the second rib d) C8–T1 roots (individually or together as the lower trunk) compressed by more anterior or forward compression of the middle scalene muscle (sharp anterior edge); the anterior edge of the muscle may also compress the C8–T1 roots First rib: a) Floor of the scalene triangle b) T1 closest to the rib c) Congenital rib anomalies, bony ridges, hypoplasia and inward curvature may compress the neurovascular bundle Scalene triangle congenital variations: a) Base of the triangle 0.77 cm in men; 0.67 cm in women b) C5–C6–C7 emerges from the apex of the triangle; the fibers of the middle and anterior scalene muscles merge at the apex. Patients with C5, C6–C7 root involvement have a greater incidence of roots emerging from the apex: (1) Interdigitation of anterior and middle scalene muscles occurs in 70% of symptomatic patients (2) Adherence of C5–C6 roots to the middle scalene muscles Costoclavicular space (compresses the brachial plexus) Pectoralis minor space (compresses the brachial plexus)
Cervical Ribs that Compress Cervical Roots
1. 0.17% to 0.74% (average 0.3%) of general population (female > males 2 : 1) have cervical ribs 2. 10% of patients that have cervical ribs are symptomatic 3. Symptomatic patients often have suffered arm trauma 4. Aneurysmal dilatation or subclavian artery stenosis is most often caused by a rudimentary rib or cervical rib 5. Neurological symptoms from cervical ribs are caused by nerve compression primarily of the lower trunk (C8–T1)
Rib-Band Syndrome of Gilliat
1. Type II band 2. Compresses the C8, T1 roots (lower trunk) 3. Paresthesias 4th, 5th finger, medial forearm to medial humerus 4. Atrophy and wasting of intrinsic hand muscle Thyroglossal duct cyst (involvement of C3–C4 roots) Branchial cleft cysts (involvement of C2–C5 roots) Short pedicle and block vertebral body: 1. Entrapment of nerve root under the pedicle and in the exit foramina 2. Achondroplasia (at all cervical levels) there are block vertebrae and cervical stenosis
Trauma of Cervical Nerve Roots
1. Flexion extension injury of the neck (whiplash): a. C8–T1 most frequently involved; congenital anatomical predisposition b. C5–C6 prior to or after having formed the upper trunk c. In association with C2, C3, C4 dorsal root injury d. Immediate pain that worsens over time e. Sympathetic symptomatology particularly with C8, T1 involvement 2. Damaged during transaxillary first rib resection: a. C8, T1 most frequently involved b. C5–C6 damaged with scalenectomy and neurolysis procedures c. Flexion and extension injury may damage the ansa hypoglossi 1) Weakness and spasm of sternocleidomastoid, scalene, trapezius muscles (C2–C4) 2) Hyoid, omohyoid muscles are involved 3. Pain: a. Preauricular nerve (C2, C3) distribution posterior roots of C2 and C3 b. Postauricular nerve (C3, C4) distribution posterior roots of C3 and C4 c. C2 root itself (radiation to basiocciput parietal and brow areas) d. Greater and lesser occipital nerve areas (C2–C4 posterior roots) 4. Surgical trauma: a. C4–C5; C5–C6 roots most often affected b. Plating and screw procedures c. Arachnoiditis or direct injury of the affected roots 5. High speed trauma (car accident or fall) a. Spondylolisthesis of cervical vertebrae b. Avulsion of nerve roots c. Jumped facet joint d. Rotary subluxation of facet joint 1) Pain in the neck with radiation into affected segmental distribution
Chapter 3. Cervical Root Disease
2) Torticollis (to the affected side) 3) Segmental weakness e. Injury by epidural catheterization with bupivacaine >0.25% or trauma by the catheter itself
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3. Posterior ligament ossification syndrome (primarily Japanese patients) 4. Idiopathic pachymeningitis 5. Hayakawi Syndrome (ligament laxity with cord compression)
Complex regional pain syndrome (Type I/II)
a. Most often after injury to the arm (T2 sympathetic fibers of T1–T14 recurrent nerve of Kunz) carries sympathetic innervation into the arm) b. Multiple nerve roots involved; characteristic hyperalgesia, allodynia (mechanical and thermal; dynamic and static); autonomic dysregulation, movement disorder, atrophy and dystrophy Red ear syndrome
a. b. c. d.
Ears beet red Slightly edematous Nonpainful Neurogenic edema (release of substance P (SP) and calcitonin gene related peptide (CGRP) from fibers that innervate blood vessels of the ear; mismatch of arteriolar and capillary circulations and sympathetic innervation. There is vasodilatation of the capillaries in the ear (CGRP) and leakage of plasma through the endothelium by SP)
Lax Ligament Syndrome (that Attach the Odontoid Process to the Axis)
1. Four ligaments involved: a. Cruciate ligament (attaches the odontoid to the axis) b. Lateral ligaments (odontoid to the lateral mass of C1) c. Ligament from the tip of the odontoid to the rim of the foramen magnum; alar ligament 2. Normal posterior odontoid displacement: a. Children 3–5 mm b. Adults 1–2 mm 3. C2 root primarily involved with spinal cord compression 4. Differential diagnosis: a. Rheumatoid arthritis 1) Frequently tingling of the arms and hands (C2-T1 involvement) 2) Subluxation and spinal cord compression 3) Pannus and erosion of the cruciate ligament b. Mongolism c. Ehlers Danlos syndrome d. Marfan’s syndrome e. Trauma (flexion/extension injury)
Ligament Hypertrophy with cervical root Impingement
1. Acromegaly 2. Mucopolysaccharidosis
Pachymeningitis with Cervical Root Compression
1. Syphilis a. Dense fibrous pachymeningitis particularly of the cervical cord 2. Sarcoid 3. Tuberculous infection 4. Idiopathic pachymeningitis 5. Subarachnoid hemorrhage with consequent arachnoiditis 6. Hodgkin’s and non-Hodgkin’s lymphoma
Tumors of the Cervical Nerve Roots
1. Schwannoma: a. Associated with NFT type I chromosome 17 b. May affect multiple nerve roots concomitantly c. Root and plexiform involvement > in lumbosacral than brachial distributions d. Dumbbell tumor; may involve the nerve and then grow through the foramina to compress the spinal cord (intradural extramedullary location) 2. Neurofibroma: a. Cannot be dissected from the nerve (grows throughout the nerve) 3. Meningioma: a. Intradural extramedullary nerve root compression b. Plexiform (en-plaque growth) 4. Lymphoma (infiltration of nerve roots) 5. Leukemia: a. Hemorrhage into nerve root (acute presentation) b. Infiltration of nerve root (insidious presentation) 6. Carcinomatosis of the meninges: a. Lung, breast, GI tract, prostate b. Asymmetric presentation c. Weakness, atrophy, anesthesia, loss of reflexes in segmental distribution 7. Chordoma: a. Most common in clivus and sacral vertebrae b. Greater than 10% at thoracic or cervical levels 8. Osteogenic sarcoma (rare) 9. Chondrosarcoma (rare) 10. Ewing’s sarcoma: a. Greater than 5% axial vertebral involvement b. Predilection for cervical vertebrae 11. Pancoast tumor: a. Apex of the lung (adeno or squamous carcinoma) b. Involvement of roots in the sternocostovertebral space
SECTION VI. RADICULOPATHY
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12. 13.
14.
15. 16.
17.
c. Pain (usually burning) along the medial forearm and into 4th and 5th fingers d. Horner’s syndrome (involvement of the sympathetics at C8–T1) e. May involve T2 sympathetic outflow to the arm Lymphomatous B cell: diffuse radiculopathy Post X-ray treatment sarcoma: a. Follows X-RT for breast cancer (most frequently) b. Involves roots of the brachial plexus C8, T1 > C5–C6 c. Follows X-RT by 15–20 years d. Associated with myokymia in the irradiated area e. Associated skin changes; hyperpigmentation, telangiectasia, proliferative endarteritis Neuromyotonia: a. Rippling fasciculations c. Anti-TA antibodies b. Hodgkin’s disease Mixed salivary gland tumors: a. Infiltrate C1–C4 roots Parotid gland tumors: a. VIIth nerve most frequently involved b. Cervical C2–C4 roots involved Salivary cylindroma: a. Cervical C1–C4 roots b. Cranial nerve involvement concomitantly
Infection Involving Cervical Nerve Roots
1. Herpes zoster: a. C5–C6 > C4–C5 > C8–T1 b. Clinical symptomatology: 1) Grouped vesicular eruption in a dermatomal distribution 2) Sensory loss in dermatomal pattern to all modalities (early) 3) Atrophy, weakness, sensory loss in involved myotome 4) May have dermatomal sensory loss weeks to occasionally months prior to vesicular eruption (herpes sine herpete); often burning pain in the dermatomal distribution 2. Post herpetic neuralgia: a. Spontaneous lancinating pain b. Deep continuous ache with lancinating exacerbations in involved dermatome c. Decreased sensory threshold to pinprick, touch or temperature of the dermatome d. Allodynia to both static and dynamic mechano and thermal stimuli e. Hyperalgesia of the involved dermatome f. Neuroma in continuity along the root of the affected dermatome may be cause of post herpetic neuralgia 3. Herpes simplex: a. Single vesicular eruption b. Painful; ecthymatous base
4.
5.
6.
7.
c. Dermatomal but often regional (several roots involved) pain Brucella: a. Rare cervical involvement (L5 most common root affected) Lyme’s disease: a. C5–C6 root most common roots that are involved b. May be bilateral c. Often arthralgia or erythema migrans have been noted prior to symptoms Staphylococcus aureus (contiguous spread) a. Usually seen in IV drug abusers b. Following surgery with accompanying osteomyelitis c. Disc space involvement first; nerves compromised in foraminal exit areas or laterally Viral infection: a. Parsonage Turner syndrome: 1) Sudden onset of severe lancinating, burning and deep pain 2) C5–C6 dermatomes affected; may be bilateral 3) Cause of neuralgic amyotrophy 4) May affect individual nerves (phrenic) b. EBV virus c. Hepatitis C (associated cryoglobulinemic neuropathy) d. Polio myelitis acute: 1) Usually groups of anterior horn cells are affected 2) Isolated finger involvement 3) Non-dermatomal distribution 4) Fasciculations and atrophy prominent long after cessation of infection 5) Post polio syndrome follows in a significant percentage of patients e. Adenovirus f. Coxsackie virus
Systemic Disease Affecting Cervical Roots
1. Diabetes mellitus: a. Diabetic amyotrophy much more common in L2–L4 distribution b. Putative involvement of vasonervorum (infarction of roots and plexus) 2. Acute intermittent porphyria: a. C5–C6 roots most commonly involved b. Most often motor; severe atrophy of involved dermatome that recovers c. Sensory loss patchy; most often out of a dermatomal distribution 3. Variegate porphyria (rare root involvement) may have associated skin rash 4. Post X-RT therapy (myokymia) 5. Pachymeningitis syndrome (idiopathic) 6. Sicca complex:
Chapter 4. Thoracic Root Disease
a. Autoimmune (putative) b. May have patchy anhidrosis and sensory loss out of a dermatomal distribution c. Probable dorsal root ganglion neuropathy d. May involve definable cervical roots 7. Amyloidosis: a. Familial amyloid b. FOLMA 1) Meningeal involvement with nerve root compression 8. Isolated angiitis of the CNS/PNS: a. Arteritis of the vaso vasorum of cervical nerve roots 9. Inflammatory spondyloarthritis with radiculopathy a. Rheumatoid arthritis d. Crohn’s disease b. Psoriasis e. Ulcerative colitis c. Ankylosing spondylitis f. Behçet’s disease
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1) Severe burning pain in several dermatomal distributions 2) Usually regional rather than clear radicular pattern 3) CT/myelogram demonstrates clumping of nerve roots or a featureless dural sac; MRI demonstrates gadolinium enhancement of the scar 4) Minimal weakness; burning pain predominates 5) Asymmetric loss of reflexes 6) Rare bladder involvement 7. Aneurysmal rupture of vertebral or anterior spinal artery a. Arachnoiditis b. Superficial siderosis Differential Diagnosis of Cancer vs. X-RT Involvement of Cervical Nerve Roots Cancer
Vascular Disease of Cervical Nerve Roots
1. Arteriovenous malformation: a. Nerve root (on the root itself) b. Dural AVM with accompanying compression of the nerve root 2. Dilated vein compressing nerve root: a. Venous congestion from severe cervical spondylosis or stenosis b. Concomitant venous congestion of the spinal cord (causes myelomalacia) 3. Foix–Alajouanine syndrome: a. Arteriovenous malformation involving the anterior spinal artery b. Cervical nerve roots and cord may be compressed 4. Weber–Klippel–Trenaunay syndrome: a. Arteriovenous malformation of an extremity b. Enlargement of the bone and soft tissue components of the extremity c. Enlarged epidural veins may compress segmental nerve roots d. May be genetic 5. Superficial siderosis: a. Hemosiderin deposits on nerve roots: 1) Radiculopathy 2) Cranial nerve I and VIII concomitantly involved 3) Repeat bleeds from aneurysms, cavernous hemangiomas or rarely telangiectasia 4) Demonstrated by gradient ECHO MRI evaluation (hemosiderin) 6. Arachnoiditis (following admixture of blood): a. Clumping together and scar formation of nerve roots 1) Secondary to: a) Multiple surgeries b) A mixture of blood and myelogram dye c. Clinical Features:
1. 2. 3. 4.
Painful (burning) C8, T1 roots primarily involved Horner’s syndrome Pancoast tumor of lung apex (adeno or squamous cell carcinoma)
X-RT Treatment
1. 2. 3. 4. 5.
Dysesthesia or paresthesia; not painful C5–C6 primarily involved No Horner’s syndrome Myokymia of the involved segment X-RT of breast or Hodgkin’s disease most common systemic illness treated
Chapter 4 Thoracic Root Disease A. Disc Disease 1. General Features: a. Trauma: 1) Severe trauma (high speed motor vehicle accidents, heavy lifting, direct spinal injury) 2) Radicular lancinating pain 3) Intercostal or abdominal radiation 4) Exacerbated by specific movements 5) If associated myelopathy: a) Weakness of the legs b) Babinski’s signs c) Hyperactive reflexes d) Bladder, bowel, sexual dysfunction e) Sensory level, two segments below the injury
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SECTION VI. RADICULOPATHY
2. Clinical features: a. Radicular lancinating pain b. Intercostal or abdominal radiations c. Exacerbated by specific movements (torsional or compressive) d. Weakness of the legs e. Babinski signs f. Hyperactive reflexes g. Bladder, bowel, sexual dysfunction with acute spinal cord compression B. Traumatic radicular disease: 1. General Features: a. Jumped facet joint: 1) Overriding of the inferior over the superior facet joint 2) Traction or direct injury of the segmental root b. Rotary subluxation of the facet joint: 1) Facet joint twisted; synovial interfacet joint breached 2) Missed by conventional X-ray; CT for diagnosis 3) Segmental radiculopathy; pain most prominent symptom c. Burst fracture of vertebral body: 1) Vertebral body star fracture 2) Bilateral radicular pain 3) Fractured bone fragment often displaced into the spinal canal or foraminal exit area 4) Concomitant spinal cord injury d. Lateral vertebral body translocation: 1) Severe trauma (high speed MVA) 2) Bilateral radicular pain 3) Associated severe spinal cord injury e. Anterior vertebral body compression fracture: 1) Middle aged and elderly women with metabolic bone disease 2) Minimal trauma (opening a window, fall or hug) 3) Severe lancinating radicular pain at the segmental level
Rarer Causes of Thoracic Root Disease
1. Syrinx a. Atrophy at the segmental level b. Early hyperhidrosis followed by anhidrosis of the affected segment c. Dissociated sensory loss at the segmental level d. Long tract motor and sensory signs below the syrinx 2. Post traumatic syrinx: a. Further cystic degeneration of the spinal cord that occurs months after injury b. Usually 2–3 segment loss of function above and below the level of injury c. Bilateral root involvement at the segment levels 3. Chest surgery
a. b. c. d.
Open heart surgery Lung surgery Retraction (neuropraxic or direct radicular injury) Prolonged neuropathic pain of the involved roots or intercostal nerve
Thoracic Nerve Root Involvement from Systemic Disease
1. Diabetes mellitus: a. Infarction and ischemia of the thoracic roots (vaso vasorum) 1) Elderly type II diabetes 2) Associated with weight loss 3) Abrupt onset 4) Much more frequent in lower extremities b. Diabetic dying back neuropathy: 1) Shield chest sensory loss 2) Associated with distal dying back neuropathy of the hands and legs 3) Single or multiple dermatomal involvement of the chest or abdomen 4) Distributions of the ventral or dorsal rami of the spinal nerves; branches of these rami or various combinations of these distributions 2. Amyloid neuropathy: a. Associated with primary amyloid neuropathy b. FOLMA; amyloid with meningeal involvement c. Denervation of the segmental disc; radicular pain due to root compression 3. Ochronosis: a. AR; homogentisic acid synthetase deficiency b. Homogentisic aciduria (dark urine) c. Calcification and degeneration of multiple thoracic discs d. Rugger–Jersey X-ray findings (calcification of discs) e. May be asymptomatic 4. Ankylosing spondylitis 5. Hyperparathyroidism 6. AIP 7. Toxins 8. Immune mediated processes: a. AIDP (acute GBS) 1) GM1, Gd1b, Gal-NAc-GD1a antibodies b. CIDP c. Sjögren’s Disease 1) Dorsal root ganglion involvement 2) Involvement of dorsal primary division and its medial and lateral branches (thoracic roots) d. SICCA complex: 1) Dry eyes, mouth, serous membranes 2) Segmental and regional anhidrosis 3) Segmental and regional sensory loss e. Radiculopathy with increased sed rate: 1) Usually lumbosacral roots involved
Chapter 4. Thoracic Root Disease
9.
10.
11.
12.
13. 14. 15. 16. 17. 18. 19. 20.
21.
2) Idiopathic (occasionally noted with increased sed rate) Cancer and Benign Tumors: a. Leukemia b. Hodgkin’s and non-Hodgkin’s lymphoma c. Carcinomatosis of the meninges Tumor: a. Anterior mediastinal tumors (rarely involve thoracic roots) 1) Thymoma 2) Thymic carcinoma 3) Thymic carcinoid (associated with MEN-1) 4) Thymolipoma 5) Hodgkin’s and non Hodgkin’s lymphoma (NHL) b. Primary mediastinal germ cell tumor 1) Mature teratoma 2) Seminoma 3) Nonseminomatous germ cell tumor Posterior mediastinal tumors: a. Peripheral nervous system benign and malignant neoplasms are more frequent in the posterior mediastinum b. Develop from peripheral nerves, sympathetic and parasympathetic ganglia and neural tube embryonic remnants: 1) Schwannoma 2) Neurofibroma 3) Melanotic schwannoma 4) Ganglioneuroma 5) Granular cell tumor 6) Malignant melanocytic nerve sheath tumor 7) Neuroblastoma 8) Ganglioneuroblastoma 9) Neurofibrosarcoma (Von Recklinghausen’s disease) Metastatic disease (similar to cervical root): a. Anhidrosis or hyperhidrosis if sympathetic chain involved (T2-sympathetic innervation of the arm) b. Multiple myeloma d. Plasmacytoma c. Osteoclastic myeloma e. Paget’s (sarcoma) Multiple myeloma Osteoclastic myeloma Plasmacytoma Paget’s Disease (degenerate to sarcoma) Multiple myeloma (vertebral fractures with secondary radicular involvement) GI cancer (sacral bone involvement; lumbar and sacral roots > thoracic) Giant articular bone cyst (vertebral fracture) Osteoid osteoma: a. Refractory to narcotics; respond to prostaglandin inhibitors b. Involve posterior elements of the vertebral body (pedicles and facets) c. Radicular symptoms Vertebral body sarcoma
331
22. Chondrosarcoma 23. Enchondroma: a. Involves the nerve root exit foramina 24. Chordoma: a. 4% in thoracic vertebra 25. Brown bone cyst 26. Hemangioma of vertebral body: a. Most often incidental (MRI T2 weighted image) b. May weaken vertebral body c. Bloody d. May compress exiting nerve root e. May have concomitant spinal cord compression due to hemorrhage 27. Thoracic meningoma in women: a. Extremely rare in men b. Possible association with growth in pregnancy and with breast cancer 28. Schwannoma: a. Typical enlargement of foraminal nerve root exit canal b. Scalloping of affected vertebral body c. Dumbbell tumor d. Intradural extramedullary location; meniscus sign on myelography 29. Neurofibroma
Infection Involving the Thoracic Root
1. HZ (Herpes Zoster): a. Thoracic dermatomes most commonly involved b. Clinical symptoms (see cervical dermatomes) c. Dorsal root ganglionitis; pain of burning nature may occur prior to vesicular eruption d. Rarely hemorrhagic spinal cord infarction associated (paraparesis; most often at T4–T6) 2. HIV: a. Usually cervical cord involvement b. Vacuolar degeneration of the cord c. Rare radicular complaints 3. Staphylococcus aureus: a. Young IV drug abusers; endarteries to the disc b. Disc space infected: 1) Enhancement of disc space on MRI 2) Bone spared; pre and post vertebral ligament inflammation 3) Lancinating radicular pain; minimal movement initiates pain (touching patient’s bed) 4) Spinal cord involvement from direct spread or by venous infarction 4. Gram negative disc space infection following surgery: a. Involvement may be delayed for up to six weeks b. Pain, swelling, erythema, and edema at the operative site c. High sed rate
SECTION VI. RADICULOPATHY
332
d. Exquisitely sensitive to mechanical perturbation of the root 5. Tuberculosis: a. T4–T6; T11–T12; L1–L2 usual location of the infection b. Infection more common in cervical regions in Asian patients c. Disc space infection > bone; bony sclerosis of the vertebral body end plate d. Pott’s disease (thoracic cord): 1) Occurs with compression and loss of disc integrity 2) May cause spastic paraparesis e. Cold abscess along the iliopsoas muscle; T10–L1 root involvement; blurring of the psoas stripe of X-ray 6. Actinomycosis: a. Extension into thoracic vertebrae from active lesions of the lung b. Abscess with radicular symptoms c. Sulfur granules d. Rural population 7. Nocardia: a. Immunocompromised patients b. Venous (epidural vein involvement) c. Often noted in lung abscess d. Associated with osteomyelitis
Chapter 5 Lumbosacral Root Disease L1–L5; S1–S5
A. General Features: 1. Higher lumbar root involvement: a. Autoimmune processes b. Connective tissue diseases c. Retroperitoneal processes (tumors, hemorrhage, fibrosis) d. Diabetes e. Vasculitic processes 2. Lower root involvement L4–S1: a. Degenerative disc disease b. Lumbar spondylolysis c. Lumbar spondylolisthesis d. Spinal stenosis e. Facet hypertrophy f. L5, S1 recess syndrome g. Surgical procedures 3. Combined lumbosacral root disease: a. Tumors (metastatic) b. Surgical and post surgical complications c. Arachnoiditis d. Congenital abnormalities
Congenital Defects of Lumbosacral Roots
1. Scoliosis and lordosis: a. Neurapraxia of nerve roots of contralateral side (side opposite scoliosis) b. More susceptible to further compression by disc or bone or ligament involvement c. Sharp angle of L5 on S1; the more towards 180◦ plane > pressure on L4–L5–S1 roots 2. Conjoined nerve roots: a. May occur at any level; two spinal nerves exit one neural foramina b. Radicular symptoms at segmental level c. Symptomatic frequently after trauma 3. Lumbosacral perineural cysts: a. Cystic dilatations of the lumbosacral nerve roots at or distal to the junction of the posterior root or DRG b. Wall is composed of perineurium and neural tissue c. Most often asymptomatic d. Most often sacral nerve roots are involved if there is sciatic pain e. Occasional hypertrophy of leg muscles innervated by specific roots 4. Cyst of the ligamentum flavum: a. Usually sacral b. Sciatic nerve pain 5. Achondroplasia: a. Block vertebrae b. Short pedicles c. Narrowed exit foramina d. Spinal stenosis with nerve root entrapment at T11–T12 6. Congenital spinal stenosis: a. Trefoil appearance of the spinal canal particularly at L4–L5 b. Narrow diameter of the canal c. Short thickened pedicles with compromised nerve exit foramina 7. Congenital narrowing of lateral recess of L5 and S1 (nerve foraminal exit canals) a. Exit foramina congenitally compromised b. S1 > L5 level c. Chronic radicular symptoms; usually become symptomatic after repetitive motion injury or trauma d. Associated with abnormalities of the sacrum e. Urinary symptoms may occur concomitantly 8. Tethered cord: a. General Features: 1) Traction of the conus medullaris and cauda equina by tight, thickened filum terminale 2) Two clinical groups: a) Asymptomatic in childhood and present for the first time in adult life b) Patients with pre-existing static skeletal/neurologic abnormalities that progress in adult life b. Clinical features: 1) Pes cavus
Chapter 5. Lumbosacral Root Disease L1–L5; S1–S5
2) Cutaneous stigmata (strawberry hemangioma; cutaneous dimple) over the sacrum 3) Back pain; may have anal and perianal pain; gluteal or diffuse leg pain 4) Motor and sensory radicular deficit (L5–S1) is rare 5) Sphincter function depressed 6) Associated with terminal syringomyelia (caudal 1/3 of the cord) 7) Associated with diastematomyelia 8) Associated with lipoma of the conus and lipomyeloschisis 9) May be associated with pes cavus of one foot 10) Urgency symptoms of spastic neurogenic bladder 11) Symptomatic with specific positions; particularly the dorsal lithotomy position 12) Symptomatic following delivery or vaginal surgery (dorsal lithotomy position) c. Urodynamic findings: 1) Hyperreflexia of the bladder 2) Internal and external detrusor-sphincter dyssynergia 3) Decreased sensation (bladder) 4) Decreased compliance (bladder) 5) Hypo contractility of detrusor muscle d. MRI: 1) Tethered cord; tip of the conus medullaris below the body of L2 instead of the L1–2 disc space 2) Associated with intra or extradural lipoma
Classification of Lumbosacral Nerve Root Anomalies with Tethered Cord
1. Type I and II a. One or more nerve roots exit the thecal sac at a more cranial (Type I) or caudal (Type II) level 2. Type III a. Two or more roots emerge from the thecal sac through a closely adjacent dural opening 3. Type IV a. Two or more roots emerge from the dural sac as one nerve trunk 4. Type V a. Two or more roots are connected by an anastomotic branch after exiting the dural sac
Clinical Characteristics of Congenital Root Anomalies
1. Anomalies primarily of L5 and S1: a. Type III and IV most common anomaly b. 20% of patients have other lumbosacral anomalies; rarely congenital absence of a facet joint on the side of the anomaly c. Clinical symptoms are severe d. Reduced mobility of the anomalous roots
333
2. Extra foraminal stenosis of the lumbosacral spine: a. Affected roots are compressed between the transverse process of the last lumbar segment and sacral ala 3. Conjoined lumbosacral roots: a. Found in 1% of lumbar disc operations b. L5–S1 level c. Often not associated with a herniated disc d. Radiographic features: 1) Asymmetric subarachnoid space 2) Widened axillary pouch 3) Two or more individual nerve roots in the axillary pouch Degenerative Diseases Affecting Lumbosacral Nerve Roots (see Cervical Spine)
Differential Diagnosis: a. Disc disease b. Spondylosis c. Degenerative spondylolisthesis d. Foraminal exit arthritis (osteophytes) e. Facet hypertrophy (tropism and rotation) f. Stenosis (disc; spondylosis, ligamentous hypertrophy) g. Synovial cysts of facet joints Benign Bone Tumors Affecting Lumbosacral Nerve Roots
Benign Osteoblastic Tumors
1. Osteoid osteoma/osteoblastoma a. Lamina and pedicle often involved b. Pain is often nocturnal and relieved by aspirin > narcotics (prostaglandin dependent) c. Radicular pain in 50% of patients d. Tenderness in the area of the lesion e. Osteoblastomas frequently extend into the neural exit foramina f. Painful scoliosis is a common presentation Osteochondroma
1. Osteochondroma comprises approximately 50% of benign bone neoplasms 2. Involvement of the spine in 2.5–5% of cases; spine involvement often seen in a setting of multiple osteochondromatosis 3. Usual occurrence is in long bones 4. Usual spine predilection is for cervical or upper thoracic levels 5. Cases described at L4 and L5 with radicular involvement Extraosseous Extension of Vertebral Hemangioma
1. Asymptomatic vertebral hemangiomas are common 2. Extraosseous extension can cause intracanalicular and spinal cord compression
SECTION VI. RADICULOPATHY
334
Aneurysmal Bone Cyst
1. Benign, sometimes expansive and destructive (osteolytic) 2. Occurs most frequently between 10–20 years of age 3. Posterior elements of the spine involved with extension into the vertebral body 4. Annual incidence 0.14/100,000 people; age range 1–59; slightly more common in females than males 5. Most commonly found in the metaphyseal areas of long bones Dermoid
1. 2. 3. 4. 5. 6. 7.
Dermoid cysts are intradural in the lumbar and sacral spine Rupture causes chemical arachnoiditis May occur at site of meningocele repair Midline dermal sinus (may be associated) Paravertebral dermal sinus May be associated with meningitis Associated with spina bifida
Lipoma
1. Association: a. Tethered cord b. Anorectal malformations c. Meningocele d. Sacral agenesis (caudal regression syndrome) e. Lumbar vertebral dysgenesis f. Lumbosacral skin lesions: tufts of hair, skin tags, pigmental nevi, hemangiomas Rare Benign Bone Lesions that Can Affect Axial Skeleton with Consequent Radiculopathy
1. 2. 3. 4. 5.
Giant cell tumor of bone Leiomyomas Chondromyxoid fibroma Fibrous histiocytoma Differential points for malignancy or benignancy a. Pedicle change with expansion is most often malignant b. Normal marrow preservation of a collapsed vertebral body on T1, on an MRI sequence is most compatible with an osteoporotic fracture
Chapter 6 Epidural and Vertebral Metastasis
A. General features: 1. Metastatic tumor is the most common neoplasm of the intraspinal canal and nerve roots 2. Epidural > leptomeningeal > intraspinal tumor involvement of nerve roots
3. Epidural metastasis occur primarily from direct extension of metastatic vertebral tumors; rare metastasis occur through the intervertebral foramina or by direct metastasis to the epidural space 4. Radiculopathy is secondary to direct compression of the tumor, metabolic and cytokine effects; rarely a pathologic fracture of a vertebra may compress the entire cauda equina 5. Differential diagnosis of vertebral metastasis: a. Lung e. Renal cell b. Breast f. Sarcoma c. Prostate g. Multiple myeloma d. Melanoma 6. Prostate and colon metastasize to lumbosacral spine 7. Lymphoma has a predilection for paravertebral lymph nodes; wraps around the lumbosacral roots; may also start in the epidural space 8. Most frequent sites of metastasis: thoracic >70%; lumbosacral >20%; cervical 10% B. Clinical Presentation: 1. Local pain is the initial symptom. It is particularly sensitive to mechanical stimuli (fist percussion over the spine) 2. Radicular pain: 1) Thoracic metastasis usually presents with bilateral radicular pain 2) Lumbosacral roots most often have a unilateral presentation 3) HZ may be reactivated at the site of the lesion 4) Motor, sensory and sphincter involvement follow the pain 5) Hyperhidrosis may occur at an upper thoracic T1– T2 level with sympathetic nerve irritation c. Destroys posterior portion of vertebrae and pedicle d. Affects nerve roots by continuity e. Enters the intradural space through the nerve exit foramina f. Deep boring pain; worse at night g. Nerve root pain is often a deep ache, constant may have lancinating features h. Weakness, sensory loss, atrophy, decreased or lost reflexes at the affected level i. Solitary vertebral collapse: 1) Malignant features by MRI: a) Ill defined lesion margin b) Abnormal signal involvement of the pedicle c) Heterogeneous enhancement pattern d) Irregular nodular paravertebral soft tissue lesion e) Erosion of end plate (malignant) f) Star burst pattern fracture (traumatic) 2) Clinical Presentation: a) Destroys posterior portion of vertebrae and pedicle b) Affect nerve roots by continuity
Chapter 6. Epidural and Vertebral Metastasis
c) Enter the intradural space through the nerve exit foramina d) Deep burning pain; worse at night e) Nerve root pain often a deep ache, constant, may have lancinating fractures f) Weakness, sensory loss, atrophy, decreased or lost reflexes at the affected level Prostate Cancer
1. 2. 3. 4.
Osteoblastic and clastic bone destruction Multiple levels are involved L4–S1 most frequent levels May metastasize through the perivertebral plexus to the posterior fossa (Batson’s plexus) 5. Petrous apex may be affected (posterior fossa; Batson’s plexus route of the metastasis) 6. Midline vertebral pain Ovarian Caner
1. L1–L3 nerve roots > L4–S1 roots 2. Associated with peritoneal implantation 3. Higher incidence of anti-Yo and associated paraneoplastic syndromes 4. Often bilateral 6.1. Gastric and Colon Cancer
1. Colon cancer may destroy sacrum and sacral roots 2. Krukenberg metastases (dropped metastases to the ovaries) 3. Associated nonbacterial thrombotic emboli (NBTE) with stroke (adenocarcinoma) 4. Hypercoagulable state Lung Cancer (Squamous Cell)
1. 2. 3. 4.
Multiple vertebral levels are involved Most common metastatic lesion L5–S1 most common level Carcinomatosis of meninges frequently occurs concomitantly 5. Anti-Hu (antineuronal antibodies) Breast Cancer
1. Multiple vertebral levels are involved 2. May be associated with thoracic meningioma (only in women) 3. Carcinomatosis of the meninges prominent 4. Hematogenous spread 5. May have delayed onset (years after bilateral mastectomy)
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Lymphoma (Hodgkin’s/non-Hodgkin’s)
1. 2. 3. 4.
Arise in the epidural space Associated with spinal cord and plexus involvement L1–L3 > than L5–S1 roots Associated paraneoplastic neuropathy (rare anti MA antigens)
Leukemia (CLL and Chronic Myelogenous Leukemia)
1. May affect all lumbar nerve roots 2. May have explosive onset due to hemorrhage 3. Insidious onset with carcinomatosis of the meninges
Malignant Bone Tumors of Lumbosacral Spine
1. Chordoma: a. Chordomas (excluding plasmacytoma) are the most frequent primary malignant tumor of the spine b. Occur in elderly men; mean age 54 years c. Slow course; locally invasive d. Metastasizes late; local recurrence is usual e. The most common presenting symptom is severe back pain; painful sacral mass f. Autonomic dysfunction at presentation (sacral location); impaired bladder and bowel control if S1 and sacral roots are involved g. Dedifferentiated chordoma may develop at the primary site after X-RT 2. Liposarcoma: a. Retroperitoneal origin; may be extremely large b. Most frequent mesenchymal tumor c. Presents as a palpable abdominal mass d. May involve L5 and sacral nerve roots e. Recurrence rate is high 3. Ewing’s Sarcoma of Lumbosacral Spine a. Rare; may arise from the pedicles of L4–L5, L5–S1 b. Greater incidence of bone and cerebral metastases c. Involves local lumbar and sacral nerve roots 4. Osteosarcoma of the Pelvis a. Chondroblastic in type b. Macroscopic tumor emboli found in regional large vessels in a significant number of patients c. Telangiectatic osteosarcoma may present as sacral mass d. Familial incidence of Paget’s disease and secondary osteogenic sarcoma
Chondrosarcoma
1. Chondrosarcoma most commonly involves the pelvis 2. Increased risks of local recurrence are: the tumor is epicenter, is in the pubis and high grade
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SECTION VI. RADICULOPATHY
3. High rate of metastases occurs with differentiated tumors 4. May enlarge during pregnancy 5. Pain, numbness and lumbosacral root involvement; L1–L2 and L5 pedicle origin; progressive weakness at presentation
Intrinsic Spinal Cord Tumors That Involve the Lumbosacral Roots
A. General Features: 1. Ependymomas (myxopapillary) 2. Neurofibromas of the cauda equina 3. Cauda equina tumors (rare): a. Hemangioblastomas d. Osteoma b. Paragangliomas e. Plasmacytomas c. Ganglioneuromas B. Clinical Presentation: 1. Back pain: a. Presenting symptom b. Increases and becomes unrelenting c. Worse with recumbency d. Exacerbated at night (burning pain) e. Motor and sensory symptoms of the affected dermatomes follow pain by weeks or months 2. Cauda equina involvement is signaled by sphincter and sexual dysfunction
Benign CT Features of Acute Vertebral Lesion
1. Cortical fractures of the vertebral body without cortical bone destruction 2. Retropulsion of a bone fragment of the posterior cortex of the vertebral body into the spinal canal 3. Fracture lines within the cancellous bone of the vertebral body 4. Intravertebral vacuum phenomena 5. Thin diffuse paraspinal soft tissue mass
Malignant Features of Spine Lesions by CT and SPECT
1. Posterior portion of the vertebral body involved 2. Concomitant vertebral body and pedicle involvement 3. Extensive abnormalities that involve the vertebral body and vertebral arch but spare the pedicle are benign 4. Destruction of the anterolateral or posterior cortical bone of the vertebral body 5. Destruction of the cancellous bone of the vertebral body
Systemic Disease Affecting Lumbosacral Nerve Roots
1. Diabetes mellitus:
a. Diabetic amyotrophy (femoral nerve or thoracolumbar plexitis) b. Vasculitis of vasovasorum c. Clinical features: 1) Patients >60 years of age 2) Present with pain 3) Neuropathic quality 4) Prominent weakness 5) Concomitant weight loss 6) Thoracoabdominal nerve root involvement 7) Lumbar pattern referred to as diabetic amyotrophy 2. Sarcoid 3. Periarteritis nodosa a. Proximal L1–L3 nerve roots; all may be affected 4. Meningeal amyloid 5. Acute intermittent porphyria (L5, S1) 6. Coproporphyrinuria 7. Variegate porphyria 8. Mixed connective tissue disease 9. Necrotizing arteritis 10. Collagen vascular disease
Immune Mediated Processes Affecting Lumbosacral Roots
1. AIDP a. May affect proximal nerve roots b. May present with apparent radiculopathy (usually L5– S1) 2. CIDP a. L5–S1 roots may be affected first 3. Multiple sclerosis a. Affects the dorsal root entry zone at a junction of the central and peripheral myelin b. More often encountered in familial cases: 4. Autoimmune epitopes: a. GM1 c. GQ1b b. MAG d. GAL-NAc-GDT1a 5. Radiculopathy with increased sed rate (usually at L5) 6. Acute disseminated encephalomyelitis 7. Post vaccination 8. Post viral infection
Infection Affecting Lumbosacral Roots
1. Herpes zoster (lumbosacral, thoracic, cervical) 2. Brucellosis (L5) 3. Lyme’s disease (L5) a. General features: 1) Borrelia burgdorferi (spirochete) is causative organism
the
Chapter 6. Epidural and Vertebral Metastasis
4.
5. 6. 7. 8. 9.
10. 11.
2) Radiculopathy occurs early in the course of the illness; may be associated with cranial neuropathy and meningitis; may be chronic manifestation a) Single root or asymmetric multiple root involvement 3) Chronic radiculopathy: a) Presents months after the initial infection b) Mild motor and sensory loss; not associated with meningitis or VIIth nerve involvement c) Distal paraesthesia or radicular pain CMV a. General Features: 1) Affects lumbar and sacral nerve roots 2) HIV patients with CD count lumbosacral involvement; tabetic pain of thoracic > lumbosacral roots) HTLV1 (cervical cord) Spinal epidural abscess a. General Features: 1) Thoracic and lumbosacral cord > cervical 2) Chronic lesions occur in the thoracic cord 3) Infecting organisms: a) Staphylococcus aureus b) Gram negative rods c) Anaerobes d) Mycobacterium e) Fungus 4) Risk factors:
337
a) IV drug abuse b) Spinal surgery c) Diabetes mellitus d) Epidural catheters e) Epidural steroid injection f) Immunocompromise b. Clinical features: 1) Onset with severe back pain; delayed from onset of the infection 2) Spinal cord compression syndrome or that of cauda equina involvement 3) Fever, leukocytosis and elevated sed rate 4) MRI demonstrate gadolinium enhancement of involved roots Miscellaneous 1. Endometriosis: a. Endometrial tissue adherent to pelvic nerve roots (L5– S5) b. Catamenial pain with bleeding and irritation of the lumbosacral roots 2. Laparoscopy: a. L1–L3 roots > L5–S1 3. Epidural catheter trauma: a. Prolonged exposure to bupivacaine (direct root toxicity) b. Direct trauma during insertion 4. Arachnoiditis: a. General Features: 1) Clumped scarred nerve roots in the dural sac (MRI evaluation) 2) Following multiple surgeries or hemorrhage during myelography with pantopaque b. Myelogram/CT evaluation: 1) Clumped roots centrally 2) Root sleeve cut off 3) Featureless dural sac c. Clinical Presentations: 1) Severe burning pain in several root distributions > motor weakness 2) Constant; no exacerbating or relieving factors 3) Asymmetric reflex loss 5. Neurenteric cyst (usually asymptomatic) 6. Spina bifida: a. May be associated with congenital defects of the pedicle and foraminal exit cord b. Associated with congenital defects of the nerve roots 7. Congenitally enlarged nerve roots: HSMNI and III; rarely CMT2E which may cause myelopathy (compression) 8. Myxopapillary ependymoma: a. Asymmetric lumbosacral nerve root involvement b. Lower extremity weakness c. Bowel, bladder and sexual dysfunction 9. Dropped metastases:
SECTION VI. RADICULOPATHY
338
10.
11. 12.
13. 14.
a. Medulloblastoma b. Lung, breast, gastrointestinal tumor Traumatic nerve root avulsion a. Usually cervical cord (C5–T1) b. Severe trauma (motor cycle accidents) Plate fixation screw displacement Demyelinating Polyneuropathy (HSMN I and III) a. Compression of hypertrophic nerve roots b. Concomitant compression of the spinal cord c. Cauda equina dysfunction Hematoma: a. Epidural in location c. Blood dyscrasia b. Anticoagulation d. Lumbar puncture Complications of Epidural and Spinal Anesthesia a. General Features: 1) Toxic effects of anesthetic 2) Direct injury by needle or catheter 3) Subarachnoid injection of medication during epidural procedure 4) Contamination of anesthetic with detergents or chemicals (adhesive arachnoiditis) 5) Epidural abscess 6) Risk of epidural anesthesia increased with: a) Lumbar spinal stenosis (“pooling”) of anesthetic around specific nerve roots b) Inadvertent subarachnoid injection of high volume of anesthetic c) Combination of general and epidural anesthesia d) Advanced age b. Clinical features: 1) Radicular pain and weakness 2) Lower extremity myoclonus and severe spasm 3) Cauda equina syndrome 4) Usually clears after days to weeks
B.
C.
D.
E.
Chapter 7 Differential Diagnosis of Radiculopathy
F.
Cervical Roots
A. Congenital Defects: 1. Abnormalities of odontoid ossification centers (C1– C2) 2. Failure of odontoid tip fusion (C1–C2) 3. Platybasia (C1–C2) 4. Basilar impression (C1–C4) 5. Klippel-Feil Syndrome (C4–C7) 6. Sprengel’s deformity with Klippel-Feil (C4–C7) 7. Arnold Chiari Malformation (C1–C3) 8. Roos’ cervical bands (C4–T1) 9. Cervical ribs (C8–T1) 10. Perineural cyst (C1–T1; L1–S1)
G.
11. Thoracic outlet syndrome (C4–T1) 12. Branchial cleft cyst (C1–T1) 13. Spinal stenosis (lumbar > cervical > thoracic); L4– L5; C4–C5 often primary level 14. Achondroplasia (all roots); particularly severe C1– C3 15. Free fragment disc (lumbar > cervical; migrates up and down the cord) Lax ligament (hypermobility of odontoid process C1–C2 and concomitant cord compression) 1. Rheumatoid arthritis 2. Mongolism 3. Marfan’s syndrome 4. Ehlers–Danlos syndrome 5. Type VI collagen defects 6. Trauma (flexion–extension) Ligament hypertrophy (of all cervical roots) 1. Acromegaly 2. Mucopolysaccharidoses 3. Posterior ligament ossification syndrome Pachymeningitis 1. Syphilis (cervical > lumbar > thoracic) 2. Lymphoma (all roots) 3. Sarcoid (cervical > lumbar > thoracic) 4. Idiopathic pachymeningitis (cervical > lumbar > thoracic) 5. Tuberculosis (cervical > lumbar > thoracic) 6. Subarachnoid hemorrhage (lumbar > cervical > thoracic) 7. Arachnoiditis (lumbar > cervical) Degenerative disease 1. Cervical spondylosis (C5–C6; L5–S1 primary levels) 2. Spondylolisthesis 3. Spinal stenosis (L4–L5; L5–S1, primary levels) 4. Disc disease (hard desiccated disc; C5–C6; C6–C7; L4–S1 primary levels) 5. Foraminal exit osteophytes 6. Uncovertebral joint hypertrophy Tumor 1. Schwannoma 2. Neurofibroma 3. Meningioma 4. Pancoast (lung apex tumors) (C8–T1 primary level) 5. Lymphoma; lymphomatous B-cell 6. Leukemia 7. Salivary gland (adenocarcinoma) 8. Metastatic (carcinomatosis) 9. Post X-RT of breast (late onset) (C5–C6) 10. Chordoma (cervical C1–C4) 11. Osteogenic sarcoma 12. Ewing’s sarcoma 13. Chondrosarcoma 14. Hodgkin’s disease (neuromyotonia) 15. Lymphomatous B-cell radiculopathy Infection
Chapter 7. Differential Diagnosis of Radiculopathy
H.
I.
J.
K.
1. HIV 2. HTLVI; (mixed HTVI and concomitant HIV infection) 3. Herpes zoster 4. Herpes simplex 5. Brucella 6. Lyme’s disease 7. Bacterial infection a. Staphylococcus aureus (IV drug) b. Gram negative (post surgery) 8. Parsonage–Turner syndrome (C5–C6); viral 9. Polio 10. Hepatitis C 11. EBV 12. Adenovirus Immune mediated cervical radiculopathy 1. AIDP 2. CIDP 3. Post vaccination 4. Demyelinating (dorsal root entry zone; DREZ) 5. ADEM (Acute Disseminated Encephalomyelitis; overwhelmingly CNS demyelinating rare DREZ) 6. Specific Epitopes: a. GM1 d. Gd1b b. GAL-NAc-GDT1a e. SGPG c. GQ1b Trauma 1. Jumped facet joints 2. Rotary subluxation of facet 3. Disc Disease 4. Burst fracture 5. Anterior compression fraction 6. Spondylolisthesis 7. Plate fixation screw displacement 8. Epidural catheter trauma 9. Avulsion of the nerve root (C5–C6; C8–T1) Systemic disease 1. Diabetes 2. Acute intermittent porphyria 3. Variegate porphyria 4. Coproporphyrinuria 5. X-RT (myokymia, atrophy, sensory loss) 6. Idiopathic pachymeningitis 7. Sicca complex 8. Wegener’s disease 9. SLE 10. PAN 11. Amyloidosis: FOLMA/FAP-1 12. Necrotizing angiitis 13. Mixed connective tissue disease Vascular disease: 1. AVM of the root 2. Dural AVM 3. Dilated vein compression of the root 4. Klippel–Weber–Trenaunay
339
L. Plasmacytoma M. Paget’s Syndrome (sarcoma) N. Systemic disease: 1. Severe dying back neuropathies a. Diabetes mellitus b. Toxin c. AIP d. Severe B vitamin deficiencies 2. Ankylosing spondylitis 3. Hyperparathyroidism O. Immune mediated (similar to cervical root) Differential Diagnosis of Thoracic Root Disease
1. 2. 3. 4. 5. 6.
Disc disease (nerve root involvement by compression) Trauma (direct nerve injury) Amyloid (Charcot joint; loss of innervation) Diabetes (Charcot joint) Syphilis (Charcot joint) Ochronosis (homogentisic aciduria); multiple levels of degeneration 7. Spondylosis (dissection of disc; nerve root exit foramina compression) Infection
1. 2. 3. 4. 5. 6. 7. 8. 9.
HZ HIV Bacterial infection (staff aureus) TbC (T12) L1–L2 Nocardia Actinomycosis Herpes simplex Surgical disc space infection Epidural abscess
Trauma
1. 2. 3. 4. 5. 6.
Compression fracture Chest surgery (heart, lung) Intercostal neuralgia Jumped facet Rotary subluxation of facet joint Reflex sympathetic dystrophy (CRPS I and II) a. T1–T4 recurrent nerve of Kuntz; Intercosticobrachial nerve (derived from the medial cord of brachial plexus)
Systemic Disease
1. 2. 3. 4. 5.
Diabetes Amyloid Sicca complex Epidural hematoma (coagulopathy; anticoagulation) Homogentisic aciduria (ochronosis)
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SECTION VI. RADICULOPATHY
Tumor
Bone Tumors of the Lumbosacral Area
1. 2. 3. 4. 5. 6. 7.
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Anhidrosis/hyperhidrosis, CA of lung Meningioma Neurofibrosis Metastatic Leukemia Carcinomatosis of the meninges Lymphoma
Immune Mediated
1. 2. 3. 4.
CIDP AIDP Radiculopathy with increased sed rate Autoimmune epitopes a. MAG, SGPG, Gd1b, GQ1b, GM, Asia lo Gm1
Dermoid Lipoma Liposarcoma Chordoma Osteoblastoma Giant cell tumor of bone Osteosarcoma Chondrosarcoma Hemangioblastoma Hemangioma Aneurysmal bone cysts Metastatic disease a. Lung d. Prostate b. Breast e. Ovarian c. GI 13. Endochondroma
Differential Diagnosis/Lumbosacral Root Disease
Cancer Affecting Lumbosacral Nerve Roots
A. L1–S1 congenital defect 1. Conjoined nerve roots 2. Scoliosis (T12–L1–L3) 3. Block vertebrae (achondroplasia (T12–L1–L2) 4. HSMN-I, II, V (compression of roots) 5. Perineural cysts (all lumbar and sacral roots) 6. Congenital spinal stenosis; short pedicles; trefoil canal 7. Congenital midline/paravertebral dermal sinus (L4– S1) 8. Deep lordotic curve (L4–L5) 9. Meningomyelocele (L5–S1) 10. Diastematomyelia (T10–T12–L1–L2) 11. Reduplicated cord (L1–S5 roots) 12. Achondroplasia (L1–S5) 13. Spondylosis (pars interarticularis defect) 14. Sacral agenesis; caudal regression syndrome (L4–S5)
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Degenerative Disease of Lumbar and Sacral Roots
1. Disc disease: L4–L5; L5–S1 primarily a. Free fragment (penetrates posterior longitudinal ligament) b. Schmorl’s nodes (vertebral midline herniation) c. Far lateral disc (L1–S1) 2. Lateral recess syndrome (L5; S1) 3. Spinal stenosis (spondylosis, ligament, facet hypertrophy) 4. Facet hypertrophy (trophism) 5. Synovial cyst of the facet joint 6. Osteophyte formation in the foraminal exit canal 7. Spondylolisthesis
Carcinomatosis of the meninges (all cancers) Leukemia Hodgkin’s and non-Hodgkin’s lymphoma Myxopapillary ependymoma Metastases Prostate Lung Ovarian GI tract Renal carcinoma Any solid tumor
Systemic Disease
1. Diabetes mellitus: a. Amyotrophy b. Vasculitis 2. Connective tissue disease (similar to other roots) 3. Amyloid 4. AIP, variegate porphyria and coproporphyrinuria 5. Endometriosis 6. Sarcoid
Immune Disease (Similar to Cervical Root Illness) Toxins/Anesthesia
1. Epidural anesthesia (bupivacaine; direct trauma) 2. Pantopaque (contrast) 3. Metronidazole (contrast)
Chapter 7. Differential Diagnosis of Radiculopathy Trauma (Specific to Lumbosacral Nerve Roots)
1. 2. 3. 4. 5. 6. 7.
Surgery to decompress of nerve roots Transverse vertebral body displacement (MVA) Laparoscopy (higher pelvic roots > L5–S1) Instrumentation (plate and pedicle screw placement) Obstetrical–Gyn Surgery Hip replacement surgery (L4–S1) Decompressive laminectomy
Vascular Disease (similar to other roots) Infections (similar to other roots)
1. Cytomegalic virus infection more common in lumbosacral roots (late stage HIV) 2. Brucellosis (L5) 3. Lyme’s (L5) Miscellaneous
1. 2. 3. 4. 5. 6.
CRPSI Pyriformis syndrome (L4–S1) Osteomalacia Sacrum ala compression T1 damage causes Horner’s syndrome (C8–T1) T2 damage (sympathetic symptoms noted in the upper extremity abnormal sweating, pain, swelling, autonomic dysfunction)
Differential Diagnosis of Cauda Equina Syndrome or Polyradiculopathy
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
Spondylosis (multilevel neuroforaminal stenosis) Spondylolisthesis (congenital and acquired) Disc disease Spondylolysis Spinal stenosis Trauma (falls, skiing accidents, MVA) Primary spinal cancer Metastatic cancer; dropped metastasis Carcinomatosis of the meninges Neurofibromatosis “en plaque” Bone cysts Tarlov (perineural cysts) Pathologic fracture HIV CMV HZ; HS Lyme’s Disease Brucellosis Mycobacterium Syphilis (HIV patient population) Complication of spinal anesthesia Tethered cord Congenital defects Arachnoiditis CIDP HSMN (I/II)
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Section VII BRACHIAL PLEXUS
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Chapter 1. Introduction
Chapter 1 Introduction
1. General Features: a. Brachial plexus is in close proximity to mobile components of the neck and shoulder which make it susceptible to traction injury b. The brachial plexus has 5 anterior primary rami (APR) that are derived from the C4–T1, primary dorsal foramina between the scalenus anterior and medius muscle c. Trunks are superficial in the supraclavicular fossa d. The lower trunk is adjacent to the subclavian artery and apex of the lung e. Divisions of the plexus (retroclavicular area) are between the clavicle and the first rib f. Infraclavicularly: the cords surround the axillary artery and are close to the proximal humerus and the glenohumeral joint g. Proximal portions of the median, ulnar and radial nerves are adjacent to the proximal humerus and the axillary artery h. Trunks of the plexus form at the lateral border of the anterior and middle scalene muscles: 1) C5–C6 APRs coalesce to form the upper trunk 2) C8–T1 APRs form the lower trunk 3) C7 primary anterior ramus forms the middle trunk 4) Trunks split into anterior and posterior divisions: a) Divisions are located deep to the midportion of the clavicle in front of the first rib (during arm adduction) b) Anterior divisions of the upper and middle trunk from the lateral cord; the lower trunk anterior divisions form the medial cord c) Posterior division of the upper trunk, medial trunk and lower trunk fuse to form the posterior cord 5) Cords are situated below the clavicle in the axilla and are the longest components of the plexus 6) The terminal nerves are the median, ulnar, radial, musculocutaneous and axillary; they take origin in the peripheral axilla i. Supraclavicular plexus is injured more frequently than infraclavicular plexus j. Anterior primary rami (APR) injury occurs in: 1) Post median sternotomy incisions 2) Cervical rib-band syndrome k. Primary root and mixed spinal nerve involvement occurs in: 1) Neuropraxic injury 2) Costoclavicular space neoplasm (primary apical lung tumors)
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3) Root involvement: C5 to T1; C5–C6 most common; C7–T1 rarest l. Middle plexus is rarely affected alone m. Upper plexus is injured by severe trauma more than the lower plexus; an exception might be lower trunk involvement from closed neuropraxic injury (MVA) n. C8–T1 roots are most susceptible to avulsion; C7 is the next most susceptible o. Severe trauma ruptures the upper trunk > the C5–C6 roots lie within the foramina or lateral recess and are covered by fascia. C8–T1 and C7 are not covered by fascia 2. Nerves that arise from the brachial plexus above the clavicle: a. Dorsal scapular nerve (C5 anterior ramus): 1) Innervates the rhomboid muscle 2) A branch is a component of the phrenic nerve b. Long thoracic nerve: 1) Originates from the anterior ramus of C5, C6, C7 2) Innervate the serratus anterior muscle c. Suprascapular nerve: 1) Arises from the C5, C6 APR of the upper trunk 2) Traverse the suprascapular notch 3) Innervates the supra and infraspinatus muscles 4) Nerve to the subclavius derives from the upper trunk 3. Nerves that innervate the arm: a. Primarily arise from the cords b. Are below the clavicle c. Lateral cord: musculocutaneous nerves lateral head of the median nerve, lateral pectoral nerve d. Medial cord; ulnar nerve, medial head of the median nerve, medial pectoral nerve, medial brachial and ante brachial cutaneous nerves e. Posterior cord: axillary, radial, thoracodorsal and subscapular nerves f. No exact end between the terminal nerves and the major nerve trunks
Anatomic Variations
1. C4 anterior ramus sends a branch to C5 (a prefixed plexus); T1 component is small or absent 2. T2 anterior ramus contributes to T1 (a post fixed plexus); T2 component large and C5 may be absent 3. Pre and post fixed plexus occur in approximately 2% of patients 4. If C4 contribution to C5 is large, then the caudal portion of the plexus T1 may be attenuated 5. Plexus may expand from C4 through T2
Blood Supply of the Brachial Plexus
1. Primary artery is the subclavian:
SECTION VII. Brachial Plexus
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a. Supraclavicular components of the plexus are supplied by the ascending cervical, deep cervical, and superior intercostal arteries b. Roots are supplied by branches from the vertebral artery c. Infraclavicularly: cords are supplied by the subclavian, axillary and subscapular vessels
Chapter 2 Differential Diagnosis by Plexus Component
Middle Trunk by Location
1. Rarely occur alone (concomitant with upper and lower trunk lesions) 2. Weakness of forearm and wrist and some components of finger extension; weakness of forearm pronation, radial hand flexion 3. Sensory loss: a. Tinel’s sign at the Arcade of Frohse (medial to the lateral epicondyle) b. Dorsal portion of thumb, index and long finger c. Decreased triceps reflex (if proximal)
Supraclavicular
Clinical Signs and Symptoms
A. General Features: 1. Supraclavicular lesions present in myotomal and dermatomal distribution B. Infraclavicular Lesions are in Peripheral Nerve Distributions: 1. Obstetric palsy (Duchenne Erb) C5–C6; C8–T1 2. Brachial plexus traction injury (flexion–extension) neck injury); neurogenic thoracic outlet syndrome (neuropraxic lesions) 3. Neuralgic amyotrophy (parsonage Turner); C5–C6 roots most severely affected 4. Pack palsy (poorly packed knapsack) 5. Burner or Stingers (face mask injuries; sudden neck torsion) 6. Direct lateral neck trauma; open traction injuries 7. Cervical rib anomalies (C8–T1 roots) 8. Trauma from TOS surgery, C8–T1 > C5–C6 9. Infraclavicular lesions: 1) Trauma 2) Neurovascular causes 3) X-RT 4) Fractures of the humerus
1. Muscle involvement from lower trunk lesions: a. Ulnar innervated muscles of the hand and forearm (C8– T1 roots) b. Median innervated hand intrinsic muscles; muscles innervated by the anterior interosseous nerve c. Extensor indicis proprius; extensor pollicis brevis; innervated by the radial nerve d. Wasted medial forearm and hand (Klumpke’s paralysis from obstetric injury) e. Sensory loss: 1) Medial forearm to medial humerus in the axilla 2) Entire 4th and 5th fingers; ulnar nerve territory ends slightly above the wrist 3) Often Tinel’s sign at the cubital tunnel 4) T1 damage causes Horner’s syndrome 5) T2 damage, sympathetic symptoms noted in the upper extremity (abnormal sweating, pain, swelling, autonomic dysregulation)
Upper Trunk Lesions by Location
1. Involvement of serratus anterior, spinate, rhomboids, brachialis, brachioradialis 2. Abduction, external rotation of the shoulder; forearm flexion and supination are primarily involved 3. Sensory loss has two patterns: a. Lateral deltoid and lateral forearm b. Trapezius ridge and medial scapular border (most common) in neuropraxic injuries (C4–C7 roots are involved) 4. Lesions at the level of formation of the trunks: a. Serratus anterior and rhomboids are normal 5. Lesions at mid or distal upper trunk level: a. The supra and infraspinatus muscles are normal
Lower Trunk Lesions (C8/T1 root)
1. Most frequently involved with moderate to severe brachial plexus traction injury (neuropraxic) 2. Metastatic plexopathy 3. Pancoast tumor (apical lung) 4. Medial sternotomy 5. Breast surgery (arm hyperabducted during anesthesia); Intercosticobrachial nerve damaged 6. Thoracic outlet surgery 7. Klumpke’s paralysis (rare now; birth injury)
Differential Diagnosis of Subclavicular Lesions
1. At the level of the anterior and posterior divisions 2. Clavicular trauma (fractures): a. Immediate onset with direct neurological injury
Chapter 3. Traumatic Brachial Plexus Injury
b. Delayed: inadequate bony fixation; compression by excess callus formation 3. Compression between clavicle and first rib during surgical procedure for repair of Sprengel’s deformity 4. Component of neurogenic brachial plexus traction injury
Differential Diagnosis of Infraclavicular Plexus Lesions
1. Cords and terminal nerves affected: a. Deficits in distribution of two or more peripheral nerves or portions of their territories b. Differential diagnosis: 1) X-RT 2) Trauma 3) Neuropraxic injury (flexion–extension and torsional neck injury) 2. Lateral cord lesion Clinical symptoms and signs: a. Weakness of elbow flexion, forearm pronation, radial hand flexion (musculotendinous; lateral portion of median nerve) b. Sensory loss: 1) Lateral forearm 2) Thumb (particularly the base) index and radial side of the third finger) 3. Medial Cord Lesions: 1. Weakness of finger flexion; extension and abduction; ulnar wrist flexion and abduction 2. Medial half of the median nerve and the ulnar nerve are involved 3. Sensory loss: a. Medial forearm and arm b. Ulnar side of the 3rd finger; complete 4th and 5th finger 4. Posterior cord lesions: 1. Injury to the subscapular, thoracodorsal, axillary and radial nerves (proximal lesion) 2. Weakness of the abduction, forward elevation and extension of the shoulder; internal and external arm rotation; diminished forearm, hand and finger extension 3. Sensory loss is often partial: a. Posterior deltoid b. Triceps c. Dorsal base of the thumb d. Dorsal forearm
Differential Diagnosis of Infraclavicular Brachial Plexus Injury
1. Brachial Plexus traction injury (BPTI) of mild to moderate severity: a. MVA (flexion–extension or torsional neck injury) b. Falls
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c. Repetitive overhand arm movements d. Rotator cuff injuries 2. Severe infraclavicular plexus injuries: a. Motor cycle and car injuries b. Falls c. Gun shot d. Knife wounds e. X-RT plexopathy 3. Associated injuries in which infraclavicular plexus is involved: a. Long crutch injury (improperly used) b. Humeral head dislocation c. Clavicular, scapular, humeral fracture d. Axillary artery or vein rupture (surgical procedures)
Chapter 3 Traumatic Brachial Plexus Injury
A. General Principles: 1. The longitudinal excursion of the brachial plexus is 15.3 mm 2. The greater the traction the greater the injury 3. Primary roots are most susceptible to traction injury (arranged in parallel bundles rather than lattice and therefore decreased tensile strength) 4. Shoulder depression, lateral head flexion contralaterally injure the upper and medial trunk 5. Traction on the hyperabducted arm; greatest traction on the lower > middle > upper trunk 6. Preganglionic injuries usually are caused by a avulsion of the root 7. Traction injury may affect all or a portion of the plexus to a varying degree 8. C5 and C6 ruptures after leaving exit foramina; C8, T1 rupture closer to the spinal cord
Avulsion Injury
1. Differential diagnosis: a. High speed MVA; motorcycles most common b. Football, skiing, mountain climbing accidents 2. C5–C6 lesions after severe trauma: a. 27% avulsions; 33 ruptures 3. C8–T1 roots: a. 98% avulsion b. 1–2% rupture 4. Clinical signs and symptoms: a. Violent trauma b. Total plexopathy involvement common, C8–T1 > C5– C6
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SECTION VII. Brachial Plexus
c. Early consistent burning pain in an anesthetic hand; severe proprioceptive loss d. Horner’s syndrome (C8–T1 avulsion) e. Paralysis of serratus anterior, rhomboid, infra and supraspinatus muscles f. Negative supraclavicular Tinel’s signs g. Associated spinal cord symptoms and signs
Radiographic Features
1. 2. 3. 4.
Traumatic meningocele Fracture of the transverse process Flattening of the root sleeve Extravasation of contrast through the torn root sleeve during a myelogram
Obstetric Complications
A. General Features: 1. Rare in modern times; lateral neck traction or possibly damage in utero (seen following C-sections) 2. Preganglionic root avulsion, extra foraminal rupture, lesions in continuity 3. Males = females; R > L arm 4. Diabetic, multiparous, obese mothers; >4500 gram fetuses 5. C5–C6 upper trunk; C5–C6, C7 upper and middle trunk type: a. Most common type b. Extraforaminal rupture c. During vertex > breach delivery d. Sensory involvement < than motor e. Right extremity > left (right shoulder caught under the pubic bone) f. Bilateral involvement rare < 6%; associated with breach delivery 6. C8/T1 (in isolation): a. Rare b. Most often avulsion c. Rarely upper, middle and lower plexus are involved
Post Anesthesia Brachial Plexopathy
1. Follows surgical procedure; usually under general anesthesia 2. Abdominal operation (usually cholecystectomy or hysterectomy) 3. Usually unilateral; rarely bilateral; R = L arm 4. Upper plexus > lower plexus initially. Entire plexus may be involved 5. Weakness and paresthesias predominant symptoms 6. Rarely painful
7. Recovery begins 2–3 weeks after onset and may require several months to be complete 8. Sensory loss recovers first, followed by lower plexus, then upper plexus; then motor function 9. Rarely Horner’s syndrome; aching in dermatomal distribution with muscle tenderness 10. Malpositioning of the patient; probable traction injury of the plexus 11. Positions causing post operative paralysis: a. Supine b. Trendelenburg (steep and prolonged) c. Abduction of one or both arms to 90◦ or greater d. Extension and external rotation e. Rotation and lateral flexion of the head to the contralateral side f. Lower shoulder and arm compressed (lateral position) g. Flexed and prone position (back procedures); excessive and abduction and anterior arm flexion
Post Medial Sternotomy
1. Middle aged and elderly patients; open heart procedures 2. Sternum split vertically and retracted laterally 3. Lower plexus affected; ulnar fibers are disproportionately affected (C8; APR) 4. Unilateral hand weakness 5. 4th/5th finger and medial forearm paresthesias 6. Weakness of the lower trunk innervated fibers, damage to the C8 APR occurs 7. Incidence approximately 2–5% 8. May occur with cardiac transplantation 9. Probable sternal injury (fracture of the proximal first rib) 10. Recovers in approximately 4 months
Brachial Plexus Surgery
1. Most lesions occur during transaxillary first rib resection; less frequently with scalenectomy and neurolysis 2. No gender difference; young and middle aged patients are affected 3. Direct surgical injury or tractions of the plexus during surgery 4. Phrenic nerve may be involved concomitantly (particularly if the procedure involves the middle scalene muscle) 5. Site of lesion: a. Proximal lower trunk b. Distal C8 and T1 APR 6. Lower trunk usually involved (transaxillary rib resection); weakness immediately noted 7. Pain is the predominant symptom and gradually increases in severity (central sensitization)
Chapter 3. Traumatic Brachial Plexus Injury Shoulder Injuries with Concomitant Brachial Plexus Involvement
1. Humeral fracture or dislocation 2. Scapular fracture 3. Rotator cuff tear: a. Approximately 30% of these injuries are associated with brachial plexopathy b. All components of plexus may be injured c. Axillary mononeuropathy; posterior and medial > than upper trunk and lateral cord d. Falls > MVA > direct shoulder trauma are causative e. Traction injuries (neuropraxic) f. Older patients are more susceptible g. Humeral fractures and dislocated shoulders cause ischemic or a vascular compressive lesion h. Supra and infraclavicular (trunk and cord); terminal nerve injuries occur with reduction of shoulder dislocation i. Clavicular fracture with plexopathy: 1) Excess motion at fracture site 2) Exuberant callus formation 3) Tight figure of eight brace 4) Delayed onset (months to years) 5) Upper arm pain exaggerated by arm elevation 6) Weakness of the extremity (division compression)
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Laceration Injuries
1. Caused by knives or glass (fall through glass windows); dog bites, chain saws, propeller fans 2. Associated damage to blood vessels of the neck; axilla and upper lung 3. 33% injuries are in continuity 4. Knife or glass injury often focal
Postoperative Brachial Plexopathy
A. Clinical Features: 1. Clinical presentation transaxillary first rib resection: a. Weakness and wasting in lower trunk distribution b. Paraesthesias and burning pain in 4th and 5th fingers and medial forearm c. Less commonly: a. Patients awaken with flail arm, numbness and pain of the entire upper extremity b. Above pattern evolves to medial cord distribution B. Anterior Scalenectomy and Neurolysis: 1. Patients awaken with pain across the trapezius ridge and down the medial scapular border 2. Minimal weakness of the rhomboids, spinati, biceps 3. Occasional paresthesias of lateral deltoid and lateral forearm 4. Occasional weakness of ipsilateral phrenic nerve
Back Pack Palsies
1. Noted in military personnel and civilians using back packs; males > females 2. Related to pack design and weight; multiple mechanical and time dependent features 3. Possible congenitals structural or prior trauma as predisposing factors 4. Dominant or nondominant extremity affected 5. Preceded by transient episodes prior to fully developed syndrome 6. Muscle weakness and wasting of the shoulder, arm or forearm > pain; upper > middle trunk plexus innervated muscles involved; deltoid particularly involved 7. Sensory loss and reflex changes occur 8. EMG: conduction block > axon loss
Gunshot Wounds (Civilian)
1. 2. 3. 4.
85% male; average age 28 years 23% supraclavicular; 77% infraclavicular 50% affect cords or terminal nerves At surgery: majority of patients have plexus in continuity
Orthopedic Surgical Procedure
1. Chronic recurrent anterior shoulder dislocation: a. Putti-Platt; Bristow procedures b. During surgery: trauma to the musculocutaneous nerve most frequent; median, ulnar, radial and axillary nerves may be injured c. Concomitant damage to the axillary artery and vein d. Delayed onset plexopathy following modified Bristow procedure: 1) Bone screw that attaches the coronoid process to the glenoid rim works loose 2) Axillary artery pierced, pseudo aneurysm formation that compresses infraclavicular plexus 2. Shoulder joint replacement: a. Trauma to the axillary and supra scapular plexus 3. Arthroscopy of the shoulder: a. Trauma to infraclavicular nerves: 1) Musculocutaneous 2) Axillary 3) Ulnar 4) Radial b. Traction injury
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SECTION VII. Brachial Plexus
4. Surgical procedures that compromise the costoclavicular space: a. Operations to correct Sprengel’s deformity b. Midportion of clavicle surgery (fracture or to obtain access to subclavian vessels); regeneration of lateral clavicle with excess callus formation compresses the plexus 5. Direct trauma from arteriography and cannulas: a. Infraclavicular trauma brachial plexopathy from: 1) Cords of the plexus are adjacent to the second segment of the axillary artery; median nerve is on the surface of the artery 2) Leakage of blood from the puncture site that causes direct compression of terminal nerves median > ulnar > radial 3) Combination of median and ulnar nerve trauma 4) Clinical symptoms: a) Pain and paresthesias b) Arm weakness in characteristic patterns c) Onset of symptoms may be delayed up to two weeks 5) Nerve lesions from pressure in the medial brachial fascial compartment: a) Extends from the axilla to the elbow b) Formed by the medial intermuscular septum and surface of the medial upper arm c) Encloses the neurovascular bundle and the fascial axillary sheath b. Percutaneous cannulation of the subclavian and internal jugular vein: 1) Direct instrumentation induced trauma 2) Hematoma compression 3) Axillary mono neuropathy (occasional) 4) Upper trunk plexopathy (rare) c. Percutaneous brachial plexus block: 1) Injuries may be caused by: a) The block itself b) Tourniquet induced ischemia c) Post operative casting d) The surgical procedure 2) Axillary block approach more injuries than interscalene blocks 3) Usual symptoms are paresthesias in the median and ulnar nerve distributions 4) Slight weakness 5) May have delayed onset (up to 2 days) following the procedure
Neurovascular Brachial Plexus Injury
A. General Features: 1. Blood vessel and plexus may be injured simultaneously 2. Brachial plexus involved by secondary ischemia B. Clinical Presentations:
1. Latent period between injury and blood extravasation or pseudo aneurysm may be prolonged greater than a month 2. Neurologic symptoms may progress rapidly 3. Damage can extend over a long segment 4. Compressed nerves may have rapid functional decline 5. Pain and paresthesias are the presenting symptom 6. Traumatic neurovascular injuries often compromise one or more cords 7. Median and ulnar terminal nerves affected by iatrogenic injury 8. Rarely neurovascular injures are due to blood dyscrasias or as a consequence of anticoagulation
Closed Brachial Plexopathy (Specific Entities)
1. Recoil force of a rifle or shotguns against the clavicle: a. Upper trunk involved 2. Coma from drugs or alcohol: a. Lower trunk/medial cord involved 3. Traumatic asphyxia (crowd crush) 4. Miliary brace posture: a. Upper trunk injury (usually) 5. Body arm; vest restraints: a. Upper trunk
Arterial Vascular Thoracic Outlet Syndrome
1. Extremely rare 2. Adson’s maneuver positivity much more frequently seen in neuropraxic brachial plexus injuries 3. Males equal to females in incidence 4. Unilateral 5. Bony abnormality causes post stenotic dilatation, then aneurysm formation of the subclavian or axillary artery 6. Distal emboli from thrombi in the artery to the fingers 7. Ischemia of the hands and fingers 8. May have severe ischemic pain 9. Subgroup of patients suffer severe symptomatic ischemia of the extremity (when abducted)
Effort Venous Thrombosis of the Upper Extremity (Paget Von Schroetter Disease)
1. Thrombosis of the subclavian and axillary vein: a. Follows extreme exercise of the extremity b. Prolonged compression of axillary vein on a hard surface (arm outside window and resting on the door of a car) c. Abrupt presentation d. Upper extremity swelling, cyanosis, livedo reticularis e. Dilated venous collaterals over chest and shoulder f. Brachial plexus not involved
Chapter 4. Differential Diagnosis of Thoracic Outlet Syndromes Unusual Causes of Direct Brachial Plexus Injury
1. 2. 3. 4. 5. 6. 7.
Transaxillary bypass Radical mastectomy Thoracic sympathectomy Axillary A–V fistula for renal dialysis Reconstruction of a bound axilla Biopsy of brachial plexus tumor Burner syndrome: a. Upper plexus may show fixed symptoms; (mild motor, sensory and reflex changes) middle and lower plexus symptoms resolve b. Young male c. Contact sports (football, wrestling) d. Burning pain that usually subsides within an hour
Chapter 4 Differential Diagnosis of Thoracic Outlet Syndromes
Anatomical Variations of the Thoracic Outlet
1. Bone defects: a. Cervical rib b. Abnormal or rudimentary first rib c. Droopy shoulder syndrome d. Costoclavicular syndrome 2. Congenital bands or ligaments 3. Pectoralis minor (hyperabduction syndrome) 4. Large subclavian muscle 5. Tight thoracic inlet 6. Scalene triangle congenital defects: a. Narrow scalene triangle b. Proximity of anterior and middle scalene muscles c. High emergence of roots from the triangle d. Interdigitated muscle fibers between the middle and anterior scalene muscles e. Adherence of nerve roots to the anterior scalene muscle 7. Congenital narrowness of the costoclavicular space 8. Clavicle (acromial head depression compresses the costoclavicular space) 9. Tight pectoralis minor space (below the insertion of the pectoralis minor tendon into coracoid process): hyperabduction of arm closes the space
Anatomy of the Thoracic Outlet
1. The major components of the thoracic outlet: a. Sternocostovertebral space: 1) Most proximal part of the thoracic outlet tunnel
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2) Anatomy: a) Anteriorly demarcated by the sternum b) Posteriorly by the spine c) Laterally by the first rib 3) Subclavian artery, subclavian vein C4–T1 roots of the plexus traverse this space 4) Nerve roots have exited spine and have not formed trunks 5) Associated structures: a) Apex of the lung and pleura b) Sympathetic trunk c) Jugular vein d) Lymphatics of the neck 6) May rarely be congenitally narrowed 7) Usual pathology of the sternocostovertebral space: a) Thyroid mass b) Thymus enlargement c) Parathyroid mass d) Lymph nodes e) Lung f) Pancoast tumor (squamous or adenocarcinoma of the lung) b. Scalene triangle: 1) Anatomy: a) Bounded by the anterior scalene muscle anteriorly b) Middle scalene muscle posteriorly c) First rib forms the base 2. Anterior scalene muscles: a. Origin is the transverse process of C3–C6 b. Insertion on the scalene tubercle of the first rib varies; tubercle insertion is between the subclavian artery and vein and the pleural dome c. Variants of insertion: 1) Behind the artery 2) Between the artery and the brachial plexus 3) Entire base of the scalene triangle (traps the neurovascular bundle) 4) Anterior insertion may merge with insertion of the middle scalene muscle (20% of patients) 5) C5–C6 roots may transverse the anterior scalene muscle rather than descend between the anterior and middle scalene muscles 3. Middle scalene muscle: a. Origin is the transverse process of C2–C7 b. Insertion (Chassaignac’s) retroarterial tubercle of the first rib c. May insert on the fibrous septum of the pleural dome; lateral fibers insert on the second rib d. C8–T1 roots (individually or together as the lower trunk) compressed by more anterior or forward compression of the middle scalene muscle (sharp anterior edge); congenital fibromuscular bands noted along the anterior edge of the muscle may also compress the C8– T1 roots.
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SECTION VII. Brachial Plexus
4. First rib: a. Floor of the scalene triangle b. T1 closest to the rib c. Congenital rib anomalies, bony ridges, hypoplasia or inward curvature may compress the neurovascular bundle 5. Scalene triangle congenital variations: a. Base of the triangle 0.77 cm in men; 0.67 cm in women b. C5–C6–C7 emerge from the apex of the triangle; the fibers of the middle and anterior scalene muscles merge at the apex. Patients with C5, C6–C7 root involvement greater involvement incidence that have roots that emerge from the apex, inter digitation of anterior and middle scalene muscles. It occurs in 70% of symptomatic patients. Adherence of C5–C6 roots to the middle scalene muscles is another source of pathology 6. Costoclavicular space (compresses the brachial plexus) 7. Pectoralis minor space (compresses the brachial plexus)
Cervical Ribs
1. Gruber classification of cervical ribs: Type I – distal suggests plexus lesion Gluteus muscle innervation arises directly from the plexus Iliopsoas muscle is not involved in an obturator or femoral nerve lesion because its innervation is from the plexus directly
Lumbosacral Plexus (areas of injury)
1. Susceptible to trauma of the pelvic ring: a. Disrupted by double fracture dislocations b. Traction injury from dislocation of the hip joint 2. Femoral nerve compressed due to position: a. Occupies the gutter between the psoas and iliopsoas muscle above the inguinal ligament: 1) Surgical retractors (medially) 2) Injured laterally by hematoma between the iliacus fascia and the nerve 3. Lumbosacral cord (of the plexus) vulnerable to compression at the: a. Pelvic brim by the fetal head b. Obstetric forceps c. Aneurysm of the common iliac or hypogastric arteries in the presacral areas 4. Femoral nerve compressed: a. Angulation under the inguinal ligament b. Prolonged flexion abduction of the thighs (dorsal lithotomy position under anesthesia) 5. Fixation points of the common peroneal nerve are at the sciatic notch and fibular neck a. More vulnerable to traction injury
Chapter 2 Trauma of the Lumbosacral Plexus 1. Fracture: a. Double vertical fracture dislocations of the pelvic bony ring: 1) 50% of patients suffer neurologic compromise 2) Injury ipsilateral to iliac joint damage 3) Lumbosacral plexus cord is the level affected with consequent compromise of L5, S1 innervated muscles
b. Rupture, compression and traction injuries affect: 1) Lumbosacral trunk: a) Primarily L5 (contribution of L4 root) b) Contiguous with all of the sacrum adjacent to the sacroiliac joint 2) Obturator or superior gluteal nerves are injured 3) L5–S3 anterior rami may be affected 4) Concomitant vertebral body rupture 2. Traction injury of the lumbosacral plexus: a. Fracture dislocation of the hip joint and acetabulum b. Severe deficits occur that are often permanent 3. Intra-arterial injections: a. Injections into the buttock 1) Ischemic injury due to vasoactive drugs that are injected into the inferior gluteal artery causing ischemia of the sciatic nerve 2) Weakness, pain, and sensory loss in sciatic distribution may occur minutes to a few hours after the injury 3) Widespread lumbar plexus injury may occur due to the retrograde extension of gluteal artery spasm to branches of the internal iliac artery 4) Buttock skin may be painfully swollen, cyanotic, and develop gangrene 5) Painless lumbosacral plexopathy may follow cisplatin or fluorouracil injection into the iliac artery 4. Obstetric and gynecologic procedures that damage the lumbosacral plexus a. General Features: 1) Risk factors: a) Short women with large babies b) Primigravida 2) Post partum weakness: a) Lumbosacral trunk (primarily L5 root) compression at the pelvic brim over the sacroiliac joint: 1) Cephalic pelvic disproportion 2) Protracted labor 3) Midpelvic forceps delivery (a) Weakness of the anterior tibialis, extensor hallucis longus, and everters with foot drop sensory loss in the lateral lower leg and dorsum of the foot (b) Foot drop occurs on the side compressed by infant’s brow in an occiput anterior presentation b) Involvement of the quadriceps muscle: 1) Bilateral in 25% of patients 2) Associated obturator neuropathy c) Causes of peripheral femoral neuropathy: 1) Lithotomy position under anesthesia during vaginal delivery (compression under the inguinal ligament) 2) Separation of symphysis pubis with direct compression of the nerve by the fetal head 3) Epidural anesthesia
Chapter 3. Tumors of the Lumbosacral Plexus
4) Paracervical block affecting the posterior femoral nerve (pain may be delayed by several days) 5) Lumbosacral plexus compressed at the pelvic brim by uterine leiomyoma (accelerated growth during pregnancy) 6) Intrapelvic Schwannoma d) Catamenial sciatic nerve pain: 1) Implantation of endometrium either intra abdominally or at the sciatic notch 2) Endometrial deposits in the sciatic notch may be associated with an outpouching of a pocket of peritoneum 3) Peri menstrual pain in the buttock or posterior thigh
Surgical Trauma of the Lumbosacral Plexus
1. Laterally placed retractor blades compress the femoral nerve between the iliacus and psoas muscles: a. Abdominal hysterectomy b. Renal transplantation 2. Lumbosacral plexus, sciatic and femoral neuropathy occur after: a. Vaginal hysterectomy b. Modified lithotomy position (under anesthesia) c. Pelvic procedures (ovarian tumors and cysts) d. Neuropraxic lesions: 1) Stretch of the nerves and roots 2) Angulation of the nerves by hyperabduction of the thighs under anesthesia 3. Hip joint replacement a. 0.7–1% of hip replacement surgeries complicated by femoral, obturator or sciatic palsies b. Subclinical nerve damage occurs in a large number of hip replacements from: 1) Preoperative stretch injury due to hip dislocation 2) Hemorrhage 3) Heat 4) Toxicity from methylmethacrylate bone cement 5) Direct trauma and that from retractor blades 6) Post operative aneurysm formation 4. Aneurysm of the iliac or hypogastric artery: a. Rectal exam reveals firm pulsatile mass b. Surgical repair has been associated with ischemic plexus lesions c. Hemorrhage from aneurysm may compress the femoral nerve d. Sciatic nerve pain e. Retroperitoneal hematoma from abdominal aortic aneurysm leakage f. Rare severe stenosis of the abdominal aorta is associated with L5 symptomatology
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Chapter 3 Tumors of the Lumbosacral Plexus A. General Features: 1) Occurs in less than 1% of patients with neoplasm 2) Direct extension in approximately 75%; metastasis from extra abdominal sites in approximately 25% 3) In approximately 15% of patients lumbosacral plexopathy is the initial presentation 4) The lumbar plexus is affected in approximately 1/3 of patients; the sacral plexus in 50% and the rest in both plexuses (L5); bilateral involvement is seen in 25% of patients 5) Tumors that involve the lumbosacral plexus a) Colorectal, prostate, uterus, ovary are the primary tumors b) Invade by local extension c) Most common cause of lumbosacral plexus lesions is from is a colorectal tumor b. Metastatic lesions: 1) Breast 5) Thyroid 2) Lymphoma 6) Melanoma 3) Sarcoma 7) Testicular 4) Lung B. Clinical presentations: a. Severe unilateral pain radiating into L1–L4 roots; costovertebral angle pain b. Weakness of proximal roots L1–L4 with psoas and quadriceps weakness c. Lower extremity edema d. Warm dry foot if sympathetics are involved e. Lymphoma and lymphosarcoma may attain large size and present as a mass in the abdomen f. CT scan and MRI positive > 80% of the time by the time of clinical presentation g. Sacral bone involvement is often a sign of colorectal cancer h. Poor prognosis (less than two years) 4. Primary pelvic plexus tumors: a. Neurofibroma (nerve sheath tumor) b. Schwannoma c. Sarcoma (degeneration of benign neurofibroma) 5. Benign tumors: a. Compress the lumbosacral plexus b. Dermoid of the omentum c. Uterine leiomyoma
Irradiation Therapy
1. X-RT may induce: a. Malignant nerve sheath tumor b. Post irradiation lower motor neuron syndrome
SECTION IX. Lumbosacral Plexus Lesions
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2. X-RT therapy: a. General features: 1) Usual cancers irradiated are: a) Lymphoma d) Uterine b) Testicular e) Cervical c) Ovarian 2) Median time to onset of symptom is variable; usual is 5 years; some patients symptoms appear 30 years later 3) No relation between amount of X-RT and the latent period to symptoms 4) Rarely occurs with less than 4000 rads 5) Presents 1–5 years after external or internal cavity irradiation B. Clinical Presentation: 1. Bilateral slowly progressive leg weakness 2. Starts distally; usually L5–S1 roots; wasting and absent reflexes 3. Numbness and paresthesias may be presenting symptoms 4. Mild pain is late a symptom (approximately 50% of patients); aching, burning and lancinating in character 5. May arrest after several years (usually 5 years) 6. Associated bowel and bladder symptomatology from X-RT 7. CSF protein may be increased 8. Radiation osteitis of the sacrum (rare) 9. EMG: a. Myokymia in 60% of patients
Vasculitis: A. General Features: 1. Usually a necrotizing vasculitis (PAN) B. Clinical Presentation: 1. Develops acutely 2. Painful; weakness and fixed sensory loss 3. Progresses in a stepwise manner 4. Constitutional symptoms associated; eosinophilia, weight loss, granuloma of the respiratory tract, retinitis, purpura, CNS involvement C. Differential Diagnosis: 1. Diabetic microvasculitis 2. SLE 3. Periarteritis nodosa 4. Sarcoid 5. Steroid responsive lumbosacral plexopathy 6. Wegener’s granulomatosis 7. Pregnancy 8. Hereditary temperature sensitive plexopathy (AD)
Radiation vs Tumor Invasion of the Lumbosacral Plexus
Idiopathic Lumbosacral Plexitis
Radiation Plexopathy 1. Insidious onset and progression 2. First symptom is weakness 3. Bilateral involvement 4. Distal muscle weakness (L5–S1 roots) 5. Negative CT/MRI 6. EMG: Myokymia and fasciculation
Tumor Invasion 1. Rapid onset and progressive 2. Pain is in the initial symptom 3. Unilateral 4. Proximal weakness (L1– L4 roots) 5. Enhancing mass on MRI: destruction of bone 6. No Myokymia
Post-Irradiation Lower Motor Syndrome
1. X-RT of the lower thoracic and lumbar spine 2. Painless wasting and fasciculation of leg muscles 3. May have delayed onset from end of X-RT (months to years) 4. EMG: a. Denervation in the affected muscles
b. Sensory nerve action potentials and somatosensory evoked potentials are normal 5. Sphincter function is normal
Chapter 4 Medical Causes of Lumbosacral Plexopathy
A. General Features: 1. Age of onset is 30 months to 81 years of age 2. Monophasic and mild to a recurrent and severe course 3. Bimodal incidence: a. Prior to age 20 b. Between 40–60 4. Mild trauma and viral illness have been reported to precede illness in some patients 5. Children in general have a monophasic course; adults usually have recurrences 6. Counterpart of neuralgia amyotrophic B. Clinical Presentation: 1. Abrupt onset of unilateral pain in the anterior thigh (lumbar plexitis), buttock and posterior thigh (sacral plexitis); some patients have more prolonged onset with recurrent bouts of pain 2. Muscle weakness within 5–10 days of onset of the pain; may progress for days to weeks; the pain resolves as weakness supervenes 3. Muscle weakness of L1–L4 roots most common, associated with positive femoral reverse SLR nerve test and absent quadriceps reflex
Chapter 4. Medical Causes of Lumbosacral Plexopathy
4. Lower plexus involvement; positive Tinel’s sign at the sciatic notch and posterior popliteal fossa; weakness of the anterior tibialis, everters of the ankle and the extensor hallucis longus muscle. Absent ankle reflexes. 5. Paresthesias may occur after reduction of pain. Objective sensory loss may be subtle. 6. Process may be bilateral 7. Recovery is usually prolonged (over months) and is incomplete 8. Elevated sed rate 9. Occasional slight increase of protein in the cerebral spinal fluid Diseases Associated with Lumbosacral Plexitis
1. Following administration of serum 2. May occur in patients with brachial amyotrophy 3. Heroin IV (adulterated with quinine and Librium) a. Symptoms often delayed after IV dose b. Associated with rhabdomyolysis c. Possible response to steroid Proximal Diabetic Neuropathy
A. General features: 1. Involvement of nerve roots and the lumbosacral plexus 2. 8% prevalence in Type I and II diabetic patients 3. Rarely the presenting feature of DM 4. Most common onset is sixth to seventh decade 5. Usually seen in Type I diabetes controlled by diet and oral hypoglycemic agents 6. Rare to have concomitant nephropathy, retinopathy or history of coma B. Clinical Presentation: 1. Severe anterior thigh pain is suffered early 2. Quadriceps weakness occurs over a few days to months 3. Sensory loss < weakness 4. Bilateral asymmetric involvement is frequent (usually after six weeks) 5. A history of 10–15 pound weight loss is seen 6. Knee jerks are absent; an occasional Babinski sign is noted 7. Persistent muscle deficit is noted although the majority of patients improve over a year 8. Recurrences occur 9. Sed rate is elevated in 20% of patients 10. CSF protein slightly elevated (120 mg% suggests nerve root involvement) 11. EMG: a. Affected muscles demonstrate denervation b. Demyelination and axonal loss in intramuscular nerves 12. Microangiopathic vasculitis has been recently demonstrated
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Infections Affecting the Lumbosacral Plexus
1. Abscess: a. Bacterial abscess whose origin is the psoas or paraspinal muscles is rare b. Perirectal abscess: 1) Immunocompromised patients 2) Prior rectal surgery 3) Fever in association with groin, abdominal or back pain a) Usually sciatic nerve radiation b) L4–S2 motor/sensory dysfunction 2. Anogenital herpes simplex (higher roots; L1–L4) 3. Herpes Zoster (L5; S1 roots) 4. Tuberculosis (cold abscess; involving the psoas and iliacus muscle; T12–L4 roots) 5. Pyelonephritis 6. Appendicitis (upper roots of the plexus; characteristic iliopsoas spasm) 7. Iliacus muscle abscess (following laparoscopy) 8. Schistosomiasis japonicum (recurrent) 9. Lyme’s disease (L5 root most common) 10. Brucellosis (recurrent L5 root) 11. CMV (entire lumbosacral plexitis; HIV associated) 12. Syphilis (dorsal root entry zone; meninges) stage II; HIV associated 13. Epidural abscess (surgery; catheters; osteomyelitis)
Anogenital Herpes Simplex
1. May involve lower motor neurons of the sacrococcygeal plexus 2. Paresthesias and sensory loss of the perineum, buttocks posterior thighs 3. Urinary retention, constipation and erectile dysfunction 4. Reduced tone of the anal sphincter: sensory loss in sacral dermatomes; loss of the bulbocavernous reflex 5. Dermatomal leg weakness and sensory loss 6. More diffuse weakness is attributable to associated myelitis; possible demyelinating process 7. The anogenital primary lesion may be on the cervix 8. HS Type 2 > 1 9. Mild meningeal irritation noted in some patients 10. Lymphocytic pleocytosis 11. Confirmed by PCR 12. Symptoms last 10 days to 3 weeks; good recovery 13. Approximately 1% of women with primary anogenital infection develop plexopathy 14. Most frequent incidence is in males with herpetic proctitis 15. Rare in recurrent herpetic attacks
SECTION IX. Lumbosacral Plexus Lesions
370 CMV Infection
1. Lumbosacral plexitis noted in severely ill HIV patients 2. CD4 counts less than 200/mm3 ; frequently less than 50 mm3 3. Severe pain and paresthesias in lumbar sacral areas; sexual dysfunction 4. Associated retinitis
IV Drug abuse
1. Pyogenic organisms: staph aureus most common 2. Affects the disc space (end artery) 3. Severely painful (vibration of the bed causes pain); very positive meningeal irritation signs 4. Involvement of anterior and posterior vertebral space: positive enhancement with gadolinium on MRI of muscle and infected areas 5. Lumbosacral roots themselves may enhance with MRI
EBV Infection
1. Gluteal or thigh pain 2. Leg weakness; decreased knee and ankle reflexes 3. CSF: increased lymphocytes; slightly elevated protein
Lyme Disease
1. Buttock pain 2. Sciatic nerve weakness
Hereditary Liability to Pressure Palsy
1. Chromosome 17 deletion (reciprocal of duplication of HSMN I) 2. Less frequently seen than in upper extremity 3. Clinical presentation: a. Pain in the buttock and leg b. Weakness of affected myotomes c. Loss of reflexes d. Sensory loss of affected dermatomes 4. Women may become symptomatic puberally 5. Rare to have severe pain 6. Patients may not recall the episode of nerve compression 7. Distal > proximal weakness
Chapter 5 Retroperitoneal Hemorrhage 1. Lumbar plexus may be compressed within the psoas muscle:
a. Weakness in territories of both obturator and femoral nerves 2. Femoral nerve may be compressed in isolation by hematoma within the iliacus muscle: a. Iliacus fascia is tighter than psoas fascia: smaller hematomas produce femoral compression more frequently than diffuse lumbar plexus damage 3. Iliacus and psoas hemorrhage: a. During anticoagulation b. Heparin > warfarin c. Often no preceding trauma; occasionally trivial trauma precedes the hemorrhage 4. Differential diagnosis of hemorrhagic plexus lesions: a. Athletic injury; hyper extension and avulsion of the iliacus muscle from the ilium b. Localized blunt trauma; pelvic fracture c. Disseminated intravascular coagulation d. Hemophilia or other clotting disorders e. Leukemia f. Aneurysmal rupture g. Injection site in the buttocks (patients with bleeding diathesis) h. Anticoagulation Clinical Presentation of Femoral Nerve Compression by Iliacus Hematoma
1. Pain in the groin radiating to anterior thigh and medial lower leg (L3, L4) 2. Position of comfort; flexed hip 3. Positive reverse straight leg raising test 4. Minimally painful Patrick’s maneuver (internal/external rotation of the hip) 5. Weakness of quadriceps; loss of sensation in femoral nerve territory 6. Hematoma may be palpable in the iliac fossa or the groin Psoas Muscle Hematoma
1. Causes Plexopathy 2. Negative reverse straight leg raising test (forced hip extension) 3. Hip is not usually flexed; initially severe groin and lower abdominal pain 4. No palpable hematoma; rarely a groin mass is palpable 5. Thigh adductor muscle weakness (obturator nerve) 6. Rarely hip flexion with external rotation of the leg is painful 7. Abrupt drop of hemoglobin 8. Hemorrhagic plexus lesions: a. Rarely bilateral b. Differential diagnosis includes: 1) Appendicitis 2) Post surgical procedures
Chapter 6. Immune Mediated/Toxic and Anesthetic Causes of Lumbosacral Plexopathy
Chapter 6 Immune Mediated/Toxic and Anesthetic Causes of Lumbosacral Plexopathy
1. AIDP (may hit proximal plexus) 2. CIDP (distal nerve greater than proximal roots) 3. Specific epitope syndromes: a. GM1 d. SGPG b. Gal-NAC-GTd1a e. Anti sulfatide c. MAG 4. Paraneoplastic: a. Anti-Hu c. Anti-MA b. At-Yo d. Anti-TA 5. Post vaccination 6. Post serums (anti-venoms)
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Toxins/Anesthetics
1. Lidocaine/bupivacaine 0.25% or greater concentration by epidural catheter 2. Benzyl alcohol (adjuvant of anesthetics) 3. Heroin: a. Delayed symptom (1–2 days) b. Diffuse pain c. Minimal weakness or sensory loss d. Pain clears prior to recovery of motor function
Cause of Gadolinium Enhancement of Lumbosacral Plexus on MRI
1. Carcinomatous meningitis 4. Arachnoiditis 2. AIDP 5. CMV 3. CIDP 6. Sarcoid
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Section X DIFFERENTIAL DIAGNOSIS OF PERIPHERAL NEUROPATHY
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Chapter 1. Introduction
Chapter 1 Introduction
The differential diagnosis of peripheral neuropathy is based on six major constructs: 1. The size of the fiber that is involved in the peripheral nerve that is affected 2. The pattern of motor or sensory loss 3. The time course 4. Genetics 5. Associated medical conditions 6. Exposure to toxins and medicines Seventy-five percent of peripheral neuropathies can be diagnosed. This percentage will increase as new epitopes on dorsal root ganglion cells, Schwamm cells, and peripheral myelin are identified and their corresponding genes cloned. The patient’s predominant symptoms suggest the fiber size that is involved which focuses the examination on the physical findings subserved by that fiber size. The smallest unmyelinated fibers are C-fibers and autonomic fibers that are 1u in size. The predominant symptom expressed by these patients is burning pain or autonomic dysregulation. These fibers are primarily involved in neuropathic pain in which the nerve fibers themselves are injured. A-delta (1–4u) fibers or thinly myelinated fibers are also considered small fibers and cause sharp lancinating pain, cold sensation and deep ache (muscle pain afferents). Allodynia, hyperalgesia and hyperpathia characterize neuropathic pain. These sensations are caused by direct sensitization of peripheral C-fiber endings and changes induced in the central pain projecting neurons of the dorsal root ganglion, dorsal born and central pain systems. Mechano allodynia (an innocuous mechanical stimulus is perceived as painful) is divided into static and dynamic subtypes. The former implies sensitization of C-fibers (lower threshold to fire) and the later in which a moving stimulus is painful (Aβ fibers). Dynamic allodynia is primarily a central process at the dorsal horn level. Small fiber neuropathies demonstrate spontaneous pain (ectopic firing near the DRG) as well as hyperalgesia (increased pain from a painful stimulus). Cold hyperalgesia is particularly suggestive of neuropathic pain. Hyperpathia (a higher threshold to fire pain fibers that once exceeded causes overwhelming pain that is not stimulus bound) requires central nervous system changes. This is most often associated with chronic regional pain syndrome I and II which is often secondary to peripheral C and A-delta fiber injury. Autonomic fiber symptomatology (1u unmyelinated) involves autonomic dysregulation that is seen as postural hypotension, obstipation, difficulty with sexual function, micturition, pupillary and sweating (hypo or hyperhidrosis) abnormalities. Characteristically small fiber neuropathies have decreased pain and temperature thresholds, minimal weakness and retained reflexes.
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Large fiber neuropathies (12–22u) have deficits in motor, vibratory and proprioceptive function. Patients demonstrate sensory ataxia, distal and proximal motor weakness, positive Romberg sign, poor balance and loss of reflexes. In general, both large and small fibers are involved in neuropathies and demonstrate motor, sensory and autonomic features. Frequently sensory, phenomena are noted first with the gradual development of motor and autonomic phenomena, coldness of the affected extremities is the most commonly noted symptom of autonomic involvement in mixed peripheral neuropathy. The distribution of the sensory loss is extremely important in differential diagnosis. Axonal metabolic dying back neuropathies (length dependent dying back neuropathy) affect the longest axons. Patients have deficits in the toes and legs. The hands become involved when the process crosses the knees. The center part of the chest loses sensation in what is known as a shield distribution. The maintaining dorsal root ganglia are in the thoracic spine and the most distal of their axons are in the central chest. Similarly the chin and midface may be affected before the C2 region, anterior to the ear. In general, these neuropathies progress symmetrically although initially they maybe slightly asymmetric. Some polyneuropathies demonstrate a proximal symmetrical pattern of weakness. These include Guillain–Barré Syndrome, some patients with acute intermitted porphyria and chronic inflammatory demyelinating polyneuropathy. Rarely patients may have a proximal accentuation of weakness on a distal length dependent process such as occurs with diabetes and HIV. Focal neuropathies are chronic with entrapments in the various tunnels, mononeuritis multiplex from infarction of nerves or compression. These may be genetic as is the case with hereditary neuropathy with compression palsy (deletion on chromosome 17) or mechanical from trauma, anesthesia, alcohol or coma. Mononeuritis multiplex has recently been described to present with a distal symmetric polyneuropathy. Monoradiculopathies, polyradiculopathies and plexopathies are distinguished by their characteristic patterns of involvement. Differential diagnosis becomes more complex in situations where there are several simultaneous processes. Older patients have some cervical and lumbar spondylosis particularly at C5–6 and L5–S1 levels. Shoulder injuries may damage the brachial plexus, individual nerves and nerve roots. Diabetic and HIV infected patients have pathology at root, nerve and plexus levels. Almost all patients with CRPS I/II have multiple nerve, plexus and root components that maintaining the process. As a general rule, in the upper extremities root disease is primarily felt proximally and rarely radiates to the fingers. The exception is C6 which radiate to the lateral forearm, thumb and index fingers. C7–T1 almost never gets injured as this is a non-movement segment. Plexus and nerve problems radiate to the hand. In the lower extremity the reverse is true. Radicular pain frequently radiates to the foot while plexus
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
problems are felt proximally. Nerve problems are experienced proximally and distally. At times, polyradiculopathies at L4– L5 and L5–S1 may simulate neuropathies. Most of the time patients have had back, buttock and posterior thigh radiations at some point in their course. The examination demonstrates the involved nerve roots. Multifocal neuropathies may have characteristic distributions such as cold parts of the body in leprosy (ear lobes, nose, and dorsal extremities) and a regional distribution in CRPSI. The temporal profile of a neuropathy may be divided into: 1. Acute (progressing over days to weeks) 2. Subacute (6 months to one year) 3. Chronic (6 months to years) Within this time frame the process may be: 1. Monophasic 3. Progressive 2. Intermittent Acute neuropathies are generally autoimmune, toxic exposures, critical care or acute intermittent porphyria. Subacute neuropathies may be autoimmune, paraneoplastic, metabolic or vitamin deficiencies. Chronic neuropathies are often hereditary or metabolic (uremia, diabetes, liver failure). Axonal neuropathies are characterized by distal muscle weakness, atrophy and fasciculation whereas demyelinating neuropathies demonstrate weakness and loss of deep tendon reflexes out of proportion to atrophy. In type I, III hereditary sensory motor neuropathy large nerves may be palpated. Hereditary neuropathies are suggested by pes cavus, a fore shortened foot and intrinsic foot muscle atrophy. The insertion of the gastrocnemius muscles in the lower extremities is too high and there is distal 1/3 of the quadriceps muscle atrophy. The forearm flexor muscles may also have a proximal insertion which causes thin wrists and ankles. Patients may have associated Kyphoscoliosis, ataxia, cardiomyopathy and other dysmorphisms. The process is extremely slow. Patients may note that it was always difficult for them to stand in one place without shifting weight due to deep ache in the legs. They may have had difficulty running and were clumsy in their adolescent years. 10% of patients with hereditary neuropathies have abnormally flat or “rocker bottom feet”. Most of these patients have little sensory loss. They suffer an undue number of twisted ankles due to peroneal muscle weakness. Family members are often affected, but are unaware of the condition. Almost all neuropathies that are acquired have a seminal feature that allows a clinical diagnosis. The following differential diagnosis of peripheral neuropathy will concentrate on the specific history and physical examination that allow a clinical diagnosis.
Sensory Neuropathy
As noted in the general review of differential diagnosis of neuropathy, sensory neuropathy may be divided into those that affect:
1. 2. 3. 4.
Large fibers Small fiber Dorsal root ganglion (large neurons) Proximal DRG root components. These may further be divided into those with specific autoimmune epitopes on large and small fibers as well as the DRG to which antibodies are made. Other causes include: demyelinating sensory neuropathies, inherited, infectious, toxic/metabolic and sensory neuropathy associated with systemic disease. Ataxic sensory polyneuropathy, idiopathic sensory neuropathy and chronic painful neuropathies may have a predominant DRG pathology. A-delta fibers (1–4u) mediate lancinating shooting pain and cold sensations. They may also be involved in deep muscle ache. C-fibers mediate burning pain, heat, and some deep muscle pain. Burning pain, lancinating pain, amhidrosis and autonomic dysregulation with intact strength, large fiber sensation and reflexes are characteristic of small fiber neuropathies. Blended sensations such as cold-pain also suggest small fiber involvement. The nervi nervorum that innervate plexus and nerve sheaths are also small fibers and often are activated at the site of injury from released inflammatory cytokines (TNF- alpha, IL1 and IL6). The nerves so involved are hypersensitive throughout their course. This pattern is frequently described as fibromyalgia as the entrance points of the trunks and nerves of the plexus are sensitive to pressure (Tinel’s signs) as they enter the extremity. Careful examination of the pupils for poor response to light, light near dissociation (constrict to near response greater than light), an hidrosis, severe constipation or nocturnal diarrhea, postural hypotension, (abnormalities of the RR interval on EKG (indicative of a cholinergic deficit) and sexual dysfunction make a diagnosis of autonomic neuropathy. Autonomic neuropathy can be both acute, and chronic as well as being a component of sensorimotor neuropathy.
Chapter 2 Acute Predominately Small Fiber Sensory and Autonomic Neuropathy Diabetes Mellitus
A. General features: a. Autonomic neuropathy usually occurs with type I diabetes b. Incidence is not determined c. Frequently autonomic components noted in typical dying back neuropathy B. Clinical presentation: a. Postural hypotension elicits no compensatory increase of pulse rate b. Resting tachycardia
Chapter 2. Acute Predominately Small Fiber Sensory and Autonomic Neuropathy
c. Nocturnal diarrhea d. Light near dissociation (poor pupillary response to light with constriction to convergence) e. Gastroparesis (slow intestinal transit time) f. Impotence (may occur prior to overt neuropathy) g. Patchy loss of sweating C. EMG: a. Lower extremities involved earliest b. Abnormalities may occur while the patient is asymptomatic c. Axonal neuropathy with reduced CMAP and SNAP; fibrillations d. Decreased sympathic skin responses e. In time: 1) Segmental demyelination with prolonged distal latencies 2) Conduction block 3) Temporal dispersion 4) Prolonged F waves 5) Slowed conduction velocities D. Pathology: 1. Degeneration of autonomic nerves and ganglia 2. Microangiopathy
Dimethylamino Propionitrile (DMAPN)
A. General features: 1. Catalyst in polymerization reaction for polyurethane foam 2. Toxic distal axonopathy 3. Clinical features: a. Earliest sign may be urinary hesitancy and sexual dysfunction b. Numbness develops in the feet and spreads proximally to the legs and hands c. Weakness develops first in the toe and foot extensors d. Atrophy of involved muscles is rare e. Tendon reflexes are preserved f. Often affects small fibers selectively
Pandysautonomia
A. General features: 1. Follows acute viral infection (10–14 days). Rarely it is paraneoplastic. 2. Severe postural hypotension 3. Wildly fluctuating heart rate; no RR variation with breathing 4. Patchy or generalized hypohidrosis 5. Light near dissociation of pupillary function; 3–4 mm pupils 6. Normal strength 7. Retained deep tendon reflexes
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8. Bowel, bladder and sexual dysfunction 9. May have associated decreased motor and sensory NCVs B. Pathology: 1. Degeneration of autonomic ganglia and nerve
Acute Idiopathic Small-Fiber Sensory Neuropathy
A. General features: 1. Loss of pain and temperature sensation in a stocking glove distribution 2. Suffused fingers and toes (early autonomic dysregulation) 3. Anhidrosis 4. Livedo reticularis (mottling of the skin) 5. Normal or minimal distal weakness 6. Retained deep tendon reflexes 7. Severe generalized fatigue (often signals an exacerbation)
Chronic Small Fiber Neuropathies
A. General features: 1. Hereditary Sensory Autonomic Neuropathy I a. Genetics: 1) AD; chromosome 9q 22 B. Clinical presentation: 1. Onset in the second decade 2. Loss of pain and temperature distally in the lower limbs which progresses to the upper limbs 3. Later touch vibration and position sense are affected 4. Slight distal motor weakness 5. Spontaneous lancinating pain or generalized deep ache of muscles 6. No autonomic signs or symptoms 7. Neuropathic joint degeneration (Charcot joints) 8. Persistent foot ulceration (volar first and second metatarsal) C. EMG: 1. Normal nerve conduction velocity 2. HSAN II a. AR 3. Similar clinical presentation
Hereditary Sensory Autonomic Neuropathy III (Riley–Day Syndrome)
A. General features: 1. Genetics: AR; primarily Jewish children a. Chromosome 9q 31–33 b. Incidence 1 : 50,000 people B. Clinical presentation:
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
1. Noted in infancy with recurrent vomiting, feeding problems, pulmonary infections 2. Autonomic dysfunction: a. Defective temperature regulation b. Livedo reticularis of the skin c. Episodic hypertension and postural hypotension 3. Absent fungiform tongue papillae 4. Kyphoscoliosis 5. Congenital insensitivity to pain 6. Excessive sweating from emotional stimuli 7. Progressive deficits 8. Renal complications C. EMG 1. Normal motor and sensory nerve conduction velocities D. Pathology
Congential Sensory Neuropathy with Anhidrosis (HSAN IV)
A. General features: 1. Genetics: AR B. Clinical features: 1. Presents in infancy 2. Delayed motor development 3. Episodic hyperpyrexia 4. Insensitivity to pain and decreased temperature sensibility 5. Cutaneous ulceration; bone fractures 6. Self mutilation C. EMG D. Pathology: 1. Selective loss of small myelinated fibers in sensory nerves; absence of unmyelinated fibers
3) chromosome 18 q 11–12 (apo A1 on 11 q ter) 4) most common form of hereditary amyloid neuropathy B. Clinical features: 1. Onset in the 3rd and 4th decade 2. Insidious loss of pain and temperature in the leg 3. Associated pain and paresthesias 4. Loss of position and vibratory sensation in the upper extremities 5. Distal wasting, weakness and a reflexa appear later; AJ may be spared 6. Autonomic dysfunction is seen early: a. Postural hypotension b. Impotence c. Distal anhidrosis d. Large poorly reactive pupils; light near dissociation e. Bowel and bladder dysfunction f. Neuropathic arthropathy and foot ulcers g. Amyloid deposits in the vitreous (primary uveal veil) h. Cardiomyopathy (dilatated) i. Renal involvement j. Slowly progressive k. Death within 10 years of onset
Type II (Rukavina variant)
A. General features: 1. Genetics: AD B. Clinical features: 1. Often presents with carpal tunnel syndrome 2. Similar to Type I amyloid in regard to sensory, motor and autonomic signs 3. Insidiously progressive 4. Visceral deposition of amyloid
Hereditary Sensory and Autonomic Neuropathy (Type V)
A. General features: 1. Genetics: B. Clinical features: 1. Selective loss of pain sensibility 2. Decreased sweating C. EMG D. Pathology: Loss of small myelinated fibers; large unmyelinated fibers and large myelinated fibers
Type III (Van Allen Variant)
Hereditary Amyloidosis
Type IV (Meretoja Variant)
A. General features: 1. Andrade Variant Type I: a. Genetics: 1) AD 2) mutation of the transthyretin gene
A. General features: 1. Genetics: AD B. Clinical features: 1. Cranial neuropathy 2. Lattice corneal dystrophy
A. General features: 1. Genetics: AD B. Clinical features: 1. Autonomic features less conspicuous than those noted with Type I 2. High incidence of duodena ulcers
Chapter 2. Acute Predominately Small Fiber Sensory and Autonomic Neuropathy
3. Skin laxity 4. Onset with corneal opacities is usually in the 3rd decade 5. Neuropathy in distal extremities develops later
Tangier Disease
A. General features: 1. Genetics: AR a. Mutation in the gene encoding the ATP binding cassette reporter ABC-1 b. Chromosome 9 q 31 c. Protein encoded: cholesterol efflux regulatory protein: 1) Putatively important for intracellular cholesterol transport d. Allelic to AD, HDL deficiency e. Described from Tangier Island in Chesapeake Bay; less that 100 patients described B. Clinical features: 1. Approximately 50% of patients have peripheral nerve involvement 2. Onset may be in childhood or during adult life 3. Deposition of cholesterol esters in the tonsils, spleen, lymph nodes, thymus, intestinal mucosal, cornea and peripheral nerves; most often asymptomatic 4. Enlarged orange tonsils; slight hypersplenism; premature coronary artery disease in some patients C. Patterns of Clinical neuropathy: 1. Mononeuritis, relapsing, asymmetric: a. EMG: normal NCV; rare prolonged distal latencies b. Pathology: de and re-myelination 2. Symmetric polyneuropathy: a. Legs greater than arms b. EMG: normal NCV c. Pathology: clear vacuoles in Schwann cells of unmyelinated and thinly myelinated fibers 3. Symmetric polyneuropathy: a. Slowly progressive b. Facial and intrinsic hand muscle involvement c. Loss of pain and temperature sensation that may spare the distal extremities D. EMG: 1. Low or absent SNAPs 2. Low motor amplitudes in the arms; denervation of the hands and face E. Pathology: 1. Axonal degeneration of unmyelinated and thinly myelinated fibers 2. Loss of small DRG cells, anterior horn cells and facial nuclei neurons F. Laboratory features: 1. Very low plasma HDL (α-lipoproteins) 2. Low plasma cholesterol 3. Normal or increased triglyceride levels
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Fabry’s Disease (α -Galactosidase Deficiency)
A. General features: 1. Genetics: a. X-linked recessive b. Deficiency of lysosomal hydrolase α-galactosidase c. Gene for α-galactosidase located on Xq22 d. 25–33% of patients have spontaneous mutations e. Mutations described are: gene rearrangements, splice junction deficits and point mutations f. Deposition of globotriaosylceramide in vascular lysosomes B. General presentation: 1. Presents in childhood or adolescence 2. Hypohidrosis with severe heat intolerance may occur 3. Angiokeratoma corporis diffusum (telangiectatic skin lesions): a. Bathing suit distribution b. Conjunctival c. Under the nail beds d. Oral mucosa 4. Associated medical conditions: a. Renal failure (in the forties) b. Easy bruisability c. Stroke d. Hypertension e. Myocardial infarction f. Corneal opacification g. Carrier females: lumbosacral disc degeneration 5. Neuropathy: a. Characteristically burning pain distally in the extremities; associated with anhidrosis b. Pain may be triggered by physical exertion and emotional stress c. Facial swelling and coma due to hyperpyrexia C. Laboratory: 1. Decreased α-galactosidase activity in leukocytes or cultured skin fibroblasts 2. Globotriaosylceramide in the urine D. Pathology: 1. Deposition of globotriaosylceramide in autonomic and dorsal root ganglia of the peripheral nervous system 2. Globotriaosylceramide deposits in vascular lysosomes
Autonomic Variant of GBS
A. General features: 1. Fixed tachycardia and sweating in mild form 2. ventricular tachycardia and rare asystole 3. shock with hypotension 4. alteration of RR interval 5. idioventricular arrhythmia 6. bladder dysfunction 7. paralytic ileus 8. paroxysmal hypertension
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
9. paroxysmal parasympathetic discharges flushing, chest tightness and bronchorrhea 10. associated weakness often less severe than classic form 11. minimal paresthesias and sensory deficits B. EKG: 1. ST and T wave abnormalities 2. APC and VPC (atrial and ventricular premature contractions)
Autosomal Dominant Burning Feet Syndrome
A. General features: 1. Genetics: AD B. Clinical features: 1. Burning feet C. Pathology: 1. Involvement of unmyelinated nerve fibers
Differential Diagnosis of Peripheral Nervous System Disorders with Anhidrosis
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Pure autonomic failure Diabetes Amyloidosis Fabry’s Disease Acute autonomic neuropathy (autoimmune/viral) Acute intermittent porphyria Acute inflammatory demyelinating polyneuropathy (autonomic variant) Hereditary sensory neuropathy (I, III–V) Tangiers’s Disease Sjögren’s Disease Ross’s syndrome Holmes–Adie syndrome
Differential Diagnosis of Dermatologic Anhidrosis
1. Local injury: a. Thermal c. Scarring b. X-RT d. Inflammatory conditions 2. Anhidrotic ectodermal dysplasia 3. Psoriasis 4. Exfoliative dermatitis 5. Lichens sclerosis atrophicus 6. Ichthyosis 7. Melioidosis 8. Incontinentia pigmenti 9. Dermatomally distributed vitiligo
Predominantly Small Fiber Sensory Neuropathy
1. Autoimmune epitopes: a. TTR transthyretin met 30 (amyloidosis) b. Anti-Hu (paraneoplastic) c. Sulfoglycuronic paragloboside SGPG (anti sulfatide epitopes) 2. Inherited: a. Fabry’s Disease b. Tangiers’s Disease c. Familial amyloid (FAP) d. Hereditary sensory autonomic neuropathies (I, III, IV, V) e. Hereditary thermosensitive neuropathy (AD)
Associated with Systemic Illness
1. 2. 3. 4. 5.
Amyloid (secondary) Diabetes Primary biliary cirrhosis Sjögren’s (primarily ganglio neuritis) Rheumatoid arthritis
Associated Infections
1. HIV (distal symmetrical painful neuropathy) 2. Leprosy 3. Cytomegalovirus (CMV)
Associated with Drugs and Toxins
1. 2. 3. 4. 5. 6. 7. 8. 9.
Ciguatera toxin Metronidazole Misonidazole Kepone Dimethylamino propionic acid (DMAPN) Vacor Erythromelalgia (secondary to vincristine) Ergotamine Gold
Chronic Painful Neuropathies (Small Fiber)
1. 2. 3. 4. 5. 6. 7. 8.
Diabetes (primarily burning feet) Alcohol Pantothenic acid deficiency Pyridoxine B6 excess of deficiency CRPS I/II (RSD/causalgia) Amyloid (primary or secondary) Paraneoplastic (neuropathy/ganglioneuritis) TTR-met 30 (amyloidosis)
Chapter 3. Dorsal Root Ganglion Disorders
9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
Anti-sulfatide epitopes Uremia Arsenic Fabry’s Disease Erythromelalgia ABC Syndrome (anti back firing C nociceptors) Triple/cold Syndrome Hypertriglyceridemia Niacin deficiency Thiamine deficiency
Neuropathies with Prominent Autonomic Features
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.
Diabetes Amyloidosis Paraneoplastic (DRG/ANs) SICCA complex Acquired generalized anhydrosis Acute intermittent porphyria Variegate porphyria B12 deficiency Uremia TTR-met 30 (amyloid) AIDP HSAN I, III, IV, V Fabry’s Disease Pan Dysautonomia (immune/viral) EBV (Ebstein Barr Virus) Shy–Drager Disease Holmes–Adie Syndrome Familial sensory autonomic neuropathy (Navaho) Ross Syndrome Harlequin syndrome Vacor intoxication Chronic relapsing autonomic neuropathy NISP (non-malignant inflammatory sensory polyneuropathy) 24. MISP (malignant inflammatory sensory polyneuropathy) 25. Sjögren’s Syndrome
Chapter 3 Dorsal Root Ganglion Disorders Malignant Inflammatory Sensory Polyganglionopathy (MISP)
A. General features: 1. Most common malignancy associated with the syndrome is small cell cancer of the lung (SCLC); variety of other tumors has been associated including Hodgkin’s, prostate and breast
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2. All SCLC patients smoked 3. In approximately 75% of patients neurologic syndrome preceded cancer by months 4. In approximately 20% of patients, cancer preceded the neurologic symptoms 5. Cytotoxic T cells may be involved in the pathology of the DRG and CNS structures B. Clinical patterns: 1. Ataxic 2. Ataxic-hyperalgesic 3. Ataxic-hyperalgesic with gastric dysmotility 4. The specific syndrome is related to the size of the involved DRG cells: a. Large diameter DRG cell involvement is associated with ataxia, vibratory and proprioceptive loss b. Small diameter DRG cell destruction causes hyperalgesia and loss of temperature sensibility c. Destruction of the myenteric plexus causes gastric dysmotility C. Clinical presentation: 1. Generally subacute over days to weeks; occasionally it is abrupt over hours 2. Ataxic variant often starts with paresthesias; gait unsteadiness; decreased fine motor control 3. Ataxic-hyperalgesic patients often first note lancinating and burning extremity pain (C and A-delta fibers) followed by incoordination and loss of dexterity 4. Ataxic-hyperalgesic form with gastric dysmotility presents with abdominal pain, N and V and constipation. Rarely is ataxia and limb pain noted initially although hyporeflexia and wasting may be present on exam. D. Neurologic examination: 1. Normal strength or only mild weakness 2. Proximal and distal large fiber sensitivity loss which may be asymmetric 3. Hyporeflexia; lower greater than upper extremities 4. Pseudoathetosis in severely affected patients with large fiber loss 5. Sensory process may begin in the arm and face. E. Central signs associated with malignant inflammatory sensory polyneuropathy: 1. Eye movement abnormalities (nystagmus and gaze palsy) 2. Dementia and confusion 3. Cerebellar ataxia 4. VIIIth nerve dysfunction 5. Urinary retention 6. Babinski response 7. Flaccid weakness and atrophy 8. Dysgeusia 9. Myelopathy 10. Limbic encephalopathy 11. Sensory involvement of the face and the trunk F. Laboratory evaluation:
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
1. CSF: a. Normal to moderately elevated protein (mean 104– 127 mg% in 16 patients) b. Minimal lymphocytic pleocytosis in a few patients 2. Anti-neuronal neural antibodies ANNA-I (anti Hu antibodies); (react against neuronal nuclear protein antigens) are seen in approximately 2/3 of patients G. EMG: 1. Low amplitude or absent SNAP 2. Normal CMAP 3. Occasional fibrillations H. MRI: 1. Few patients demonstrated findings associated with associated limbic encephalitis I. Pathology: 1. Inflammation early and later fibrosis of the DRG neurons; subsequent degeneration of posterior roots and myelinated sensory axons; degeneration of the posterior columns. 2. Loss of neurons in the myenteric plexus
a. Normal to slightly increased protein (early phase) b. No pleocytosis (rarely lymphocytic pleocytosis early) 2. Sjögren’s: a. Positive for extractable nuclear antigen SS-A; SS-B 3. IgM-kappa, IgG kappa, IgA-kappa immunoglobulin monoclonal proteins have been described in some patients D. EMG: 1. Absent low amplitude SNAP (disease distal to DRG) 2. Normal or minimally decreased CMAP 3. Needle EMG is usually normal; an occasional fibrillation potential noted in isolated muscles E. MRI: 1. Cervical spinal cord increased signal on T2 weighted images (dorsal columns involvement in Sjögren’s Disease) F. Pathology: 1. Sural nerve demonstrates decreased density of large myelinated fibers; some axonal atrophy 2. Inflammatory cells around DRG and in the endoneurium
Non-Inflammatory Sensory Polyganglionopathy (MISP)
A. General features: 1. Most often associated with Sjögren’s syndrome 2. Other entities reported: a. Paraproteinemia b. Celiac disease c. EBV infection d. Pure sensory GBS e. Antibodies to chondroitin sulfate C or sulfatide 3. Putative cell mediated immune attack on DRG B. Clinical presentation: 1. Two major syndromes: a. Ataxic (large DRG neurons involved) b. Hyperalgesic (small diameter and autonomic neurons are involved) c. Mixture 2. Subacute progressive onset; a few patients have explosive onset over hours 3. Ataxic form: a. Paresthesias, unsteady gait, poor manual extremity, rarely painful 4. Hyperalgesic variety: a. Burning and lancinating extremity pain are presenting symptoms. May be asymmetric and begin in the arms and face rather than the legs. 5. Normal strength; distal and proximal large fiber sensory loss, diminished reflexes 6. Autonomic involvement in some patients is manifested by abnormal Valsalva responses, Adie’s pupils and arrhythmia C. Laboratory evaluation: 1. CSF:
Toxic Polyganglionopathy
A. General features: 1. Perforating arterioles from the epineural blood vessels penetrate the perineural sheath to supply the DRG. The capillaries of the DRG are fenestrated which results in easy diffusion from the blood to the endoneurium of DRG cells. B. Usual neurologic picture of DRG toxic disease is: 1. Proximal and distal sensory loss 2. Hyporeflexia 3. Slow recovery after toxic exposure
Cisplatin (Cis-Diamine Dichloren Platinum (II) CDDP)
A. General features: 1. Neurotoxicity occurs from involvement of the DRG or its axons 2. Does not cross the blood brain barrier (BBB); access to the DRG from the serum through fenestrated capillaries of the epineural blood vessels. 3. Myelosuppression, nephrotoxicity and damage to cochlear hair cells are expected complications. 4. Neurotoxicity occurs greater than 400–500 mg/m2 . Coasting effects is often noted (symptoms persist or sometimes start after the drug is stopped) 5. Putative mechanism of action: a. CDDP binds to neuronal DNA and induces apoptosis b. Toxic level may be as low as 100 mg/m2
Chapter 4. Differential Diagnosis of Symmetric Sensory Polyneuropathies
B. Clinical presentation: 1. Neuropathy is related to total cumulative dose 2. Insidious onset with distal lower extremity paresthesias greater than upper extremities 3. Symptoms may begin proximally and evolve into severe sensory ataxia 4. Some patients report painful paresthesia 5. Lhermitte’s sign may be noted; thermal sensitivity is usually spared 6. Mild peripheral muscle weakness 7. Improvement occurs if the total dose is less than 500 mg/M2 C. EMG: 1. Decreased SNAP’s; increased distal latency; N SNCV and CMAP; severe cases have abnormal somatosensory evoked potentials (SEP)
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2. Holmes–Adie syndrome a. b. c. d. 3. Posterior column ataxia of Biemond 4. Subacute myelo-optic neuropathy (clioquinol intoxication) 5. Tabes dorsalis 6. Vitamin E deficiency B. Clinical presentation: 1. Kinesthetic and vibratory sensory loss 2. Ataxia 3. Hyporeflexia 4. Poor tandem gait (particularly with cervical stenosis and spondylosis) C. EMG: 1. Normal sensory and motor NCV
Pyridoxine
A. General features: 1. High doses cause loss of DRG neurons, axons and fibers in the dorsal columns B. Clinical presentation: 1. Toxic dose 2–6 g/day; minimum daily requirement is 2 mg/day 2. Progressive ataxia starts within weeks to months on a dose of 2–6 gm/day 3. Numbness and paresthesias are seen on doses of 250 mg to 2 gram/day which is reversible 4. Complete deafferentation has been noted with IV doses of 132 and 183 gram over three days 5. Gait ataxia 6. Loss of kinesthetic sensations 7. Hyporeflexia with normal strength C. EMG: 1. Reduced or absent SNAPs; low amplitudes of NCVs 2. Delayed central sensory conduction by SEP (somatosensory evoked potentials) D. Laboratory: 1. CSF is normal
Central Sensory Syndrome (Toxic Polyganglioneuropathy)
Definition: 1. Dysfunction limited to the central posterior column axon segment of large DRG cells A. Differential Diagnosis: 1. Compressive posterior column myelopathy: a. Cervical spondylosis b. Spinal stenosis (congenital or acquired) c. Posterior longitudinal ligament calcification (oriental patients)
Chapter 4 Differential Diagnosis of Symmetric Sensory Polyneuropathies
A. Inherited Sensory Neuropathies: 1. Hereditary sensory autonomic neuropathy I, II, IV, V: a. foot ulcers b. self mutilation c. profound associated anhidrosis, pupillary abnormalities and autonomic dysregulation d. Type II (AR large fiber greater than small fiber loss) 2. Bassen Kornsweig Disease: a. absence of apolipoprotein b; very low density and low density lipoproteins b. ataxia, poor proprioception, dysarthria, areflexia c. pes cavus and scoliosis 3. Fabry’s Disease: a. burning acroparesthesias b. angiokeratoma in bathing suit distribution c. anhidrosis d. stroke, renal failure, X-linked recessive 4. SANDO: a. sensory ataxia c. ophthalmoplegia b. dysarthria 5. Perrault syndrome: a. ovarian dysgenesis b. VIIIth nerve dysfunction c. kinesthetic and vibratory loss 6. Amyloidosis (FAP): a. decreased pain and thermal sensitivity b. primary uveal veil (Andrade Type I) c. congestive heart failure
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
d. small fiber characteristics (burning/lancinating pain) 7. Hereditary spinocerebellar degeneration: a. Friedreich’s ataxia b. SCA-5 c. primarily proprioceptive and vibratory loss d. dysarthria e. scoliosis, pes cavus, other dysmorphisms
General Features of Inherited Neuropathies with Primary Sensory Symptoms
1. Dysmorphisms: a. Pes cavus or “rocker bottom” feet b. scoliosis; high insertion of gastrocnemius muscles; intrinsic foot and hand muscle wasting 2. No paresthesias; positive paresthesias are characteristic of acquired neuropathies 3. Insidious course 4. Inherited neuropathies demonstrate selective fiber size involvement (large diameter α A or AB or C and A-delta small fiber); acquired neuropathies tend to affect all fiber sizes 5. Specific associated features: a. Orange tonsils (Tangier) c. Ulcerated foot (HSAN) b. Angiokeratoma (Fabry’s) 6. Genetic history
Sensory Symptoms as the Presenting Feature of a Generalized Neuropathy Metabolic Sensorimotor Neuropathy
1. Sensory symptoms may precede motor and autonomic signs in characteristic sensorimotor neuropathies. This pattern is common in: a. Diabetes (CTS, numb or burning feet) b. Hypothyroidism (CTS, Vth nerve involvement) c. Uremia-(numb or burning feet) d. Acromegaly (CTS and tarsal tunnel syndromes) e. Primary biliary cirrhosis (itch, numb feet) f. Hepatic failure (encephalopathy and myelopathy) g. Hypoglycemia (most often a motor neuropathy; occasionally distal lower extremity numbness) 2. Toxic neuropathies with primary sensory symptoms: a. Arsenic (nausea, keratosis of palms) b. Ethylene oxide (confusion; memory loss; rash) c. Thalidomide (allodynia and hyperalgesia; severe constipation) d. Hydralazine (numbness and paresthesias) e. Isoniazid (seizures, hyperpyrexia) f. Metronidazole/misonidazole (paresthesias, burning) g. Nitrofurantoin (rapid development of sensory loss) h. Nitrous oxide (distal arm paresthesias; myelopathy)
i. Perhexiline maleate (facial diplegia; perioral numbness) j. Propafenone (arrhythmia; blurred vision; dizziness) k. Colchicine (associated myopathy; increased CK) l. Disulfiram (optic neuropathy, gait unsteadiness) m. Amiodarone (corneal deposits; dermatitis) n. Gold (rapid development; myokymia) o. Trichloroethylene (II, V, VII cranial nerve) p. Chloramphenicol (calf pain; concomitant optic atrophy) q. Hexacarbons (sensory loss, hands and feet; rarely to knees) r. Thallium (behavioral changes; hair loss) s. Phenytoin (loss of deep tendon reflexes) t. Amylamine (hallucination; memory loss; tremor) u. Organophosphorus esters (delayed neurotoxicity) v. Carbon disulfide (retinopathy; extrapyramidal, psychiatric) w. L-tryptophan (myopathy, hallucination; rash) x. Vincristine (bowel; bladder dysfunction) y. Metal toxic syndromes (Meoes lines) z. Eosinophilia–myalgia syndrome (brown skin induration) aa. Paclitaxel (predominate sensory; weakness rare) bb. DMAPN-(small fiber; bladder and sexual dysfunction) cc. Alkyl mercury (distal paresthesias) 3. Nutritional deficiency states: a. B12 (cranial nerve I dysfunction dorsal column loss; ataxia; paresthesias; spasticity) b. B6 (burning paresthesias) c. Pantothenic acid (associated with chronic alcoholism; burning feet) d. Thiamine (ophthalmoplegia; encephalopathy; ataxia) e. Vitamin E deficiency (nutritional and tocopherol transporter genetic defect) f. Chronic alcoholic neuropathy (associated with multiple vitamin deficiencies) 4. Infections: a. Lyme (encephalopathy; bilateral VIIth nerve) b. Leprosy (enlarged nerves; cold areas of the body are anesthetic; leonine facies) c. Brucellosis (remitting fever; L5 radiculopathy) d. HIV (burning feet; wasting) e. Syphilis (stamping gait; Argyle–Robertson pupils) f. CMV (lumbosacral radiculopathy; bladder dysfunction) g. HZ-(dermatomal sensory loss with hyperalgesia and allodynia) h. Herpes simplex (regional hyperalgesia) 5. Large fiber neuropathies (ataxia; kinesthetic loss): a. Sjögren’s (NISP) b. Paraneoplastic (MISP) c. SICCA complex d. Hypothyroidism
Chapter 4. Differential Diagnosis of Symmetric Sensory Polyneuropathies
e. Uremia (may be predominately small fiber) f. Vitamin B12 g. Tabes dorsalis h. IgM paraproteinemia i. Cisplatinum j. Nitrous oxide k. Pyridoxine l. Doxorubicin m. Metastasis to DRG n. CIDP (associated IgM, anti sulfatide, Gd lb antibodies) 6. Processes that may primarily affect the posterior roots: a. Lymphoreticular or plasma proliferative disease b. Meningeal carcinomatosis c. GBS (sensory variant) d. CIDP (sensory variant) 7. Differential diagnosis of MISP from NISP NISP (non-malignant inflammatory sensory polyneuropathy) 1. Autoimmune (Sjögren’s) 2. Female 3. Less common MISP (malignant inflammatory sensory polyneuropathy) 1. Malignancy 2. Male = female 3. Ataxia (hyperalgesic associated) 4. Ataxia gastrointestinal (dysmotility) 8. Differential diagnosis of dorsal root ganglion: a. NISP (autoimmune) b. MISP (paraneoplastic) c. Pyridoxine excess d. Doxorubicin e. Cisplatin f. Tabes dorsalis g. Herpes zoster h. GBS (sensory variant) i. CIDP (sensory variant) j. Carcinomatosis of the meninges k. Lymphoproliferative disorders l. Central sensory syndrome (compression of dorsal column nuclei; thalamic or cortical SI caesius 9. Differential diagnosis of axonal sensory neuropathy (acute): a. cisplatinum b. paclitaxel c. CM Fisher (may be demyelinating) d. Paraneoplastic (hyperalgesic – ataxic form) e. Acute pyridoxine overdose f. Idiopathic sensory neuropathy 10. Subacute/chronic axonal sensory neuropathy: a. HSMN-I (large nerves) b. Paraneoplastic (ataxia; hyperalgesia; GI dysmotility) c. Dysproteinemia (IgM; osteoclastic multiple myeloma) d. Sjögren’s (cranial nerve V; mucous membrane involvement)
11.
12.
13.
14.
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e. SCCA complex (mucous membrane dryness; an hidrosis) f. Mitochondrial cytopathies (VIIIth nerve, fatigue, heart involvement) g. Thalidomide (constipation; allodynia, hyperalgesia) h. Dideoxycytidine (burning feet) i. Didanosine (burning feet) j. Pyridoxine (ataxia, numbness, paresthesias of extremities) k. CIDP (length dependent sensory loss; perioral numbness) l. Primary biliary cirrhosis (severe itching) m. Vitamin E deficiency (dorsal column dysfunction is the predominate feature) n. Friedreich’s ataxia (dementia, cerebellar signs, heart failure) Sensory neuropathy with antibodies to specific epitopes: a. MAG (myeline associated glycoprotein) b. SGPG (small fiber) c. Anti-Hu (ANNA-1) small fiber predominant d. Anti-sulfatide (small fiber) e. CM Fisher variant (Gd lb; GQ1b) f. GTA-D- (large fiber) g. GD3 Demyelinating sensory neuropathy with antibodies to specific epitopes: a. MAG c. CM Fisher variant (Gd lb) b. SGPG d. CIDP Ataxic sensory polyneuropathy: a. Carcinomatous sensory neuropathy b. Sjögren’s syndrome c. Noncancerous inflammatory sensory polyneuropathy d. Malignant inflammatory sensory polyneuropathy e. CM Fisher variant f. MAG g. Sensory CIDP h. Immunoglobulin associated paraproteinemia i. Pyridoxine excess j. Cisplatinum k. Doxorubicin l. idiopathic (acute; chronic; monomelic) Sensory neuropathy associated with systemic disease: a. Diabetes (burning feet syndrome) b. Uremia (burning feet) c. Paraneoplastic (sensory ataxia; small fiber) d. Sjögren’s (Vth nerve; SICCA complex) e. Hypothyroidism (CTS, TTS, upper extremity; Vth nerve) f. Sensory perineuritis (primarily around the ankle) g. Ischemic neuropathy (lower extremities; all modalities) h. Malabsorption (B12, Vit E-primary large fibers) i. Hypertriglyceridemia (predominately small fiber)
SECTION X. Differential Diagnosis of Peripheral Neuropathy
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Chapter 5 Inherited Peripheral Neuropathies
The history and physical examination of patients with hereditary neuropathies provides a very good chance for a correct clinical diagnosis that is later confirmed with EMG, laboratory and genetic testing. Patients have specific dysmorphic features. Pes cavus, high arches, intrinsic foot muscle atrophy, hammer toes and a fore shortened foot is most common. Distal 1/3 of quadriceps atrophy, anterior compartment wasting and high insertion of the gastrocnemius and soleus muscles lead to thin ankles. The forearm flexor muscle also inserts too proximally which lead s to thin wrists. Patients often have kyphoscoliosis. They may have associated enlarged nerves, (ulnar, peroneal supraclavicular) foot ulceration, hearing loss, vocal cord and diaphragmatic weakness and cardiomyopathy. Isolated muscles may be atrophied. Patients often are not aware of sensory deficits, but have noted inability to stand in one spot and aching of their lower legs with exercise. They have suffered frequent sprained ankles. Poor gym performance with clumsiness and slight tremor of the upper extremities may be noted. AD, AR and sex linked hereditary is noted. Sporadic mutations may be confused with AR transmission. Unusual susceptibility to pressure at the entrance areas of the nerve to the extremities may be noted with reversible pressure palsies. Gradual and insidious distal weakness of the lower extremities with anterior compartment atrophy becomes apparent. Over time, asymmetric spasticity, optic atrophy and retinitis pigmentosa identify other hereditary neuropathies. Patients have no positive sensory symptoms with time which is prominent in acquired neuropathy. Weakness and atrophy is noted in hand muscles Classification has been accomplished with EMG, genetic and clinical categories that are now generally established.
Classification Hereditary Sensory Motor Neuropathies
1. 2. 3. 4. 5. 6. 7.
HSMN – I (demyelinating; Charcot Marie Tooth) HSMN – II (axonal; CMT-2) HSMN – III (Déjérine–Sottas Disease; CMT-3) HSMN – IV (demyelinating; Refsum’s Disease) HSMN – V (peripheral neuropathy and spastic paraplegia) HSMN – VI (peripheral neuropathy and optic atrophy) HSMN – VII (peripheral neuropathy and retinitis pigmentosa)
Charcot–Marie–Tooth Neuropathy Type I (CMT IA)
A. General features: 1. Epidemiology: Incidence of 1 : 4000; 50% of hereditary neuropathies 2. Genetics: a. AD; duplication of 1.5 mega base DNA on chromosome 17 p 1.2–12 b. Frequently sporadic (defect primarily in spermatogenesis; 10% occur from defect of oogenesis) c. 500 kilobase Sac II junctional fragment d. Trisomy patients of duplicated region demonstrate: 1) Mental retardation 2) Pes cavus 3) Micrognathia 4) Low set hypoplastic ears e. Gene: PMP-22 gene: 1) Encodes a 160 amino acid membrane associated protein localized to compact peripheral nerve myelin f. Some patients have point mutation of PMP-22 gene B. Clinical presentation: 1. Presents 2nd to 3rd decade, may have delay in motor milestones 2. Pes cavus, atrophy of all muscle below the calf (anterior compartment greater than posterior compartment); wasting distal 1/3 of quadriceps (“Champagne bottle leg”) 3. Asymmetric gradual involvement of thenar and hypothenar compartment of the hands; thinning of the distal forearms 4. Motor manifestations predominate; diminished vibration, proprioception and light, touch; cramps are common 5. Absent ankle and knee reflexes; depressed upper extremity reflexes 6. Enlarged nerves; brachial plexus; supraclavicular, ulnar, peroneal 7. Insidiously progressive 8. Patients remain ambulatory 9. Kyphoscoliosis C. EMG: 1. Severely slowed motor and sensory NCV ( PNS b. The chemical state of the element determines the effect of mercury on the nervous system and whether there are systemic affects c. Elemental mercury: 1) Lipid soluble 2) Micro mercurialism (low level toxicity): a) anorexia; weight loss; constipation b) fatigue c) tremor d) personality change and insomnia 3) Predominant CNS symptoms 4) Larger exposure: a) tremor that involves the face, head and eyelids b) severe GI symptoms and the nephrotic syndromes d. Organic mercury compounds: 1) Short chain compounds (methyl mercury): a) tremor, hearing loss, dysarthria b) constriction of visual fields c) cognitive dysfunction and dysarthria d) sensory ataxia (dorsal root ganglioneuritis); benign distal to proximal and may involve the tongue 2) Complex organic mercurials cause nephrotoxicity
Clinical Neuropathy of Mercury Poisoning
1. Mercury metal vapor: a) Causes subacute diffuse motor peripheral neuropathy; if severe may mimic acute demyelinating poly neuropathy b) Alkyl mercury intoxication; severe distal limbs paresthesias c) Mercury metal vapor: 1) Peripheral neuropathy 2) CMAP decreased > SNAPs
Thallium
1. Exposure: insecticide and rodenticide accidental exposure; suicide and homicide; consumption of contaminated food and water. 2. Pathogenesis: a. Absorption occurs through the respiratory, GI tract or skin. b. Complete with potassium for sodium potassium ATPase. 3. Clinical Features 4. Acute High Level Exposure (>29 grams) a. Abdominal pain, nausea and vomiting may begin within an hour; may be delayed for 24 hours. b. Cardiovascular shock with lethargy, coma and death reported within 24 hours 5. Moderate exposure: a. Paresthesias occur distally within 24–48 hours; occasionally up to five days b. Limb pain is more severe in the lower extremities-joint pain may be severe c. Large and small fiber sensory modalities are affected d. Alopecia usually begins within 15–39 days e. Increasing distal to proximal extremity sensory loss, distal muscle weakness and atrophy supervene. Proximal loss of deep tendon reflexes occur. f. Weakness and sensory loss may involve the cranial nerves and respiratory muscles. g. Ptosis is common. h. Neuropathy may progress for several weeks after a single exposure (coasting effect) i. Sensory loss greater than weakness j. Central nervous system signs and symptom are directly related to dose and include: 1) Anxiety 2) Psychosis and behavioral changes 3) Tremor 4) Abnormal chewing movements 5) Fever; loss of sweating, hypertension, tachycardia 6) Chorea and ataxia k. Mee’s lines; hyperkeratosis and alopecia may occur concomitantly.
Chapter 8. The Neuropathy of Heavy Metals and Industrial Agents
6. Chronic exposure (low level): a. Extrapyramidal signs b. Minimal sensorimotor neuropathy 7. EMG: a. Mild slowing of motor conduction velocities; reduced SNAP amplitudes; evidence of motor axonal degeneration 8. Laboratory: a. Thallium can be measured directly in blood, urine, hair and nails; potassium will cause a rise in urinary excretion b. Negative CSF 9. Pathology: axonal neuropathy affecting larger > smaller fibers. Distal axons affected > proximal segments; small unmyelinated fibers may be affected.
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a. Causes autonomic dysfunction with impairment of reflex changes in heart rate, blood pressure and dysregulation of the peripheral circulation. b. Sleep disturbance, hallucinations and memory loss also occur with acute high dose intoxication. c. The coasting phenomenon occurs. D. Laboratory evaluation E. EMG: 1. Normal motor NCV 2. SNAPs and CMAPs are reduced 3. CSF: a. Protein may be elevated F. Pathology: 1. Reduced numbers of large diameter thick myelinated fibers (αα and AB fibers). 2. Severe poisoning central and small fiber demyelination is seen.
Acrylamide
A. General features: 1. Exposure: a. The agent is used to seal pipes, stabilizers in the paper industry; cosmetic additive, coating on paper products; engineering; polyacrylamide is used as a flocculate in waste water treatment plants. 2. Pathogenesis: a. The monomeric form is neurotoxic; polyacrylamide is nontoxic. Industrial poisoning is usually through the skin, but it can be absorbed by inhalation or through the GI tract. Greater than 0.3 mg/M2 is toxic. Its metabolite glycinamide is also neurotoxic. The toxin interferes with axonal transport that causes axonal swelling and accumulation of neurofilaments par anodally. B. Pathology 1. Central peripheral distal axonopathy. Early exposure causes damage to the lungs peripheral axons. Continued exposure cause damage to the longest central axons of the corticospinal and cerebellar system. C. Clinical Presentation: 1. The earliest symptoms are focal skin irritation, redness and desquamation. 2. Mild to moderate exposure causes loss of vibration, touch, paresthesias and depressed reflexes. 3. Severe exposure causes weight loss, muscle weakness and atrophy, areflexia, sensory ataxia, dysarthria and tremor; clumsiness and intention tremor in the upper extremities and gait abnormalities may be early signs. a. Sensory ataxia b. Dysarthria c. Tremor d. Clumsiness and intention tremor in the upper extremities e. Gait abnormalities may be early signs 4. Acute high dose exposure:
Dimethylamino Propionitrile (DMAPN) (pp ) Ethylene Oxide
1. Exposure: a. The compound is utilized in sterilizing heat sensitive biomedical equipment. Exposure occurs during sterilization procedures or handling sterilized hospital gowns. 2. Pathogenesis: a. FDA limits for toxic exposure are 250 ppms. 3. Clinical presentations: a. Acute exposure: 1) Causes confusion 2) Memory loss and encephalopathy. 3) This is followed by distal extremity numbness and weakness. Tendon reflexes are depressed and ankle jerks are absent. b. Chronic exposure causes: 1) Loss of vibration sensitivity 2) Decreased IQ 3) Depressed speed of cognitive processing 4) Neurologic symptoms are often preceded by a rash. 5) Encephalopathic symptom and signs may accompany the neuropathy 4. Laboratory evaluation 5. Pathology 6. EMG: a. Motor NCVs are mildly decreased
Carbon Disulfide
A. General features: 1. Exposure:
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
a. Carbon disulfide vaporizes at room temperature and may be inhaled. It is a metabolic breakdown product of disulfiram that is used in the treatment of alcohol abuse. The chemical is used in viscose and cellophane; film; rayon manufacture, pesticides and in chemical laboratories. 4 mg/M3 is toxic. 2. Pathogenesis: a. The chemical is usually absorbed by dermal contact, but patients have been seen with inhalation and GI exposure. It reacts with amino sulfhydryl and hydroxyl groups. P-450 cytochrome enzymes are affected due to the formation of reactive sulfur atoms. They may inactivate metalloproteinase; the compound is metabolized to isothiocyanate which may link cytoskeletal proteins. B. Clinical presentation: 1. Massive exposure: a. Psychiatric and extrapyramidal manifestations. 2. Chronic exposures: a. Distal paresthesias, sensory loss, weakness and hyporeflexia. Retinopathy, microaneurysm and hemorrhage are seen. b. Rarely, optic neuropathy and loss of the corneal reflex occurs. c. Extrapyramidal signs are tremor bradykinesia and cogwheel rigidity. d. Rarely chronic exposure leads to spasticity and hemiparesis. The coasting phenomenon occurs after exposure has ceased. C. Laboratory: 1. Urinary level of 2-triothiazolidine-4-carboxylic acid a metabolite of CS2 measures the degree of exposure 2. CSF is normal D. EMG: 1. Distal motor and sensory NCVs; some evidence of denervation. Prolongation of the motor and sensory latencies. E. Pathology: 1. Giant axonal swellings are noted. Primarily a severe axonal degeneration is present. 2. CSF is normal.
Hexacarbons (N-Hexane, Methyl n-Butyl Ketone; Mn BK)
A. General features: 1. Exposure: a. Both toxins are metabolized to 2,5-hexane etiane (2,5-HD) which is responsible for the toxic effects of the compounds. b. N-Hexane is widely used as a solvent and is a component of lacquers, glues and glue thinners. Industrial exposure and inhalation abuse occur (glue sniffers).
c. Methyl n-butyl ketone is more common. Cluster epidemic resulted from the substitution of Mn BK form ethylethyl ketone and methyl butyl ketone during the process of color and plastic coated fabrics. d. High level exposure occurs with glue sniffing. Methyl ethyl Ketone (MN BK) may potentiate the toxic effects of n-hexane. 2. Pathogenesis: a. Compounds are absorbed most often by inhalation and dermal contact. The distinctive pathology of giant axonal neuropathy occurs by disruption of axonal transport and accumulation of neurofilaments at para nodal aerosis. B. Clinical Presentation: 1. Severe exposure causes anorexia, abdominal pain, weakness and cramps in the lower extremities. 2. Acute high level exposure causes narcosis and coma. 3. Repeated high level exposure that occurs with glue sniffing causes a subacute predominately motor and cranial neuropathy. There is the insidrosis onset of distal sensory paraesthesias, followed by distal weakening, calf pain, atrophy and loss of ankle deep tendon reflexes. 4. The intrinsic muscles of the hands and long extensors or flexors of the digits are affected, which progresses to involve proximal muscles. 5. Glue sniffers may suffer bulbar and phrenic nerve paralysis. 6. The neuropathy usually progresses for 1–4 months after exposure is terminated (coasting phenomenon) in severely affected patients. 7. Autonomic dysfunction with hypo or hypertension impotence and bowel and bladder abnormalities are frequent. 8. Chronic low level exposure: a. Central peripheral axonopathy with involvement of the longest central fibers (spinocerebellar, dorsal column and corticospinal). b. Pin prick, temperature are initially impaired with gradual proximal sensory loss. c. Some glue sniffing abuse patients suffer a subacute distal to proximal progressive weakness early in the course of the illness. d. Severely affected patients may develop signs of spasticity several years after exposure which reflects spinal cord damage. C. Laboratory Evaluation: 1. Measurement of 2,5-hexanedione in the urine D. EMG: 1. Severe slowing of motor nerve conduction velocities and distal latencies 2. Prolonged somatosensory, auditory and visual evoked potentials E. Cerebral spinal fluid (CSF):
Chapter 8. The Neuropathy of Heavy Metals and Industrial Agents
1. Protein is elevated in severe intoxications without pleocytosis F. Pathology: 1. Giant axonal swelling. This pathology is also seen with CS2 , acrylamide intoxication and congential giant axonal neuropathy. The paranoidal regions accumulate neurofilaments.
Organophosphates
A. General features: 1. Exposure: The three major industrial applications of these compounds are: a. Insecticides c. Plastic modifiers b. Petroleum additives These are also utilized as flame retardants, antioxidants and lubricants. Agricultural exposure is the most common form of intoxication. Dermal contact from sitting on bags of the chemical in hot climates also occurs as does exposure during preparation of the compounds for spraying. B. Clinical Presentation: 1. Most organophosphorus (OP) esters inhibit acetylcholinesterase 2. DEP/TEPP, sarin and their derivatives are extremely potent. They cause irreversible inhibition of acetylcholinesterase in both erythrocytes and in the central nervous system (CNS) which induces excess stimulation of muscarinic receptors in the CNS and nicotinic receptors in the PNS. The acute type I OP syndrome: 1. Stimulation of CNS muscarinic receptors 2. Commences hours after exposure 3. Nausea and vomiting, increased salivation micturition, sweating, and cardiac rhythm abnormalities (brady or tachycardia) 4. High toxic exposure is dominated by CNS manifestations: a. Emotional lability b. Cognitive impairment c. Convulsions d. Coma e. May be the only manifestations Intermediate Type II OP Syndrome 1. Onset is within 12–96 hours of exposure 2. Activation of nicotinic Ach receptors on skeletal muscle 3. Respiratory insufficiency 4. Weakness of neck flexors and proximal muscles 5. Rare cranial muscle involvement 6. Distal muscles are spared 7. Dystonic posturing 8. Sensation is intact 9. Recovery starts 5–15 days after exposure Organophosphate-induced delayed polyneuropathy (OIDP)
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1. Occurs most often with chronic low level exposure 2. Phosphates, phosphoramidites and phosphonates inhibit neuropathy target esterase 3. These effects do not involve inhibition of acetylcholinesterase 4. The neuropathy has a delayed onset following a single exposure; usually between 10–20 days 5. Related compounds that inhibit neuropathy, target esterase (NTE) are: mipofox, leptazol, trichlorfon, Trichlormate, dichlorovos; methmetaphase Clinical Presentation 1. Most OP in pesticides do not cause CIDP 2. Maximal deficit occurs by 14 days of exposure 3. Initial manifestations are cramping, pain in the calves and painful leg paraesthesias 4. Early foot drop; later weakness of intrinsic hand muscles 5. Proximal muscles spared until late 6. Prominent gait ataxia 7. Ankle jerks depressed or lost; other deep tendon reflexes reflect CNS damage 8. Rare CN or ANS involvement
Triorthocresyl Phosphate (TOCP)
A. General features: 1. Produced the most cases of neuropathy 2. Mild cholinergic symptoms in humans 3. Exposure: a. Softeners in the plastics industry b. High temperature lubricant B. Clinical presentation: 1. Early mild cholinergic response with diarrhea, perspiration and fasciculation for 24 hours 2. Asymptomatic interval for 7–21 days 3. Cramping calf pain 4. Tingling and burning sensations in hands and feet 5. Weakness of the feet and hands that may involve proximal muscles in severe cases 6. Weakness and flaccidity may be prominent early in addition to the paraesthesias 7. TOCP is predominantly a motor neuropathy although some sensory loss is invariant 8. Other organophosphorus ester intoxications cause progressive weakness of legs greater than arms which may be proximal greater than distal. 9. Gait ataxia, loss of reflexes and signs of hyper reflexa are late features 10. RBC acetylcholine is depressed early in the intoxication 11. Reduced lymphocyte NTE may predict later development of delayed peripheral neuropathy C. EMG: 1. Axonal neuropathy and may improve if there is no super composed myelopathy
406
SECTION X. Differential Diagnosis of Peripheral Neuropathy
1. GBS 4. Carbon disulfide intoxication 2. MG 5. Acrylamide poisoning 3. Solvent neuropathies
1. Sensory-motor polyneuropathy 2. Optic neuropathy with loss of green color detection F. Ethionamide: 1. Distal paraesthesias 3. Slow recovery 2. Reversible neuropathy
Drug Induced Neuropathies
Antiretroviral Agents
Differential Diagnosis of Organophosphate Poisoning
A. General features: 1. Most drugs cause a distal axonopathy after prolonged use 2. Discontinuation of the drug or decreasing the dose may initiate recovery or prevent further damage 3. Pathologic changes may occur in the dorsal root ganglion, the cell body (neuronopathy) or the myelin sheath (myelinopathy) 4. Deterioration of nerve function may continue after cessation of the drug (coasting) 5. Specific fiber sizes may be differentially affected (C, A-alpha, AB, or autonomic)
Infectious Disease – Antituberculous Drugs
Isoniazid
A. General features: 1. Metabolized by acetylation; slow acetylator may have high blood levels 2. Tbc (tuberculosis) therapy 3. Toxic effects are caused by interference with vitamin B6 (pyridoxine, pyridoxal and pyridoxamine); inhibits pyridoxal phosphokinase B. Clinical presentation: 1. Slowly progressive 2. Burning sensory neuropathy 3. At 3–5 mg/day a 2% incidence of neuropathy; 6 mg/day a 17% incidence of distal axonopathy 4. Loss of vibration, pain and temperature sense greater than position and deep pain sensibility 5. Aching cutaneous calf pain 6. Late effects are distal muscle atrophy ataxia and severe sensory loss; fasciculations 7. Recovery starts within weeks of withdrawal and may be prolonged 8. Risk factors are: a. Alcohol abuse c. Pregnancy b. Liver disease d. Poor nutrition C. EMG: 1. Sensory motor neuropathy D. Pathology: 1. Axonal degeneration and loss of both myelinated and unmyelinated fibers E. Ethambutol:
A. General features: 1. Risk factors: a. Coexistent diabetes b. Nutritional deficiency c. Weight loss d. Advanced HIV 2. Zalcitabine (Dideoxycytidine): a. Nucleotide analog to block HIV infection b. Alternate agent is Didanosine; ddI c. Associated risk factors for developing neuropathy: 1) Low cobalamine levels 2) Alcohol abuse 3) Toxic heavy metal exposure 4) AZT use 5) Renal insufficiency 3. 80% of HIV patients are on 0.06 mg/day B. Clinical presentation: 1. Painful distal sensory neuropathy 2. Intrinsic foot muscle weakness begins 7–9 weeks after therapy initiated 3. Dose related; median onset at 16 weeks 4. Rash, fever, headaches and stomatitis are side effects 5. 10% of patients develop granulocytopenia 6. Rare pancreatic and cardiac toxicity that carries an increased risk in diabetic patients 7. Decreased pin prick, hyperpathia and loss of ankle jerks 8. Loss of vibration sensibility in 1/3 of patients 9. Coasting for 2–3 weeks after discontinuance of therapy D. EMG: 1. Increased F-wave latency, low sural nerve SNAP 2. Quantitative sensory testing is the best technique to follow neuropathy Stavudine and Didanosine (ddI)
A. General features: 1. Similar clinical feature to ddC 2. Stavudine: a. 2 mg/kg/day small fibers e. Sensory ataxia from decreased proprioception f. Decreased or absent reflexes g. Normal strength h. Slow improvement with discontinuation of the drug C. EMG: 1. Normal motor NCVS 2. Absent SNAPs D. Pathology (sural nerve biopsy): 1. Loss of large and small axons 2. Normal CSF Amphetamines
A. General features: 1. Weight loss and hyperexcitability 2. CNS arteries (usually large vessel): a. Acute increase of blood pressure with ICH B. Clinical presentation: 1. Necrotizing hypersensitivity angiitis with distal motor sensory neuropathy 2. Mononeuritis multiplex Heroin
A. General features: 1. Neuropathy and CNS manifestations probably secondary to autoimmune reaction to adulterants (quinine, librium) 2. Acute pulmonary edema with second exposure B. Clinical presentation:
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
1. Painful plexopathy; lower extremity greater than upper extremity 2. Associated transverse myelopathy Etretinate (Tegison)
A. General features: 1. Used for treatment of psoriasis B. Clinical presentation: 1. Sensory polyneuropathy C. EMG: 1. Normal motor NCVs 2. Decreased or absent SNAPs D. Pathology: 1. Axonal degeneration of small and large fibers
B. Clinical presentation: 1. Painful distal extremity paresthesia 2. Distal sensory loss C. EMG D. Pathology Sodium Cyanate
A. General features: 1. Sickle cell crisis prevention B. Clinical presentation: 1. sensory motor neuropathy C. EMG: D. Pathology Stilbamidine
Ammoniated Topical Mercury
A. General features: 1. B. Clinical presentations: 1. Burning distal paraesthesias 2. Stocking glove sensory loss; small fibers greater than large fibers 3. Absent lower extremity reflexes C. EMG D. Pathology: 1. Axonal polyneuropathy with secondary demyelination Podophyllin
A. General features: 1. Used for the treatment of candidemia acuminata; absorption through the skin 2. Multiorgan failure is associated with significant absorption 3. CNS manifestations include: hallucinations, seizures, ataxia, autonomic dysregulation 4. Pancytopenia B. Clinical presentation: 1. Stocking glove sensory loss 2. Distal weakness 3. Loss of ankle deep tendon reflexes 4. Associated CNS signs and symptoms C. EMG: 1. Decreased sensory and motor nerve potentials; increased distal latencies 2. Denervation D. Pathology: 1. Loss of small and large axons 2. CSF demonstrates elevated protein Acetazolamide
A. General features: 1. Used for increased intracranial pressure migraine and seizure prophylaxis; some channelopathies
A. General features: 1. Used in treatment of blastomycosis B. Clinical presentation: 1. Involvements of the Vth cranial nerve 2. Distal sensory paresthesias C. EMG D. Pathology L-Tryptophan-Induced Eosinophilia-Myalgia Syndrome
A. General features B. Clinical presentation: 1. Associated myopathy 2. Stocking glove sensory loss all modalities; distal weakness C. EMG D. Pathology: severe axonal large and small fiber neuropathy Tagamet
A. General features: 1. Reversible motor neuropathy B. Clinical presentation C. EMG D. Pathology
Differential Diagnostic of Drug Induced Neuropathy by Seminal Features
Sensory motor: 1. Allopurinol (rare associated CTS) 2. Amiodarone (skin pigmentation) 3. Amitriptyline (depression) 4. Atorvastatin (vascular disease) 5. Captopril (lacunar stroke) 6. Chloroquine (muscle disease/macular degeneration) 7. Colchicine (gout, familial Mediterranean fever) 8. Disulfiram (acute presentation) 9. Docetaxel (breast cancer; paraneoplastic syndrome)
Chapter 8. The Neuropathy of Heavy Metals and Industrial Agents
10. Ethambutol (green gene dysfunction) 11. FK SO6 (myoclonus, tremor, posterior leukoencephalopathy) 12. Gold (associated rheumatoid, hand intrinsic muscle wasting) 13. Hexamethylamine 14. Indomethacin 15. Interferon alfa (encephalopathy, fever) 16. INH (burning pain) 17. Lithium (myoclonus, tremor, movement disorder) 18. Lovastatin (CVD; muscle cramps) 19. Methaqualone 20. Nitrofurantoin 21. Pachytene 22. Perhexiline (lumbosacral radiculopathy 23. Phenytoin (asymptomatic loss of reflexes, mild ataxia) 24. Podophyllin 25. Pravastatin (muscle cramps) 26. Sodium cyanate 27. Suramin 28. Thalidomide (severe constipation) 29. Vincristine (pupillary involvement; bowel and bladder)
Primary Sensory Neuropathy
1. Acetazolamide (paresthesias of upper extremities; kidney stone) 2. Alma tine 3. Clerambault 4. Chloramphenicol 5. Cisplatinum (Severe sensory ataxia) 6. Chlorquinol (optic neuropathy); spinal cord 7. Colistin 8. Cytarabine-ara (ataxia) 9. Dideoxycytidine (burning feet) 10. Didanosine (burning feet) 11. Ethionamide 12. Etretinate 13. Flecainide 14. Glutethimide 15. Hydralazine 16. Mercury (basal ganglion dysfunction, cognitive decline) 17. Methimazole 18. Niacin (flushing) 19. Nitrous oxide (spinal cord involvement) 20. Paclitaxel (retinopathy) 21. Procarbazine 22. Propylthiouracil (thyroid storm, atrial fibrillation) 23. Pyridoxine (burning feet) 24. Stavudine (associated HIV neuropathy) 25. Streptomycin (VIIIth nerve dysfunction) 26. Thalidomide (small fiber modalities; constipation) Differential Diagnosis
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1. Chloramphenicol: a. Optic neuropathy b. Anemia (RBC vacuoles) 2. Nitrofurantoin: a. Rapidly of onset; may be fulminant resemble GBS; pure motor neuropathy 3. Metronidazole: a. Encephalopathy INH 1. Burning sensory neuropathy; hot coma hypoglycemia Ethambutol 1. Optic neuropathy; and of green cones Vincristine 1. Hands earlier than feet 2. Pupil/bowel/bladder/orthostasis Cis-platin 1. Sensory ataxia; VIIIth nerve Elavil (overdose) 1. GBS syndrome Differential: Axonal/Demyelinating Asymmetric weakness Rapid onset GBS picture, those carnial neuropathies Myokymia Burning pain Concomitant neuropathy features Del myoid onset (OP) DRG-sensory ataxia Dose dependent Gold 1. Acute weakness (may be profound) 2. Myokymia 3. GBS-like syndrome Perazine 1. Bilateral facial palsy with recovery 2. Photo induced 3. Monophasic illness Nitrous Oxide 1. Myelopathy/B12 decrease Dapone 1. Optic neuropathy 2. Predominantly motor 3. Muscle atrophy hands prominent Heroin 1. Plexopathy Amphetamine 1. Mononeuritis multiplex Podophyllin 1. Skin absorption 2. Seizures
SECTION X. Differential Diagnosis of Peripheral Neuropathy
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3. Sensory loss 4. CSF increase (root involvement): a. B1 (thiamine) Strachan’s 1. Ulcers of cornea; dermatitis; optic neuropathy and polysensory neuropathy Vitamin E 1. Spinocerebellar ataxia with polyneuropathy (setting of fat malabsorption)
Chapter 9 Nutrition Associated Neuropathies
1. General features: a. Dietary nutritional deficiency in the West is most often secondary to alcoholism or specific malabsorption syndromes such as pernicious anemia, gastrectomy, sprue, intestinal surgery. Usually there are multiple vitamin deficiencies.
Primary Motor Neuropathy
1. 2. 3. 4. 5. 6.
Chloroquine (macular degeneration; muscle Cimetidine (extremity) Dapsone (associated skin rash) Imipramine Methimazole Zimeldine
Drug Induced Axonal Neuropathies
1. Allopurinol 19. Hydralazine 2. Almititrine 20. Isoniazid 3. Amidoxime 21. Lithium 4. Chloroquine 22. L-Tryptophan 5. Cisplatinum 23. Metronidazole 6. Clioquinol 24. Nitrofurantoin 7. Colchicine 25. Nitrous oxide 8. Cytarabine 26. Misonidazole 9. Dapsone 27. Paclitaxel 10. Dideoxycytidine (ddC) 28. Perazine 11. Disulfiram 29. Perhexiline 12. Docetaxel 30. Phenytoin 13. Ethionamide 31. Podophyllin 14. Etretinate 32. Pyridoxine 15. Flecainide 33. Sodium cyanate 16. Glutethimide 34. Suramin 17. Gold 35. Thalidomide 18. HMG CoA inhibitors 36. Vincristine Ganglioneuropathies
1. Cisplatinum 4. Simvastatin 2. Paclitaxel 5. Thalidomide 3. Pyridoxine 6. Doxorubicin Demyelinating
1. Amiodarone 2. Cytarabine 3. Chloroquine 4. Tacrolimus
5. Gold 6. Misonidazole 7. Perhexiline 8. Suramin
Alcoholic Neuropathy
A. General features: 1. Occurs in 9–30% of hospitalized alcoholics; seen in >80% of alcoholics with Wernicke’s–Korsakoff syndrome 2. Women and men equally susceptible 3. Usually require 100 grams of alcohol daily for a prolonged period of time 4. Pathogenesis: a. Primarily a nutritional deficiency b. Direct neurotoxic effect 5. Many asymptomatic patients have both clinical and autonomic features of neuropathy 6. Neuropathy may occur in a setting of severe weight loss B. Clinical Presentation: 1. Subacute onset of paresthesias followed by severe burning feet (25% of patients) 2. Painful calves, cramps and distal weakness 3. Sensory ataxia in severe patients 4. Distal areflexia that progress proximally 5. Autonomic dysfunction (rare clinically) 6. Associated Type II atrophy of proximal muscle 7. Dying back clinical picture most common, some patients demonstrate dynamic and static mechano allodynia 8. Rarely proximal lower extremity involvement 9. Decreased RBC transketolase activity C. Central manifestations: 1. “Martinet” anterior cerebellar gait (trunk is extensor; stiff legged) 2. Central pontine myelinolysis 3. Dementia, white matter primarily; partially reversible D. EMG: 1. Distal denervation 2. Reduced or absent SNAPs mild slowing of motor NCV 3. Prolongation of distal sensory and motor latencies E. Pathology (nerve biopsy): 1. Decreased are myelinated fibers of all sizes 2. Axonal destruction
Chapter 9. Nutrition Associated Neuropathies Thiamine B1 Deficiency
A. General features: 1. Occurs in the setting of starvation, alcoholism, prolonged vomiting, post gastric stapling, dialysis and a diet of carbohydrate without vitamins 2. Absorbed in small intestine by passive diffusion and active transport; phosphorylated in the jejunum to thiamine pyrophosphate (TPP) 3. Involved in: decarboxylation of alpha ketoacids that are transketolated to alpha ketols 4. Develops with total parenteral nutrition B. Clinical presentation: 1. Features of symmetric sensory motor polyneuropathy 2. Evolves over weeks or months; rarely develops over several days 3. Some patients develop painful small fiber neuropathy 4. Distal paresthesias and weakness; ankle areflexia 5. Associated Wernicke Korsakoff syndrome 6. Rare involvement of vagus and recurrent laryngeal nerves; tongue and facial weakness g. Central and centrocecal scotomata; may be due to Strachan’s syndrome 3. EMG; reduced or absent SNAPs, decreased CMAP, distal denervation 4. Pathology: axonal degeneration; decreased RBC transketolase activity
B12 (Cobalamin) Deficiency
A. General features: 1. Most often due to autoimmune induced intrinsic factor deficiency 2. Vegan diet 3. Inflammatory bowel disease 4. Blind loop syndrome (diphyllobothrium latum) 5. Gastrectomy 6. Nitrous oxide anesthesia (acute) 7. In association with other autoimmune diseases 8. Severe steatorrhea 9. Infestation of the fish, tapeworm 10. Required for methionine synthase and methylmalonic CoA reductase 11. Seen with folic acid deficiency; if folate deficiency is treated without B12 replacement neurologic signs may exacerbate. 12. Pathogenesis possible inhibition of the cobalamindependent enzyme methionine synthase B. Clinical presentation: 1. Active large fiber neuropathy; paresthesias and burning in hands and feet 2. Cranial nerve I and II dysfunction 3. Myelopathy: spasticity; bilateral Babinski signs; posterior column dysfunction
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4. Reflexes intact in the face of distal atrophy 5. Frontal lobe dysfunction; psychiatric manifestations 6. Recovery worse for vibration sensibility; paresthesias may improve 7. Cerebellar and cerebral demyelination 8. Low levels of cobalamin may be associated with neurologic signs and symptoms C. Laboratory evaluation: 1. Methylmalonic acid and homocysteine may be elevated 2. Large hyper segmented neutrophiles; low platelets and a macrocystic anemia that may be severe 40%) 7. Compression mononeuropathy; peroneal and ulnar nerves 8. Pseudotumor cerebri (1–3%) 9. Rare pulmonary emboli B. EMG evaluation: 1. Prolonged distal motor latencies early in the course 2. Conduction block with >20% progressive reduction in CMAP (30% of patients) 3. Slowing of motor nerve conduction with dispersion of the wave form; conduction velocities become slower during recovery due to remyelination 4. Slowed sensory nerve conduction velocities by three week of illness in 75% of patients; decreased sensory amplitudes 5. Median and ulnar sensory potentials are reduced or absent when the sural nerve is normal 6. Fibrillations in 20–64% within the first four weeks 7. CM Fiber variant: a. Reduced or absent sensory potentials with normal motor studies 8. Abnormal spontaneous activity noted in 2–4 months in affected muscles 9. Myokymia may be seen in the face and extremities early in illness 10. Axonal forms of GBS: a. Reduced or absent motor and sensory potentials; inexcitable nerves 11. AMAN has normal sensory potentials CSF Abnormalities
1. Cytoalbuminologic dissociation in 80–90% of patients 2. In general, 5 lymphocytes; occasionally up to 20 lymphocytes; the more cells noted the more likely another problem such as lymphoma, carcinomatosis, or leukemia is involving the nerve roots; HIV and Lyme are the exception and may demonstrate greater than 40 lymphocytes/mm3 . 3. Protein elevation: a. Starts approximately day 3–10 b. Usual levels are 100–180 mg/dl; extremely rare to note greater than 500 mg/dl (this level suggests a spinal block; Freund’s reaction)
Chapter 10. Immune Mediated Neuropathies The Differential Diagnosis of AIDP
The diagnosis of AIDP in general is very straight forward. However, patients may present without an obvious history or with associated neurological or medical problems that alter their mental status. A high cervical spinal cord injury causes flaccid quadriparesis, loss of bowel and bladder control, hypothermia (97 degree Fahrenheit) and hypotension. Acute inflammatory myopathy is often associated with sore muscles, rare diaphragmatic weakness, depressed, but intact reflexes and no bowel or bladder dysfunction. Metabolic muscle disease, the periodic paralysis’s, hypophosphatemia, hypercalcemic states spare the cranial nerves, bowel and bladder. They are areflexic and are clear mentally. Myasthenia gravis usually affects the facial muscles more than the muscles of mastication, has no sensory loss and normal pupils. Hyperkalemia has normal mentation, no bowel or bladder dysfunction and inexcitable reflexes or muscle. Toxic neuropathies often have concomitant CNS involvement.
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Toxins: MO organophosphate insecticides, hydrocarbons; buck thorn, toluene, solvents Autoimmune processes: Demyelinating disease (CIDP) spinal cord and peripheral nerve involvement from vasculitis Acute Quadriparesis
Periodic paralysis (hypokalemic; lid retraction, no myotatic reflex) Tick paralysis (ataxia then weakness and areflexia) Organophosphates (miosis, sweating, seizures) Myasthenia gravis (cranial nerve involvement; reflexes are spared) Botulism (ptosis, pupillary dilatation, pharyngeal paralysis, GI symptoms) Polymyositis (painful, swollen muscle, reflexes present) Critical care neuropathy (three weeks in ICU; sepsis, multiorgan/involvement, difficult to wean off respirator) Acute Quadriparesis with Severe Pain
Acute Peripheral Neuropathies
Toxic Neuropathies
A. General features: 1. History of exposure 2. Involvement of other organ systems B. Clinical seminal features: 1. Thallium (hair loss; distal extremity pain) 2. Arsenic (hyperkeratosis, GI symptoms) 3. Lead (encephalopathy, hypertension, abdominal pain) 4. N-hexane (encephalopathy)
AIP (acute abdominal pain; soft abdomen autonomic dysfunction, nondermatomal patchy sensory loss) Thallium (acute vascular collapse; distal weakness, late alopecia) Arsenic (distal extremity weakness and hyperkeratosis of palms and soles) Vasculitis (distal extremities; associated medical problems such as asthma, eosinophilia) Mononeuritis multiplex (underlying autoimmune cause; quadriceps pain in femoral nerve infarction) Acute Neuropathy with Prominent Sensory Abnormalities
Acute Demyelinating Neuropathies
1. 2. 3. 4.
Amiodarone-painful, skin changes Perhexiline-lumbosacral roots Gold-rash; intrinsic hand muscle Alcoholics-axonal EMG: normal CSF protein
Drugs: Vincristine/vinblastine, gold, chloroquine, Mevacor (all cholesterol lowering agents) emetine, dd., AZT; disulfiram, nitrofurantoin, INH Infection: Diphtheria, tick paralysis, poliomyelitis, Lyme disease, rabies (pharyngeal-cervical variant); HIV Metabolic: AIP, variegate porphyria, coporphyrinuria, hypermagnesemia, hypophosphatemia (less than 2 mg/dl) uremia (hyperkalemia, K+ > 6 mg/dl; secondary hypokalemic periodic paralysis renal tubular acidosis, diuretics, acidosis, hyperaldosteronism
Acute sensory neuropathy (dorsal column functional loss; large fiber modalities) Rabies (simulating the pharyngeal, cervical, brachial variant of GBS; pharyngeal spasms and muscle pain; a motor neuropathy) Vasculitis neuropathies (mononeuritis multiplex; 15% distal symmetrical involvement) Ciguatera toxin (burning pain, large joint involvement, mouth involved; paradoxical temperature perception) Thallium (alopecia; distal pain) Arsenic (hyperkeratosis, burning distal extremity pain, vascular collapse) Perhexiline (lumbosacral root involvement) Paralytic (shell fish: domoic acid, small fiber neuropathy, GI symptoms) Increased CSF Protein and Acute Neuropathy
1. Carcinomatous meningitis 2. Leukemia and lymphomatous meningitis
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3. 4. 5. 6. 7.
SECTION X. Differential Diagnosis of Peripheral Neuropathy
Arsenic Lead Vincristine Perhexiline Thallium
Disorders of the Neuromuscular Junction Simulating (AIDP)
1. MG (reflexes retained; cranial nerve involvement) 2. Botulism (internal ophthalmoplegia, nasopharyngeal weakness > ophthalmoplegia) 3. Snake envenomations (pain at the site; perioral numbness; pharyngeal paralysis) 4. Hypermagnesemia (no myotactic reflexes; cranial nerves spared) 5. Gentamicin (setting of gram negative infection; less cranial nerve involvement) 6. Tetanus (opisthotonus, pharyngeal and masseter spasm) 7. Succinylcholine (prolonged exposure; failure to move after surgery)
Acute Myopathy Simulating AIDP
1. Polymyositis (no VIIth nerve involvement; reflexes relatively preserved) 2. Acute rhabdomyolysis (severe edema of affected muscles; skin blisters; pain) 3. critical care myopathy (often associated with axonal neuropathy; hard to wean from respiratory; diaphragmatic involvement)
CNS Abnormalities Simulating AIDP
1. Acute transverse myelitis 2. Cervical cord intrinsic disease (cavernous hemangioma ADEM, bleed) 3. Rhombencephalitis (herpes simplex in 6 HIV patient; CMV (lumbosacral roots prominently affected) listeria (pregnancy, ENT surgery, dorsal pons involvement) 4. Locked in syndrome (vertical gaze intact; quadriplegia, no horizontal eye movements) 5. Basilar artery infarction (pin point pupils, herald hemiparesis; may have prominent sensory loss)
Acute Motor Axonal Neuropathy (AMAN)
A. General features: 1. Primarily in children 2. Most patients affected in Spring epidemics in Northern China
3. Prior Campylobacter jejunum infection 4. Neurological features preceded by gastrointestinal symptoms 5. Symmetric limb weakness 6. Oropharyngeal and respiratory muscle weakness 7. No sensory loss 8. No extraocular muscle involvement 9. Facial diplegia is common 10. Areflexia 11. Rapid recovery in some patients B. EMG: 1. Reduced or absent motor unit potentials 2. Normal motor, nerve conduction velocities C. Laboratory: 1. CSF protein elevated 2. Elevated antibody titers to C. jejunum, anti-DM1 and anti Gal Nac-GD1a D. Pathology: 1. Axonal degeneration 2. Macrophages in the periaxonal spaces Pure Motor Variant of AIDP (GBS)
A. General features: 1. Probably less than 5% of GBS patients 2. Preceding C. jejuni infection 3. High anti-GM1 antibody titers; elevated CSF protein greater than 45 mg/dl within B. Clinical features: 1. Progression of weakness over one day to four weeks 2. Symmetric weakness in the extremities 3. Generalized hyporeflexia or areflexia within one week 4. No paraesthesias or sensory loss 5. No cranial nerve involvement C. EMG: 1. Axonal features; absent, impersistent or dispersed Fwaves in at least two limbs or motor NC block or slowing ( weakness)
Sensory Variant of GBS (AIDP)
A. General features: 1. Rare B. Clinical presentation: 1. Abrupt onset 2. Rapid progression 3. Large fiber modality involvement greater than small fiber
Chapter 10. Immune Mediated Neuropathies
4. Sensory ataxia (decreased vibration and proprioception sensibility 5. Paresthesias in feet and hands at onset 6. Radicular features occur in some patients 7. Proximal progression of sensory loss over days to one month; face frequently affected early with paresthesias around the mouth 8. Improvement of sensory parameters within 1–2 months after onset 9. No weakness or respiratory failure 10. Generalized hypo or areflexia within one week 11. CSF protein elevation (>45 mg/dl within 1–3 weeks) C. EMG: severe diminution of sensory nerve conduction velocities; minimal slowing of motor NCV
Miller–Fisher Variant of AIDP (GBS)
A. General features: 1. Approximately 5% of GBS patients 2. May evolve to generalized GBS 3. C jejunum infection as well as other viral infections may precede illness B. Clinical features: 1. Diplopia often the first symptom; VI nerve weakness often evolves to complete ophthalmoplegia 2. Ptosis bilateral and symmetrical; rarely it is accompanied by internal ophthalmoplegia 3. Ataxia of all limbs; gait is impaired 4. Loss of reflexes by one week 5. Cerebellar outflow tremor 6. Minimal or absent flaccid or pharyngeal weakness 7. Minimal or absent paraesthesia 8. Absent Babinski signs 9. Usually good recovery in six weeks C. EMG: 1. Absent sensory nerve action potentials 2. Minimal or no deficits in motor NCV D. Laboratory: 1. Increased antibodies to GQ1b, epitopes; paranoidal regions of III, IV, VI nerves are enriched with these epitopes 2. CSF: slightly elevated protein
Pharyngeal-Cervical-Brachial Variant (Munsat’s Variant)
A. General features: 1. Regional pattern of involvement; descending paralysis B. Clinical presentation: 1. Weakness limited to pharyngeal and neck muscle with subsequent appendicular spread; legs are spared early 2. Ptosis is common 3. Severe swallowing and respiratory embarrassment C. EMG:
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1. NCV normal early; demyelinating features noted later in the upper extremities 2. Blink reflexes may be positive D. Laboratory: 1. Increased levels of Gal Nac-GD1a antibodies 2. Slightly elevated CSF protein Leg Weakness Variant AIDP (GBS)
A. General features: 1. Isolated leg weakness and areflexia suggestive of canda equina or spinal cord involvement B. Clinical presentation: 1. Ocular, facial, oropharyngeal muscles spared 2. Arms are normal 3. Radicular leg pain is common; other sensory features are inconsistent 4. Bowel and bladder are spared 5. MRI of lumbar spinal roots may demonstrate gadolinium enhancement C. EMG: 1. Demyelinating features
Partial Post Infectious Peripheral Neuropathy
A. General features: 1. Abrupt onset 2. Bilateral in one region 3. Evolve over days to weeks 4. Monophasic 5. Associated with an elevated CSF protein 6. Demyelinating characteristics on EMG B. Clinical presentation: 1. Acute distal weakness without severe sensory loss or cranial nerve involvement. The epitope is Nacetylglucosamine-GDIA 2. Acute ataxia 3. Facial diplegia with or without VIth nerve palsy and distal paresthesia 4. Asymmetric ocular nerve palsies 5. Isolated cranial nerve X (EBV) 6. Peroneal palsies with hand paraesthesias
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
A. General features: 1. Heterogenous group of neuropathies 2. Core feature is recurrent multifocal demyelination of peripheral nerve B. Clinical presentation: 1. Onset and relapses often triggered by infections; approximately 80% of patients
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
2. Relapsing; monophasic or progressive course 3. Mean age of patients (30–50) all decades; males > females 4. Triggers in approximately 30% of patients: a. Infection c. Surgery b. Vaccination d. Trauma 5. Eight week duration of initial illness (AIDP no longer than 4–6 weeks) 6. Usually the onset of weakness is in the lower extremities 7. Some degree of numbness or paresthesias; occasionally painful (14–20%) 8. Proximal weakness equal or at times greater than distal; legs > than arms; neck flexors may be involved 9. Facial muscles rarely affected 10. Approximately 6% present with pure sensory involvement; 10–20% with pure motor involvement 11. Papilledema has been reported (CO2 narcosis) 12. Touch and vibration sensibility most affected; some have severe ataxic proprioceptive loss 13. Rare cranial nerve involvement that includes facial numbness, dysphagia, diplopia, ptosis 14. Decreased or absent reflexes in majority of patients C. EMG: 1. Motor NCV decreased in two or more motor nerves 2. Conduction block or abnormal temporal dispersion in one or more motor nerves 3. Prolonged distal latencies in two or more nerves 4. Absent F waves or prolonged F wave latencies in two or more motor nerves 5. Supportive, but not necessary: absent H reflexes or reduction in sensory NCV less than 80% of the lower limit of normal D. Laboratory: 1. CSF: increased protein (130–145 mg/dl) 2. MRI: enhancement of involved nerve roots (unusual) E. Pathology (sural nerve biopsy): 1. Demyelination in most patients: a. Approximately 20% are axonal b. 15% mixed pattern
CIDP Associated with Monoclonal Gammopathy of Undetermined Significance (MGUS)
A. General features: 1. Definition: low levels of serum M protein 2. Exclusion of: a. Anemia b. Bence Jones protein in the urine c. Bone lesions d. Plasma cell count of greater than 5% 3. IgM antibodies noted against MAG epitopes 4. CIDP (MG US may have IgG or IgA, and IgM antibodies) B. Clinical presentation: 1. Slower progression than idiopathic CIDP 2. Associated with anti-MAG antibody: a. Incidence: 1–5/100,000 people b. Greater than 90% are IgM monoclonal antibodies: IgM-MAG antibodies c. Demyelination: IgM and complement found in myelin sheath; IgM-Kappa monoclonal proteins C. Clinical presentation: 1. Males greater than females 2. Age of onset 40–80 3. Predominantly sensory dysfunction greater than 50% of patients; a few patients may have a predominantly motor neuropathy 4. Sensorimotor neuropathy presentation is common; action tremor often noted 5. Possible correlation of IgM-anti-MAG and anti MGAG-SGPG antibody with a preceding CMV infection 6. May develop a lymphoproliferative malignancy months to years after onset D. EMG: 1. Slowed motor and sensory conduction velocities 2. Possibly IgM, MGUS different than IgA or IgG MGUS: a. More frequent sensory loss and ataxia b. Greater progressive over time c. Higher frequency of nerve conduction deficits
Differential Diagnosis of CIPD Associated with Concurrent Illness
Lewis–Sumner Syndrome
1. Malignancy: a. Adenocarcinoma b. Cholangiocarcinoma c. Seminoma d. Pancreatic adenocarcinoma e. Malignant melanoma (most common) 2. HIV 3. Chronic active hepatitis (B) 4. Some CIDP patients have central demyelinating lesions similar to multiple sclerosis 5. Diabetes mellitus
A. General features: 1. Acquired asymmetric sensorimotor polyneuropathy 2. Demyelinating 3. Multifocal conduction block in motor nerves B. Clinical presentation: 1. Age at presentation varies, 20–80; mean in 6th decade 2. Slowly progressive course over years 3. Arms involved earlier than legs 4. Asymmetric involvement of discrete nerves 5. Weakness and numbness predominate; rare painful presentation
Chapter 11. Vasculitic Peripheral Neuropathy and Neuropathies Associated with Connective Tissue Disorders
6. Rare cranial neuropathy 7. Reflexes are depressed more often they are than absent C. EMG: 1. Multifocal demyelination of motor nerves 2. Prolonged distal latency, temporal dispersion and conduction block; asymmetric prolongation of F waves 3. Active and chronic denervations D. Pathology: 1. Demyelinating and remyelinating aspects of the neuropathy 2. Normal CSF to slightly elevated protein
Multifocal Motor Neuropathy (MNN)
A. General features: 1. Slowly progressive, asymmetric multifocal weakness 2. Atrophy 3. No sensory loss 4. Multifocal conduction block 5. 50% have elevated anti GMI antibodies B. Clinical presentations: 1. Onset from 20–70 years of age 2. Men > women 3. Gradually progressive asymmetric weakness 4. Upper extremity > lower extremity; distal muscle predominance 5. Weakness out of proportion to atrophy 6. Decreased reflexes in affected areas 7. Progressive course C. EMG: 1. Conduction block 2. Temporal dispersions 3. Slowed motor NCVs 4. Prolonged distal latencies 5. Prolonged F wave latencies 6. Decreased conduction velocity in two or more motor nerves D. Laboratory: 1. Antibodies agent GM1 ganglioside positive in high titers in greater than 50% of patients 2. Usually are IgM in class and are polyclonal 3. 10–15% of patients with very high titers of IgM-M protein is demonstrated by immunofixation 4. Serum may react with SG PG sulfa-glucuronyl paragloboside antibodies and may associated with a GD1a ganglioside E. Pathology: 1. Demyelinations and axonal degeneration of motor nerves
Probable CIDP with or without Systemic Disease
1. Clinical presentation:
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a. Progressive or relapsing motor and sensory involvement of two extremities developing over two months; may be motor or sensory alone b. Hypo or areflexia of all limbs 2. Supportive of the diagnosis: a. Proprioceptive, vibration or light touch sensory disability > loss of pain or temperature 3. Exclusion criteria: a. Mutilation of hands or feet b. Retinitis pigmentosa c. Ichthyosis d. Drug or toxin exposure e. Genetically identified neuropathy 4. CSF studies: a. Cell count of c) in approximately 75% of patients 3. Eosinophilia in all patients 4. Increased IgE in 75% of patients 5. RF increased in one half of patients D. Pathology: 1. Intravascular and extravascular granulomatous eosinophilic tissue infiltrate 2. Necrotizing vasculitis of small and medium sized blood vessels 3. Infiltrate of CD8 positive suppressor/cytotoxic and CD4 positive helper T cells 4. Axonal degeneration
Wegener’s Granulomatosis
A. General features: 1. Granulomatous vasculitis of the upper and lower respiratory tract 2. Glomerulonephritis 3. Pulmonary involvement in greater than 75% of patients 4. Ocular vasculitis in 50% of patients 5. Dermatological lesions in approximately 50% of patients B. Clinical Presentation: 1. Cranial nerve involvement of V, IX, X 2. Mononeuritis multiplex 3. Symmetrical distal polyneuropathy (10–20%) 4. Ocular involvement in 50% C. EMG: 1. Positive sharp waves 2. Fibrillations D. Pathology: 1. Disseminated vasculitis of small and medium sized blood vessels 2. Granulomas of lung, kidney and sinuses 3. Capillaries, veins and venules are involved
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E. Laboratory: 1. RF in approximately 60 2. c-ANCA (epitope against proteinase 3) 3. p-ANCA (epitope is myeloperoxidase)
Rheumatoid Vasculitis
A. General features: 1. All vessel sizes affected 2. Overwhelming joint involvement (small joints) 3. Systemic feature of anemia and weight loss in severely affected patients; adenopathy, pericarditis, intersitial lung disease, glomerulonephritis, skin serosal surfaces are involved B. Clinical presentation: 1. Peripheral neuropathy in 1–10% of patients 2. Entrapment neuropathy: median nerve (CTS); digital, ulnar, anterior and posterior interosseous nerves; ulnar nerve entrapment in the cubital tunnel or Guyon’s canal, sciatic nerve entrapment in the posterior popliteal fossa; tarsal tunnel syndrome 3. Distal symmetric polyneuropathy: a. Insidious onset of paresthesias and decreased sensibility in both upper and lower extremities b. Minimal motor deficit c. Hands often severely wasted 4. Mononeuritis or mononeuritis multiplex: a. Acute or subacute onset; evolves into a severe distal sensorimotor neuropathy b. Cranial nerve mononeuritis is rare 5. Severe distal sensorimotor neuropathy: a. Rapid evolution b. Multiple mononeuritis attacks evolving into symmetrical distal weakness and sensory loss c. Seen in longstanding severe RA in a setting of systemic features of malaise, weight loss, skin involvement and rheumatoid nodules d. Active disease with increased rheumatoid factor and decreased complement
SLE
A. General features: 1. Prevalence of 1/1000 people; more common in women than men; black patients greater than white 2. Multiple susceptibility genes; complex II; deficiency of complex cascade have been implicated 3. Autoantibodies bind directly to specific antigens or form immune complexes 4. Concomitant systemic involvement of joints, serosal surfaces, heart, lung, kidney, skin and blood 5. Inflammatory demyelinating polyradiculopathy: a. Acute to GBS presentation
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
b. CIDP form c. Relapsing CIDP form 6. Cranial neuropathy: a. Occurs in 5–10% of patients b. II, V, VI, III, VII, laryngeal (X) 7. Rare neuropathies: a. CTS b. Acute sensory ataxic neuronopathy c. Neuromyotonia B. EMG: 1. Overlapping mononeuritis 2. Severe generalized axonal neuropathy; positive sharp waves decreased CMAPs and SNAPs; often asymmetric; fibrillations in potential in weak muscles C. Laboratory: 1. ANA positive greater than 95% 2. Double stranded DNA positive in approximately 70% of patients 3. Smooth muscle antibodies 4. Ro and La antibodies greater >25% of patients ANCA greater than 10% of patients 5. RF + >75% 6. Cryoglobulins are found in 15% D. Pathology: 1. Necrotizing vasculitis; proliferative endarteritis; vasculopathy > vasculitis in cerebral vessels; small and medium sized vessel involvement; scattered perivascular inflammatory cells 2. Dorsal root ganglion biopsy; cytotoxic/suppressor CD8 T cells surrounding neurons 3. Involvement of small and medium sized vessels that includes arteries, arterioles, capillaries and venules
2. Arthritis (small joints) 3. Rare arteritis of CNS B. Clinical presentation: 1. Distal sensory or sensory motor neuropathy; approximately 75% of neuropathies in Sjögren’s syndrome 2. Rare arm involvement 3. Greater than 50% minimal or no motor involvement 4. Rare autonomic involvement 5. Mononeuritis multiplex 6. Cranial neuropathy: a. Trigeminal nerve is the most commonly affected; usual numbness of V2 and V3; 50% have bilateral symptoms; may have associated facial pain; usually is associated with generalized sensory neuropathy. This is differential point from other CTD with Vth nerve involvement, but no generalized sensory involvement b. Rare involvement of I, II, oculomotor nerves and VIII. Rare recurrent cranial polyneuropathy is seen c. Associated CIDP, carpal tunnel syndrome, primary autonomic neuropathy C. EMG: 1. Absent SNAP (in ataxic neuropathy form); low amplitude and decreased sensory conduction velocities in less affected nerves 2. F waves and MNC velocities are normal 3. Some denervation noted 4. Axonal neuropathy features of sensory motor neuropathy; decreased SNAPs and CMAs D. MRI: 1. Dorsal column increased T2 signal E. Pathology (sensory nerve biopsy): 1. Loss of large myelinated fibers 2. Arteriopathy greater than arteritis of CNS blood vessels
Group 2: Hypersensitivity Vasculitis Henoch–Schönlein Purpura
A. General features: 1. Involves capillaries arterioles and venules 2. Leukocytoclastic vasculitis B. Clinical presentation: 1. Cutaneous manifestations predominate 2. Peripheral nerve and internal organ involvement occurs 3. Self limited 4. Glomerulonephritis; gastrointestinal and heart involvement occur concomitantly C. Laboratory: 1. Increased SED rate > 50%; rhF 10% 2. ANA positive in approximately 15% 3. Decreased complement rare
Sensory-Motor Neuropathy (Sjögren’s)
A. General features: 1. Sicca syndrome predominant
A. General features: 1. Erythematous macules that become papules; urticarial purpuric and necrotic; external portions of limbs and buttocks 2. Abdominal pain; joint and renal involvement 3. Most frequent in children following a streptococcal infection B. Clinical presentation: 1. Sensorimotor neuropathy (rare) 2. Cerebral vasculitis, small vessel (rare) C. Laboratory evaluation: 1. Increased sed rate in approximately 20% of patients 2. Increased IgA in approximately 50% 3. Decreased compliment (rare) D. Pathology: 1. Leukoclastic reaction in the skin; IgA vascular deposits noted 2. Arterial, capillaries and venules are affected
Chapter 11. Vasculitic Peripheral Neuropathy and Neuropathies Associated with Connective Tissue Disorders Cryoglobulinemic Vasculitis
A. General features: 1. Presence of protein in serum that precipitates on cooling 2. Usually IgG or IgM; mixed types occur IgM most often symptomatic 3. Mixed monoclonal and polyclonal gammopathies seen in CTD; may form immune complexes 4. Neuropathy is seen in 7% of patients with essential cryoglobulinemia 5. Secondary cryoglobulinemia associated with: a. Monoclonal gammopathies (myeloma, macroglobulinemic, lymphoma, PAN and multiple myeloma) b. Polyclonal gammopathies (connective tissue disease; mesothelioma and chronic infections) B. Clinical presentation: 1. General medical: Raynaud’s phenomena; bleeding diathesis (platelet dysfunction); retinal hemorrhage; arthralgias, malaise; weakness; skin ulcers; blue cyanotic toes 2. Neuropathy: a. Precipitated by cold b. Pain and paresthesias of the distal extremities c. Wasting and weakness of distal muscles; slowly progressive; may have an acute presentation 3. Rare small vessel vasculitis of CNS C. EMG: 1. Decreased sensory NCV’s 2. Mild slowing of mNCVs D. Laboratory: 1. RF increased in approximately 80% 2. Decreased complement > 75% 3. Hepatitis C > 80%; Hepatitis B 5% 4. ANA elevated in approximately 20% 5. SM and ANCA elevated in approximately 5% E. Pathology: 1. Necrotizing vasculitis; occlusive microangiopathy; LCV in the skin 2. Involvement of small arteries, arterioles; capillaries and venules 3. Wallerian degeneration; perineuritis and perivascular mononuclear cell infiltration; center of nerve fascicle involved to a greater degree than peripheral involvement
Group III – Giant Cell Arteritis
A. General features: 1. May involve the subclavian, brachial and aortic arch; occasionally origin of the carotid artery 2. Cause of the aortic arch syndrome
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3. Blindness from infarction of the watershed between the central retinal artery and the posterior ciliary arteries from the external carotid system (at the optic nerve head) 4. Greater than 50% are associated with polymyalgia rheumatica B. Clinical presentation: 1. Infarction of the optic nerve head 2. Rare CNS conducting vessel stroke 3. Rare sensory motor neuropathy 4. Low grade headache with allodynic scalp (maybe seen with normal sed rate) C. Laboratory: 1. Increased Sed rate greater than 80% of patients 2. Arteriogram and biopsy positive external carotid artery in greater than 50% of patients D. Pathology: 1. Small arteries and arterioles involved 2. Necrotizing vasculitis 3. Epineural greater than perineurial involvement 4. Granulomas and giant cells are seen in approximately 50% of patients
Takayasu’s Disease
A. General features: a. World wide distribution: Japan > Mexico > West b. Aortic arch is primary area of involvement c. Isolated subaortic and supravalvular pulmonary stenosis d. Hypothyroidism (thyrosis cervical trunk collagen) e. Systemic vessel occlusion B. Clinical presentation: 1. Intermittent claudication of vision (walking and with head position) 2. Large vessel stroke 3. Subclavian steal is frequent, but most often asymptomatic 4. Atrophy of soft tissue of the face 5. Early cataracts C. Laboratory D. Pathology
Group IV: Localized Vasculitis
A. General features: 1. Isolated granulomatous angiitis of the central nervous system 2. May involve the gall bladder, uterus, muscle and the skin B. Clinical presentation: 1. Mononeuritis multiplex 2. Distal symmetrical axonal sensorimotor neuropathy
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
C. Laboratory: 1. Sed rate increased in greater than 50% of patients D. Pathology: 1. Small arteries and arterioles are involved 2. Necrotizing vasculitis; greater epineural than perineural involvement
Nonsystemic Vasculitic Neuropathy
A. General features: 1. Incidence: 5 new cases/million people/year B. Clinical presentation: 1. Weakness; sensory loss and pain in isolated nerves (45% of patients) 2. Overlapping episodes of mononeuritis multiplex (40%) 3. Symmetrical distal neuropathy usually of the legs in 15% of patients C. EMG: 1. Denervation (positive sharp waves and fibrillation in affected muscles) 2. Decreased motor and sensory NCV’s
Vasculitic Neuropathy Associated with Systemic Disease
A. General features: 1. Incidence not determined 2. Major entities: Polyarteritis nodosa, Wegener’s granulomatosis; Churg–Strauss syndrome; SLE; rheumatic arthritis, mixed collagen vascular disease; scleroderma; cancer; hypersensitivity reaction; hepatitis B or hepatitis C infections; Lyme disease; HIV B. Clinical presentation: 1. Fever, weight loss, anorexia, skin rash, renal, lung, gastrointestinal disease 2. Clinical features noted for necrotizing vasculitides
a. Calcinosis b. Raynaud’s phenomenon c. Esophageal dysmotility d. Sclerodactyly e. Telangiectasia 8. CREST: a. Associated with vasculitic neuropathy B. Clinical presentation: 1. Raynaud’s phenomenon in 95% of patients 2. Slowly progressive skin and systemic signs over years 3. Trigeminal inflammatory ganglionitis: a. Affects 3% of scleroderma patients b. Bilateral and asymmetrical in 60% of patients c. Rare involvement of other cranial nerves 4. Entrapment neuropathies: a. Carpal tunnel syndrome is seen in 10% of patients; often most prominent in the early inflammatory stage of the disease b. Pressure palsies of the other major nerves occur 5. Sensory motor neuropathy: a. Asymmetric at onset b. Later stages symmetric, distal polyneuropathy c. Vasculitic neuropathy; asymmetric multifocal, sensory motor neuropathy d. Motor greater than sensory involvement; 60% of patients 2. Anti nucleolar antibodies-anti-RNA polymerase I, II, and III; anti ribonucleoprotein (RNP) E. Pathology (nerve biopsy): 1. Nonvasculitic form: a. Loss of myelinated fibers with axonal atrophy b. Increased endoneurial and perineurial tissue c. Endoneurial microvasculopathy d. Vasculitis (rare)
Neuropathy Associated with Rarer Connective Tissue Diseases Mixed Connective Tissue Disease (Overlap Syndromes)
Scleroderma A. General features: 1. Fibrosis of the skin and visceral organs from proliferation of extracellular matrix proteins and collagen 2. Scleroderma limited to the skin, rarely causes neuropathy (linear scleroderma, morphea, diffuse cutaneous scleroderma) 3. Incidence of 10–15 patients per million people; ethnic differences are important 4. Peak incidence is third to fifth decade 5. Women to men, 3 : 1 6. Microvascular changes in the skin may predate fibrosis 7. CREST (sub variant):
A. General features: 1. Clinical overlap of SLE, scleroderma and polymyositis 2. ANA titers against RNP-V1 3. Women > men; 3rd to 4th decade at onset 4. Fatigue, sclerodactyly, arthralgia early in the disease; later rash, GI, renal and muscle involvement; severe pulmonary hypertension a cause of death in some patients B. Clinical presentation: 1. Trigeminal sensory neuropathy 2. Symmetric sensory polyneuropathy 3. CTS (carpal tunnel syndrome)
Chapter 11. Vasculitic Peripheral Neuropathy and Neuropathies Associated with Connective Tissue Disorders
4. Acute autonomic neuropathy 5. CIDP presentation C. EMG: 1. Polyradiculopathy presentation 2. Demyelinating or mixed axonal-demyelinating features D. Pathology: 1. Enhancement of cauda equina on MRI 2. Primarily axonal alterations
Behçet’s Disease
A. General features: 1. Oral and genital ulcers 2. Ocular involvement 3. Large and small vessel vasculitis 4. Middle East, India and Japan have highest incidence 5. Men greater than women; presents in young adults 6. Painful oral aphthous ulcers greater than genital ulcers; anterior or posterior uveitis; retinal vasculitis 7. Associated; erythema nodosum, thrombophlebitis, arterial aneurysms, CNS manifestations (sinus thrombosis; aseptic meningitis, stroke) B. Clinical presentation: 1. Central nervous system manifestations of vasculitis: a. Dementia syndrome b. Brainstem presentations c. Purely ocular inflammation d. Stroke 2. PNS: a. Sensorimotor neuropathy b. Mononeuritis multiplex (vasculitis) c. Motor predominant poly radiculoneuropathy d. Lumbosacral polyradiculitis e. Distal sensorimotor demyelinating neuropathy (rare) C. Pathology: 1. Mixed neutrophilic and lymphocytic large and small vessel vasculitis
Relapsing Polychondritis
A. General features: 1. Inflammation and progressive destruction of cartilage 2. Peak incidence in fifth decade 3. Trachea, nose greater involvement than ear lobe; joint, cardiac valve; eye (episcleritis, conjunctivitis, uveitis, keratitis) involvement B. Clinical presentation: 1. Optic neuritis 2. Sensory neural hearing loss greater than 30% 3. Vestibular involvement greater than 30% 4. Rare involvement of III, IV, VI and V
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5. Rare sensory motor neuropathy and mononeuritis multiplex 6. Rare central nervous system vasculitis with stroke
Differential Diagnosis of Vasculitic Neuropathy by Vessel Size
1. Systemic necrotizing vasculitis (small and medium sized arteries): a. Polyarteritis nodosa (PAN) b. Allergic angiitis granulomatosis c. Wegener’s granulomatosis d. Vasculitis of connective tissue disease e. Polyangiitis overlap syndrome 2. Hypersensitivity vasculitis (small vessels; capillaries arterioles and venules): a. Henoch–Schönlein Purpura b. Vasculitis with infections disease c. In association with some drug reactions d. Connective tissue disease e. Neoplasm 3. Localized vasculitis: a. Isolated peripheral nerve vasculitis (localized form of PAN)
Differential Diagnosis of Vasculitis and Malignancy (malignancy and hypersensitivity vasculitis)
1. 2. 3. 4.
More common in myelo and lympho proliferative disease Rare in association with solid tumors Prominent in hairy cell leukemia Chédiak-Higashi disease
Differential Diagnosis of Unusual Vasculitis of Peripheral Nerves in Association with:
1. 2. 3. 4. 5.
Cryoglobulinemia Sjögren’s disease Relapsing polychondritis Reiter’s disease Hypereosinophilia syndrome
Differential Diagnosis of Vasculitis Neuropathy by Signs and Symptoms
The suspicion of a systemic vasculitic neuropathy occurring in the face of known vasculitis is raised with the onset of an asymmetric neuropathy that may evolve over time into a symmetric distal motor sensory neuropathy due to overlapping infarction or inflammation of specific peripheral nerves.
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
Trigeminal nerve involvement early and mononeuritis multiplex are seminal feature of these diseases. The specific features of each entity lead to the underlying cause of the vasculitis. In SLE the neuropathy occurs in the face of established disease. Central nervous system features usually predominate with stroke, seizures, psychosis as major signs. Transverse myelitis usually at T4–T6 (dropped cervical level) in many instances may be confused with neuropathy if bladder involvement is not prominent. Serosal surface, arthralgia, joint and skin manifestations are usually prominent when sensorimotor neuropathy begins. The major differential points at this stage are ruling out toxic metabolic or nutritional causes (and usually immune suppressive drugs such as D-penicillamine or cyclosporine. A GBS picture that may emerge in this context is more characteristic of PAN. The differential considerations are cervical myelitis or severe vasculitic neuropathy. In later stages of the illness a CIDP presentation may be noted and has to be differentiated from lymphoma, HIV, Castleman’s disease, graft versus host disease, osteosclerotic myeloma and monoclonal neuropathy. The vasculitic sensorimotor neuropathy is suggested by an asymmetric onset, stuttering course and significant motor involvement. The major differential features that are problematic for making the diagnosis of Sjögren’s syndrome are distinguishing it from other processes associated with the SICCA complex. These are sarcoid, graft versus host disease, amyloidosis; hepatitis C, HIV and HTLV-1 disease. In sarcoid, bilateral VIIth nerve involvement rather than Vth nerve is classic. Dural enhancement associated with intracranial lesions in the posterior hypothalamus and pituitary regions are diagnostic. Severe mucous ulcerative inflammation is characteristic of graft versus host disease whereas Sjögren’s is primarily glossitic and conjunctival symptomatology. Dissociated sensory loss (small fiber modality loss) and autonomic neuropathy in association with a primary uveal veil, cardiac and renal disease suggests amyloid neuropathy. HTLV-1 is a long standing myelopathy with prominent spasticity and bladder involvement associated with neuropathy. Hepatitis C is suspected in the face of a cryoglobulinemic neuropathy. HIV most commonly has parotid hypertrophy (cyst formation on MRI) prominent myelin atrophy on CNS MRI with distal burning symmetrical neuropath (late stages). Paraneoplastic sensory neuropathy can present with a severe sensory ataxia. Prominent dorsal column large fiber proprioceptive and vibratory defects are common. Many paraneoplastic neuropathies have some small fiber burning components associated with autonomic features. Idiopathic chronic ataxic neuropathy does not have autonomic involvement which is common in both Sjögren’s and paraneoplastic neuropathy. Anti-Hu antibodies are found in the majority of paraneoplastic syndromes. Other immune mediated ataxic sensory polyneuropathies are: 1. Miller Fisher variant of GBS 2. MAG (myelin associated glycoprotein)
3. 4. 5. 6. 7. 8.
Pure sensory CIDP Immunoglobulin associated paraproteinemias Anti-sulfatide antibodies Syphilis HZ SICCA complex The hypersensitivity vasculitides are diagnosed by their characteristic leukocytoclastic skin reactions. Most cryoglobulinemic neuropathies are secondary to hepatitis C and B or are in association with other collagen vascular diseases. Patients have severe Raynaud’s phenomenon and extreme cyanosis of the extremities often associated with bleeding that is clearly temperature dependent. Henoch–Schönlein purpura occurs primarily in children in association with GI pain and arthralgias as well as the seminal purpura. The sensorimotor neuropathy is a minor part of the complex. Hypersensitivity vasculitis most often occurs from an autoimmune reaction to sulfa drugs or penicillin and may present with dramatic swelling and burning of the fingers and toes. Temporal arteritis usually presents with headache and involvement of the external carotid vascular system affecting the watershed of the posterior ciliary arteries and the central retinal artery with concomitant loss of vision. Elderly patients with several months of fatigue, polymyalgia rheumatica and weight loss are usually affected. Rarely the arch of the aorta, carotid and subclavian arteries may be affected. Sensorimotor peripheral neuropathy and mononeuritis multiplex may be seen in this context. Polyarteritis nodosa in the majority of patients strikes the peripheral nervous system. It should always be suspected in a middle aged man who has developed late onset asthma, eosinophilia, liver, kidney or testicular infarction. Microaneurysms of the long medullary arteries of the kidney are diagnostic. In this setting vasculitic involvement of the brachial and lumbosacral plexus presents as subacute GBS. Raised palpable infarction of skin arterioles of the quadriceps should be sought. Mononeuritis multiplex is common. Central nervous systems stroke is rare. Microscopic polyangiitis is a subvariant of PAN and strikes the kidneys primarily, but vasculitis may also be seen in the eyes, lung, muscle and rarely the brain. ANCA antibodies (p > c) are seen in up to 90% of patients. A sensorimotor neuropathy in the face of severe renal involvement should suggest this diagnosis. Decreased complement and increased rheumatoid factor are supportive. The lungs are involved in approximately 50% of patients and the neuropathy is not burning in the feet, which separates it from uremic neuropathy. Churg–Strauss sensorimotor neuropathy is suggested in patients with eosinophilia and interstitial lung disease. The pituitary may be involved. IgE is increased in the serum in 75% of patients and ANCA antibodies are present (p > c) in 50–75%) of patients. Wegener’s granulomatosis invariably attacks the sinuses (greater than 90% of patients). It is also associated with granulomatous lung disease and chronic sinusitis. Orbital and
Chapter 11. Vasculitic Peripheral Neuropathy and Neuropathies Associated with Connective Tissue Disorders
Vth nerve involvement occur. Mononeuritis multiplex is more common than an asymmetric, stuttering, slowly progressive distal predominant sensorimotor neuropathy. Rheumatoid arthritis invariably involves the carpal tunnel and less commonly the tarsal tunnel. Differential diagnosis must entertain hand paresthesias from subluxation at C1–C2. Severe intrinsic hand muscle atrophy out of proportion to the arthropathy is common. High sed rate and RF are seen in greater than 90% of patients. Low level eosinophilic ANA and ANCA antibody response with decreased complement are supportive. Rarely mononeuritis and asymmetric peripheral vasculitis occurs. Scleroderma is easily diagnosed from its distinctive physical findings. Often not recognized is its penchant for trigeminal involvement which may be bilateral. Carpal tunnel syndrome is common in its early inflammatory stages. Later a subtle sensorimotor neuropathy develops. It should always be suspected in patients with early severe Raynaud’s phenomena. The CREST syndrome (calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly and telangiectasia is associated with a sensorimotor neuropathy. Raynaud’s is often severe in SLE and rheumatoid arthritis. Scleroderma presents no difficulty in differentiation from other CTD or vasculitic neuropathies. Realizing that Vth nerve, carpal tunnel, tarsal tunnel and a vasculitic neuropathy may occur is what is overlooked. Mixed connective disease has features of scleroderma, SLE and polymyositis. It is the most common connective tissue disease that presents with trigeminal neuropathy. Rarely, a sensorimotor neuropathy is present. High (antibody titers of ANA antibodies to extractable nuclear RNP ribonuclease-V1 are present). Behçet’s disease primarily affects the CNS with anterior and posterior uveitis, optic neuritis, a brainstem syndrome or vasculitic stroke. Its seminal feature is aphthous ulceration of the mouth and genitals. Occasionally patients have a well demarcated extra genital, erythematous ulcer on the body that is extremely painful. Large joint and GI involvement occurs. Venous thrombosis of the cortical veins is increasingly recognized. Rarely, patients have a concomitant distal predominant sensorimotor polyneuropathy. Relapsing polychondritis may present with a painful swollen ears. Ochronosis and uremia may also involve the pinna. This inflammatory autoimmune disease of cartilage causes tracheal stenosis, saddle nose deformity and heart valve inflammation. The central nervous system features of optic neuritis, vestibulopathy and conductive hearing loss from eustachian tube involvement are the seminal central features. Rarely mononeuritis multiplex and a sensorimotor polyneuropathy are seen concomitantly. The major differential diagnostic problems occurring in the diagnosis of vasculitic neuropathy is not in differentiating one connective diseases from another in which it
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may occur, but rather diagnosing it in the absence of systemic features. The differential diagnosis includes an infectious etiology such as Lyme disease, multifocal demyelinating neuropathy, multiple lumbar plexopathy, neuralgic amyotrophy and hereditary neuropathy with liability to pressure palsy. The non systemic vasculitic neuropathies may present as mononeuropathy, multiple mononeuropathy or mononeuropathy multiplex in addition to an asymmetric distal sensorimotor polyneuropathy which may occur from overlap of infarction of large nerves.
Differential Diagnosis of Mononeuropathy or Multiple Mononeuropathy
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
Pressure palsy Multiple entrapments Traumatic Electrical injury X-RT Immunization Herpes Zoster Carcinomatous infiltration Lymphoma Diphteritic wound infection with neuropathy (local toxin production) Diabetes Collagen vascular disease Monomeric sensory neuropathy Sensory perineuritis Cholesterol emboli syndrome Idiopathic thrombocytopenic purpura Tangier disease AIP and variegate porphyria Drug induced neuropathies Subacute bacterial endocarditis Leprosy CMV Leptospirosis Mycoplasma pneumonia Ascaris Plasmodium falciparum Sarcoid HIV HTL-V-1 Sarcoidosis Diabetes mellitus
Differential Diagnosis of Mononeuropathy Multiplex
Axonal
1. Vasculitis (non-systemic) 2. Vasculopathy (vessel wall abnormalities)
SECTION X. Differential Diagnosis of Peripheral Neuropathy
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3. Necrotizing vasculitis: a. PAN b. Microscopic polyangiitis c. Churg–Strauss syndrome d. Wegener’s granulomatosis e. Rheumatoid arthritis f. Systemic Lupus erythematosus g. Sjögren’s syndrome 4. Hypersensitivity vasculitis: a. Penicillin b. Sulfonamide c. Henoch–Schönlein purpura d. Cryoglobulinemic vasculitis 5. Temporal arteritis 6. Cocaine 7. Heroin 8. Amphetamine 9. Sarcoid 10. Mixed cryoglobulinemia 11. Relapsing polychondritis 12. Behçet’s disease 13. Mixed connective tissue disease 14. “Overlap Syndromes” 15. Leprosy 16. Cytomegalovirus (AIDS patients) 17. Diabetes 18. Neurofibromatosis Demyelinating Neuropathies
1. CIDP 2. Hereditary liability to pressure palsy (HNPP) 3. Hereditary polyneuropathies (HSMN) I, III, V with superimposed neuropathy (DM; chemotherapy) Differential Diagnosis of Vasculitic Neuropathy by Category
1. 2. 3. 4. 5. 6. 7.
Inflammatory or immune mediated Ischemic Drug induced Infectious Genetic (systemic collagen vascular disease) Malignancy Related to systemic disease (non collagen vascular): a. Cholesterol emboli b. Bleeding into nerve sheaths
Chapter 12 Neuropathies Associated with Infection A. General features: 1. Leprosy 10 million cases world wide
2. HIV-1 major new epidemic greater than 50 million people affected with neuropathy world wide in and of itself and secondary to drug treatments 3. Herpes Zoster affects the aging population
Neuropathies of Viral Origin
Cytomegalovirus
A. General features: 1. Encountered most frequently in terminal HIV patients 2. Associated with retinitis B. Clinical presentation: 1. Polyradiculitis 2. Motor cauda equina syndrome; asymmetric muscle involvement of these roots (L1–S5) 3. Bowel and bladder incontinence 4. All modality sensory loss 5. Painful cauda equina syndrome 6. Areflexia 7. Rapidly progressive and often fatal C. EMG: 1. Widespread denervation of affected muscles 2. Absent F waves D. Laboratory: 1. Polymorphonuclear pleocytosis 2. PCR positive E. MRI: 1. May demonstrate gadolinium enhancement of the cauda equina Herpes Simplex
A. General features: 1. Latent infection initiated at an early age 2. Latent in trigeminal and dorsal root ganglion 3. Travels down V1 innervation of the fifth nerve to reach the meninges 4. Environmental stress, tooth extraction ultraviolet light 5. Operations for tic douloureux may induce active infection B. Clinical presentation: 1. Cutaneous grouped vesicular eruption 2. Contiguous pain and secondary hyperalgesia around the skin lesions; may involve a much larger area than that involved by the eruption (on extremities or trunk) 3. Possible etiology for Bell’s palsy 4. Recurrent aphthous ulcers C. Laboratory evaluation: 1. CSF-RBC’s, sugar of 30–40 mg% 2. Slightly elevated protein D. MRI: 1. Bitemporal increased signal on T2 weighted images 2. Insular cortex involved; frontal lobe involved; occasionally one lobe of brain alone is involved
Chapter 12. Neuropathies Associated with Infection
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Herpes Zoster
Hepatitis C
A. General features: 1. Latent dorsal root ganglion or Vth nerve infection initiated during childhood; reactivated with immune deficiency 2. 95% of the US population is infected 3. Transmission is respiratory or direct contact 4. Hz causes deep dermal invasion with infarctive necrosis 5. Recurrence is common in HIV patients and patients undergoing chemotherapy 6. Virus migrates from sensory nerve fibers that originate in the dorsal root ganglia to invade the skin and subcutaneous tissue in a dermatomal distribution 7. Patients with motor involvement may have an increased incidence of malignancy 8. Incidence increases with age: a. May be generalized (infancy and HIV patients) B. Clinical presentation: 1. Radicular distribution of severe lancinating pain: a. Decreased threshold to primary modalities of cold and pin prick in affected dermatome b. Mechano dynamic and static allodynia of the affected dermatome c. Secondary hyperalgesia at times in the dermatome above and below the affected one d. Motor weakness may accompany the sensory symptoms e. Cranial nerve involvement infrequent; ophthalmoplegia rare; IIIrd nerve involvement occurs: V1 involvement is often associated with meningoencephalitis f. Sensory symptoms (usually burning pain) may occur prior to the skin eruption; possibly greater than six months; herpes sin herpete g. Differential diagnosis of radicular pain without rash on the thorax includes: cancer of the lung, lymphoma, and diabetic radiculopathy h. Rarely optic neuritis; VII nerve and the VII–VIII involvement of Ramsay-Hunt syndrome (Vesicles noted in the external auditory canal) i. Central features included transverse myelitis and delayed MCA stroke often after V1 involvement C. Laboratory: 1. Cerebral spinal fluid: a. RRC seen (40–50 RBC/mm3 ); increased protein in 50% of patients with a normal glucose b. Rarely glucose is arms 2. Mild distal weakness 3. Reduced or absent ankle jerks 4. Weight gain precedes recovery which occurs over months
Insulin Neuropathy
A. General features: 1. Occurs at the initiation of insulin or oral hypoglycemic therapy 2. Intense burning pain B. Clinical presentation: 1. Normal distal muscle strength in extremities 2. Normal reflexes except for decreased AJ 3. Loss of small caliber axons; axonal regeneration
Proximal Diabetic Neuropathy
A. General features: 1. Diabetic amyotrophy (Bruns–Borland Syndrome) 2. Inflammatory vasculitis causing ischemic nerve damage; nerve infarction (vasovasorum is site of infarction) 3. Associated with weight loss (metabolic factors)
Chapter 13. Diabetic Neuropathy
4. Vasculitis possibly due to immune complex deposition 5. Nerve fiber loss is multifocal 6. Site of pathology in PDN (proximal diabetic neuropathy) is proximal branches of the lumbosacral plexus and the spinal nerves B. Clinical presentation: 1. Affects older patients with Type II Type I DM (age 50–60 years) 2. Usually during a long period of poor diabetic control 3. Anorexia and weight loss occur prior to or during the process 4. Acute thigh pain that evolves into the hip and thigh muscle weakness 5. Pain in the anterolateral thigh, buttock and perineum (plexus distribution) 6. Atrophy of affected numbness of the upper lumbosacral plexus; iliopsoas, quadriceps and thigh adductors > extensors and hamstrings; peroneal innervated muscles may be affected 7. No sensory loss; concomitant diabetic polyneuropathy 8. Loss of dartos scroti reflex; rare hyperesthesias of the thigh 9. Contralateral leg affected concomitantly or during a second episode in six weeks 10. Weakness is progressive over weeks to months; spontaneous recovery in some patients; some patients symmetrical slowly progressive weakness 11. Rarely upper extremities may be affected (C5–C6 roots) C. EMG: 1. Associated axonal neuropathy in approximately 50% of patients 2. Decreased femoral nerve innervated muscles; CMAP amplitude loss of largest diameter motor fibers 3. Fibrillation potentials early in the illness; polyphasic MUAP; large amplitude and long duration MUAP (chronic denervation) D. Laboratory evaluation: 1. Slightly elevated CPK 2. Elevated CSF protein (mean protein 90 mg/dl) due to root involvement E. Differential Diagnosis: 1. CIDP 2. Polymyositis 3. MND (motor neuron disease)
Diabetic Mononeuropathies and Radiculopathies
1. General features: 1. Acute or subacute onset; middle to late life 2. Painful 3. Setting of weight loss or poor glycemic control 4. Remits in 6–12 months
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2. Clinical presentation: 1. Setting of long standing DM 2. Frequent involvement of the external carotid circulation that supplies the cranial nerves 3. III, IV, VI – most commonly involved; onset is acute and painful 4. Partial involvement of the IIIrd nerve; central fascicular ischemia; pupil is spared; painful ophthalmoplegia; lamp shade ptosis greater than that seen with a P-com aneurysm that compresses the nerve (pupil affected) 5. Bell’s palsy common in diabetic patients; more commonly in older patients 6. Involvement of the intermediate lateral trunk of the external carotid artery causes V and VII deficits; infarction of the ascending pharyngeal artery IX, X, XI are involved (rare); superior and inferior division infarction causes infarction of III, IV, VI; V and VII are most common combination of nerve deficits from infarction of the external carotid system in a diabetic patient (lateral trunk of ECA) 7. Improves within 3–6 months, no unusual synkinesia on reinnervation as is seen with aneurysm or other mechanical lesions 8. Bell’s palsy in diabetic patients affects taste less than non-diabetics
Intercostal Neuropathy
A. General features: 1. Older patients; males > females; in both Type I or II diabetes 2. Occurs during a fluctuation of diabetic control or during weight loss B. Clinical presentation: 1. May occur concomitantly will diabetic peripheral neuropathy 2. Pain and hyperalgesia; burning (C fiber) or a deep ache (A-delta fiber) 3. Usually the thoracic and abdominal intercostal nerves are involved a. Affected roots often are contiguous b. Sensory loss may be incomplete and not follow classic dermatomal distributions c. Unilateral bilateral d. Dorsal or ventral root involvement can occur e. Focal motor deficits of the abdominal wall occur f. May resolve in 4–12 months 4. Differential Diagnosis a. Herpes Zoster (sine Herpete; no concomitant rash) b. Carcinomatous involvement of the nerve root (lung ca most common) 1) Anhidrosis or hyperhidrosis of the affected dermatome c. Central cord syndrome
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
d. Shield and abdominal sensory loss of a length dependent type polyneuropathy C. EMG: 1. Site of the lesion may be the proximal root of the intercostal and abdominal nervi the posterior primary rami of the affected root 2. Fibrillation potentials noted in the paraspinal muscles in some patients
Diabetic Sensory Neuropathy
A. General features: Large 10–20 μ to small unmyelinated fibers (“C” fibers). Thinly myelinated A-delta fibers (lancinating pain) involved B. Clinical presentation: 1. Distal numbness; anesthesia with acropathy (ulceration of fingers and toes) in severe sensory loss; destruction of distal small bone with severe neuropathy (diabetic foot) 2. Stocking glove sensory loss 3. Shield midthorax sensory loss (dying back of intercostal nerves) 4. Pseudotabetic form with severe loss of 10–20 u vibration and proprioceptive fibers; imbalance and sensory ataxia is severe 5. Predominant small fiber involvement; 1 u (C fibers; unmyelinated sympathic fibers): a. Pain and temperature loss greater than vibration and proprioceptive loss b. Dramatic decrease of cutaneous blood flow (laser Doppler) c. Reflexes slightly depressed d. Spontaneous lancinating pain, dysesthesia, paresthesia (1–4 u thinly myelinated fibers); burning pain in the feet (C-fiber) e. Orthostatic hypotension and sexual dysfunction f. Mechano dynamic and static allodynia; hyperalgesia are common g. Cramps of the feet and thigh (neurogenic cramps) Differential diagnosis of burning feet a. DM b. HIV (Distal neuropathy) c. INH d. Pyridoxine excess or deficiency e. Uremia f. Alcohol g. Pantothenic acid and B1 deficiency h. SGPG (epitope) i. TTR-met 30 (amyloidosis) j. Anti-Hu antibody (cancer) k. Fabry’s disease l. Ergotism m. Drugs (AIDS, chemo therapy, idiosyncratic)
n. Collagen vascular disease (vasculitis) o. Cigueteras poisoning (paradoxical thermal sensation; nerve receptor) p. CRPS I/II (chronic regional pain syndrome)
Diabetic Pseudotabes
A. Clinical presentation: 1. Severe symmetric loss of cutaneous and deep pain and joint position and vibration sensibility 2. Tabetic gait; positive Romberg sign 3. Absent reflexes 4. Frequent foot ulcers and arthropathy
Mononeuritis or Mononeuritis Multiplex
A. General features: 1. Affects less than 1% of diabetic patients 2. Disputed; many favor plexopathy or asymmetric neuropathy B. Clinical presentation: 1. Cranial nerve involvement a. Lateral trunk of the external carotid artery may involved V and VII concomitantly (other cranial nerve involvement, see above) 2. Intercostal nerve infarction 3. May improve after 12 months; often residual deficits
Alternative Diabetic Neuropathy Classifications
1. Distal Symmetric Polyneuropathy: a. Mixed sensorimotor neuropathy with some autonomic features (approximately 70% of all diabetic neuropathy) b. Predominantly sensory neuropathy by modality: 1) Large fiber (50% diabetic neuropathy); pseudotabes 2) Mixed large and small fiber (C-fiber, sympathic fibers, low threshold mechanoreceptors (LTM) approximately 15% of diabetic neuropathy 3) Small fiber predominant (10%); C-fibers, thinly myelinated A-delta fibers and sympathetic fibers c. Predominantly motor neuropathy less than 1% d. Autonomic neuropathy (less than 1%) 2. Focal and multifocal neuropathy: a. Diabetic amyotrophy d. Asymptomatic neuropathy b. Cranial neuropathy e. Inflammatory neuropathy c. Intercostal neuropathy
Compression Neuropathy in Diabetics
1. Median nerve at the carpal tunnel:
Chapter 14. Neuropathies Associated with Tumors
a. b. c. d.
2.
3. 4. 5.
Related to body mass index in diabetic patients 6–12% of CTS patients have diabetes 10% of diabetic patients has asymptomatic CTS Median nerve neuropathy increases with duration of the diabetes Ulnar neuropathy at the cubital tunnel: a. 1–5% of diabetic patients b. 17% of patients with ulnar neuropathy at the elbow have diabetes Peroneal neuropathy at the fibular head: a. Rare; possibly 8% occur in diabetic patients Lateral femoral cutaneous nerve (meralgia paresthetica): a. Occurs in 1% of diabetic patients Rare compression neuropathies in diabetic patients: a. Radial neuropathy at the spiral groove of the humerus b. Tarsal tunnel syndrome
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6. A progressive process that rarely stabilizes; rarely improves with tumor removal 7. 50% of patients demonstrate associated dementia, cerebellar ataxia (Purkinje cell) or myelopathy 8. Minimal muscle weakness; depressed reflexes 9. Sensory ataxia; pseudoathetosis C. EMG: 1. Decreased sensory nerve conduction velocity D. Laboratory: 1. Antinuclear-1 antibodies (anti-Hu); anti Yo antibodies (ovarian cancer; often associated with cerebellar involvement) 2. CSF: elevated protein; upper limbs 6. Relapsing remitting neuropathy of demyelinating type associated (with testicular seminoma (anti Ta antibody)) C. EMG: 1. Sensory action potentials are absent in sensory neuropathy 2. Motor NCVs are normal or minimally decreased 3. Sensorimotor neuropathy demonstrates increased terminal motor latencies 4. Mildly decreases or normal motor NCVs 5. Relapsing form demonstrate slowed motor NCVs D. Laboratory: 1. CSF protein is mildly increased E. Pathology: 1. DRG, peripheral sensory fibers and posterior column degeneration 2. Axonal degeneration with loss of myelinated fibers
Motor Neuropathy or Motor Neurons Disease Syndrome with Cancer
A. General features:
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
1. Associated with lymphoma, breast cancer, thymoma, Hodgkin’s and non-Hodgkin’s’ lymphoma 2. Breast cancer: a. Predominately an upper motor neuron syndrome b. Syndrome initially resembles primary lateral sclerosis c. Symptoms of upper motor neuron disease occur within three months of the diagnosis of cancer or its recurrence d. Negative serum antineuronal antibodies e. Patient has been described with pure lower motor neuron syndrome with involvement of the brainstem and cervical cord; antibodies reacted with the axonal initial segment and nodes of Ranvier 3. Lymphoma: a. Rare b. Sometimes associated with IgM anti GM1 antibodies c. Increased CSF protein d. Clinical presentation: 1) Variable extremity weakness; upper motor neuron signs are frequent 2) Subacute course; may has a primary spinal muscle atrophy profile 3) Course may be independent of the activity of the lymphoma 4) May improve spontaneously B. Pathology: 1. Neuronal degeneration of anterior horn cells 2. Mild demyelinations of the posterior columns C. Differential diagnosis of cancers that may produce motor neuron disease: 1. Waldenström’s macroglobulinemia 2. Follicular cell lymphoma 3. Hodgkin’s’ disease 4. Multiple myeloma 5. Chronic lymphocytic leukemia 6. POEMS associated with angiofollicular lymphoma
Neuropathy Secondary to Dysproteinemia (50% associated with bone marrow malignancy)
A. General features: 1. Prevalence: a. 50% are associated with bone marrow malignancy b. 5–10% of patients have polyneuropathy; major proportion of which are monoclonal gammopathies of unknown significances (MGUS) c. MGUS: 1) 50% are IgM gammopathies: a) Half have Ab against MAG b) Anti-MAG neuropathy possibly 1–5/100,000 persons 2) remainder are IgG or IgA gammopathies
3) Monoclonal protein: a) Composition: (a) M, G, or A heavy chain (b) Kappa or Lambda light chain (c) Rarely only a light or heavy chain 4) Polyclonal gammopathy: a) Composition: (1) Contain both light and heavy chains (2) Often more than one heavy chain 5) M Protein: a) Found by SPEP analysis (serum protein cellulose acetate electrophoresis): (1) Further analysis accomplished with immunoelectrophoresis (IEP) or immunofixation IFE (2) IFE and IEP are more sensitive than SPEP for small proteins: (a) Characterize the single heavy or light chain (b) IFE greater than IEP in sensitivity 6) Monoclonal light chain: a) May be seen in urine when serum is negative (Bence Jones proteins) b) Associated with plasma cell dyscrasia or light chain amyloidosis 7) Plasma cell dyscrasia a) A proliferation of a single clone of plasma cells b) Neoplastic or non-neoplastic (1) Associated with monoclonal serum or urine protein
Monoclonal Gammopathies of Undetermined Significance (MGUS)
A. General features: 1. Largest proportion of polyneuropathies with plasma cell dyscrasia 2. IgM and non-IgM associated 3. IgM associated with or without anti-nerve activity
Immunoglobulin M Monoclonal Gammopathy Associated Neuropathy
A. General features: 1. Ab directed against myelin associated glycoprotein 2. Located in the myelin sheath of PNS and CNS B. Clinical presentation: 1. Insidious onset over months to years 2. Sensory gait ataxia; vibration and position loss 3. Progressive ascending numbness 4. Not painful 5. Minimally autonomic involvement
Chapter 14. Neuropathies Associated with Tumors
6. Enlarged nerves (occasionally) 7. Minimal weakness C. EMG: 1. Absent or decreased SNAPs 2. Slowing of motor NCVs 3. Prolonged distal latencies; conduction block; dispersion of CMAPs D. CSF: 1. Increased protein greater than 100 mg/dl E. Pathology: (sural nerve biopsy) 1. M protein deposited on myelin sheath 2. Axonal and demyelinative features 3. EM: a. Splitting and widening of the outer myelin lamellae 4. Antibodies against glycosphingolipid epitopes in myelin
Myelin-Associated Glycoprotein-non-Reactive Immunoglobulin M Neuropathy
A. General features: 1. Diverse IgM react with different antigens 2. Less clearly related to neuropathy B. Clinical presentation: 1. Features of an axonal neuropathy 2. Other demyelinating clinical presentations: a. Similar to anti MAG polyneuropathy b. No myelin lamellae splitting c. Negative immunofluorescent studies
Immunoglobulin G and A monoclonal Gammopathy Associated Polyneuropathy
A. General features: 1. Chronic and mild axonal neuropathy patterns 2. Respond poorly to therapy if axonal; those patients with demyelinating features respond to immunosuppressive treatment B. Clinical presentation: 1. Less sensory loss than IgM neuropathy 2. Less demyelinative features by EMG 3. Differential points: a. Rule out amyloidosis if there is pain b. Prominent autonomic dysfunction c. Rapid progression in an axonal pattern
Primary Systemic Amyloidosis
A. General features: 1. Approximately 25% of primary systemic amyloidosis have M proteins; 15% of these patients develop peripheral neuropathy
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2. Occurs in the 6–8th decade in men > women: a. Rare underlying illness except for Waldenström’s; macroglobulinemia and multiple myeloma b. Presents as a multisystem illness due to deposition of fragments of the variable portion of light chains in tissue (lambda) B. Clinical presentation: 1. Presents as a medical illness with a polyneuropathy in 60% 2. Generally a dying back pattern of painful sensory neuropathy; sparing of proprioception initially 3. Similar presentation occurs with TTR met 30 (prealbumin) and inherited small fiber neuropathy a. Polyneuropathy does not occur secondary to chronic inflammatory conditions or familial CNS amyloidosis 4. Dissociated sensory loss small fiber modality > large fibers; numbness of distal extremities; pain is lancinating 5. Orthostatic hypotension 6. Nocturnal diarrhea; chronic wasting 7. Concomitant involvement of heart, kidney, gut wall 8. Carpal tunnel presentation in 20% of patients 9. Rarely autonomic dysregulation overshadows sensory loss 10. Rare predominant motor presentation with severe wasting 11. Infiltrative proximal myopathy 12. Autonomic presentations: a. Light near dissociation (better response to accommodation than light) b. Orthostatic hypotension (coat hanger headache) c. Bowel, bladder, sexual dysfunction, xerostomia and decreased sweating d. Progressive; rarely stabilizes C. EMG evaluation: 1. Distal axonopathy legs greater than arms; decreased motor NCVs (90% positive for amyloid
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
Multiple Myeloma Neuropathy
A. General features: 1. Incidence of 0.1/100,000 per year; most common with osteosclerotic myeloma 2. High serum and urinary monoclonal proteins IgM > IgG > IgA 3. Destruction of the bone marrow by malignant plasma cells 4. Bony plasma cytomas B. Clinical presentation: 1. Peripheral neuropathy in 30% of patients; more commonly nerve root infiltration or spinal cord involvement: may herald the onset of myeloma 2. Sensorimotor neuropathy is mild; slowly progressive (axonal); tends to parallel status of the patient 3. Primary sensory neuropathy; proprioceptive loss; minimal motor loss; subacute presentation with subsequent stabilization 4. Demyelinating primarily motor neuropathy; course independent of the disease; may be remitting (CIDP pattern) 5. Amyloid neuropathy from light chain deposition D. EMG: 1. Axonal variant with minimal decrease of NCVs 2. Relapsing form slower NCV 3. Primary sensory of conduction velocity 4. Neuropathy minimal EMG changes
Osteosclerotic Myeloma with Peripheral Neuropathy
A. General features: 1. Found in 3% of MM patients 2. 50% develop polyneuropathy 3. No systemic manifestations 4. Rare involvement of bone marrow, no anemia, hypercalcemia or renal failure 5. Low serum M protein 6. Long course 7. Japanese > Occidental > African patients B. Clinical presentation: 1. Primarily motor; distal to proximal 2. Slowly progressive course; symmetric with proximal spread 3. Sensory loss large fiber > small fiber 4. Pain and autonomic dysfunction is rare 5. Enlarged nerves 6. Younger patients; less illness C. EMG: 1. Mixed axonal and demyelinating features 2. Slowing of NCV in CIDP form D. Laboratory: 1. M protein in the serum in 75–80% of patients often need IFE and IFP to detect:
a. M protein is IgG or IgA; Lambda > Kappa light chain; not in the urine (amyloid and MM) M protein is in the urine) b. CSF-high protein > 100 mg/dl E. Pathology (sural nerve biopsy): 1. Mixed demyelination and axonal degeneration 2. Decreased myelinated fibers 3. Mononuclear infiltrate of the epineurium surrounding blood vessels 4. Osteosclerotic lesions: a. Axial skeleton and proximal long bones; spine distal long bones and skull b. Sclerotic or mixed sclerotic and lytic c. Small number have only one lesion (“soup, bubble” with a sclerotic rim) d. Radionuclide bone scan positive prior to bone destruction
POEMS Syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M Protein, Skin Changes)
A. General features: 1. Organomegaly (liver, spleen, lymph nodes) hyperplastic changes resemble angiofollicular lymph node hyperplasia (Castleman’s syndrome) 2. Patients with Castleman’s Syndrome a. May have clinical features of Crow–Fukase Syndrome without bone lesions, but with serum M proteins or polyclonal gammopathies 3. Endocrinopathy (hypothyroidism, hyperglycemia, hypogonadism with low testosterone levels, gynecomastia); hyperestrogenemia 4. Hyperpigmentation, hypertrichosis 5. Digital cribbing; white nails 6. Bilateral papilledema 7. Polycythemia, leukocytosis, thrombocythemia B. Clinical presentation: 1. Similar to OSM (osteosclerotic multiple myeloma) C. Pathology: 1. Endoneural deposits of immunoglobulin; axonal loss with demyelinative features 2. Over production of vascular endothelial growth factor or vascular permeability factor; microangiopathy, neovascularization; accelerated vasopermeability (VEFG 165 isoform of Crow–Fukase Syndrome)
Neuropathies Associated with IgM Monoclonal Gammopathies
1. Associated diseases: a. Waldenström’s macroglobulinemia b. Chronic lymphocytic leukemia or lymphoma
Chapter 14. Neuropathies Associated with Tumors
c. IgM monoclonal gammopathy of unknown significance (MGUS) 2. Associated IgM antibodies to MAG, GM1 sulfatides, GD1a or GD1b 3. Abnormal bone marrow or lymph node biopsy may be concomitant
Waldenström’s Macroglobulinemia
A. General features: 1. Plasma cell dyscrasia of B lymphocytes that make IgM globulins 2. Large quantity of M type IgM globulins in the serum 3. Anemia and bleeding manifestations; petechiae below the knees 4. Lymphadenopathy, splenomegaly and hepatomegaly evolve B. Features of IgM globulins that cause neurologic symptoms: 1. Cryoglobulins: a. Raynaud’s; cold urticaria, vascular occlusion with gangrene after exposure to cold b. Viscosity related manifestations: 1) Retinal changes with sausage shaped veins and hemorrhages 2) Cerebral sludge syndrome (poor perfusions due decreased laminar flow); rare hemorrhages in the brain c. Protein–protein interactions: 1) Complex formation between IgM globulins and fibrinogen, prothrombin, factor V and VII; leads to epistaxis and mucosal bleeding C. Clinical presentation: 1. Primarily a demyelinating sensorimotor neuropathy 2. Neuropathy associated with anti-MAG antibodies (similar to IgM-MGUS) 3. CIDP presentation 4. Distal axonal neuropathy 5. Sensory neuropathy 6. Neuro lymphocytosis variant: a. Meningeal and nerve infiltration by lymphoplasmacytic cells b. Rapidly progressive proximally by weakness c. CSF pleocytosis of lymphoplasmacytic cells d. MRI: tissue infiltration of nerve roots and the leptomeninges e. May respond to chemotherapy and X-RT D. EMG: 1. Marked slowing of NCVs E. Laboratory: 1. High sedimentation rate; hemoglobulin of 5–6 gram/100 ml 2. Associated Comb’s positive autoimmune hemolytic anemia
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3. Seropositive rheumatoid arthritis laboratory values 4. IgM-cardiolipin syndrome 5. 50% of patients have serological autoimmune features; 40% have autoimmune manifestations at the time of diagnosis 6. Whole blood viscosity measured at low shear rates is the best indicator of rheological symptoms F. Pathology (sural nerve biopsy): 1. Primarily demyelinating 2. A few patients have axonal degeneration or endoneurial amyloid deposition
Osteolytic Myeloma Associated with Systemic Amyloidosis
A. General features: 1. Rare 2. Associated Bence Jones protein; monoclonal gammopathy B. Clinical presentation: 1. Distal axonal sensorimotor neuropathy 2. Autonomic neuropathy 3. Bilateral CTS; tarsal tunnel syndrome 4. Superimposed radicular syndrome; may resemble mononeuritis multiplex 5. Treatment of the myeloma does not improve the neuropathy
Differential Diagnosis of Malignancies Associated with M Proteins and Polyneuropathy
A. General features: 1. Cryoglobulinemia (primary) 2. Lymphoma (anti-MAG) 3. Solid cancers 4. Leukemia 5. Waldenström’s macroglobulinemia B. Clinical presentation: 1. Motor neuropathy 2. Sensory neuropathy 3. Sensorimotor: a. Dependent upon the specificity of the IgM antibody
Differential Diagnosis of Plasma Cell Dyscrasia
1. Monoclonal gammopathy of unknown significance (MGUS) 2. Osteosclerotic myeloma 3. Multiple myeloma 4. Waldenström’s macroglobulinemia 5. Primary systemic amyloidosis 6. Gamma light chain disease
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
Late Sensorimotor Neuropathy in Advanced Cancer
A. General features: 1. Occurs in 10–50% of patients with cancer B. Clinical presentation: 1. Distal sensorimotor neuropathy C. EMG: 1. Slow motor and sensory NCVs D. Pathology: 1. Primarily axonal degeneration
2. Paraneoplastic neuropathy more common in chronic lymphocytic leukemia than red cell leukemia (di Guglielmo’s) or in acute leukemia B. Clinical presentation: 1. Paraneoplastic neuropathy: a. Acute GBS presentation b. Sensorimotor neuropathy c. Rarely sensorimotor neuropathy with myeloid leukemia C. EMG D. Pathology
Mononeuropathy or Mononeuritis Multiplex Polycythemia Vera
A. General features: 1. Incidences is rare 2. Misdiagnosed in the presence of overlapping radicular involvement B. Clinical presentation: 1. Focal or multifocal weakness in the distribution of the affected nerves 2. Painful 3. Sensory loss prominent C. EMG: 1. Denervation of the involved nerves 2. Decreased motor and sensory NCVs D. Pathology: 1. Nerves are infiltrated by tumor 2. Vasculitis of vas vasorum 3. Cryoglobulinemia with immune deposition in the vasovasorum
A. General features: 1. Possibly 25% of patients have sensory or motor symptoms 2. Definable peripheral neuropathy is rare 3. Associated signs and symptoms; stroke, vertigo, headache, tinnitus B. Clinical presentation: 1. Paresthesias and burning pain in the distal extremities 2. Decreased sensibility in all modalities 3. Full strength; depressed reflexes 4. Itch with heat (C-fiber activation) C. EMG: 1. Significant decrease of sensory NCV 2. Minimal decrease of motor NCV D. Pathology: 1. Mild chronic axonal degeneration
Chapter 15
Lymphoma
A. General features: 1. Neuropathy incidence is approximately 8% 2. Subclinical involvement detected by EMG maybe 30% B. Clinical presentation: 1. Sensory neuropathy; similar to that seen with cancer; paresthesias, dysesthesias; pain, sensory ataxia 2. Sensorimotor neuropathy 3. GBS presentation 4. Relapsing remitting (CIDP presentation) C. EMG: 1. Axonal features D. Pathology: 1. Malignant infiltration of nerve roots and peripheral nerves; lymphoma > carcinoma
Peripheral Neuropathy of Leukemia
A. General feature: 1. Incidence: rare
Neuropathies Associated with Medical Illness Hypothyroidism
a. General features: 1. Concurrent hypothyroid myopathy (Hoffmann’s syndrome): a. Pseudohypertrophy; proximal weakness b. Hyperexcitability of the sarcolemmal membrane (lumping phenomenon with percussion) c. Axonal neuropathy >40%; CTS in approximately 30% of patients 2. Associated central nervous system signs and symptoms: a. Decreased mentation b. Cranial nerve V involvement (pain) c. Cerebellar ataxia (Purkinje cell dysfunction) d. VIIIth nerve dysfunction B. Clinical presentation:
Chapter 15. Neuropathies Associated with Medical Illness
1. 2. 3. 4. 5. 6. 7.
Distal sensory loss Burning and lancinating distal pain Leg muscle cramps Distal leg weakness Concomitant CTS with hand paresthesias Decreased relaxation phase of AJ and other reflexes Hoarseness (micropolysaccharide deposition in the vocal cords) C. EMG: 1. Axonal demyelinating or mixed features 2. Decreased sensory NCVs; decreased SNAPs 3. Prolonged CMAP distal latencies D. Pathology (sural nerve biopsy): 1. Myelinated fiber loss; large > small fibers 2. Glycogen deposition in Schwamm cells, myelinated and unmyelinated axons, endothelial cells and perineurial cells 3. Axonal degeneration; some patients have demonstrated demyelination and remyelination 4. Mucopolysaccharide accumulation in synovium and connective tissue; causing CTS and Tarsal tunnel syndrome
Acromegaly
A. General features: 1. 35% of patients suffer CTS; 35–45% have a peripheral neuropathy 2. CTS may be the presenting complaint 3. Enlarged sinuses; cardiac failure, arthropathy, myelopathy 4. Pituitary gland usually not enlarged; the severe endocrinopathy elicits an early diagnosis B. Clinical presentation: 1. Paresthesias of the hands and feet; legs greater than hands; decreased light touch, vibration and proprioception 2. Rare distal wasting 3. Absent reflexes 4. Concomitant proximal myopathy: a. Type II fiber atrophy 5. Severe CTS often precedes the diagnosis: a. Enlargement and edema of the nerve itself as well as surrounding connective tissue C. EMG: 1. 80% have CTS or subclinical NCV at the wrist 2. Decreased amplitude of sensory and mixed nerve action potentials 3. Decrease mNCV (mild) 4. Mixed axonal and demyelinating symmetric polyneuropathy D. Laboratory features: 1. Increased insulin like growth factor; somatostatin-C and growth hormone
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2. CSF may be normal E. Pathology: 1. Increased connective tissue in the perineurium and endoneurium 2. Decreased myelinated and unmyelinated axons 3. Onion bulb formation
Hyperthyroid Neuropathy
A. General features: 1. Cognitive dysfunction 2. Apathetic hyperthyroidism 3. Davidoff Syndrome: a. Hyperactive reflexes c. Nystagmus b. Babinski signs 4. Proximal myopathy: a. Iliopsoas often severely involved; wasting of the rhomboids 5. Thyroid storm; fever to 105◦ Fahrenheit, atrial fibrillation; wide pulse pressure; hypotension; most associated with increased T4; rarely increased T3 with a normal T4 B. Clinical presentation: 1. Bandow’s paraplegia: a. Proximal and distal leg weakness b. Hypotonia c. Areflexia in the legs 2. Neuropathy: a. Sensory signs and symptoms are mild b. Proprioceptive loss C. EMG: 1. Slowed M/S NCVs 2. Denervation of distal musculature D. Pathology (muscle biopsy): 1. Acute denervation
Hypoglycemia Secondary to Insulinoma
A. General features: 1. Rare 2. CNS symptoms of personality change and seizures predominate 3. Multiple episodes occur prior to an anterior horn cell or motor neuropathy is evident B. Clinical presentation: 1. Predominately or entirely a motor neuropathy 2. Distal and symmetrical 3. Upper limb more involved than the lower 4. Prominent wasting; no fasciculations 5. Painful paresthesias are common; no objective sensory loss 6. After treatment of the insulinomas; weakness improves; complete resolution of the sensory symptoms; wasting persists
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
7. More common in males greater than females 8. Neuropathy is more frequent during hypoglycemic epidoes C. EMG D. Pathology
Hepatic Disease
A. General features: 1. Peripheral neuropathy occurs in at least 20% of patients; possibly greater than 50% 2. Concomitant CNS and PNS neurological complications: a. Hepatic coma (3 stages) b. Optic neuritis; changing pupil signs c. Wernicke/Konakoff Syndrome d. Acquired hepatolenticular degeneration e. Acute increased intracranial pressure (severe acute liver failure) f. Complications of coagulopathies g. Dementia h. Choreoathetosis i. Spastic paraparesis j. Seizures k. Reversible decortication and decerebration l. CTS m. Type II muscle atrophy B. Clinical presentation: 1. Length dependent 2. Distal sensory loss; small fiber greater than large fiber modalities 3. Loss of distal reflexes 4. Correlation of severity of the neuropathy and liver disease 5. Autonomic neuropathy; possibly parasympathetic > sympathetic fiber C. EMG: 1. Length-dependent decrease of SNAP and CMAP; normal NCV 2. Concomitant CTS 3. Some patients concomitant IgA or IgM monoclonal gammopathy D. Pathology: 1. Confounding factors are diabetes mellitus or alcoholism 2. Segmental demyelination; no active demyelination or inflammatory cells; thinly myelinated fibers that are affected may reflect axonal degeneration and regeneration; short internodes suggest demyelination
Primary Biliary Cirrhosis
A. General features:
1. Incidence not known; primarily case reports B. Clinical presentation: 1. Mild distal sensory neuropathy 2. Case report (asymmetrical sensory neuropathy) 3. Severe itching: a. Class of skin C-fiber involvement carry the itch modality C. EMG: 1. Normal motor NCVs 2. Decreased sensory NCVs D. Pathology: 1. Myelinated fiber loss 2. Xanthomatous infiltration of the fascicles
Viral Hepatitis
A. General features: 1. Type A and B viral hepatitis B. Clinical presentation: 1. GBS presentation in both A and B hepatitis 2. Occurs after the onset of jaundice; may rarely proceed jaundice 3. Mild sensory neuropathy C. EMG: 1. Slowing of NCVs during episodes of severe hepatitis B D. Pathology: 1. Segmental demyelination
Tropical Sprue
A. General features: 1. Far East India and the Caribbean 2. Nutritional deficiency and bacterial contamination of the small bowel 3. Improvement with folic acid 4. Stages: a. Fatigue, asthenia, bulky stool b. After months of true malnutrition disease; weight loss glossitis, stomatitis, cheilosis and hyperkeratosis c. Anemia and megaloblastosis B. Clinical presentation: 1. Predominant distal sensory paresthesias C. EMG D. Pathology
Adult Celiac Disease (Gluten Enteropathy)
A. General features: 1. Intestinal mucosa affected; villous atrophy, columnar to cuboidal change of absorbing cells; infiltration of the laminae propria with plasma cells and lymphocytes; jejunum greater than ileum
Chapter 15. Neuropathies Associated with Medical Illness
2. Increased HLA-B8 and DW3 3. Patients with IgA deficiency are predisposed 4. Antibodies to gliadin B. Clinical presentation: 1. Distal dying-back neuropathy; fluctuates depending on gluten exposure 2. Associated with myelopathy and cerebellar degeneration C. EMG: 1. Axonal feature D. Pathology: 1. Axonal degeneration
Vitamin E Deficiency
(see above pp )
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4. Symmetrical polyneuropathy 5. Rare acute GBS like presentation 6. Chronic forms may have little associated systemic disease 7. Peripheral neuropathy occurs in approximately 15% of patients 8. Patients with mononeuritis multiplex may have anesthetic trunk areas (intercostal neuritis) C. EMG: 1. Decreased motor nerve amplitudes 2. Absent sensory responses SNAPs 3. Slowed m/r NCVs; rare conduction block 4. Denervation of affected muscles D. Pathology: 1. Localized granulomatous nerve infiltration; noncaseating granuloma within the endoneurium of peripheral nerves, roots and cranial nerves 2. Angiopathy a component of the pathology
Chronic Obstructive Pulmonary Disease Critical Illness Polyneuropathy
a. General features: 1. Associated with severe COPD with weight loss B. Clinical presentation: 1. Mild distal sensory neuropathy 2. Associated with Type II fiber muscle atrophy of proximal muscles C. EMG D. Pathology
Sarcoidosis
A. General features: 1. Granulomatous multisystem disease most frequently affecting the lung (hilar adenopathy or infiltrative pattern) heart, joints, skin, ocular and reticuloendothelial systems 2. CNS involvement: a. Pituitary; chiasm, posterior hypothalamus; any location in the parenchyma; stroke presentation b. Dural involvement c. Uveitis and bilateral VIIth nerve palsy (Hereford’s syndrome) d. Myelopathy from involvement of the dura with compression of the spinal cord e. CSF; sugar 30–40 mg%; protein 80–150 mg% and lymphocytic pleocytosis f. Rarely cranial nerve VIII and II are involved B. Clinical presentation: 1. Neuropathy may occur as isolated manifestation or as part of generalized disease 2. Mononeuritis multiplex 3. Sensory loss over the trunk; may be associated with dysesthesias or pain, posterior column dysfunction
A. General features: 1. Exact incidence is unknown; appears common in patients that have been in the ICU for greater than four weeks 2. Need to distinguish it from concomitant acute myopathy (Type II fibers; thick myosin; corticosteroid induced myopathy; neuromuscular blocking agents) B. Clinical presentation: 1. Occurs in patients with sepsis and multiorgan failure (cardiac, pulmonary, renal, liver) 2. Quadriparesis 3. Difficulty weaning from the respirator 4. Reduced or absent deep tendon reflexes 5. Less clear sensory deficit 6. Often concomitant encephalopathy 7. Residual weakness in distal muscles C. EMG: 1. Reduced CMAP and SNAP amplitudes 2. Normal distal latencies and NCVx 3. Denervation D. Pathology: 1. Axonal degeneration
Neuropathy of Renal Failure
A. General features: 1. Present in 80% of severely uremic patients; large percentage may be asymptomatic but demonstrable by NCV abnormalities 2. Primarily related to the duration and severity of the renal failure 3. Males more often affected than females
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
4. Stable or improves with dialysis 5. Improves following successful renal transplantation B. Clinical presentation: 1. Insidious onset; rarely acute or subacute 2. Sensory neuropathy; painful tingling of the feet; burning; band-like constrictions around the toes 3. Restless legs; muscle cramps d. Impaired position and vibration sensibility; there may be small fiber predominant variant 4. May have marked muscle wasting; concomitant Type II atrophy of proximal muscles 5. Distal lower extremity weakness of anterior tibialis, extensors of the toe and eversion 6. Decreased or absent deep tendon reflexes 7. Orthostatic hypotension, impotence and constipation are common 8. Increased incidence of CTS 9. Arteriovenous shunt placement in the arm may cause ischemic high median neuropathy 10. CTS may be secondary to deposition of beta2migroglobulin (systemic amyloidosis as consequence of the renal failure) 11. Ulnar and peroneal compressive neuropathy may occur concomitantly C. EMG: 1. Decreased motor and sensory NCVs 2. No correlation between NCVs and clinical signs of neuropathy 3. After transplantation there may be rapid improvement of NCV followed by consistent improvement over time 4. Progressive reduction of SNAPs and CMAPs 5. Prolonged F-wave latencies 6. Denervation and reinvention noted by needle EMG in distal muscles 7. Small parasympathetic fiber abnormalities (R-R variability) greater than sympathetic fiber loss D. Laboratory: 1. Creatinine clearance of less than 10 ml/minute has decreased NCV 2. serum PTH inversely correlated with NCV 3. CSF a. Usually normal; may have slight increase in protein E. Pathology: 1. Axonal degeneration 2. Some segmental demyelination and remyelination
2. Occurs despite hemodialysis 3. Livedo reticularis 4. Retinopathy 5. Renal and liver transplant are beneficial C. EMG: 1. Axonal feature D. Pathology: 1. Calcium oxalate within endoneural blood vessel walls and axon cylinders 2. Axon loss 3. Demyelination
Hyperlipidemia
A. General features: 1. Rare 2. Serum cholesterol moderately increased, triglycerides levels are very high B. Clinical presentation: 1. Slowly progressive 2. Pain in the feet without proximal extension or hand involvement 3. No weakness or autonomic symptoms 4. 50% of patients have decreased ankle jerks C. EMG: a. Axonal features (subclinical) in greater than 30% of patients with hypertriglyceridemia D. Pathology (nerve biopsy): 1. Axonal degeneration
Sicca Complex
A. General features: 1. Rare 2. Probable autoimmune etiology B. Clinical presentation: 1. Diffuse patchy loss of sweating over the body surface 2. Panautonomic dysfunction 3. Greater than 50% of patients; mixed pattern of autonomic dysfunction with abnormal sudomotor, cardiovagal and adrenergic function 4. Autonomic neuropathy with distal sensorimotor neuropathy 5. Rare in association with extraglandular disease 6. Extractable nuclear antigen ENA; SSA-SSB Ag noted in 20% of patients
Primary Hyperoxaluria
A. General features: 1. AR (primary hyperoxaluria Type I) 2. Accumulation of calcium oxalate crystals in cutaneous arterioles, kidneys and eyes B. Clinical presentation: 1. Rapidly progressive motor and sensory neuropathy
CREST Syndrome
A. General features: 1. Calculosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, telangiectasis are the major systemic features
Chapter 16. Tumors of Peripheral Nerves
B. Clinical presentation: 1. Onset of neuropathy may occur up to 25 years after the first symptoms of scleroderma 2. Multiple mononeuropathy C. EMG: 1. Infarction of individual nerves D. Pathology: 1. Necrotizing vasculitis 2. Axonal degeneration
Chapter 16 Tumors of Peripheral Nerves A. General features: 1. Mass can be displaced at right angels to the course of the nerve 2. Mechanosensitivity expressed as paresthesias when stimulating the tumor 3. Inability to distinguish a neurofibroma, Schwannoma or malignant tumor by clinical examination Benign Neural Sheath Tumors
Schwannoma
A. General features: 1. The most common benign neural sheath tumor 2. Higher incidence in women than men 3. May develop with Von Recklinghausen’s disease (neurofibroma muscle more common) 4. Well encapsulated and cause lateral displacement of adjacent fascicles B. Clinical presentation: 1. Positive Tinel’s sign (paresthesias elicited by mechanical stimulation) over the tumor in the distribution of the affected nerve 2. Rare presentation as a neurologic deficit of the affected nerve 3. Most common nerves affected: a. Supra greater than infraclavicular components of the brachial plexus b. Axillary and musculocutaneous nerve c. Tibial nerve greater than sciatic nerve in the thigh d. Median > ulnar > radial nerve; proximal portions of nerve > distal C. Pathology: 1. Schwannomas putatively arises from Schwann cells: a. Hypercellular compact or palisading regions (Antoni Type A) 1) Verocay bodies are prominent b. Loose hypocellular regions (Antoni Type B) 2. Well encapsulated; displace adjacent fascicles laterally; slow enlargement with rare loss of function
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Neurofibroma not Associated with Von-Recklinghausen’s Disease
A. General features: 1. The nerve can be displaced side to side, but not longitudinally 2. More painful than Schwannomas 3. Neurologic deficit at presentation > Schwannoma 4. Fusiforme > plexiform (noted in non Von Recklinghausen’s disease patients) 5. Tinel’s signs nearly universal 6. Females > males 7. R > L side of the body 8. Arise from the motor more often than sensory portion of the nerve 9. Occur as a localized mass; may involve long segment of the nerve 10. No cleavage plane; total removal requires nerve section B. Clinical presentation: 1. Location: a. Supraclavicular > infraclavicular brachial plexus, 4:1 b. Axillary nerve greater than deltoid c. Pelvic plexus > sciatic nerve in the thigh d. Sciatic nerve in the buttock, peroneal and tibial nerve have equal incidence 2. Painful particularly if partially resected a. Tinel’s sign in the distribution of the nerve D. Pathology: 1. Arise from the perineural fibroblast 2. Myo-collagenous background that stains intensely with reticulin stain
Neurofibromas Associated with Von Recklinghausen’s
A. General features: 1. Chromosome 17; AD with full penetrance, but variable expression 2. Incidence 1/300 persons; often patients have few symptoms 3. Females > males; R > L side of the body 4. Tumors are found in nerve endings in the skin as well as proximal nerves 5. 15% chance of malignant degeneration 6. Present at early age than solitary ones B. Clinical presentation: 1. Both motor and sensory symptoms 2. Anesthesia in the middle of a small neurofibroma of the skin 3. Painful; Tinel’s usually present 4. Location: a. Supraclavicular > infraclavicular brachial plexus, 3:1
SECTION X. Differential Diagnosis of Peripheral Neuropathy
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b. c. d. e.
Axillary > musculocutaneous nerve Ulnar > median > radial nerve Pelvic plexus > sciatic nerve in the thigh Tibial > peroneal > saphenous
Plexiform Neurofibroma
A. General features: 1. Tumors are intrafascicular, extrafascicular with no capsule 2. Difficult to operate without further loss of functions 3. Most associated with VRD; some are solitary 4. Concomitant multiple neurofibromas of the nerve of origin that occur proximally and distally: a. May involve other nerves of the same extremity (neurofibromatosis type 5) b. Malignant transformation in 8% of patients: 1) Signaled by pain and rapid growth 2) Recurrence following resection is common
Differential Diagnosis Points to Delineate Schwannoma from Neurofibroma
1. Neurofibroma is suspected in the face of other stigmata of VRD (rarely Schwannomas can appear in this setting) 2. Neurofibroma more local and radicular pain 3. Tinel’s sign is prominent in both 4. Incidence of Schwannoma higher in women than men 5. Both displace nerves side to side but not longitudinally 6. Neurologic deficit at the time of presentation favors Schwannoma Neurothekeoma
A. General features: 1. Benign nerve sheath tumor 2. Occurs in patients less than 30 years of age B. Clinical presentation: 1. Mistaken for Schwannomas 2. Soft mobile tumors of the dermis C. Pathology: 1. Schwamm cell or perineural cell origin 2. Tumor cells in fascicles circumscribed by a myoid stroma
Benign Non-Neural Sheath Tumors
Dermoids
A. General features: 1. Arise from muscle 2. Abdominal wall as well as neck, shoulder, and extremity location
3. May compress or adhere to nerves 4. Involve soft tissues 5. Do not metastasize B. Clinical presentation: 1. Very firm lesions; tight adherence to nerves with consequent deficit C. Pathology: 1. Mesenchymal origin Myositis Ossificans
A. General features: 1. Idiopathic form; abnormal calcification starts in the lumborum quadratus (paraspinal muscles) 2. Large separation of the great and second toe 3. May be related to trauma or previous surgery B. Clinical presentation: 1. Neural and vascular tissues may be involved which present with specific local symptoms 2. Compresses nerves C. Pathology: 1. Calcification of muscle Myoblastoma
A. General features: 1. Spread as a sheet of tumorous tissue that can envelop or adhere to nerves B. Clinical presentation: 1. Involve brachial plexus C. Pathology: 1. Compact angular cells with acidic granules Lymphangioma
A. General features: 1. Spread of tumor around nerves B. Clinical presentation: 1. Median and ulnar nerve; brachial plexus are major locations of the tumor C. Pathology: 1. Sheets of lymphoid type cells Lipoma
A. General features: 1. Subcutaneous location 2. Sites; forearm (posterior interosseous nerve compression; popliteal fossa (peroneal palsy); supraclavicular fossa, buttock, leg or arm B. Clinical presentation: 1. Rarely involves major nerves except when they arise from deep tissue planes 2. Median nerve most commonly affected 3. Cauda equina involvement is usually asymptomatic unless there is malignant degeneration C. Pathology: 1. Normal fatty tissue
Chapter 16. Tumors of Peripheral Nerves
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Lipohamartoma
Epidermoid Cysts
A. General features: 1. Intrinsic to nerve B. Clinical presentation: 1. Involves the median nerve at the wrist or in the palm with median nerve dysfunction C. Pathology: 1. Normal fatty tissue 2. Tumor may envelop the nerve
A. General features: 1. Compress adjacent nerves B. Clinical presentation: 1. Sciatic nerve is the commonest location at the: a. Sciatic notch b. Posterior popliteal fossa
Hemangiopericytoma
A. General features (“onion-whorl disease”): 1. Encasement of the fascicles and individual nerve fibers 2. Possible endoneurial proliferation B. Clinical presentation: 1. Affects children or young adults 2. Peroneal and median nerves are most often affected; rarely the brachial plexus, ulnar radial and sciatic nerves are involved 3. Pain and loss of affected nerve’s function C. EMG: 1. Nerve action potentials can be maintained across the affected part of the nerve D. Pathology: 1. Proliferation of perineural cells 2. Endoneural fibrosis fibrotic replacement of the perineurium 3. Decreased myelin
A. General features: 1. May originate within the nerve; usually symptoms produced by compression 2. Usually arise in the mediastinum 3. May metastasize to normal tissue B. Clinical presentation: 1. Brachial plexus compression (from mediastinum) 2. Upper extremity nerves Hemangioma
A. General features: 1. Benign vascular neoplasm; closely resembles normal tissue 2. May be found in all organs of the body 3. High or low flow characterization by MR angiography B. Clinical presentation: 1. May compress adjacent nerves
Hypertrophic Neuropathy
Malignant Neural Sheath Tumors (MNSTs)
Ganglions
A. General features: 1. Arise form joints and may compress contiguous nerves 2. Tender mass that causes pain and paresthesias of the affected nerve B. Clinical presentation: 1. Compress adjacent nerves at the following levels: a. Thenar sensory branch of the median nerve b. Ulnar palmar branch c. Median and ulnar major trunk’s d. Radioulnar (posterior interosseous) e. Knee (peroneal nerve) f. Ankle (posterior tibial nerve) g. Hip (sciatic nerve) h. Shoulder (brachial plexus); suprascapular nerve at the scapular notch i. Elbow; radial > median > ulnar nerve Ganglions without Joint Connection 1. Deep peroneal nerve over the head of the fibula 2. Intraneural ganglions: a. Extend great distances with the nerve b. Cause motor and sensory deficits
A. General features: 1. Malignant Schwannoma or neurofibroma (neurogenic sarcoma or fibrosarcoma as alternate designations) 2. Mitotic activity, cellular pleomorphism, necrosis and hemorrhage within the tumor 3. Heterogeneous cells noted in 15% of MNSTs; neurofibroma > Schwannoma 4. 50% of MNSTs arise in VRD; spontaneous solitary lesions occur without VRD 5. Malignant degeneration of benign Schwannoma rarely occurs 6. Previous radiation is a risk factor B. Clinical presentation: 1. Firmer than benign neural sheath tumors 2. Mass with irregular borders 3. Progressive loss of function of the affected nerve 4. Adherent to adjacent structures 5. Earliest manifestation is pain 6. Rapid increased in size 7. May present with metastasis in lung, bone or liver 8. Recurrence after treatment with X-ray and chemotherapy is high
SECTION X. Differential Diagnosis of Peripheral Neuropathy
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Local and Malignant Schwannoma (Neurosarcoma)
1. Brachial plexus > sciatic nerve > femoral and ulnar > tibial and peroneal nerve 2. Location of malignant neurofibroma (fibrosarcoma) a. Brachial plexus > femoral nerve 3. Location of neuroblastoma a. Sacral plexus
Metastatic Carcinoma to Nerves
A. General features: 1. Direct extension from the primary site 2. Breast cancer the most common; also occurs with lung, melanoma, thymoma and pancreatic cancer 3. Most metastasis occur in the brachial plexus B. Breast cancer: 1. At the infraclavicular axillary level it occurs by direct extension 2. At the supraclavicular plexus occurs from lymph nodes C. Pulmonary cancer: 1. Pancoast tumor involves the brachial plexus by direct extension (4th/5th finger burning pain, Horner’s syndrome, hand weakness; involvement of the lower trunk and sympathetics from C8–T1) D. Hematogenous metastasis to nerve: 1. Lymphoma 2. Bladder cancer 3. Melanoma
2. Seldom used classification of peripheral nerve injury: a. Neurapraxia-axons are intact, but fail to conduct action potentials due to focal demyelination b. Axonotmesis-transection of axons, but the nerve trunk is intact c. Neurotmesis-transected nerve trunk B. Sunderland classification of peripheral nerve injury: 1. First degree injury: a. Disruption of myelin sheath with intact axons and stroma 2. Second degree injury: a. Transection of axons with intact stroma 3. Third degree injury: a. Transection of axons and endoneural tubes; perineurium is intact 4. Fourth degree injury: a. Transection of axons, endoneurial tubes and the perineurium; fascicular transection occurs; epineurium is intact 5. Fifth degree injury: a. Transection of the nerve trunk
Prognosis for Peripheral Nerve Injury
1. 2. 3. 4.
Degree of injury Damage to the nerve Distance from the muscle that is innervated Gradual or higher injuries cause Wallerians degeneration
Long Thoracic Nerve Differential Diagnosis of Benign Non-Neural Sheath Tumors
1. Ganglioneuroma 2. Myoblastoma 3. Lipoma 4. Meningioma 5. Desmoid 6. Cystic hygroma 7. Epidermoid cyst 8. Ganglion cyst 9. Hemangioma
10. Hemangiopericytoma 11. Glomus tumor 12. Hemangioblastoma 13. Myositis ossificans 14. Osteochondroma 15. Hidradenitis 16. Lymphangioma 17. Venous angioma 18. Titin tumor
Chapter 17 Traumatic and Compressive Neuropathy A. General features: 1. Peripheral nerve injury occurs in 2–3% of patients admitted to level I trauma centers; addition of root and plexus injuries increases this figure to 5%
A. General features: 1. Derived from C5, C6, C7 roots prior to origin of the brachial plexus 2. Innervates the serratus anterior muscle 3. Pathogenesis of injury: a. Lesions affecting the component roots b. Associated with neuralgia amyotrophica c. External compression and stretch B. Clinical presentation: 1. Paralysis of the serrates anterior with scapula winging 2. Shoulder stabilization is decreased 3. No cutaneous innervation 4. Inferior scapular border is rotated medially; vertebral border is more prominent when arm pushes against resistance C. Differential diagnosis: 1. Intercosticobrachial nerve from the medial cord of the brachial plexus: a. Purely a sensory nerve that innervates the lateral and upper anterior chest wall and radiates under the breast to the midline 2. Neuralgia amyotrophica:
Chapter 17. Traumatic and Compressive Neuropathy
a. May be damaged in isolation (the long thoracic nerve) b. Severe shoulder pain for days to weeks c. Difficulty with shoulder movement 3. Scapular winging occurs with: a. Rhomboid weakness: 1) Moves away from the back midline when the arm is pushed forward b. Trapezius weakness: 1) Dropped shoulder 2) Poor shrug 4. Limb girdle muscular dystrophia
Suprascapular Nerve
A. General features: 1. C5–C6 roots; arise from the upper trunk of the brachial plexus 2. Passes through the suprascapular notch 3. Anomalous fibers may supply the distribution of the axillary nerve distribution B. Pathogenesis of injury: 1. Entrapment usually occurs at the suprascapular notch; may be compressed at the spinoglenoid notch 2. Repetitive movements 3. Ganglion cysts, sarcoma, metastatic disease 4. Positioning during surgical procedure (knee, chest position) 5. Weight lifting (shoulder abduction and protraction) 6. Volleyball, dancing, baseball pitchers (injury distally at the spinoglenoid notch) 7. Neuralgia amyotrophic (with other shoulder girdle nerves) C. Clinical presentation: 1. Impingement at the suprascapular notch causes shoulder pain 2. No cutaneous innervation; sensory innervation to deep tissues (muscles of the capsule of the glenohumeral joint) 3. Deep seated throbbing pain along the superior border of the scapular toward the shoulder (exacerbates by stretching the adducted arms across the chest) 4. Entrapment in the suprascapular notch both supra and infraspinati weakness; at the lateral border of the spine involves the infraspinatus muscle alone 5. Weakness of shoulder abduction and external rotation of the arms; atrophy of the infraspinatus may be prominent 6. Infraspinatus injury at the spinoglenoid notch is painless and only involves this muscle 7. Pain may be prominent at the suprascapular notch D. EMG: 1. No sensory nerves to test; lateral antebrachial cutaneous median, radial sensory involvement rule it out.
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2. NCV with stimulation at Erb’s point and recording over corresponding muscle denervation 3. Needle EMG demonstrate denervation in infra and suprascapular muscles (infraspinatus alone if the lesion is at the spinoglenoid notch)
Differential Diagnosis of Supra and Infrascapular Nerve Lesions
1. Musculoskeletal pains around the shoulder; subacromial bursitis, bicipital tendonitis, acromioclavicular arthritis or separation; pericapsular fibrosis 2. Rotator cuff injury (no weakness) 3. C5, C6 radiculopathy; often referred pain to the deltoid cap (C5); C6 (thumb and lateral forearm); often pain radiates to the upper arm; weakness of biceps; depressed biceps and brachial radialis reflexes 4. Brachial neuritis; neurologic amyotrophy; abrupt onset of pain and weakness of other muscles innervated by the plexus; may be bilateral 5. Brachial plexus traction injury (neuropraxic): Tinel’s sign throughout the arm (supra and infraclavicular fossa, neurovascular bundle; Arcade of Frohse, pronator canal); positive Roo’s abduction stress maneuver; trunk and cord sensory loss and weakness.
Axillary Nerve
A. General features: 1. Originates from the posterior cord of the brachial plexus; derived primarily from C5, C6, C7 roots (upper trunk/posterior cord) 2. Passes through the quadrangular space 3. Innervates the teres minor and deltoid (external rotation and abduction of the shoulder) 4. Lateral shoulder sensory innervation (at the caps of the shoulder) B. Pathogenesis of the injury: 1. Dislocation and fracture of the shoulder 2. Fracture of the humerus 3. Surgical positioning 4. Entrapment in the quadrilateral space C. Clinical presentation: 1. Sensory loss over the lateral shoulder 2. Weakness of shoulder abduction and external rotation 4. EMG: 1. Denervation of the deltoid and the teres minor E. Differential diagnosis: 1. Orthopedic shoulder conditions 2. C5–C6 radiculopathy 3. Brachial plexus traction injury 4. Neuralgia amyotrophica 5. Suprascapular neuropathy
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
Spinal Accessory Nerve
A. General features: 1. Pure motor nerve; C1–C4 ventral root denervation; ascends through the foramen magnum and exits through the jugular foramen (pars venosum) 2. Supplies sternocleidomastoid muscle and then runs in posterior cervical triangle to innervate the trapezius muscle B. Pathogenesis of the injury: 1. Stretch or compression of the posterior cervical triangle 2. Carotid endarterectomy 3. Lymph node biopsy 4. Compression from tumor (lymphoma) C. Clinical presentation: 1. Distal lesions cause: a. Atrophy and weakness of the trapezius muscle resulting in a dropped shoulder; mild scapular winging in abduction, weakness of shoulder abduction and external rotation (due to lack of fixation) b. Traction of the brachial plexus with pain due to stretch of the cords and trunks c. Proximal lesions causes weakness of the sternocleidomastoid muscle with weakness of neck flexion and contralateral head turning D. EMG: 1. Decreased CMAP of the upper trapezius muscle 2. Denervation of upper, middle and lower fibers of the trapezius E. Differential Diagnosis: 1. Brachial plexus traction injury 2. Skull based tumors 3. Surgical damage to the posterior cervical triangle 4. Jugular foramen tumors (glomus jugulare) 5. Compression injuries
Musculocutaneous Neuropathy
A. General features: 1. Arise from the lateral cord of the brachial plexus; innervates the coracobrachials, biceps brachialis; after the elbow it is the lateral antebrachial cutaneous nerve (does not innervate the thumb); lateral and slight component of the posterior forearm innervation; posterior sensory branch may anastomose with the radial sensory nerve or the posterior cutaneous nerve of the forearm; rare anastomosis of the anterior branch with median nerve sensory fibers. B. Clinical presentation: 1. Weakness of elbow flexions 2. Decreased or absent biceps reflex 3. Sensory loss in lateral forearm
4. Lateral antebrachial cutaneous neuropathy sensory loss is increased with pronation and extension (entrapped between the biceps tendon, and fascia and the brachialis muscles) C. Pathogenesis of the injury: 1. Trauma of upper arms and shoulder 2. Fracture of the proximal humerus 3. Positioning during surgery 4. Upper extremity strenuous repetitive injury 5. Benign humeral exostoses D. EMG: 1. Denervation of biceps and brachioradialis 2. Sensory conduction deficits of the lateral antebrachial cutaneous nerve 3. Decreased SNAPs of this nerve with proximal and distal lesions E. Differential diagnosis: 1. C5–C6 radiculopathy 2. Brachial plexus pathologies (upper trunk)
High Median Nerve Compression in the Region of the Shoulder or Proximal Humerus
A. General features: 1. Uncommon; most often traumatic 2. Anterior dislocation of the shoulder 3. Axillary compression from long arm crutches 4. Hanging the arm over chairs 5. Aneurysm of the brachial or axillary artery B. Clinical presentation: 1. Forearm pronation deficit: paralysis of the pronator teres and pronator quadratus 2. Weak wrist flexion with ulnar deviation due to weakness of the flexor carpi radiales 3. Paralysis of: flexor pollicis longus, flexor digitorum superficiale of the digits (therefore absence of flexion of the distal inter phalanges joint and proximal interphalangeal joint of the index finger). The weakness of grasp of the fourth and fifth digits (flexor digitorum superficialis); Slight weakness of the flexor digitorum profundus with consequent weakness of distal interphalangeal flexion. Paralysis of thenar muscles (motor branch of the median nerve) and decreased sensory supply to median nerve innervates digits.
Median Nerve Compression at the Elbow
A. General features: 1. Five centimeters above the medial epicondyle of the humerus there is a supracondylar process (occurs in approximately 0.7–2.7% of the population. The median nerve and brachial artery and vein course under this ligament of struthers
Chapter 17. Traumatic and Compressive Neuropathy
2. In the antecubital fossa the median nerve courses adjacent to the brachial artery 3. In the forearm it courses below the thick fibrous band known as the lacertus fibrosus (originates from the medial biceps tendon and attaches to the forearm flexor musculature) 4. Between the two heads of the pronator teres; after it passes this area the anterior interosseous nerve is given off posteriorly. 5. Passes deep to the flexor digitorum sublimes muscle and its aponeurotic tendinous edge the sublimus bridge B. Pathogenesis of nerve injury: 1. Trauma; casting, direct injury, venipuncture, tumor or hematoma 2. Neuralgia amyotrophia can involve the anterior inter osseous nerve 3. Chromosome 17; CMT1a; hereditary neuropathy with sensitivity to pressure (HNPP) 4. Elbow dislocation 5. Persistent median artery Ligament of Struthers Compression
A. Clinical presentation: 1. Pain in the volar forearm 2. Paresthesias in the median nerve innervated digits 3. Sensory symptoms exacerbated by forearm supination and extension at the elbow 4. Palpation of the distal spur on the medial humerus 5. Weakness of the pronator teres > other median innervated muscles Pronator Syndrome
A. Clinical features (evocative maneuvers): 1. Lacertus fibrosis site: a. Forced supination and elbow flexion b. Pronator teres: 1) Forced pronation and elbow extension c. Sublimus bridge: 1) Flexion of the proximal interphalangeal joint of the middle finger d. All three sites of entrapment: 1) Weakness of the FPL and APB; rarely FDP 2) Paresthesias of median nerve innervated digits 3) Aching of the proximal forearm; may radiate to the elbow or shoulder 4) Tenderness of the proximal forearm over the pronator teres 5) Clumsiness and weakness of the hand B. EMG: 1. Abnormal in a minority of patients; acute and chronic denervation of median nerve innervated muscles 2. Focal slowing of the median nerve at the elbow 3. Denervation of median forearm and hand muscles
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Differential Diagnosis of Pronator Teres Syndrome
1. Carpal tunnel syndrome: pronator teres is associated with weakness of the forearm flexor muscles; palmar cutaneous nerve numbness (includes the thenar eminence absent in CTS) Tinel’s signs at the wrist rather than the elbow (pronator canal) 2. Cervical radiculopathy; C6 or C7 root may cause forearm pain; vague sensory loss into the thumb index and third finger. Positive Spurling’s sign at the nerve root exit foramina in the neck; lateral rotation of the neck causes paresthesias in the thumb and index finger; pain down the spinous processes of the neck; weakness of the biceps (C6); triceps (C7); decreased biceps reflex for C5, C6 and triceps reflex for C7. 3. Brachial plexus traction injury (upper trunk and lateral cord) 4. Musculoskeletal disease at the elbow: a. Sprains of the flexor pronator muscle b. Vascular anomaly; aneurysms of the median artery; AV shunts for dialysis; fistulas due to traumas (knife > bullet) c. Minimums or no sensory loss
Anterior Interosseous Nerve
A. General features: 1. Nerve arises from the median nerve 5 to 8 cm distal to the lateral epicondyle 2. Innervates flexor pollicis longus, flexor digitorum profundus to index and long finger and pronator quadratus 3. No cutaneous sensation; proprioception and pain afferents to the wrist joint 4. Anomalous innervations: a. Anterior interossei may supply all of the flexor digitorum profundi (patient is unable to flex any distal digital joints); all median hand. b. Flexor digitorum profundus to index or long finger spared (innervated by the ulnar nerve) c. 50% of Martin–Gruber anastomosis arise from the anterior interosseous nerve B. Pathogenesis of nerve injury: 1. Repetitive elbow flexion and pronation 2. Trauma with casting 3. Open reduction of forearm fractures 4. Anatomic anomalies: tendinous origin of the deep head of the pronator teres; tendinous compression of the flexor digitorum superficialis of the third finger C. Clinical presentation: 1. Inability to flex the distal phalanx of the thumb and index finger; weak pronation (pronator quadratus) D. EMG: 1. Decreased distal motor latencies from the elbow to the pronator quadratus
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
2. Denervation of the flexor digitorum profundus (I–II); FPL, pronator quadratus E. Differential diagnosis of anterior interosseous injury: 1. Paralytic brachial neuritis with concomitant anterior interosseous involvement (pain that lasts for days to weeks) 2. Vascular anomaly of the lateral cord of the brachial plexus (no motor involvement) 3. Rheumatoid arthritis; rupture of the FPL and FDP to the tendons index finger on the tubercle of the scaphoid bone 4. Cervical radiculopathy (sensory loss with biceps, triceps or brachialis reflex loss)
Carpal Tunnel Syndrome
A. General features: 1. Proximal to the wrist and carpal tunnel, the palmar cutaneous sensory branch arises and innervates the thenar eminence 2. Carpal bones make up the floor and sides of the carpal tunnel; transverse carpal ligament forms the roof. 3. In the palm the motor branch arises to innervate the first and second digits and the thumb, the recurrent thenar motor branch supplies the opponens pollicis, APB, superficial head of the flexor pollicis brevis; sensory branch supplies the medial thumb, index, long finger and radial side of the 4th finger. B. Pathogenesis of median nerve neuropathy at the wrist: 1. Narrow carpal tunnel (congenital) 2. Most common in middle aged women 3 : 1 female to male; often bilateral; dominate hand most severely involved 3. Edema, vascular sclerosis and fibrosis of transverse carpal ligament 4. Repetitive hand use 5. Hypothyroidism, diabetes mellitus, scleroderma, rheumatoid arthritis, amyloidosis 6. Lyme disease 7. Sarcoid 8. Colles fracture 9. Pregnancy 10. Hemodialysis 11. Anomalous flexors tendons 12. Flexor tenosynovitis (rare) 13. Gout 14. Secondary to brachial plexus fixation with compromised movement through the carpal tunnel (often bilateral) C. Clinical presentation: 1. Numbness; index, middle finger and radial ½ of the fourth finger; larger percentage of patients complain of paresthesia of all fingers
2. Nocturnal paresthesias; awaken patients from sleep; hand held off the bed as a position of comfort 3. Activities that elicit pain or paresthesias; driving, writing, holding a phone or book, typing on a computer 4. Pain: hand, forearm, rarely the shoulder; wrist flexion exacerbates distal and proximal pain radiations (Phalen’s sign; usually flexion needs to be held 1–2 minutes to elicit pain); Tinel’s sign over the carpal tunnel (not specific as it may occur in normal people). 5. Weakness or tiredness during writing; dropping objects 6. Raynaud’s phenomenon and autonomic dysregulation of the hand (median nerve supplies bulk of the sympathetic fiber to the hand) 7. Hypesthesia in the median nerve distribution in 70% of patients. The thenar eminence is spared (palmar branch of the median nerve) leaves the nerve 3 cm prior to the carpal tunnel). The tip of the index finger is the earliest and most severe area of sensory loss. Two point discrimination is affected prior to pin prick and temperature loss. The radial split of the 4th finger is characteristic. Tinel’s sign is positive at the wrist. D. EMG: 1. Decreased sensory conduction at the wrist is most sensitive 2. Prolongation of the distal motor latency 3. Reduction of median motor and sensory amplitudes. E. Differential diagnosis: 1. Brachial plexopathy (lateral cord; upper trunk) 2. Cervical radiculopathy (C6; C7) 3. Median neuropathy at the elbow (sensory loss of the thenar eminence; weakness of distal thumb flexion, arm pronation, and wrist flexion) 4. Lacunar infarction of the motor knuckle or lateral thalamus 5. Rarely TIA 6. Seizure 7. Migraine
Ulnar Entrapment at the Elbow
A. General features: 1. Second most common nerve entrapment of the upper arm ( men) demonstrate an anomalous band or vessel in the sciatic notch in proximity to the sciatic nerve 4. Muscle spasm with pyriformis compressions of the nerve induced by rheumatic disease, bursitis or trochanteric disease at its insertion 5. Muscle tendon or fascial inflammation 6. History of minimal trauma to the buttock B. Clinical presentation: 1. Buttock pain and tenderness without sciatic radiation; sciatic notch point tenderness 2. Pain exacerbated by sitting, bending at the waist 3. Maneuvers requiring hip adduction and internal rotation 4. Relieved with standing and walking 5. Dyspareunia in women
6. 7. 8. 9. 10. 11.
Paresthesia in sciatic distribution that is patchy No weakness, reflex change or hard sensory loss Positive Trendelenburg sign Leg externally rotated with walking Rarely mild wasting of the glutens maximus Positive Freiberg, Pace Beaty tests, pain on adduction, internal rotation and flexion 12. Myofascia band between the biceps femoris and abductor magnus: a. Distal thigh pain above the posterior popliteal fossa 13. Baker’s cyst in posterior distal thigh of either the peroneal or posterior division of the nerve 14. Sciatic compression from muscle fibrosis (pentazocine) C. EMG: 1. NCV and muscle studies are negative 2. Denervation in both peroneal and tibial division 3. Peroneal more affected 4. Short head of biceps less affected than other hamstring muscles 5. Flexor digitorum longus and medial and lateral gastrocnemius reveal fibrillation potentials.
Differential Diagnosis of Sciatic Nerve Injury
1. Peroneal nerve lesion at the fibular neck: a. Tinel’s sign at the fibula neck b. Foot pain is rare c. No back pain or L5–S1 radiations d. Negative stretch maneuvers (SLR test) e. Normal ankle jerk, inversion, toe flexion and plantar flexion f. Sensory loss at an area between great toe and first digit 2. Herniated lumbar disc: a. Long standing back pain b. Position of comfort (flexed knees in recumbency) c. Cough, sneezing, laughing are painful as are all Valsalva maneuvers d. Monoradicular symptoms S1 > L5 > L4 e. Proximal pain primarily in the buttocks or posterior thigh f. Often bilateral asymmetric symptoms (loss of foraminal exit maintenance as the uninvolved as well as the involved side) 3. Spinal stenosis: a. L4–L5 > L5–S1 levels; mid lumbar to midsacral levels; epidural compression b. Progressive calf and foot pain induced by walking and relieved by rest; frequent calf neurogenic cramps. c. Simian posture (forward flexed back) 4. Vascular monomeric neuropathy: a. Primarily in diabetic patients b. Acute onset (several days)
Chapter 17. Traumatic and Compressive Neuropathy
c. Wasting is prominent d. No back pain e. Sciatic symptoms are mixed with those of the femoral or saphenous nerves f. Prior history of leg ischemia g. Sensory loss is stocking and glove; sciatic lesions the saphenous territory is spared 5. Malignancy of the spinal cord: a. Intraspinal tumor 1) Gastrocnemius more severely involved than anterior tibialis or extensor hallucis longus b. Lymphoma 1) Wraps around the lumbosacral cord on MRI; often involves lower sacral roots c. Myeloma 1) Root compression by fracture and displacement of bone; marrow signal lost at multiple spinal levels on MRI
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a. Anomaly in approximately 20% of people; arises as a continuation of the muscular branch of the superficial peroneal nerve and innervates peroneus brevis muscle; distally innervates part of EDB, ankle joint and ligament C. Clinical manifestation: 1. Sensory loss lower lateral leg and dorsum of the foot; exacerbated with walking or running 2. Tinel’s sign at 10 cm (fascia) 3. Pain in distal anterolateral leg 4. Ankle pain with or without numbness over the dorsum of the foot if affected at the ankle; increased pain with plantar flexion or inversion D. Pathogenesis: 1. Blunt trauma, boots, lipoma neuromas E. EMG: 1. Absent or low amplitude superficial peroneal SNAPs Common Peroneal Mononeuropathy at the Fibular Neck
Peroneal Nerve
A. General features: 1. Branch exits near gluteal fold to innervate the short head of the biceps femoris 2. In the popliteal fossa: a. Exit of the lateral cutaneous nerve of the calf (upper 1/3 of lateral leg) b. Sural communicating nerve (joins the sural nerve) 3. Common peroneal nerve passes through the fibular tunnel (tendon of the peroneus longus muscle and fibula); divides into deep and superficial branches 4. Anterior peroneal nerve (deep peroneal branch): a. Motor; course in the anterior compartment b. Innervates: tibialis anterior; EHL; peroneus tertius; EDL c. Under the extensor retinaculum (proximal to the ankle joint the nerve divides into): 1) Lateral motor branch innervating the EDB 2) Medial sensory branch-webspace between the great and second toe 5. Superficial peroneal nerve B. Clinical presentation: 1. Innervate the peroneus longus and brevis (lateral compartment) 2. In the distal leg it becomes the superficial peroneal sensory nerve: a. Becomes subcutaneous 10 cm proximal to the lateral malleolus; intermediate and medial cutaneous branches innervate the skin of the lower 2/3 of the leg and the dorsum of the foot except for the webspace between the first and second toe. 3. Accessory or deep peroneal nerve:
1. Men > women, 3 : 1; R = L; bilateral in 10% 2. Weakness of the ankle and toe dorsiflexion is predominate; process many develop gradually 3. Weakness of eversion 4. Invertors of the foot, toe and plantar flexion are spared 5. Sensory abnormalities are noted in the lower 2/3 of the lateral leg 6. Rarely Tinel’s sign is positive at the fibular neck 7. Intact ankle jerk
Deep Peroneal Nerve Mononeuropathy
A. General features: 1. Anterior tibialis muscle and extensors of all toes are affected 2. Sensory loss between the first and second toes; webspace 3. Extensor digitorum brevis is supplied by either the superficial or deep branch 4. Distal peroneal lesion (traction injury from ankle sprain) there is selective weakness of the toe extensors with normal ankle dorsiflexion B. EMG: 1. Peroneal CMAPs, EDB and TA are low in amplitude 2. Normal superficial peroneal SNAP
Acute Peroneal Palsy at the Fibular Neck
A. General features: 1. Few or no sensory symptoms 2. Loss of motor function; deep peroneal nerve more affected than the superficial nerve
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
3. Entrapment or a progressive lesion due to tumor, cyst; radiating pain with slowly progressive motor or sensory symptoms B. Pathogenesis: common peroneal palsy at the fibular neck: 1. Compression: a. Poor positioning during anesthesia b. Coma (diabetic, drug overdose) c. Habitual leg crossing d. Weight loss (HIV, anorexia nervosa) e. Positional; Yoga, childbirth f. Casts g. Lithotomy position with stirrups h. Pneumatic compression devices 2. Trauma: a. Blunt and direct trauma b. Tibial plateau fracture c. Dislocation of the knee d. Knee joint ligament rupture e. Superior tibia-fibular joint dislocation f. Arthroscopic knee surgery g. Knee replacement (joint) h. Knee surgery
6. Mass lesions: a. Ganglia from the superior tibia-fibular joint (originate from the synovial membrane) b. Bakers’ cyst c. Osteochondroma d. Giant cell tumor e. Pseudoaneurysm f. Schwannoma g. Sarcoma h. Neurofibroma i. Intraneural ganglion cyst 7. Infections: a. Leprosy b. HIV 8. Vasculitis 9. Entrapment (fibular turmoil syndrome) 10. EMG: a. Denervation of anterior tibialis, EHL or EDB (Deep peroneal innervated muscles); peroneus longus (superficial peroneal muscle) b. Need to r/o proximal common peroneal mononeuropathy by demonstrating no denervation of the short head of the biceps; nerve conduction evaluation of the common peroneal nerve and its branches
Differential Diagnosis of Deep Peroneal Neuropathy at the Fibular Neck Tibial Nerve Injury at the Knee
1. L5 radiculopathy: a. Normal ankle inversion and toe flexion in peroneal palsy, but weak in L5 radiculopathy 2. Anterior compartment syndrome: a. Follows contusion or fracture, snake envenomation (hematoxin with DIC) b. Strenuous exercise c. Anterior compartment contains AT (anterior tibialis), EDL (extensor digitorum longus), EDB is outside of the compartment d. All muscles of the compartment are weak; EDB may be denervated when peroneal nerve is involved e. Differential points of anterior compartment syndrome from deep peroneal nerve involvement: 1) Severe pain (peaks 1–3 days in anterior compartment) 2) Pain on toe and plantar flexion of the ankle 3) Swelling and heat over the compartment 4) Tissue pressure above 60 mmHg is diagnostic at the ankle 3. Forcible inversion of the foot (hemorrhage into the nerve trunk); inversion/plantar flexion ankle sprain; childbirth 4. Prolonged squatting position (tendon of the posterior border of the peroneus longus at the fibular head versus tendon of the biceps femoris of the distal thigh as cause of compression) 5. Rarely: compression between fibula and tendinous edge of peroneus longus (nerve passes between two levels of the muscle)
A. Pathogenesis: 1. Baker’s cyst; ganglia; trauma to the knee; traction injuries from ankle sprains B. Clinical presentation: 1. Weakness of foot plantar flexion 2. Sensory loss on bottom of the foot C. EMG: 1. Denervation in tibial innervated muscles below the knee D. Lumbar plexopathy: 1. General features: a. Occurs with pelvic surgery; retroperitoneal hematoma; prolonged labor; metastatic disease E. Clinical presentation: 1. Weak ankle inversion 2. Weak toe flexion 3. Normal plantar flexion 4. Well demarcated to the L5 dermatoma 5. AJ present unless the S1 root is involved 6. Pain is common and may be radicular
Deep Peroneal Mononeuropathy at the Ankle
Sciatic Mononeuropathy Affecting the Peroneal Nerve Selectively
A. General features:
Chapter 17. Traumatic and Compressive Neuropathy
1. Lateral (peroneal division is affected more frequently than the medial tibial division 2. Peroneal division injured during: a. Hip trauma; fracture dislocation; femoral fracture b. Hip joint replacement; coma, abnormal positions c. Gluteal injection (penicilli, Na2 ++, Fe2 ); gluteal compartment syndrome d. Peroneal division has fewer and larger nerve fascicles with less supportive tissue e. Peroneal nerve is fixed at the sciatic notch and fibular neck (more taut than the tibial nerve) B. Clinical presentation: 1. Similar to lesions at the fibular neck: a. Subtle tibial nerve involvement b. Absent or depressed AT (due to tibial nerve involvement) c. Weak ankle inversion (due to partial tibial nerve involvement) d. Sensory loss on the sole (concomitant tibial nerve involvement) e. Sensory loss in the upper lateral third of the leg (territory of the lateral cutaneous nerve of the calf originates from the common peroneal nerve proximal to the fibular neck) 2. EMG: a. Short head of the biceps femoris is the only hamstring muscle innervated by the peroneal nerves
Superficial Peroneal Nerve
A. General features: 1. Injured 10 cm proximal to lateral malleolus (pierces the fascia and become superficial) 2. Runner or other athletic pursuits B. Clinical presentation: 1. Numbness lateral distal 1/3 of the leg
Differential Diagnosis of Peroneal Mononeuropathy
1. L5 radiculopathy: a. L5 radiculopathy; usual cause is an herniated nucleus pulposus (HNP); back pain and sciatic nerve radiations (hip pain and great toe; dorsum of the foot) b. Inversion weakness of the foot (posterior tibialis nerve) not innervated by the peroneal nerve c. Sensory loss above the midpoint of the calf (laterally) is peroneal mononeuropathy. Upper part of the calf is supplied by a separate sensory branch from the popliteal fossa. d. Greater weakness of EHL than AT suggests an L5 lesion (it has more of innervation) e. Ankle jerk is intact. Primarily innervated from S1
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Deep Peroneal Neuropathy at the Ankle (Anterior Tarsal Tunnel Syndrome)
A. General features: 1. Floor is the fascia overlying the talus and navicular bones, roof is the inferior extensor retinaculum 2. Lesion of the distal segment of deep peroneal nerve B. Clinical presentation: 1. May be unilateral or bilateral; more common in women than men 2. Numbness and paresthesias deep peroneal sensory distribution (web space of the first and second toe) 3. Wasting of EDB 4. Ankle and foot pain worse at night C. Pathogenesis: 1. Pressure from straps, shoe rims, ganglion cyst, pes cavus; osteophytes of the talonavicular bones, plantar flexion of the foot with extension of the toe (high heels); extreme inversion of the foot as occurs in dystonia or spasticity D. EMG: 1. Neurogenic MUAP and denervation of EDB 2. Prolongation of peroneal motor distal latency to EDB E. Differential diagnosis: 1. Lateral division alone: foot pain may be combined with arthritis, ligament damage, bone abnormalities; EDB is atrophied in ATT syndrome 2. Superficial peroneal nerve; no motor loss; sensory loss of the dorsum of the foot and base of the lateral toes 3. L5 root: S1 may be heel pain alone; L5 dorsum of the foot
Differential Diagnosis of Unilateral Foot Drop
1. HSMN/CMT: a. Flat foot (rocker bottom): foot and ankle weakness in all fields of movements; usually bilateral: 1) Hereditary sensory motor neuropathies b. Weakness of ankle and toe dorsiflexion with intact plantar flexion is a true foot drop 2. Deep peroneal neuropathy 3. Common peroneal palsy at the fibular neck 4. L4 and L5 radiculopathy (not as severe as nerve injury) 5. Poliomyelitis and postpolio syndrome (usually pain in the latter and weakness occurs after period of stability) 6. Cerebral vascular disease: a. Anterior cerebral artery (shoulder involved) b. Corona radiata (medullary arteries) c. Ventral pons (lacunar infarction) 7. ALS (common painless foot drop; fasciculations and hyperactive reflexes) 8. Anterior compartment syndrome of the leg (repetitive exercise; snake bite; rhabdomyolysis) 9. Lumbosacral plexopathy (weak toe and plantar flexion)
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
10. Hereditary neuropathy with sensitivity to pressure palsy (concomitant involvement of other nerves) 11. Mononeuritis multiplex (setting of autoimmune disease) 12. Multifocal motor neuropathy with conduction block (GM1 gangliosidosis; usually upper extremities affected first) 13. Parasagittal meningioma (presents with seizure in one leg)
Differential Diagnosis of Bilateral Foot Drop
1. Neuropathies: a. GBS (subacute; usually with numbness) b. CIDP (Facial numbness; depressed reflexes-throughout) c. MMNCB (GMI, asymmetric; upper extremity often first) d. Bilateral peroneal lesions (autoimmune pathologies) e. Bilateral sciatic compressive lesions f. Bilateral lumbosacral plexopathies (metastasis, lymphoma, metastasis, retroperitoneal hemorrhage) 2. Anterior Horn Cell: 1. ALS (usually unilateral; weakness at onset; associated upper motor signs and symptoms) 2. Spinomuscular atrophy (SMA) 3. Poliomyelitis 4. Leukemia and lymphoma 5. Radiculopathies: a. Cauda equina syndrome (disc; spondylolisthesis) b. Conus medullaris (cancer; glioma, syrinx; bladder and bowel predominant over motor loss) c. S1 greater than L5 root suggestive of intraspinal tumor 6. Myopathies: a. Myotonic dystrophy (concomitant masseter, neck and distal arm weakness) b. Fascioscapulohumeral dystrophy (face severe involvement) c. Scapuloperoneal dystropy (upper shoulder girdle dramatically atrophic) d. Distal congenital myopathies: 1) Welander 2) Nonaka 3) Markesburry–Griggs – UDD 4) Liang
Tibial Nerve
A. General features: 1. Innervates all of the hamstring muscles except the short head of the biceps femoris (common peroneal nerve) 2. Sural branch given off in the upper popliteal fossa; 80% of patient’s the common peroneal nerve gives off a medial branch that joins the sural nerve 3. In the upper calf the tibial nerve lies under the tendinous arch of the soleus muscle (innervate FDP, FHL, gastrocnemius, soleus and tibialis posterior muscles)
4. At the ankle passes posterior to the medial malleolus in the tarsal tunnel 5. Terminal branches are: a. Calcaneal branch c. Lateral plantar nerve b. Medial plantar nerve 6. Interdigital branches arise from the medial and lateral plantar nerves on the soles of the foot
High Tibial Nerve Injury
A. General features: 1. Most often the nerve is injured in or near the popliteal fossa B. Clinical presentation: 1. Foot pain and numbness; increased by dorsi or plantar flexion of the foot 2. Tenderness and a positive Tinel’s sign in the posterior popliteal fossa 3. Weakness of plantar and toe flexion and inversion of the foot 4. Absent ankle jerk C. Pathogenesis: 1. Synovial cyst or superior tibial-fibular ganglion cyst 2. Fibrous band or aponeurotic arch of the soleus 3. Knee surgery 4. Schwannomas and neurofibromas D. EMG: 1. Low or absent MUAP of the abductor hallices and abductor digit minimi pedis muscles 2. Sural nerve SNAP may be absent depending on the location of the take off of the nerve in the popliteal fossa
Tibial Nerve Injury at the Ankle Tarsal Tunnel Syndrome
A. General features: 1. Compression of tibial nerve or its terminal branches under the flexor retinaculum 2. Usually insidious onset 3. Women greater than men in frequency 4. 10–20% of patients it is bilateral 5. Anatomy: the root is the lancinate ligament extends between the medial malleolus and the calcaneum (flexor retinaculum; posterior tibial artery, tendons of the tibialis posterior, FDL, FHL B. Pathogenesis: 1. Injured in runners and dancers 2. Rheumatoid arthritis 3. Acromegaly 4. Diabetes mellitus 5. SLE 6. Hyperlipidemia 7. Hypothyroidism 8. Ganglion cyst
Chapter 17. Traumatic and Compressive Neuropathy
9. Lipoma 10. Schwannoma 11. Varicose veins 12. Heel varus and valgus deformities 13. Hypertrophic or anomalous abductor hallices muscles 14. Mobile pes planus C. Clinical presentation: 1. Burning pain and numbness on the sole of the foot and heel; may radiate to the calf 2. Nocturnal pain 3. Increases with rest after activity 4. May be exacerbated by walking or jogging 5. May be in medial plantar, lateral plantar or calcaneal branch distributions 6. Tinel’s sign is positive over the tunnel 7. In 40% of patients, the calcaneal branch is spared as it takes off proximal to the retinaculum 8. 25% of patients have the sensory loss only in medial branch; 10% only in the lateral branch 9. Rare weakness of FHB; FDB (medial plantar); quadratus plantar; interossei (lateral plantar); impairs pushing off phase of walking; weakness of plantar flexion of the lateral toes D. EMG: 1. Decreased conduction of distal posterior tibial nerve 2. Decreased SNAP, slowed NCVs of the medial and lateral plantar nerves 3. Rare denervation of the abductor hallices and abductor digiti pedia quinti
Differential Diagnosis of Tarsal Tunnel Syndrome
1. 2. 3. 4. 5. 6.
7. 8. 9. 10. 11.
Plantar fasciitis (entree sole equally involved) Stress fractures (lateral metatarsals > medial) Bursitis (insertion of the anterior tibial muscle) Rheumatoid arthritis (severe joint deformities) Chronic regional pain syndrome II (severe allodynia, hyperalgesia, autonomic dysregulation) Proximal tibial mononeuropathy (compression by the tendinous arch of the soleus muscle); plantar flexion weakness; decreased AJ Tibial component of the sciatic nerve (nerve sheath tumor); calf weakness, decreased AJ S1 and S2 radiculopathy; concomitant weakness these root muscles and back pain Peripheral neuropathy (usually bilateral which is rare with TTS) Entrapment of the medial plantar nerve (area of insertion of AT which originates from the calcaneus) Burning in the sole and aching in the arch ; medial plantar nerve against the tuberosity of the navicular bone
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Lesions of the Medial Plantar Branch of the Tibial Nerve
1. 2. 3. 4. 5.
Bunion surgery Pes cavus Synovial cyst of the first metatarsal phalangeal joint Schwannoma Running
Lateral Plantar Nerve Injury of the Tibial Nerve
1. Trauma 3. Schwannoma 2. Fracture
Joplin’s Neuroma
1. Medial plantar proprius digital nerve to the great toe: a. Cutaneous innervation of the medial aspect of the great toe b. Due to ill-fitting shoes, trauma, or bunion c. Positive Tinel’s sign at the first metatarsophalangeal joint
Morton’s Neuroma (Interdigital Neuropathy)
A. General features: 1. Generally refers to interdigital neuropathy between the 3rd and 4th toes; may occur between web space of all toes 2. Anatomy: metatarsal tunnels are between the deep and transverse metatarsal and superficial ligaments that connect the metatarsal heads 3. Medial plantar nerves, arteries and veins transverse the metatarsal tunnel of the first, second and third toes 4. Lateral plantar nerves supply the IV, Vth toes 5. Chronic compression of the interdigital nerve between the metatarsal head; hyperextension of the metatarsophalangeal joint exacerbates the angulation of the nerve B. Pathogenesis: 1. Distortion of the metatarsophalangeal joints 2. Trauma; high heels 3. Fractures 4. Subluxation of the joint 5. Rheumatic inflammatory disease 6. Synovial cysts 7. Hyperextension of the toes narrows the canals and compresses the nerves 8. Flexion contraction of the hip and knees causes toe hyperextension 9. Dystonia and spasticity C. Clinical presentation: 1. Lancinating electric-like pain in the territory of the involved interdigital nerve
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
2. Triggered by pressure between III, IV metatarsal head (classic) 3. Hypoesthesias in the distribution of the involved digital nerve 4. Arch pain 5. Exacerbated by standing and walking 6. Pain may radiate to the ankle and calf 7. Web space compression test is positive D. Differential diagnosis of Morton’s Neuroma: 1. Bursitis 2. Plantar fasciitis 3. Arthritis (head of joint is tender not the web space) 4. TTS may involve only one plantar nerve Diagnostic Evaluation
1. Ultrasound demonstrates an ovoid hypoechoic nonparallel to the long axis of the metatarsal bone 2. Decreased sensory NCV’s of the interdigital nerves
Sural Nerve Injury
A. General features: 1. Branch of the distal sciatic from both divisions in the posterior popliteal fossa 2. Injured at the ankle or calf 3. Post operative complications following biopsy of the sural nerve are common (approximately 50% of patients) 4. Sural neuralgia may occur in 5% of patients after surgical procedure and biopsy (neuroma) B. Clinical presentation: 1. Pain and paresthesias in the lateral ankle and foot; sensory loss in the lateral sole to the base of the Vth toe 2. Normal AJ and gastrocnemius strength (differentiate it from S1 radiculopathy) 3. Tinel’s sign after its emergence 20–25 cm above the foot C. EMG: 1. Low amplitude or absent SNAP
Femoral Nerve
A. General features: 1. Formed by the posterior divisions of the ventral rami of L2, L3, L4 spinal roots 2. Innervate psoas muscle; passes between the psoas and iliacus muscle; covered by the iliacus fascia (roof of the iliacus compartment) 3. Passes under the inguinal ligament; innervates the iliacus muscle (4–5 cm proximal to the ligament) 4. After the ligament it innervates: a. Four heads of the quadriceps and the sartorius muscle
b. The medial and the intermediate cutaneous nerve of the thigh (innervates the anterior thigh) and the saphenous nerve; the saphenous nerve is posteromedial in the femoral triangle and passes through the adductor canal; it is the origin of the infrapatellar branch that innervates the skin of the anterior patella; the saphenous nerve become subcutaneous 10 cm proximal and medial to the knee (pierces the fascia between the sartorius and gracilis muscle); crosses the pes anserinus bursa at the upper medial tibia. In the lower third of the leg it divides into two terminal branches that innervate the medial surface of the knee, leg, medial malleolus and medial arch of the foot. B. Clinical presentation: 1. Usually unilateral; exception is lithotomy position with concomitant pressure on the adductor canal (during delivery or GYN surgery) 2. Acute thigh weakness 3. Weakness and atrophy of the quadriceps 4. Sensory loss over the anterior thigh and medial calf 5. Hip, flexor weakness (L1–L3) suggests lumbar plexus weakness 6. Unstable leg; knee buckles when partially flexed; frequent falls 7. Sensory loss in the medial and intermediate femoral cutaneous nerve distribution 8. Acutely, groin and thigh pain; later on deep pain 9. Femoral nerve involvement from retroperitoneal hematoma has severe back abdominal, groin, buttock and anterior thigh pain; position of comfort is a flexed thigh 10. Hip flexion weakness (iliopsoas involvement with intrapelvic lesion); spared if lesion is at the inguinal ligament (lithotomy position) 11. Positive reversed straight leg raising test (particularly with proximal lesions) 12. Depressed or absent knee jerk C. Pathogenesis: 1. Primarily injured during surgical or diagnostic procedures; retractor compresses the nerve against the pelvic wall 2. Pelvic injury: a. Abdominal hysterectomy b. Prostatectomy c. Renal transplantation d. Colectomy e. Inguinal herniorrhaphy f. Lumbar sympathetectomy g. Tubal ligation h. Aortic aneurysm surgery 3. Retroperitoneal hematoma: a. Fascial layer pressure; blood is trapped over the iliacus muscle beneath the femoral triangle and under the fascia
Chapter 17. Traumatic and Compressive Neuropathy
b. c. d. e. f. g. h.
Renal transplantation (bleeding) Hemophilia Anticoagulation Coagulopathy Ruptured abdominal aneurysms Femoral artery catheterizations Large hemorrhages extend into the psoas muscle and retroperitoneal space that compromises lumbar or lumbosacral plexus i. Femoral artery or vein catheterization: 1) Approximately 0.5% of femoral artery catheterization for coronary artery disease bleed; often there is concomitant use of anticoagulation); approximately 1/3 lead to lumbar plexopathy or femoral nerve injury 4. Compression at the inguinal ligament: a. Prolonged lithotomy position (hip flexion and external rotation): 1) Associated with vaginal delivery 2) Vaginal hysterectomy, prostatectomy and laparoscopy b. Inguinal hematoma 5. Total hip replacement: a. Nerve injury may occur up to 2–3% of patients b. Anterior acetabular retraction compress the nerve c. Most common in revisions and complicated reconstruction of the hip 6. Lymphadenopathy at the inguinal area 7. Pelvic mass lesions: a. Lymphoma b. Metastatic tumor (ovary, prostate, colon) c. Abscess d. Aortic or iliac aneurysm 8. Neurapraxia injuries (stretch) 9. Radiation therapy 10. Laceration (blood drawing, cauterization) 11. Diabetic femoral neuropathy (radicular plexopathy) 12. Femoral nerve tumors; neurofibroma, schwannoma and neurogenic sarcoma D. EMG: 1. Slowing of motor nerve conduction at the inguinal ligament 2. Decreased SNAP of the saphenous nerve 3. Denervation of femoral nerve innervated muscles E. Differential diagnosis: 1. L2, L3, L4 radiculopathy (rare disc disease) 2. Lumbar plexopathy (L2, L3, L4); if the thigh adductors are denervated the lesion is proximal to the femoral nerve (obturator nerve) 3. Weakness of ankle dorsiflexion (L4 and L5) from the peroneal nerve suggests L4 radiculopathy or lumbar plexopathy; back and buttock pain with positive reverse straight leg raising test favor radiculopathy; maybe positive as well with retroperitoneal hematoma or mass lesion
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Saphenous Nerve Injury
A. General features: 1. Courses through the adductor canal; penetrates the fascia above the knee 2. Supplies the medial calf; medial malleolus and medial arch of the foot B. Clinical presentation: 1. Pain or numbness in the distribution of the nerve; medial calf most noticeable 2. Tinel’s sign over the site of entrapment 3. Entrapment oftens occur at exit from Hunter’s canal (10 cm above the medial femoral condyle) 4. Knee pain is common 5. Infrapatellar branch entrapment causes anterior, anteromedial or anterolateral knee pain C. Pathogenesis: 1. Stripping of the long saphenous vein as well as harvesting the vein for coronary bypass 2. Superficial femoral thromboendarterectomies 3. Femoropopliteal bypass grafts 4. Meniscectomies 5. Arthroscopic procedures 6. Infrapatellar branch maybe entrapped behind the sartorius tendon 7. Medial knee trauma 8. Schwannoma D. EMG: 1. Low or absent saphenous SNAP E. Differential diagnosis: 1. L4 radiculopathy 3. Femoral neuropathy 2. Lumbar plexopathy
Lateral Femoral Cutaneous Nerve Injury
A. General features: 1. Sensory fibers of dorsal rami of L2 and L3 spinal roots 2. Passes within or under the inguinal ligament anterior or medial to its insertion at the anterior superior iliac spine. There are significant anatomical variations of its passage 3. Pierces the fascia lata to innervate the lateral thigh B. Clinical presentation: 1. Numbness and paresthesias in the lateral thigh (burning); never below the knee 2. Hyperesthesias and dynamic and static mechanoallodynia may occur 3. Exacerbated by standing, walking or turning and relieved by hip flexion 4. “Wind-up phenomenon” present; increasing dysesthesias with temporal summation 5. Alopecia maybe present in the area of sensory loss C. Pathogenesis:
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
1. Entrapment of the LFCN through or under the inguinal ligament (meralgia paresthetica): a. Diabetes c. Obesity b. Pregnancy d. Constricting belts 2. Direct injury a. Iliac bone grafts b. Injections c. Renal transplantation d. Gastric bypass surgery e. Herniorrhaphy f. Intrapelvic retraction injury g. Abnormal positioning (hip flexion) h. Blunt trauma (seat belt; avulsion of the anterior superior iliac spine) i. Metastasis to iliac crest j. Abdominal aortic aneurysm D. EMG: 1. Decrease SNAP and NCVs of the nerve E. Differential Diagnosis: 1. Lumbar radiculopathy: a. Not as well circumscribed sensory loss b. Associated back and groin pain 2. Femoral neuropathy: a. Numbness involves the anterior thigh; may extend medially and to the leg b. Weakness of the quadriceps and depressed KJ exclude the diagnosis 3. Lumbar plexopathy: a. Anterior thigh pain b. Weakness; loss of KJ 4. Lumbar spinal stenosis: a. “Simian” forward, flexed posture b. Weakness primarily in the L4–S1 distribution c. Loss of AJ at times; other patients have increased reflex due to concomitant cervical stenosis 5. Tensor fascia lata bursitis: 1. Lateral thigh pain often with specific point tenderness
Ilioinguinal Nerve Injury
A. General features: 1. Originates from T12–L1 spinal roots; pierces the transverse and internal oblique muscles and passes along the inguinal canal 2. Associated with the genital branch of the genital femoral nerve and the spermatic cord in men; the round ligament in women 3. Innervates the lower abdominal muscle 4. Cutaneous innervation along the ilial ligament and the labia majora in women and base of the penis and scrotum in men 5. Entrapment usually slightly medial to the anterior iliac spine with a positive Tinel’s sign
B. Clinical presentation: 1. Burning pain in the lower abdomen; inner portion of the thigh; scrotum; labia majora 2. Bulging of the anterior abdominal wall (transversalis; internal oblique muscle weakness) 3. Pain is exacerbated with extension of the thigh or hip; position of comfort is a flexed hip 4. Tinel’s sign elicited by tapping the lower abdomen C. Pathogenesis: 1. Laparoscopy 2. Hernia repair 3. Appendectomy 4. Bladder suspension 5. Pfannenstiel incision 6. Blunt trauma 7. Entrapment medial to the anterior superior iliac spine D. EMG: 1. Denervation of lower abdominal muscles E. Differential diagnosis: 1. High lumbar radiculopathy (L1 or L2) 2. Iliohypogastric neuropathy 3. Genitofemoral neuropathy
Iliohypogastric Nerve Injury
A. General features: 1. Originates from T12–L1 spinal roots; crosses the psoas and quadratus lumborum muscles; passes through and innervates transverse and internal oblique muscles 2. Two terminal cutaneous branches that innervate lateral buttock (lateral branch) and over and along the pubic symphysis (anterior branch) B. Clinical presentation: 1. Pain and sensory loss above the symphysis pubis 2. Rarely weakness of the abdominal wall 3. Lateral buttock numbness (strip) C. Pathogenesis: 1. Most often injured with the ilioinguinal nerve 2. Appendectomy 3. Hernia repair 4. Pfannenstiel incision (gynecologic surgery) 5. Abdominoplasty D. EMG: 1. Denervation of the lower abdominal muscles E. Differential diagnosis: 1. Ilioinguinal neuropathy 2. Genitofemoral neuropathy 3. L1 and L2 radiculopathy
Genitofemoral Nerve Injury
A. General features:
Chapter 17. Traumatic and Compressive Neuropathy
1. Originates from L1 and L2 spinal roots; passes through the psoas muscles; divides into femoral and genital branches at the inguinal ligament 2. Femoral branch innervates small area of anterior thigh; genital branch innervates scrotum and labia majora 3. Innervates the cremasteric muscle B. Clinical presentation: 1. Pain in the medial inguinal area, scrotum or labia majora 2. Sensory loss may overlap with that of ilioinguinal nerve 3. Absent cremasteric reflex C. Pathogenesis: 1. Appendectomy 2. Inguinal herniorrhaphy 3. Nephrectomy 4. Cesarean section 5. Abdominal trauma 6. Adhesions and scarring (delayed presentations) 7. Concomitant genital branch and ilioinguinal nerve injury occurs at the inguinal ligament D. EMG: 1. No NCS have been delineated from this nerve E. Differential diagnosis: 1. L1–L2 radiculopathy 2. Ilioinguinal neuropathy: a. No anterior femoral distribution
Posterior Cutaneous Nerve of the Thigh Injury
A. General features: 1. Origin is S1–S3 spinal roots 2. Exits the pelvis with the inferior gluteal nerve through the sciatic notch under the pyriformis muscles 3. Cutaneous innervation of the lower buttock, posterior thigh, popliteal fossa and at times the proximal 1/3 of the calf; perineal, scrotal and labia majora branches 4. Injured with sciatic and inferior gluteal nerves B. Clinical presentation: 1. Paresthesias of the lower buttock and posterior thigh; exacerbated with sitting or lying down C. Pathogenesis: 1. Gun shot and laceration wounds 2. Colorectal tumors 3. Venous malformations 4. Bicycle riding; specific compressions 5. Intramuscular injections D. EMG: 1. Decreased SNAP of the nerve E. Differential diagnosis: 1. S1 or S2 radiculopathy 2. Sacral plexopathy: the above root lesions would be accompanied by a depressed or absent ankle jerk; sciatic nerve lesions would have concomitant hamstring or gastrocnemius muscle weakness
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Obturator Nerve Injury
A. General features: 1. Origin is the ventral divisions of L2, L3, L4 spinal roots; courses at the medial edge of the psoas muscle and over the sacroiliac joint and divides into anterior and posterior divisions at the obturator canal 2. Innervate the adductor longus, brevis and magnus (also innervated by the sciatic) 3. Cutaneous innervation of part of the inner thigh B. Clinical presentation: 1. Pain in the medial thigh (often in athletes or associated with obturator hernia); adductor muscle weakness 2. Pain may radiate to the medial calf; exacerbated by extension or lateral leg movement 3. Adductor weakness causes destabilization of the hip joint; difficulty with walking; wide based gait C. Pathogenesis: 1. Lumbar plexopathy (accompanies femoral nerve lesions; it arises from the dorsal divisions of the same roots) 2. Pelvic trauma (fractures) 3. Hip surgery: a. Retractor blade c. Fixation screws b. Cement extrusion 4. Aorta femoral bypass 5. Oophorectomy 6. Laparoscopic lymphadenectomy 7. Vaginal delivery (forceps) 8. Obturator hernia 9. Endometriosis 10. Pelvic malignancy 11. Rare; entrapment under adductor fascia 12. Schwannoma 13. Sacroiliac joint lesion may impinge on the nerve D. EMG: 1. Adductor denervation 2. Fibrillation potentials and large MUAP E. Differential diagnosis: 1. L3, L4 radiculopathy 2. Lumbar plexopathy (diabetes, infection, malignancy, collagen vascular disease) The above are ruled out by iliopsoas, quadriceps weakness, loss of knee jerks and ankle jerks. Medial thigh sensory loss is seminal. Symphysis pubis lesions may radiate to the medial thigh.
Gluteal Nerve Syndromes
A. General features: 1. The superior and inferior gluteal nerves originate from the lumbosacral plexus and traverse the infrapiriform and suprapiriform foramen
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
2. The foramen is bounded by: superior edge of the piriform muscle, the lower edge of the gluteus medius muscle, ischium of the greater sciatic notch; the piriformis muscle divides the sciatic notch into a superior and inferior foramen 3. Inferior gluteal nerve course through the: a. L5, S1 and S2 roots; exit through the infra piriformis foramen b. Innervate the gluteus maximus muscle; supplies hip capsule 4. Superior gluteal nerve: a. Origin is L4, L5, S1; exits the pelvis through the suprapiriform foramen in juxta position with the sciatic and posterior femoral cutaneous nerve b. Innervates the gluteus medius, minimus, and the tensor fascia lata B. Pathogenesis: 1. Superior gluteal nervi is injured with misplaced injections 2. Inferior gluteal nerve is injured by intrapelvic mass lesion, lymphoma or colorectal cancer and iliac artery aneurysms 3. Both inferior and superior nerves may be damaged following hip replacement 4. Superior gluteal nerve is rarely entrapped by the piriformis muscle 5. Inferior gluteal nerve may be compressed by the sciatic nerve 6. Pelvic fracture may damage both nerves 7. Prolonged traction during hip replacement C. Clinical presentation: 1. Superior gluteal nerve: pelvic tilt to the opposite side during walking or standing on the affected leg (Trendelenburg sign); waddling gait; weakness of hip abduction 2. Inferior gluteal nerve: a. Difficulty climbing stairs; standing from a sitting position b. Pain in the gluteus muscle that radiates into the posterior thigh c. Weakness of hip extension d. Atrophy of the buttock D. EMG: 1. Fibrillation potentials and loss of MUAP in the tensor fascia lata and gluteus medius are noted with superior gluteal nerve lesions 2. Inferior gluteal nerve lesions demonstrate denervation of the gluteus maximus E. Differential diagnosis: 1. Disease of the hip joint 2. L5 and L1 radiculopathy
Unusual Entrapments
Lumbosacral Tunnel Syndrome
A. General features: 1. L5 root entrapped across the sella of the sacrum or under the lumbosacral ligament 2. Lumbosacral ligament: fibrous bone originates from the fifth lumbar vertebra and inserts on the upper border of the sella of the sacrum 3. L5 root courses under the ligament with the iliolumbar artery and vein B. Pathogenesis: 1. Thickening of the ligament 2. Bony osteophytes 3. Tumor 4. Artery or venous disease C. Clinical presentation: 1. Sensory loss and pain in L5 dermatome without objective findings Rectus Abdominis Syndrome
A. General features: 1. Trapped branches of the T7–T12 intercostal nerves within the rectus muscles B. Clinical presentation: 1. Localized pain in the abdominal wall 2. Aggravated by direct pressure or leg elevation in the supine position Cheiralgia Paraesthetica
A. General features: 1. Superficial branch of the radial nerve B. Clinical presentation: 1. Pain and sensory loss over the dorsum of the lateral aspect of the wrist and first two fingers Gonyalgia Paraesthetica
A. General features: 1. Infrapatellar branch of the saphenous nerve B. Clinical presentation: 1. Numbness and paraesthesias over the patella (often medial) 2. Sharp lancinating pain induced by nerve stretch
Chapter 18 Nonvasculitic Ischemic Nerve Injury Compartment Syndrome
A. General feature: 1. Increased pressure within a closed muscular space
Chapter 18. Nonvasculitic Ischemic Nerve Injury
2. Nerves are injured by compromise of the vasonervorum which decreases their capillary perfusion 3. Normal compartment pressure is usually 0–8 mmHg 4. Acute compartment syndromes: a. Anterior compartment of the leg (most common) in the lower extremity b. Volar forearm compartment (most common) in the upper extremity 5. Chronic compartment syndrome: a. Overuse and exercise: 1) Often anterior and posterior leg compartment are involved 6. Acute compartment syndrome: a. Incipient as they develop; full blown after they are established 7. Crush injury: a. Multiple compartments are involved or large muscle mass such as the gluteal muscle b. Systemic manifestations of crush injury: 1) Rhabdomyolysis with myoglobinuria 2) Increased serum K+ with cardiac arrhythmia 3) Renal failure 4) Shock B. Clinical presentation: 1. Acute compartment syndrome: a. Often occurs hours after the inciting event b. Pain in the involved compartment c. Swelling, tenderness, edematous skin d. Dysfunction of the nerves located within the compartment (anesthesia and paralysis) e. Distal circulation is spared 2. Chronic compartment syndrome: a. Pain in the compromised compartment: 1) Provoked by exercise and relieved by rest 2) Muscle tenderness c) Paraesthesias and muscle weakness of the affected nerves B. Pathogenesis: 1. Acute compartment syndrome: a. Post ischemic edema (arterial surgery; tourniquets) b. Immobilization and compression (casts, anesthesia, coma) c. Hematoma (transfusion, anticoagulants) d. Fracture and soft tissue (edema, blood) e. Burns (severe edema) 2. Chronic compartment syndrome: a. Exertion or overuse D. Pressure measurements of the compartment: 1. 30–45 mmHg may be critical 2. 10–40 mmHg may be within diastolic pressure 3. Arteriogram 4. Doppler blood flow evaluation E. Differential diagnosis of compartment syndrome: 1. Acute compartment syndrome:
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a. b. c. d.
Primary arterial injury Fracture with nerve injury Cellulitis Venous thrombosis (particularly with clotting disorders if in forearm) e. Snake bit (common in upper and lower extremity) f. CRPS I/II 2. Chronic compartment syndrome: a. Vascular claudication b. Tendonitis c. Periostitis d. Fractures e. Lower extremity: 1) Shin splints (periosteal blood) 2) Fasciitis (high eosinophil count; tenderness and swelling after exercise) 3) Tenosynovitis of the anterior tibial or peroneal muscles f. Upper extremity: 1) Cardiac pain
Ischemic Monomelic Neuropathy
A. General features: 1. Distal nerve damage in an extremity due to proximal compromise of the arterial supply; a. Compression of the vessel b. Diversion of blood 2. Occurs in upper and lower extremities 3. Distal to proximal gradient of clinical and EMG deficits 4. At any limb level different peripheral nerves are affected uniformity B. Clinical presentation: 1. Deep burning pain in the hand or foot 2. Coexisting paresthesias (different nerve distributions) 3. The upper extremity has greater distal sensory deficits than the lower extremity 4. Weakness and wasting of intrinsic hand and foot muscles; distal > proximal 5. Symptoms appear acutely; reach maximum intensity in days 6. Impairment of all sensory modalities; distal > proximal; no sensory changes to mid forearm or mid leg 7. Rare signs of vascular insufficiency C. Pathogenesis: 1. A-V shunts in the antecubital fossa or proximal arm for dialysis 2. Lower extremity arterial compromise: a. Superficial femoral artery: 1) cardiopulmonary bypass cannulation 2) Intra aortic balloon pump b. Iliofemoral thrombosis c. Aortoiliac embolus d. Ergotamine poisoning; methylsurgicide 3. Sudden decrease of blood flow to the distal limb
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
4. Nerve pathology: a. Axonal loss distal to proximal D. EMG: 1. NCV, sensory and motor responses low in amplitude; sensory > motor 2. Fibrillation and decreased MUAP in intrinsic hand and foot muscles 3. No concomitant myopathic changes E. Differential diagnosis of ischemic monomelic neuropathy: 1. Compressive neuropathy (anesthesia positioning) 2. Radiculopathy (L4, L5) 3. Intermittent claudication 4. Plexopathy from axillary block 5. Steal syndrome (venous sink): a. A-V shunt; reversal of distal arterial flow: 1) Non-healing wounds; tissue loss b. Neurologic dysfunction with no ischemic damage
Acute Ischemic Mononeuropathy and Plexopathy
A. General features: 1. Vasculitis and acute compartment syndrome are the most common causes 2. Large vessel atherosclerotic occlusion: a. Injured during repair 3. Lower extremity nerves and the lumbosacral plexus may be involved concomitantly B. Clinical presentation: 1. Abrupt weakness and sensory loss after reconstructive procedure 2. Concomitant signs of vascular insufficiency overshadow neural dysfunction prior to surgery 3. Neurogenic claudication: a. Exercise induced paresthesias of the buttocks and legs (or pain) b. Weakness of leg muscles with exercise c. Impotence C. Pathogenesis: 1. Usual ischemic vessels: a. Distal aorta (Leriche’s syndrome) b. Internal > external iliac artery c. Common iliac artery 2. Cauda equina and sacral plexus: a. Blood supply from the internal iliac artery; ilioinguinal artery; Adamkiewicz, great radicular artery whose origin is T12–L1–L2. 3. Femoral nerve and lumbosacral plexus most frequently ischemic 4. Surgical causes for ischemia: a. Abdominal aortic iliac surgery: 1) Aneurysms 2) Infected grafts and graft failure b. Atherosclerotic distal aorta or iliac artery stenosis
c. Pelvic radiation d. Intra aortic balloon pumps e. Intra arterial injection into the iliac or gluteal arteries 5. Nerve fiber ischemia: a. Hypotension b. Emboli c. Inadequate heparinization d. Cross clamping the aorta or major vessels 6. Rare sciatic and common peroneal neuropathies: a. Ischemia of the common iliac artery D. Differential Diagnosis of acute ischemic mononeuropathy/plexopathy: 1. Cauda equina lesions 2. Conus medullary lesions (bowel/bladder involved; no pain) 3. Ischemic femoral neuropathy: a. Psoas and iliacus anterior compartment syndrome 4. Sciatic neuropathy: a. Incomplete cauda equina lesions b. Sacral plexopathy c. Ischemic monomelic neuropathy E. Differential features: 1. Lumbosacral plexopathy: a. Unilateral b. Bladder involvement occurs c. Motor and sensory loss is in the distribution of more than one nerve d. Buttock pain occurs first with ischemic lumbosacral plexopathy 2. Ischemic femoral neuropathy: a. Quadriceps weakness b. Saphenous medial (lower leg paresthesias) c. Femoral nerve sensory loss d. Depressed knee jerk 3. Iliacus acute compartment syndrome: a. Groin mass b. Pain with hip flexion 4. Ischaemic sciatic neuropathy: a. Present in distribution of the common peroneal and tibial nerve b. Weakness/sensory loss below the knee c. Hamstring, lumbosacral, paraspinal muscles, glutei are normal
Chronic Limb Ischemia
A. General features: 1. May involves both upper and lower extremities 2. Caused by peripheral atherosclerotic disease B. Clinical presentation: 1. Not stereotyped 2. Asymptomatic to persistent rest pain; intermittent claudication
Chapter 19. Differential Diagnosis of Neuropathy by Pathology, Evolution Overtime and Precipitating Cause
C. EMG: 1. Conflicting evidence 2. Denervation of affected muscles by needle studies
Frostbite
A. General features: 1. Tissue injury from temperatures below the freezing point of intact skin 2. Men > women, 10 : 1; adult men 30–49 years of age 3. High incidence in psychiatric patients 4. Feet are involved in more than 90% of patients; less often ears, nose, cheeks and penis B. Clinical presentation: 1. Exposure occurs in: a. Homeless patients c. Trauma b. Psychiatric illness d. Outdoor activities 2. Direct injury phase: a. Prior to freezing: 1) Skin temperature less than 10◦ C 2) Microvascular vasoconstriction with endothelial extravasation b. Freezing phase: 1) Skin temperature at 2◦ C 2) Ice crystals in the extracellular fluid causes increased osmotic pressure 3) Intracellular shrinkage; disruption of membrane lipid complexes 4) Cells die an osmotic death when they lose 1/3 of their volume 3. Indirect phase during thawing: a. Vascular stasis with progressive ischemia b. Tissue destruction occurs during this phase c. Occurs during first few hours after tissues are rewarmed d. Microvascular destruction: 1) Affects venules prior to arterioles e. Release of pro inflammatory mediators such as prostaglandin F2 and thromboxane A2 B. Clinical presentation: 1. Pre freeze stage: a. Loss of light touch, pain and temperature perception b. Edema c. Poor coordination of hands and feet 2. Freezing stage: a. Direct injury of frostbite occurs b. Superficial frostbite: 1) Minimal, if any, tissue loss 2) Supple skin; painful 3) Large blisters with fluid (after thawing) 4) Sensation is intact c. Deep frostbite: 1) Significant tissue loss 2) Anesthetic tissue
479
3) Blue grey discoloration 4) Edematous and suffused tissue 5) Hemorrhagic blisters occur with thawing 3. Residual symptoms: a. Burning pain b. Hyperhidrosis c. Autonomic dysregulation of the affected part d. Sensory loss of all modalities e. Cold intolerance f. Hyperpigmentation and atrophic skin
Hand-Arm Vibration Syndrome (HAVS)
A. General features: 1. Secondary Raynaud’s phenomena 2. Sensory dysfunction of the fingers 3. Skeletal abnormalities of hand and forearm (X-ray changes) 4. Vibrating tools are causative; pneumatic: drills, electric grinders, and polishers, gasoline powered chain saws 5. Occurs often after 1000 hours of exposure B. Clinical features: 1. Numbness and decreased sensitivity of the affected extremity; tip of the fingers are affected first 2. Palms not involved 3. Specific vasospastic attacks last 1–60 minutes; more common in the morning 4. Continued exposure increases the numbers and duration of attacks 5. Attacks aborted by warmth; pain and hyperemia occur during warming 6. Intrinsic hand muscle atrophy 7. Vibration at less than 40 Hz causes wrist and elbow osteoarthritis 8. After initial symptoms further exposure causes progressive dysfunction
Chapter 19 Differential Diagnosis of Neuropathy by Pathology, Evolution Overtime and Precipitating Cause
1. Axonal necropathies: a. Acute onset: 1) Acute demyelinating axonal neuropathy (AIDP) 2) Acute intermittent porphyria 3) Variegate porphyria 4) Coproporphyria 5) Tick paralysis b. Acute intoxications (axonal destruction):
480
SECTION X. Differential Diagnosis of Peripheral Neuropathy
1) Heavy metals (Pb, arsenic, mercury, thallium, gold, antimony, zinc, bismuth) 2) Organic solvents (n-hexane; methyl-N-butyl ketone; organophosphates, toluene) 3) Toxins: a) Antineoplastics b) Sedative/hypnotics c) Antibiotics d) Nutritional deficiency e) Medicines c. Subacute and chronic axonal neuropathies associated with systemic disease: 1) Diabetes mellitus 2) Hypothyroidism 3) Liver failure 4) Chronic obstructive lung disease 5) Acromegaly 6) Critical care neuropathy 7) Celiac disease (gluten enteropathy) 8) Crohn’s disease 9) Pancreatitis 10) Uremia 11) Sarcoid 12) Paraneoplastic (antiHu, MA, TA) 13) Myeloma 14) Congestive heart failure 15) Primary biliary cirrhosis 16) Hyperlipidemia 17) Amyloidosis (acquired, TTR-met 30; familial) 18) Hyperoxaluria 19) Ethylene oxide 20) Hexocarbons 21) Acrylamide 22) Vitamin B12 (most often demyelinating) 23) Vitamin E 24) Pyridoxine 25) Thiamine 26) Lead 27) Vincristine 28) Fabry’s disease 29) Cisplatin 30) Thallium 31) Colchicine 32) Phenytoin 33) Disulfiram 34) Lithium 35) Vasculitis 36) HIV 37) Sjögren’s 38) Scleroderma 39) Rheumatoid arthritis 40) Lead poisoning
Charcot–Marie–Tooth Type 1 (HSMNI)
1. CMT – 1A – chromosome: 17 p11.2–12 – gene: PMP 22 2. CMT – 1B – chromosome: 1 q 22–q23 – gene PO 3. CMT – 1C – chromosome: same locus for CMT-2I; 2J) – gene: Po 4. CMT – 1D – chromosome: 10q 21–q22 – gene: EGR-2
Charcot–Marie–Tooth Type 2 (HSMN-II)
1. CMT-2A 2. CMT-2B 3. CMT-2C 4. CMT-2D 5. CMT-2E 6. CMT-2G 7. CMT-2L 8. CMT-2H 9. CMT-2I 10. CMT-2K 11. CMT-2J
1p35–p36 3q13–q22 7p14 8p21 12q24
Dejerine Sottas (CMT 3, HSMN III)
DSD
17p11, 2–12 1 q 22–23 10 q 21–q22
EGR2
Charcot–Marie–Tooth
CMT-X CMT-4A CMT-4B
Xq13.1 8q13–q21 5q23–q33 11q22
CX32 MTMR-2
Congenital Hypomyelinating Neuropathy
CHN 10q 22–23 EGR-2
1q 22–23
Hereditary Neuropathy with Liability to Pressure Palsy
HNPP 17p11.2–12 PMP 22
Inherited Axonal Neuropathies
1. Hereditary sensory motor neuropathy II: a. CMT 1–17 2. Hereditary sensory motor neuropathy type IV (with optic atrophy) 3. Hereditary sensory motor neuropathy type VI (II and spastic paraparesis) 4. Hereditary sensory neuropathy (autonomic neuropathy): a. Type I – AD c. Type III – Rily Day b. Type II – AR d. Type IV 5. Leigh’s disease (mtDNA)
Chapter 19. Differential Diagnosis of Neuropathy by Pathology, Evolution Overtime and Precipitating Cause
6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
NARP (neuropathy, ataxia, retinitis pigmentosa) Porphyrias (AIP, variegate) Coproporphyrinuria Fabry’s disease MNGIE (mtDNA) myopathy, neurogastrointestinal, encephalopathy Ataxia telangiectasia Giant axonal neuropathy Associated with spinocerebellar degeneration Friedreich’s variant’s; SCA 3 Amyloidosis-TTR-met 30 (transthyretin); familial amyloid
3. 4. 5. 6. 7.
481
Vasculitides Entrapment Compression Traumatic neuropathy Autoimmune (primarily lower extremity)
Acute Demyelinating Neuropathy
1. AIDP (GBS) 2. Diphtheria 3. HIV 4. Lyme
Chronic Demyelinating Neuropathy Hereditary Demyelinating Neuropathies
1. 2. 3. 4. 5. 6.
HSMN I, III, IV Krabbe’s globoid leukodystrophy Tangiers’s disease Metachromatic leukodystrophy Adrenomyeloneuropathy Cockayne’s syndrome
Segmental Demyelinating Neuropathies
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
AIDP CIDP Arsenic Carcinoma Lymphoma Hereditary neuropathy with sensitivity to pressure palsy (HNNP-chromosome 17) Hypothyroidism Ulcerative colitis Amiodarone Perhexiline Arabinoside (Ara-C) Waldenström’s macroglobulinemia Monoclonal gammopathy of undetermined significance (IgM, IgG, IgA) Diphtheria Leprosy Diabetes HIV Lyme’s disease SLE Cryoglobulinemia Osteosclerotic myeloma
Asymmetric Single or Multiple Neuropathies
1. Diabetic proximal asymmetric neuropathy 2. Polyarteritis
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.
Hypomyelinating neuropathy (CHN) HSMN (I, III) Refsum’s (IV) Metachromatic leukodystrophy HNPP (deletion chromosome 17) Hypothyroidism Diabetes Uremia Perhexiline Sodium cyanate Allergic (vasculitis) HIV Paraproteinemia CIP/CDIP/multifocal Waldenström’s macroglobulinemia Osteosclerotic myeloma Monoclonal gammopathy of unknown significance (MGUS) SLE Melanoma (immunotherapy) Plasma cell dyscrasia Inflammatory bowel disease MAG, SGPG-autoimmune epitopes SICCA complex CID-codon 200 MtDNA neuropathy 3243
Toxic Neuropathies
1. Heavy metals: a. Thallium e. Gold b. Zinc f. Lead c. Bismuth g. Arsenic d. Mercury h. Platinum 2. Organic solvent’s (hexocarbons): a. M-hexane e. Toluene b. Methyl-n-butyl ketone f. Carbon disulfide c. Organophosphates g. Vacor d. Acrylamide
SECTION X. Differential Diagnosis of Peripheral Neuropathy
482
3. Drugs: a. Vincristine e. Cis-platinum b. Vinblastine f. Docetaxel c. Nitrogen mustard g. Paclitaxel d. Taxol Antiretroviral Agents
1. Stavudine 3. HAART drugs 2. Dideoxycytidine (ddc) Miscellaneous Drugs
1. Penicillin 2. Fe injection 3. FK-506 (tacrolimus) 4. Lithium 5. Amiodarone
6. Interferon-a 7. Methylbromide 8. Tegretol/Dilantin 9. Colchicine 10. Allopurinol
Antibiotics
1. Amphotericin B 2. Chloramphenicol 3. Clioquinol 4. Streptomycin 5. Ethambutol 6. INH
7. Nitrofurantoin 8. Sulfonamide 9. Pyridoxine 10. Stilbamidine 11. Dapsone
4. Anti-sulfatide (small fiber) 5. Gdlb (Miller–Fisher variant) 6. GD3 7. Gal (B1-2) Gal Nac 8. GTDIA 9. GALOP 10. GQ1b B. Demyelinating sensory neuropathy: 1. MAG 3. CM Fisher variant of GBS 2. SGPG 4. CIDP (sensory variant) C. Inherited sensory neuropathy: 1. HSN I-V: a. HSAN-I: AD (hereditary sensory autonomic neuropathy) b. HSAN-II: AR: myelin > unmyelinated c. HSAN-III-Riley–Day syndrome d. HSAN-IV e. HSANV 2. Bassen Kornsweig disease (beta hypolipoproteinemia) 3. Fabry’s disease (α galactosidase) 4. SANDO (sensory ataxia/dysarthria/ophthalmoplegia) 5. Perault’s syndrome (ovarian/VIIIth nerve) 6. Neuropathy with spinocerebellar degenerations: a. SCA-5 b. Friedreich’s ataxia (large fiber)
Sedative/Hypnotic/Antidepressants
1. Amitriptyline 4. MAO inhibitors 2. Imipramine 5. Glutethimide 3. Meprobamate Nutritional Deficiencies
1. 2. 3. 4. 5. 6. 7. 8.
Alcohol (associated with multiple vitamin deficiency) Thiamine (Wernicke’s) Pyridoxine Pantothenic acid (associated with chronic alcoholism) Riboflavin Vitamin B12 Vitamin B6 Vitamin E
Chapter 20 Differential Diagnosis of Neuropathy by Predominant Symptom, Hereditary or Feature
Toxic Metabolic Sensory Neuropathy
1. 2. 3. 4. 5.
Vitamin B6 excess (pyridoxine); burning neuropathy Methyl mercury Docetaxel/paxcetaxel (large and intermediate fibers) Vitamin E deficiency (a-toxophil transporter I deficit) Vitamin B12 deficiency (large fiber modalities; dorsal column) 6. INH (decreased vitamin B6) 7. Ciguatera poisoning (paradoxical channelopathy) 8. Adriamycin (dorsal ganglionopathy)
Infectious Cause of Sensory Neuropathy
1. HIV (distal painful sensory neuropathy) 2. Tabes dorsalis (posterior column deficits, Hertig’s spots on the trunk) 3. Herpes zoster (dermatomal) 4. Herpes simplex (regional) 5. HTLV-I (primarily small fiber)
Sensory Neuropathy Sensory Neuropathy Associated with Systemic Disease
A. Autoimmune epitopes: 1. MAG 2. SGPG (small fiber) 3. Anti-HU (Small fiber)
1. Diabetes (burning feet syndrome) 2. Uremia (small fiber) 3. Paraneoplastic (sensory ataxia; small fiber)
Chapter 20. Differential Diagnosis of Neuropathy by Predominant Symptom, Hereditary or Feature
4. Sjögren’s (posterior column deficit) 5. Hypothyroidism (carpal tunnel; tarsal tunnel; Vth nerve; generalized peripheral neuropathy) 6. Sensory perineuritis (primarily around the ankle) 7. Ischemic neuropathy (painful; all modalities) 8. Malabsorption syndromes (primarily B12; large fiber)
483
Associated Infections and Sensory Neuropathy
1. HIV 3. CMV 2. Leprosy
Sensory Neuropathy Associated with Drugs and Toxins Ataxic Sensory Polyneuropathy (large fiber)
Immune mediated: 1. Carcinomatous sensory neuropathy 2. Sensory ganglionitis neuropathy 3. Sjogren’s 4. Miller Fisher variant 5. MAG 6. Sensory CIDP 7. Immunoglobulin associated paraproteinemia Idiopathic Sensory Neuropathy
1. Acute 2. Chronic 3. Monomelic sensory neuropathy
1. Ciguatera toxin 5. Vacor 2. Metronidazole 6. Erythromelalgia (vincristine) 3. Misonidazole 7. Ergotamine 4. Kepone
Associated with Trauma
1. 2. 3. 4.
Chronic regional pain syndrome (CRPSI/II/RSD) CRPS II (associated with nerve injury) Triple cold syndrome Anti backfiring C nociceptor syndrome (ABC syndrome; transmodality sensitization)
Chronic Painful Neuropathies Demyelinating Sensory Neuropathy
1. 2. 3. 4.
CM Fisher variant of GBS CIDP-sensory variant SGPG (epitope) MAG (epitope)
Predominantly Small-Fiber Sensory Neuropathy – Autoimmune Epitopes
1. TTR-transthyretin met 30 (amyloidosis) 2. Anti-HU 3. Anti sulfatide Inherited Small Fiber Sensory Neuropathy
1. 2. 3. 4.
Fabry’s disease Tangiers’s disease Familial amyloid (FAP) Hereditary sensory neuropathies II; IV (HSAN I, III, IV, V) 5. Hereditary thermosensitive neuropathy (AD) Sensory Neuropathy Associated with Systemic Illness
1. Amyloid (secondary) 4. Sjögren’s syndrome 2. Diabetes 5. Rheumatoid arthritis 3. Primary biliary cirrhosis
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
Diabetes Alcohol Pantothenic acid deficiency Pyridoxine B6 excess or deficiency CRPS I/II (RSD/causalgia) Amyloid (primary or secondary) Paraneoplastic (sensory neuropathy/ganglionitis) TTR-met 30 (amyloidosis) Anti-sulfatide epitopes Uremia Arsenic Fabry’s disease Erythromelalgia ABC syndrome Triple cold syndrome Hypertriglyceridemia Niacin Thiamine
Motor Neuropathies
1. 2. 3. 4. 5. 6. 7.
Acute intermittent porphyria (AIP) Variegate porphyria Coproporphyrinuria Lead Vincristine Diphtheria Diabetes (amyotrophy); plexopathy
484
SECTION X. Differential Diagnosis of Peripheral Neuropathy
8. Acute inflammatory demyelinating polyneuropathy (AIDP) 9. Rabies 10. Thallium 11. Phenytoin 12. HIV 13. Insulinoma (recurrent hypoglycemia) 14. Osteoclastic multiple myeloma 15. GMI ganglioside antibody 16. Multifocal motor neuropathy with conduction block (MMNCB) 17. Dapsone 18. Phenytoin 19. MAG
Acute Ascending Motor Paralysis with Minimal Sensory Dysfunction
1. AIDP: a. Hepatitis B virus b. EBV (Ebstein Barr Virus) c. Mumps d. HIV e. Lymphoma (Hodgkin’s or non-Hodgkin’s) f. Post vaccination (influenza, typhoid, hepatitis, rabies, small pox) g. Surgery h. Campylobacter jejuni 2. Tick paralysis 6. Ethylene oxide 3. Lyme’s disease 7. Triorthocresyl phosphate 4. Porphyria (AIP/variegate) 8. Diphtheria 5. Thallium
Neuropathies with Prominent Autonomic Features
1. Diabetes (gastroparesis; sexual dysfunction) 2. Amyloidosis: a. Transthyretin-related FAP (familial amyloid polyneuropathy) b. Apolipoprotein A-1-related FAP c. Gelsolin-related FAP 3. Paraneoplastic 4. SICCA complex 5. Acquired generalized anhidrosis 6. Porphyria: a. AIP c. Hereditary coporphyruria b. Variegate porphyria 7. B12 deficiency 8. Uremia 9. AIDP (acute demyelinating inflammatory neuropathy) 10. HSNI–IV (hereditary sensory neuropathy I–IV) 11. Fabry’s disease
12. 13. 14. 15. 16. 17. 18. 19. 20.
Pandysautonomia (paraneoplastic/acute infectious) EBV Shy–Drager syndrome Holmes–Aides syndrome Familial sensory autonomic neuropathy (Navaho Indian) Ross syndrome Harlequin syndrome Vacor intoxication Chronic relapsing autonomic neuropathy
Hypertrophic Neuropathies
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
HSMN-I, (CMT 1A-D) CIDP Longstanding diabetes Hypothyroidism Mucopolysaccharidoses (Scheie’s variant) Amyloidosis Multifocal hypertrophic neuropathy Leprosy HSMN-III (Dejerine–Sottas) HSMN-IV (Refsum’s disease) Acromegaly (compression/entrapment)
Infectious Causes of Peripheral Neuropathy
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
HIV Syphilis Lyme’s disease C/MV EBV Brucellosis (L5 root) Campylobacter jejuni (AMAN) GBS (specific virus/nonspecific virus) Mumps Tick paralysis Herpes simplex Herpes zoster Whipple’s disease Mycoplasma Sepsis syndrome Infective endocarditis Leprosy
Intermittent Neuropathies
1. 2. 3. 4. 5. 6.
CIDP Vasculitis MAG SGPG Gal (B1-3) Gal Nac Asialo GM1
Chapter 20. Differential Diagnosis of Neuropathy by Predominant Symptom, Hereditary or Feature
7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
Anti sulfatide Gd 1 B GQ 1 B Acute relapsing axonal GBS Acute intermittent porphyria Variegate porphyria Coproporphyrinuria Refsum’s disease Fabry’s disease Tangiers’s disease Hereditary heat sensitive neuropathy Hereditary sensitivity to pressure (HNPP) Chronic relapsing autonomic neuropathy Hereditary neuralgic amyotrophy Hereditary sensory motor neuropathy (steroid sensitive)
Neuropathies from Traumatic/Physical Agents
1. Overuse syndromes (tunnel entrapments particularly of the upper extremity) 2. Brachial plexus fixation with secondary peripheral nerve tunnel syndromes 3. Compartment syndromes (arm/leg) 4. Perioperative neuropathies (compression during malplacement/anesthesia) 5. Lithotomy position 6. Diaphragmatic neuropathy (trauma); surgery (thoracic outlet; neck) 7. Peripheral nerve (direct trauma) 8. X-RT (ischemia of the vasovasorum) 9. Bone marrow transplant (perineural/intraneural hemorrhage) 10. Heat 11. Cold (frost bite) 12. Snake bite (compartment syndrome) 13. Entrapment syndromes 14. Double/triple crush syndromes (C5–C6 with concomitant CTS)
485
Autoimmune Neuropathy with Specific Epitopes
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
GM 1 (IgG/IgM) acute axonal (Campylobacter jejuni) GDIB – Miller Fisher variant GQIb – Miller Fisher variant SGPG (sensorimotor; small fiber) MAG (demyelinating) Anti sulfatide (IgM) with/without M protein Anti-Hu Anti-MA Anti-TA GALOP GM 1 (IgM) motor neuron/demyelinating Anti-TTR-30 (small fiber/painful) Asialo-GM 1 (demyelinating; sulfur containing epitopes; small fiber) 14. Anti chondroitin sulfate 15. 301–314 B tubulin antigen
Inherited Neuropathies
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.
HSMN-I (CMT 1 A; CMT 1 B; CMT 1 C; CMT X) HSMN-II (CMT 2 A-L) HSMN-III (CMT3); Déjérine Sottas HSMN-IV (CMT4); Refsum’s HSMN-V HSMN-VI (optic neuropathy with spastic paraparesis) Hereditary neuropathy with pressure palsy (deletion of chromosome 17); HNPP CMTX (1,2,3) AR-CMT with deafness Hereditary sensory autonomic neuropathy I (AD) HSAN-II (AR) HSAN-III; Riley Day HSAN-IV HSAN-V Hereditary neurologic amyotrophy (HNA) Hereditary motor neuropathy (AR) CMT (optic atrophy/VIII nerve; AD; AR; X-linked) Mutilating neuropathy 3q 13q–q22 HSMN – hand variant
Large Fiber Neuropathy (12–22 μ) Hereditary Causes of Demyelinating Neuropathy
1. 2. 3. 4. 5. 6. 7. 8.
Vitamin B12 Vitamin B6 Vitamin E (acquired/genetic variants) Tabes dorsalis Diabetes Paraneoplastic (DRG form) HSMN I, III, IV Bassen–Kornsweig disease
1. HSMN-I, III 2. HNPP – familial liability to pressure palsy (deletion chromosome 17) 3. Refsum’s disease (HSMN – IV) 4. Metachromatic leukoencephalopathy A, B, C 5. Globoid cell (Krabbe’s disease) 6. Cockayne’s Syndrome
SECTION X. Differential Diagnosis of Peripheral Neuropathy
486 Inherited Axonal Neuropathy
Immune Mediated Neuropathy
1. 2. 3. 4. 5.
1. 2. 3. 4. 5. 6. 7.
HSMN-II (CMT-2A-2L) HSN-I–IV Axonal neuropathies with spinocerebellar degenerations Giant axonal neuropathy (GAN) Ataxia telangiectasia
Specific Inherited Neuropathies
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
Refsum’s disease Krabbe’s disease Amyloid polyneuropathy of Andrade Abetalipoproteinemia (Bassen Kornsweig) Alpha lipoproteinemia (Tangiers’s Disease) Metachromatic leukodystrophy Acute intermittent porphyria Variegate porphyria Coproporphyrinuria Adrenomyeloneuropathy Adrenoleukodystrophy SANDO Perrault (ovarian dysgenesis; VIII nerve) Tangiers’s Disease (classic/late onset) Pelizaeus Merzbacher Disease Familial amyloid polyneuropathy (gelsolin apolipoprotein A-1) Vitamin E deficiency (a-tocopherol transporter defect) Multiple symmetric lipomatosis (Madelung’s); mitochondrial DNA dysfunction Fabry’s disease Palmoplantar keratoderma Polyneuropathy, dementia, dysautonomic AR hypomyelination neuropathy Familial sensorimotor neuropathy with callosal agenesis Hereditary neuropathy with excessive myelin folding Wolman’s syndrome (variant of adrenomyeloneuropathy) Familial polyglucosan body neuropathy Carbohydrate deficiency syndrome Gerstmann Straüssler syndrome (codon 102)
Mitochondrial Neuropathies
1. 2. 3. 4.
Leber’s hereditary optic neuropathy NARP (neuropathy/ataxia/retinitis pigmentosa) Leigh’s syndrome MNGIE (mitochondrial neurogastrointestinal encephalopathy) 5. PEO (progressive external ophthalmoplegia)
AIDP CIDP Neuropathy with specifically identified epitopes Vasculitis with specific syndromes Vasculitis without specific disease association Allergic peripheral neuropathies Monoclonal gammopathies of undetermined significance (MGUS); IgA, IgG, IgM 8. Neuropathy following insect and bee sting 9. Transplantation polyneuropathy (graft vs host)
Neuropathy with Specific Enzyme Defects
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Fabry’s disease (alpha-galactosidase) Krabbe Shies’s disease (heparitin sulfatase) Familial B12 deficiency (biopterin tetrahydrofolate dehydrogenase deficiency) Metachromatic leukodystrophy (A, B, C, sulfatase) Refsum’s disease (phytanoyl hydrolase) Phenylketonuria (phenylalanine dehydrogenase) Cystinuria (cystathionine synthetase) Phenytoin (folate dehydrogenase) GM2 (Sandhoff’s disease) Tryptophane pathway defects Polyglucan body disease Glycogen branching enzyme defect
Entrapment Syndromes
Upper Extremity 1. Long neck sloping shoulder syndrome 2. Roos’ congential bands (12 bands) 3. Cervical rib syndrome 4. Thoracic outlet syndrome 5. Rib-band syndrome (C8–T1) 6. Costo-clavicular syndrome 7. Secondary entrapment syndrome (primary plexus lesions) 8. Brachial plexus entrapment: a. Upper trunk d. Lateral cord b. Medial cord e. Posterior cord c. Lower trunk 9. Cubital tunnel (ulnar) 10. Arcade of Frohse (posterior interosseous, radial sensory) 11. Ligament of Struthers (median) 12. Pronator canal (median) 13. Guyon’s canal (ulnar) 14. Medial antibrachial cutaneous nerve 15. Dorsal scapular nerve
Chapter 20. Differential Diagnosis of Neuropathy by Predominant Symptom, Hereditary or Feature
16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48.
Suprascapular nerve (suprascapular notch) Musculocutaneous nerve Intercosticobrachial nerve (from medial cord) Radial nerve (radial grooves of the humerus) Anterior/posterior interosseous nerve Recurrent nerve of Kunz (T1–T4 sympathetics) Lumbosacral syndrome (L5) Ilioinguinal nerve Genitofemoral nerve Sciatic nerve (sciatic notch compression) Pyriformis syndrome Posterior popliteal fossa syndrome Peroneal (common; superficial; deep) Intercostal nerve Rectus abdominis syndrome Sural nerve Obturator nerve (canal compression) Femoral nerve (under inguinal ligament) Lateral femoral cutaneous nerve Anterior femoral cutaneous nerve Intermediate femoral cutaneous nerve Recurrent nerve of Gonyea (branch of tibial nerve) Recurrent nerve of Spurling (L5 dura); radiate to anterior thigh) Medial plantar nerve (tarsal tunnel) Calcaneal branch of plantar nerve (posterior tibial) Gluteal nerve Iliohypogastric nerve Saphenous nerve Posterior tibial Anterior tarsal tunnel syndrome Digital nerves Metatarsal tunnels (digital nerves) Lumbrical canal (digital nerves)
Mononeuropathy Multiplex
Axonal
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Vasculitis Vasculopathy Rheumatoid arthritis Connective tissue diseases Systemic necrotizing vasculitides Polyarteritis nodosa Allergic granulomatous angiitis (Churg–Strauss) Hypersensitivity angiitis Wegener’s granulomatosis “Overlap syndromes” Nonsystemic vasculitis (isolated vasculitic neuropathy) Mixed cryoglobulinemia Diabetes Amphetamine abuse Sarcoidosis
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16. Leprosy 17. Cytomegalovirus (AIDS) 18. Neurofibromatosis
Mononeuropathy or Multiple Mononeuropathy
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Pressure palsy Entrapments Traumatic Electrical injury X-RT Immunization Herpes zoster Carcinomatous infiltration Lymphoma Diphtheritic wound infection with neuropathy (local toxin production) 11. Diabetes 12. Collagen vascular disease 13. Monomelic sensory neuropathy
Bilateral Carpal/Tarsal Tunnel Syndromes
1. Occupational 2. Rheumatoid arthritis 3. Double crush syndrome (CTS and brachial plexus traction injury) 4. Scleroderma 5. Hypothyroidism 6. Mucopolysaccharidoses 7. Acromegaly 8. Ganglion cysts 9. Diabetes mellitus
Neuropathies Involving the Diaphragm
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Thiamine deficiency Pyridoxine deficiency Trauma (cervical fractures) Following brachial plexus decompression (injured with medial scalenectomy surgery) Chiropractic manipulation Hypophosphatemia Critical illness neuropathy Hereditary sensory neuropathy II (CMT-2C) CMT-1 (4C) AIDP CIDP Acute intermittent porphyria Remote effect of cancer Viral (acute) Hereditary (brachial plexopathies) Neuralgia amyotrophica
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SECTION X. Differential Diagnosis of Peripheral Neuropathy
Peripheral Nervous System Disorders with Anhidrosis
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Pure autonomic failure Diabetes Amyloidosis Fabry’s disease Acute autonomic neuropathy (autoimmune/viral) Acute intermittent porphyria AIDP Hereditary sensory neuropathy (I–IV) Tangiers’s disease Sjögren’s disease Ross’s syndrome Holmes–Adie syndrome
Dermatologic Causes of Anhidrosis
1. Local injury: a. Thermal c. Scarring b. X-RT d. Inflammatory 2. Anhidrotic ectodermal dysplasia 3. Psoriasis 4. Exfoliative dermatitis 5. Lichen sclerosis atrophicus 6. Ichthyosis 7. Miliaries 8. Incontinent; pigmenti 9. Dermatomally distributed vitiligo
Neuropathy with Hypersensitivity Vasculitis (small vessels; capillaries, arterioles and venules)
1. 2. 3. 4. 5.
Henoch–Schönlein Purpura Vasculitis with infectious disease In association with drug reactions Connective tissue disease Neoplasm
Neuropathy with Localized Vasculitis
1. Isolated peripheral nerve vasculitis; probably localized form of PAN
Neuropathy with Vasculitis and Malignancy (malignancy and hypersensitivity vasculitis)
1. 2. 3. 4.
More common in myelo and lymphoproliferative diseases Rare in association with solid tumors Prominent in hairy cell leukemia Chediak-Higashi disease
Unusual Vasculitis of Peripheral Nerves in Association with:
1. 2. 3. 4. 5.
Cryoglobulinemia Sjögren’s disease Relapsing polychondritis Reiter’s disease Hypereosinophilia syndrome
Neuropathy of Connective Tissue Disease Acute Neuropathy (evolving over hours to days)
1. 2. 3. 4. 5. 6.
SLE Rheumatoid arthritis Scleroderma Mixed connective tissue disease (MCTD) SICCA-complex Relapsing polychondritis
Neuropathy with Systemic Necrotizing Vasculitis (small and medium sized arteries)
1. Polyarteritis nodosa (PAN) 2. Allergic angiitis granulomatosis (Churg–Strauss syndrome) 3. Wegener’s granulomatosis 4. Vasculitis of connective tissue disease 5. Polyangiitis overlap syndrome
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
AIDP Diphtheria Paraneoplastic Chronic lymphocytic leukemia Uremia Porphyrias Lead poisoning Thallium ingestion Pandysautonomia (viral) Polio Adriamycin Vasculitides Viral hepatitis Sarcoid Macroglobulinemia Carcinoma Lymphoma AMAN
Chapter 20. Differential Diagnosis of Neuropathy by Predominant Symptom, Hereditary or Feature Subacute Neuropathy (evolving over weeks to months)
1. Diabetes 2. Uremia 3. B1 4. B12 5. Toxins 6. Sarcoid 7. Paraneoplastic 8. Vasculitides 9. CIDP 10. MAG
11. SGPG 12. Anti sulfatide 13. GTID 14. GT 3 15. TTP-met-30 16. GdIb 17. GQIb 18. Asialo-GM 1 19. GTIA
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Axonal Restless Leg Syndrome
1. Diabetes 4. Anemia 2. Chronic obstructive lung disease 5. Cancer 3. Primary amyloid 6. Iron deficiency
Neuropathy Primarily of the Upper Extremity
1. GM 1 5. Multiple myeloma 2. Lead 6. Hypoglycemia (insulinoma) 3. Amyloid 7. Hypothyroidism 4. Porphyrias
Differential Diagnosis of CIDP
1. Osteoclastic myeloma 2. Plasma cell dyscrasia 3 HIV 4. SLE
5. Malignant melanoma 6. Monoclonal gammopathy 7. Hepatitis 8. Inflammatory bowel disease
Differential Diagnosis of Dorsal Root Ganglion (primary pathology)
1. 2. 3. 4. 5. 6. 7.
Herpes zoster Syphilis Paraneoplastic (sensory variant) GD 1 b Sjögren’s Anti sulfatide epitopes SICCA complex
Neuropathy Associated with Lymphoma/Leukemia/Blood Dyscrasia
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Polycythemia vera Chronic lymphocytic leukemia Direct lymphomatous involvement of the nerves Bone marrow transplant (intra perineural hemorrhage) Acute leukemia (bleeding into nerves) Following X-RT (sarcoma; ischemia of the nervi vasorum) Chediak-Higashi Hypereosinophilic syndromes (idiopathic; tryptophan impurity induced) Paraprotein associated Waldenström’s macroglobulinemia
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Section XI NEUROMUSCULAR JUNCTION DISORDERS
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Chapter 2. Myasthenia Gravis (Acquired and Congenital)
Chapter 1 Introduction The most common neuromuscular junction disorder encountered in clinical practice is acquired myasthenias gravis. It is physiologically characterized by decreased end plate potentials that fail to generate an action potential. Its primary cause is the reduction and blockade of acetylcholine receptors (AChR) at the post junctional membrane from antibodies directed primarily at the α1 subunit. Recently other antigenic targets have been; identified. The neuromuscular junction disorders are the clinical representation of deficits in: 1. Quantal release 2. Postsynaptic membrane architecture (destruction) 3. AChR conduction parameter dysfunction 4. Density of Ach receptors at the neuromuscular junction 5. Acetylcholinesterase activity 6. Calcium induced releasing factors at the motor nerve terminal. The difference between the membrane potential and the threshold for initiating an action potential in these disorders is the safety factor for neuromuscular transmission. Different physiological mechanisms for failure of neuromuscular transmission are operative in each disorder of the neuromuscular junction. Specific muscle junctions that are affected, the associated diseases and components of the CNS/PNS that are involved differentiate the entities. In general, patients with neuromuscular junction diseases have no sensory loss (unless peripheral nerves are affected concomitantly) and have intermittent symptoms particularly with exercises. Diaphragmatic and thoracic paralysis lead to hypercarbia which manifests as lethargy, asterixis, dilated cerebral veins and rarely papilledema (young patients). All forms of NMJ disease lead to muscle weakness. The pupils and reflexes are variably involved as is the autonomic nervous system.
Differential Diagnosis of NMJ Disorders
1. Neonatal myasthenia (passive transfer of maternal antibodies) 2. Congenital Myasthenic Syndrome: a. End-plate choline acetyltransferase deficiency b. Decreased synaptic vesicles c. Reduced quantal release d. Congenital myasthenic syndrome resembling the Lambert–Eaton myasthenic syndrome e. Slow channel syndromes f. Fast channel syndromes g. Primary acetylcholine receptor deficiency with or without minor kinetic abnormalities
3.
4. 5. 6. 7. 8.
9.
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h. Congenital myasthenic syndrome associated with pectin deficiency Acquired myasthenia gravis: a. Classification 1) Pure ocular 2) Mild generalized (no bulbar dysfunction); severe generalized (bulbar weakness) 3) Fulminant (respiratory failure) 4) Late severe 5) Myasthenia gravis with atrophy Lambert Eaton syndrome Botulism Drug induced/toxins Tetanus Snake envenomations: a. Elapidae: Cobra, coral snake, krait, mamba b. Hydrophiidae: Sea snake c. Crotalidae: South American rattle snake d. Viperidae: Vipers Arthropod envenomation: a. Black Widow spider (female) b. Funnel web spider c. Scorpion toxin d. Tick paralysis
Chapter 2 Myasthenia Gravis (Acquired and Congenital) A. General Features: 1. Incidences 4/1,000,000; prevalence 0.5–5/100,000 2. Peak incidence 25–30 years of age 3. Females greater than males; older age males > females B. Clinical Presentation: 1. Onset is subacute 2. Ptosis of one eyelid most common early sign 3. Symptoms and signs vary over time 4. Proximal muscle weakness particularly of the lower extremities greater than distal weakness is a common pattern 5. Weakness may increase during the day 6. Fatigue with exercise of the specific muscle group that is exercised (chewing, swallowing, and holding the head up) 7. Clinical involvement is purely ocular in 15% of patients 8. Aggravating features for weakness: a. Exercise e. Pregnancy b. Heat f. Stress c. Menses g. Hypokalemia d. Infection (viral) h. Thyroid dysfunction 9. 40–50% of patients present with ptosis or diplopia; mild ocular deviation often causes blurred vision (non-foveation)
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SECTION XI. Neuromuscular Junction Disorders
10. 20–30% of patients have ocular complaints and muscle weakness 11. Bulbar complaints at initial presentation occur in approximately 20% of patients C. Clinical examination: 1. Ptosis (usually asymmetrical); lifting the ptotic lid causes droop of the other lid 2. Normal pupils 3. III, IV or Vth nerve weakness 4. Pseudo Intranuclear ophthalmoplegia 5. Cogan’s twitch sign (over activation of co-innervated yoked muscles; over stimulation of levator palpebrae after fatigue of inferior oblique and superior rectus) 6. Lower facial muscle weakness (transverse smile); prominent jaw weakness; patients may hold jaw closed with their hand 7. Neck flexor and extensor muscle weakness to similar degree (flexors weak with myopathy and extensors weak with motor neuron disease) 8. Triple furrowed tongue (differential weakness of intrinsic tongue muscles with unequal tongue muscle contraction) 9. Peek-a-boo sign (slight opening of the eyelids occurs after forced eyelid closure (weakness of the orbicularis oculi) 10. Sluggish gag reflex, difficulty swallowing liquids and nasal speech 11. Weakness proximal greater than distal; lower extremities are involved to greater degree than upper 12. Weakness worsened by repetitive use 13. Reflexes normal to increased (spread of acetylcholine sensitivity of the sarcolemmal membrane) 14. Respiratory weakness may appear as an isolated sign 15. Isolated distal limb weakness and neck extensor weakness 16. Difficulty weaning a patient from a respirator 17. Rarely isolated bulbar weakness
Course of the Illness
1. 2. 3. 4. 5.
90–95% of patients develop extraocular muscle weakness 20% may have only ocular involvement 40% develop bulbar weakness 60–75% extremity weakness Patients who present with pure extraocular motor manifestation that generalize do so within two years 6. Mortality now at less than 3% 7. After three years, approximately 60% of patient with ocular myasthenia gravis generalize
Associated Medical Illnesses
1. Thyroid disorder (10%; most commonly hyperthyroidism)
2. Rheumatoid arthritis 3. Platelet abnormalities (ITP) idiopathic thrombocytopenic purpura 4. Antibodies to gastric parietal cells with B12 deficiency 5. Diabetes mellitus 6. Hemolytic anemia 7. Sjögren’s syndrome 8. Lymphoma 9. Nonspecific immunologic abnormalities: a. Serum anti-muscle Ab b. Antibodies against thyroid, gastric parietal cell and nuclear antigens Thymic Abnormalities
1. Thymic pathology in 75–80% of patients 2. Ten to 15% have thymoma; most frequently seen in 55–65 year old males 3. Young women demonstrate thymic hyperplasia EMG Evaluation
1. Jolly response is positive in 85% of patient with generalized MG 2. At least a 10% decrement between the first and fourth compound muscle action potential (CMAP) at 2–3 HZ 3. 30–40% will have negative repetitive stimulation in pure ocular MG 4. In the face of a decremental response: a. Maximal contraction of the muscle for 30 to 60 seconds abolishes the decrement (post-tetanic potentiation) for 120 seconds after exercise b. The decrement is increased (post-tetanic exhaustion) for 120–240 seconds following exercise 5. Single fiber electromyography: a. Jitter (latency variability between single muscle fiber potentials) innervated by the same axon is increased in MG b. Blocking (absence of the second muscle fiber potential) may be noted c. Single fiber EMG is abnormal in 95–100% of MG patients 6. Laboratory evaluation: a. Antibodies to acetylcholine receptor: 1) Positive in 85–90% of patients with generalized MG 2) Positive in 30–40% of patients with ocular MG b. Pulmonary function tests 1) Abnormal spirometry 2) Decreased mean ventilatory volume a) Fatigue b) Restrictive pattern c. CT scan of the chest 1) Evaluation for thymic tumors d. Blood evaluation to rule out associated autoimmune disease
Chapter 2. Myasthenia Gravis (Acquired and Congenital) Serum Antibodies to Muscle Specific Receptor Tyrosine Kinase (MuSK)
1. Clinical Features: a. Found in generalized seronegative MG patients; 20% of MG patients b. All patients were women c. Onset between 12–59 years of age d. Neck, shoulder or respiratory weakness e. Less prominent ocular muscle involvement f. Variable response to cholinesterase inhibitors g. EMG may be myopathic
Myasthenia Gravis with Thymoma
1. Predominantly a disease of middle aged males a. Clinical Presentation: 1) Ptosis is frequent; less often other cranial nerves are involved 2) May lose reflexes 3) May have sensory complaints: paraesthesia; deep muscle ache 4) Difficulty initiating movements 5) Anti striated A-band muscle antibodies 6) Patients with serum antibodies to the alpha 1 or alpha 3 containing neuronal AChR subunits had autonomic symptoms b. Paraneoplastic disease associated with thymoma (lymphoepithelial thymoma in one patient) developed in sequential order: 1) Limbic encephalitis 2) Neuromyotonia (with hyperhidrosis and motor neuropathy) 3) Myasthenia gravis c. Associated diseases with thymoma: 1) Hypogammaglobinemia (Good’s syndrome) 2) Macrocytic anemia, thrombocytosis and hypogammaglobinemia 3) Thymoma-associated autoimmune enteropathy 4) Loss of CD19 + lymphocytes in peripheral blood 5) Pure red cell aplasia 6) Polymyositis (rare) 7) Intersitial myocarditis
Differential Diagnosis of Myasthenia Gravis (Ocular Involvement Alone)
1. Brainstem lesions affecting the IIIrd nerve (pupil often involved); pseudo internuclear ophthalmoplegia from MG (convergence often affected) 2. Horner’s Syndrome (pupil is miotic) 3. Painless ptosis over several days (MG) 4. Alternating and recurrent ptosis (MG)
495
5. Graves ophthalmopathy: a. All ocular muscles enlarge b. Pathological retraction of the globe c. Forced ductions demonstrate decreased motility 6. Kearns-Sayre Syndrome a. Associated heart block 7. Progressive external ophthalmoplegia a. Symmetric ptosis b. Associated myocardiopathy nerve and proximal muscle weakness c. Slow saccades; MG rapid saccades within limits of weakness 8. Aneurysm (P-COM) a. Retroorbital pain b. Pupillary involvement; often oval 9. Diabetes III nerve involvement: a. Sudden onset of dysfunction b. No pupillary involvement 10. Autoimmune thyroid disease a. May coexist with MG b. Periorbital pain
Differential Diagnosis of Generalized MG Central Disorders
1. Brainstem lesions (associated long tract signs) 2. Basilar meningitis (fever, stiff neck) 3. Demyelinating disease (sensory loss: cerebellar signs; optic nerve dysfunction)
Neuromuscular disease
1. 2. 3. 4. 5.
ALS (bulbar presentation) Diphtheria (pupils involved) Polymyositis (swallowing) Inclusion body myositis (swallowing) Granulomatous myopathy
Neuromuscular Junction Disease
1. Lambert–Eaton Syndrome: a. Autonomic involvement (dry mouth) b. “Load in the pants” gait c. Minimal ptosis (less cranial nerve involvement) d. Exercise induced increased strength 2. Congenital myasthenic syndromes a. Initiation at birth b. Gradual deterioration of motor function
Congenital Myasthenia Syndrome Resembling Lambert–Eaton (LES) Pre-Synaptic Syndrome
1. EMG characteristics of LES
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SECTION XI. Neuromuscular Junction Disorders
2. Defect of the presynaptic voltage gated calcium channels (VGCC) in the synaptic release complex 3. EMG: a. CMAP is low at rest b. 100% facilitation at high stimulation frequencies
Paucity of Synaptic Vesicles and Reduced Quantal Release
1. Symptoms resemble those of acquired MG 2. Defect of synthesis or axonal transport of vesicle precursors to axon terminals 3. Less than 20% of the usual Ach quanta released by a nerve impulse 4. Partial response to acetylcholinesterase inhibitors
Post Synaptic Congenital Myasthenia Syndrome (CMS)
A. General features: 1. All are caused by mutations in AchR subunit genes a. Increase or decrease the synaptic response to Ach b. The genes coding for α, δ, subunits of the AchR are on chromosome 2q; β and ε subunits as on different loci on chromosome 17p
Increased Response to Acetylcholine
A. Slow-Channel Syndromes: 1. Varied clinical presentation: a. Early severe syndrome b. Late presentation with little disability 2. Cervical wrist and finger extensor muscle involvement 3. Prolonged openings of the AchR 4. AD inheritance 5. Quinine may be effective B. EMG: 1. Repetitive CMAP and end plate potentials demonstrate staircase summation with depolarization block
Decreased Response to Acetylcholine
A. General features: a. Clinical symptoms resemble acquired MG b. Mild to severe weakness c. Due to low affinity of ligand d. Due to gating abnormality e. Due to mode switching kinetics
Decreased Response to Acetylcholine End Plate Choline Acetyl Transferase Deficiency
A. General Features: 1. No AchR defect 2. MEPP amplitudes normal at rest a. Decreases during 10-Hz stimulation for 10 minutes b. Defect in resynthesis or packaging of vesicular Ach quanta B. Clinical Presentation: 1. Sudden episodes of apnea 2. Precipitants are fever excitement or infection 3. Presents at birth with bulbar dysfunction respiratory weakness (ventilatory support) and hypotonia 4. Recurrent apneic attacks with bulbar paralysis; may occur in later life 5. Some patients are not breathing at birth and experience attacks during infancy or early childhood 6. Ptosis and fatigueable weakness may persist between attacks 7. Extraocular muscles may be spared 8. Sluggish pupillary light reflex 9. Refractory to cholinesterase inhibitors C. EMG: 1. Repetitive CMAP D. Pathology: 1. Absence of AchR at the synaptic cleft 2. Small nerve terminals encased by Schwann cells; decreased quantal release
Fast Channel Syndromes A. General Features (3 syndromes): 1. All syndromes have brief channel openings 2. Decreased probability of channel opening 3. Responsive to: a. Pyridostigmine b. 3.4 diamino pyridine 4. Low-Affinity fast channel syndromes: a. Normal AchR and end plate morphology b. Infrequent and briefer than normal channel openings c. Mutation of the extracellular domain of the ε subunit (ε P121L) 5. Fast channel syndrome due to a gating abnormality a. Mutation of the M3 domain of the α subunit (α V285I) b. Small MEPP and decreased miniature end plate conductance 1) Slow channel-opening rate constant β 2) Fast channel-closing rate constant α 3) Reduced probability of channel opening 6. Fast channel syndrome due to mode switching kinetics a. In frame duplication in the long cytoplasmic loop of E, E1254 in 18 1) Reduces AchR expression b. Gate opens more slowly c. Closes more rapidly than normal
Chapter 4. Drugs/Toxins that Alter Neuromuscular Transmission Primary Acetylcholine Receptor Deficiency with or without Minor Kinetic Abnormalities
1. Homozygous and heterozygous recessive mutation in AchR subunit genes 2. Mild to severe symptoms similar to acquired autoimmune MG 3. Partial response to acetylcholinesterase inhibition and 3,4diaminopyridine 4. Severe end plate AchR deficiency: a. Mutations of the ε subunit of the AchR
Congenital Myasthenic Syndromes Associated with Pectin Deficiency
1. Pectin is an intermediate filament linking protein; concentrated at sites of mechanical stress 2. In association with recessive form of epidermolysis bullosa simplex and muscular dystrophy 3. Pectin is decreased in skin and absent from muscle in these conditions
Differential Diagnosis of Congenital Myasthenic Syndrome in Adults
1. Mitochondrial myopathy 4. LGMD 2. Motor neuron disease 5. Sero positive and sero neg3. FSH dystrophy ative autoimmune MG
Chapter 3 Lambert Eaton Syndrome (LEMS) A. General Features: 1. Presynaptic failure to release acetylcholine packets; there are an adequate number of acetylcholine quanta in each packet from the nerve terminal in response to its depolarization 2. Autoimmune etiology suggested by: a. Organs specific antibodies in approximately 25% of patients 3. Improvement after plasma exchange and immunosuppressant therapy 4. Associated with HLA-B8 and the IgG heavy chain markers 5. Antibodies to P/Q VGCC (voltage gated calcium channels; α1 subunit of the pore) 6. Antibodies to synaptic and to the intracellular component of the β subunit of VGCC channels 7. Small cell lung cancer is present in approximately 60% of patients
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8. Autonomic dysfunction putatively related to antiVGCC on sympathetic and parasympathetic neurons 9. Progressive atrophy and Type I fiber loss in muscle biopsy B. Clinical Presentation: 1. Peak incidence 50 years; associated with small cell lung cancer 2. Leg weakness; proximal > distal 3. Dysesthesias and pain occur in a small percent of patients 4. Increased muscle strength immediately after voluntary contraction followed by fatigue 5. Weakness increased by heat 6. Post tetanic increase of reflexes that are initially depressed 7. Autonomic symptoms of dry mouth, blurred vision, decreased sweating, and impotence 8. Less common cranial nerve dysfunction 9. Respiratory failure occurs; difficulty in breathing after surgery in which neuromuscular block agents have been used 10. Patients with cancer and those without have similar symptoms 11. LEMS may precede lung cancer by greater than two years 12. Approximately 3% of SCLC manifest features of LEMS 13. Variety of other cancers may demonstrate LEMs C. Laboratory evaluation: (P/Q type) 1. VGCC antibodies in 79% of patients 2. Positive sera may also reveal N-type VGCC D. EMG: 1. Amplitude of the resting CMAP induced by supra maximal stimulation is reduced 2. Slow repetitive maximal nerve stimulation less than 10 second causes a further decrement 3. Greater than 10 Hz stimulation or 10 seconds of maximal voluntary contraction increases the amplitude of CMAP greater than 100% 4. Single fiber EMG demonstrates abnormal firing and blocking
Chapter 4 Drugs/Toxins that Alter Neuromuscular Transmission
A. General Features: 1. All decrease the safety factor of neuromuscular transmission 2. Neurotoxins may affect both the pre and post synapse components of the NMJ
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SECTION XI. Neuromuscular Junction Disorders
3. Most common neurotoxin is envenomation (worldwide) 4. Extraocular muscles, neck flexors and extensors and girdle muscles are particularly sensitive; involvement of respiratory and pharyngeal muscles is common; cognition is spared (unless there is secondary hypercarbia) as is sensation. Reflexes are intact until late in the course of the illness. B. Analgesics: 1. Morphine and its deritatives do not depress neuromuscular transmission a. Depress respiration (centrally) b. Are potentiated by anticholinesterases C. General anesthetics: 1. Potentiation of neuromuscular blocking agents in MG patients (weakness and respiratory depression) 2. Ethrone and nitrous oxide do not cause neuromuscular blockade D. Local Anesthetics: 1. Lidocaine, procaine, mexiletine potentiate neuromuscular blockade when administered intravenously. 2. Impairment of nerve action potential propagation (not the case with lidocaine) and possible reduction of Ach release; possible decreased sensitivity of the post synaptic membrane to Ach. E. Antibiotics: 1. Aminoglycosides: a. Weakness related to dose and serum level b. Blocking effects occur by any route administration c. Inhibition of Ach release b. Tobramycin: 1) Inhibition of Ach release c. Neuromuscular toxicity demonstrated for: 1) Kanamycin 3) Neomycin (most toxic) 2) Gentamicin 4) Streptomycin d. Macrolide antibiotics: 1) Erythromycin 2) Azithromycin e. Polypeptide and monobasic amino acid antibiotics: 1) Penicillin 2) Sulfonamides 3) Tetracycline 4) Fluoroquinolone a) Potentiate neuromuscular blocking agents b) Cause weakness in MG patients alone 5) Lincomycin and clindamycin: a) Monobasic amino acids b) Difficult to reverse effects with cholinesterase inhibitors c) Mechanisms of action: (1) Decreased motor end plate potential frequency (2) Decrease evoked transmitter release (3) Decrease postjunctional Ach sensitivity d) Lincomycin:
6) 7) 8) 9)
10) 11) 12)
13) 14)
15)
(1) Effects reversed with calcium or aminopyridine (2) Cholinesterase inhibitors worsen their effect e) Clindamycin: (1) Blocks muscle contractibility (2) Has local anesthetic action f) Polymyxin B; colistimethate and colistin: (1) Renal disease patients are susceptible (2) Potentiates effects of other antibiotics and neuromuscular blocking agents (3) Decreased Ach release and postjunctional block of AchR g) Tetracycline, oxytetracycline and rolitetracycline exacerbate MG Bretylium (potentiates blocking drugs) Calcium channel blockers (presynaptic inhibitions of Ach release) Procainamide (impaired formation or release of Ach) Quinidine and quinine (prevents formation or release of Ach or a curare-like effect); potentiate depolarizing and non depolarizing blocking drugs Trimethaphan; potentiates depolarizing and non depolarizing drugs Progesterone: reported to aggravate MG after 3–5 days Interferon alpha: a) May aggravate MG weeks to months after the initiation of therapy b) Has induced MG crisis Iodinated contrast agents: possibly decrease ionized calcium that induces failure of Ach release Magnesium: a) Decreases release of Ach; blocks calcium entry at the terminal motor terminal b) Induces post synaptic membrane excitability c) Effects seen parenteral > oral administration d) Potentiates neuromuscular blocking drugs e) 10 mEq/liter may cause respiratory depression Neuromuscular blocking drugs: a) MG patients more sensitive to competitive non depolarizing agents b) Succinylcholine: (1) Potentiated by cholinesterase inhibitors (2) Prolonged weakness may occur with plasma exchange or in the setting of congenital absence of cholinesterase inhibitors (3) Corticosteroids may potentiate the effects of muscle relaxants
Ophthalmic Drugs
1. Beta-adrenergic agents 2. Echothiophate (long acting cholinesterase inhibitor)
Chapter 4. Drugs/Toxins that Alter Neuromuscular Transmission Psychotropic Drugs
1. Chlorpromazine and promazine: a. Post synaptic block b. Antagonize Ach c. Prolong the effects of succinylcholine 2. Lithium: a. Possible decrease of quantal release or synthesis of Ach b. Possibly induces increased rate of receptor degradation
Rheumatologic Drugs
1. Chloroquine: a. Decreased Ach release b. Competitive postjunctional blockade c. Depresses excitability of the sarcolemmal membrane D-Penicillamine
1. MG may be precipitated in 7% of patients treated a. May be restricted to extraocular muscles b. Mild generalized weakness
Bone Marrow Transplant
1. Autoimmune etiology 2. Possibly more common in those with aplastic anemia
D, L Carnitine
1. NMJ block occurs during dialysis 2. Presynaptic block similar to that produced by hemicholinium 3. Postsynaptic block due to possibly by the accumulation of acylcarnitine esters
Diuretics
1. MG weakness aggravated by hypokalemia
Reports of Drugs that Exacerbated MG Weakness
1. Emetine 5. Trasylol 2. Riluzole 6. Trihexyphenidyl 3. IV sodium lactate 7. Diphenhydramine 4. Tetanus antitoxin
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Drugs that Alter Neuromuscular Transmission in Specific Clinical Situations
1. Safety factor for neuromuscular transmission is reduced due to the underlying disease 2. Superimposition of drug on pre-existing disorder such as MG or ALS 3. Patients with renal, hepatic or electrolyte disorders (may have depressed NMJ or membrane excitability) 4. After general anesthesias with concomitant neuromuscular blocking drugs (succinylcholine; pancuronium) which are still active 5. Component of drug induced generalized immunologic disease (penicillamine) 6. Presynaptic induced dysfunction: a. Calcium-magnesium b. Calcium channel blocking agents; some antibiotics; some beta blocking drugs 7. Postsynaptic induced dysfunction: a. Penicillamine b. Carnitine c. Cholinesterase inhibitors 8. Pre and Post synaptic dysfunction a. Aminoglycosides b. Enhances or induces autoimmune reaction against the NMJ c. MG more commonly induced during treatment of rheumatoid arthritis rather than Wilson’s disease (penicillamine) d. 70% of patients remit within one year after discontinuance of the drug (penicillamine)
Envenomation
A. General features: 1. Usually affect the cholinergic system: a. Increase the release of Ach b. Block AchR 2. Major species: a. Viperidae (pit vipers) b. Crotalidae (rattle snakes and pit vipers) c. Elapidae (coral snakes, mamba, Kraits and cobras) d. Hydrophiidae (sea snakes) 3. Neuromuscular blockade occurs with: a. Elapidae b. Hydrophiidae c. Crotalidae (South American rattle snake) 4. Presynaptic toxins: a. β-bungarotoxins b. Tai pexin c. Decrease the release of Ach: 1) Initial augmented release 2) Late depletion of the neurotransmitter d. More potent than post synaptic toxins 5. Post synaptic toxins:
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SECTION XI. Neuromuscular Junction Disorders
a. α-neurotoxins b. Non depolarizing neuromuscular block 6. Most toxins are mixtures of pre and postsynaptic compounds 7. Sea snakes inject less toxin, but it is more potent 8. α-neurotoxins: a. Bind the nicotinic Ach receptor of muscle b. More potent than curare c. Slower onset of action and longer duration than presynaptic toxins i. β-Neurotoxins: a. Contain phospholipases b. All suppress release of presynaptic Ach c. Tai pexin has additional Myotoxin (rapid muscle necrosis) B. Clinical presentation: 1. Pit viper or cobra a. Local pain b. No pain with other Elapidae and Hydrophiidae 2. Swelling and necrosis within one hour of bite from Viperidae, Crotalidae a. No swelling from mamba, Krait or Coral snakes 3. Pre paralytic stage (Viperidae and Crotalidae) a. Headache, nausea and vomiting b. Loss of consciousness c. Paraesthesias d. Hematuria and hemoptysis e. Above manifestations rarely seen with cobra or mamba envenomation 4. Neuromuscular Toxicity: a. Usual time from envenomation to paralysis: 1) ½ hour to 19 hours 2) Mamba envenomation as short as 10 minutes 3) Location of the bite and direct venous access are determining features as is variant of injected toxin b. Sequence of clinical signs: 1) Ptosis and ophthalmoparesis 2) Facial and bulbar weakness 3) Extremity, diaphragms and intercostal weakness a) May progress over 2–3 day period 4) No sensory abnormality accept at the site of envenomation 5) Cardiovascular collapse, seizures and coma are terminal events c. Hematoxic effects: 1) Cerebral hemorrhage 2) SAH 3) ICH 4) Leading cause of Viperidae deaths d. Crotalidae: 1) Persistent fasciculations long after clinical recovery of the affected muscles
Arthropod Envenomation
A. General features: 1. Mechanism of NMJ effects a. Increased release of Ach followed by depletion 2. Facilitated release without depletion of transmitter 3. Decreased Ach release B. Clinical presentation: 1. Black widow spider (Latrodectus) release followed by depletion a. CNS and PNS stimulation; facilitation of Ach release b. Neuromuscular effects noted within 15 to 60 minutes of envenomation c. Severe painful abdominal cramps and rigidity; followed by truncal and appendicular cramps; later affects are muscle weakness (depolarizing block) 2. Funnel-Web spider; red back a. Male toxins have potency greater than female b. Nausea, vomiting, dizziness are first symptoms c. Fasciculations and paralysis of striated muscle and the diaphragm d. Death by cardiac arrest (asphyxia) 3. Scorpion a. Toxins effect sodium and potassium channel function; some enhance release of Ach b. Increased secretion of saliva c. Severe sweating, nausea, vomiting, disorientation and dizziness d. Less motor weakness Tick Paralysis
A. General Features: 1. Dermacentor (acronine, variabilis, occidentalis, amblyomma americanum and maculatum) species are toxic 2. In North America most often seen in states West of the Rocky Mountains 3. Possible temperature dependent block of Ach release B. Clinical Presentation: 1. Symptoms require 5–6 days of attachment a. Headache, malaise, nausea and vomiting b. On 6–8 days there is symmetric ascending paralysis; may affect respiration and bulbar muscles c. Normal sensation d. Depressed reflexes e. Improvement begins within hours of removing the engorged tick f. Tick attaches mot often in the scalp, perineum, and neck g. Some patients ataxia is more severe than weakness
Marine Toxins
A. General features:
Chapter 5. Botulism
1. Marine toxins affecting the NMJ a. Poisonous fish b. Mollusks c. Dinoflagellates 2. Due to ingestion 3. Shellfish poisoning: a. Caused by dinoflagellates (single-celled, bi flagellated, algae-like) b. Toxin absorbed through GI tract: 1) Within 30 minutes there is burning and paresthesias of the face and mouth that spreads to neck and limbs 2) Sensory symptoms abate and are followed by numbness, ataxia and generalized weakness; respiratory failure can ensue c. Neurotoxins from dinoflagellates and diatoms (not flagellated and are encased in a shell): 1) Sodium channel blockers 2) Include: saxitoxin and tetrodotoxin d. Brevetoxins: 1) Derived from shellfish 2) Depolarizes cholinergic systems by opening sodium channels
Gonotoxins
A. General Features: 1. Derived from predatory cone snails (mollusks); dart like proboscis that injects toxin 2. α-Gonotoxin: a. Blocks binding of Ach 3. W-Gonotoxins: a. Block voltage gated calcium channel of the presynaptic terminal B. Clinical Presentation: 1. Severe local pain 2. Within 30 minutes generalized weakness 3. Respiratory failure occurs within 1–2 hours 4. 60% of stings may be fatal Venomous Fish
A. General features: 1. Most venomous is the stone fish 2. Pacific oceans, Red Sea and Japan 3. Toxin: a. Toxin is injected from dorsal spines b. Ach release with later depletion of stores B. Clinical presentation: 1. Excruciating local pain that lasts for two days 2. Edema and necrosis: hyaluronidase injected that promotes spread of toxin 3. GI, autonomic, cognitive dysfunction 4. Generalized muscle weakness
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Plant Toxins
A. General features: 1. Hemlock (conium maculatum) 2. Piperidine alkaloid 3. Coniine is the toxin B. Clinical presentation: 1. Rapidly ascending paralysis 2. Severe sensory symptoms
Chapter 5 Botulism A. General features: 1. Neurotoxin is derived from the bacterium (Clostridium Botulinum) a. Anaerobic and alkaline conditions for growth b. Spores are heat resistant; temperatures of 120o C are required for sterilization; 85o C inactivates the toxin c. High altitude cooking (water boils at lower temperature and does not inactivate spores; inadequate sterilization of canned foods) d. Eight antigenic types of botulinum toxins: A, B, C1, C2, D, E, F, G; Zinc-dependent endopeptidase e. Human disease caused by A, B, E f. Fatal dose 0.05–0.1 ug g. 250 cases of botulism/year in the USA 1) Type A: Western USA 2) Type B: Eastern USA, Europe 3) Type E: from fish, more prevalent in Japan (20% of USA patients) h. Ingested toxin from food (USA) 1) Vegetables – 57% 3) Fish – 15% 2) Fruit – 12% i. Infantile form of the toxin is produced by organisms in the GI tract j. Wound infection as a source of poisoning is becoming rare k. Mechanism of action: enters the axon terminal by endocytosis 1) Toxins A, C, E-cleave synaptosomal proteinassociated protein (SNAP-25) 2) Types B, D, F and G-cleave synaptosomal-brevis associated membrane protein 3) Type C-cleaves syntoxin 4) Clear sensorium; no sensory loss 5) Constipation, dry mouth, postural hypotension dilated poorly reactive pupils; internal and external ophthalmoplegia 6) Initial nausea, vomiting, diarrhea followed by constipation 7) Once process is initiated there is no fluctuation of symptoms
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SECTION XI. Neuromuscular Junction Disorders
Differential Diagnosis of Botulism vs GQ1b CMS
1. GBS (C.M. Fisher variant) G Q 1b (Ab); absent DTRs 2. Pharyngeal-cervical brachial variant (GBS); GT1a (Ab) 3. Lambert-Eaton Syndrome (increase reflexes and strength with exercise) 4. MG (pupils normal) 5. Tick paralysis (ataxia with weakness) 6. Toxic shell fish (pain at site of envenomation) 7. Diphtheritic neuropathy (sore throat)
Infant Botulism
A. General features: 1. Spores are ingested and germinate in the infant GI tract 2. Honey consumption is a risk factor; Type B > A organisms B. Clinical presentation: 1. Affects infants less than six months 2. Weak cry difficulty feeding 3. Weakness of bulbar and limb muscles. Hypotonia loss of head control, decrease of spontaneous movements 4. Parasympathomimetic symptoms
Wound Botulism
A. General features: 1. Primarily in IV drug abuse patients (abscesses) 2. Sinusitis in cocaine users B. Clinical presentation: 1. Patient with a wound 2. Bulbar signs and descending paralysis
3. Autonomic symptoms in some patients C. EMG: 1. Prolonged jitter and increased block on single fiber studies at a distance from the injection site D. Laboratory Evaluation 1. Detection of C. botulinum in the stool or toxin in the serum, stool or wound 2. Evaluation of food for bacteria and toxin 3. Serum samples need to be collected by two days after ingestion; stool samples by three days E. EMG Evaluation 1. Small evoked CMAP from single supramaximal stimuli in affected muscles 2. Normal sensory (SNAP), velocities and latency 3. Normal mNCV 4. After exercise CMAP may increase 5. Post tetanic facilitation noted in some patients 6. Increased brief polyphasic motor unit potentials and fibrillation potentials 7. Single fiber EMG: increased jitter and blocking a. General clinical features suggestive of a CMS 1) Onset in infancy or childhood of ocular, bulbar or limb, muscle fatigueable weakness 2) Involved relative may be isolated) 3) Some have late onset 4) Weakness in selected muscles 5) EMG evaluation a) Decremental response at 2–3 HZ on repetitive nerve stimulation b) May be positive in restricted muscles or only intermittently 6) No anti-acetylcholine receptor antibodies
Chapter 6 Hidden Botulism
A. General Features: 1. No obvious source of toxin 2. Abnormality of GI tract as risk factor such as achlorhydria, surgery, Crohn’s disease, recent antibiotic treatment C. Clinical Presentation: 1. Similar to chronic form 2. C. botulinum in feces of an adult patient
Iatrogenic Botulism
A. General Features: 1. Toxin injected for movement disorder B. Clinical Presentation: 1. Standard doses had been given to patients 2. Moderate clinical weakness
Tetanus 1. General considerations: a. Approximately one million cases occur annually worldwide 2. Twenty five percent (approximately) from occupational injury 3. Clostridium tetani: a. Obligate anaerobe b. Requires extrachromosomal DNA (plasmid) for production of tetanospasmin) c. Inhibits release of Ach from the presynaptic terminals d. Retrogradely transported to enter the CNS e. Blocks release of glycine and GABA b from presynaptic terminals f. Toxin transported to both the sensory neurons of the dorsal root ganglia and archenteric neurons 4. Clinical features:
Chapter 6. Tetanus
a. Generalized tetanus 1) Rigid masseters (“lock-jaw”) at presentation 2) Generalized spasms with opisthotonus; no loss of consciousness 3) Painful muscles with increased reflexes b. Localized tetanus 1) May progress to generalized disease 5. Cephalic form: a. Involves the lower cranial nerves b. Facial weakness, dysphagia and rarely ophthalmoplegia c. Source is chronic middle ear infection 6. Neonatal variety
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a. 50% of tetanus infection with an approximate 90% mortality b. Infection of the umbilical stump c. Weakness and inability to suck during the second week of life Mechanisms of death are: 1. Respiratory 2. Autonomic dysregulation 3. EMG: a. Continuous and excessive motor unit activity b. Normal nerve conduction studies c. Absent silent period from affected muscles
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Section XII MUSCLE DISEASE
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Chapter 1. Inherited Myopathies
Chapter 1 Inherited Myopathies The recent explosion of molecular genetics has been particularly illuminating for the understanding of inherited muscle disease. Mutations in the dystrophin gene and genes that transcribe proteins that connect the contractile protein actin and myosin to the exterior of the cell and ultimately basal lamina. Lamina make up a significant proportion of inherited muscle disease.
The Muscular Dystrophies
1. X-Linked muscular dystrophies a. Duchene muscular dystrophy b. Becker muscular dystrophy c. Emery Dreifuss muscular dystrophy 2. Autosomal dominant muscular dystrophy a. Myotonic dystrophy b. Fascioscapula humeral dystrophy (FSHD) c. Distal (adult onset) myopathy d. Scapuloperoneal dystrophy e. Oculopharyngeal dystrophy 3. Autosomal receive muscular dystrophy a. Limb girdle muscular dystrophy b. Distal myopathy c. Congenital muscular dystrophy d. Scapulohumeral muscular dystrophy
X-Linked Recessive Dystrophinopathies
1. 2. 3. 4. 5. 6. 7.
Duchenne muscular dystrophy (DMD) Becker’s muscular dystrophy (BMD) Isolated X-linked cardiomyopathy Isolated quadriceps myopathy Muscle cramps with myoglobinuria Asymptomatic elevation of muscle enzymes DMD/BMD-manifesting female carriers
General Features of Dystrophinopathies
1. All are allelic and are generated by different mutations of the dystrophin gene 2. Dystrophin gene: a. One of the largest genes known (2.4 mega bases) b. Xp21; codes dystrophin 3. Genetics a. In DMD: 1) There is either no dystrophin expression or there is production of a truncated or dysfunctional protein
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2) Dystrophin is involved in the contractile function of muscle cells by its link between the plasmalemmal component of the sarcoplasmic membrane and laminin of the extracellular membrane via dystrophin associated protein complex 3) Dystrophin deficiency destroys the mechanical stability of the muscle sarcolemmical membrane with consequent contraction induced rupture of the cell, influx of calcium and activation of proteolytic enzymes 4) DNA analysis: a) Deletions 66% of patients b) Duplications 5% c) Rare inversions 5) May be manifest in heterozygous females: a) Carriers with gene translocations (1) Break points at Xp21 with preferential inactivation of the normal chromosome b) Biased X-chromosome inactivation (Lyon’s hypothesis): (1) Most common in twin pregnanciescr c) Turner’s syndrome or mosaic (1) XO/XX (2) mosaic XO/XX/XXX (a) X-chromosome carries a mutated gene; female child is affected 6) Other genetic mechanisms: a) Spontaneous mutation of a single germ cell of the mother b) Mutation of probands gene early in post zygotic embryo development c) Germline mosaicism: (1) Mother is not a somatic carrier (2) Has more than one affected child (3) 20% of new DMD mutations (4) Due to mutation at the mitotic stage of germ cell lineage development (5) Maternal mutation (a) Risk of more than one affected male child (6) Paternal mutation (a) Female children at risk of being carriers 7) “Hot Spots” of deletion a) Intron 44 and 45 b) Exon 45
Clinical Manifestations
1. Elevated enzymes at birth 2. Delayed walking (some patients) 3. Weakness usually apparent at 2–3 years a. Proximal muscles prior to distal b. Lower extremities prior to upper
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SECTION XII. Muscle Disease
4. By ages 3–6 a. Waddling gait (hip flexors are weak; function substituted by hip abduction) b. Exaggerated lumbar lordosis c. Calf enlargement (“rubbery” feel) d. By pain e. Gower’s maneuver noted f. Neck flexor weakness: 1) More severe in DMD than in Becker’s or intermediate forms g. May have pseudohypertrophy of: 1) Deltoids 3) Quadriceps 2) Gluteal muscles 4) Masseter (rare) h. Ankle flexors and invertors stronger than dorsiflexors 1) Equinovarus position of feet 2) Toe walk 3) Heel cord contraction a) May be accelerated if gastrocnemius muscle is biopsied 5. Boys clinical pattern of weakness, ages 6–11 a. Linear loss of muscle strength b. Loss of proximal muscle strength accelerates c. Loss of deep tendon reflexes 1) Exception is resistance of brachioradialis and ankle jerks a) Involvement of intrafusal fibers of the muscle spindle 6. Scoliosis and contractures develop a. Contractures start at ankle, hip > knee > elbow > wrist 7. Usually wheelchair bound by 12 years of age a. Death during the late teens: 1) Pulmonary complications 2) Cardiomyopathy b. 25% of patients survive past 21
Respiratory Musculature
1. Cough is ineffective due to decreased maximum end expiratory and inspiratory pressures 2. Death occurs: a. In the second or third decade from pulmonary infection b. Respiratory and cardiac failure
Cognitive Function
1. Most patients demonstrate a non-progressive intellectual impairment (at least 1/3); IQ < 75 a. One standard deviation below normal b. Brain type 427 isoform of dystrophin c. Verbal ability > performance skill d. Occasional child with normal or above average IQ
Smooth Muscle Dysfunction:
1. Degeneration of gastrointestinal tract smooth muscle: a. Intestinal pseudo obstruction b. Presentation with: pain, distention, vomiting, gastric dilatation
Osteoporosis
1. May be severe and starts while patients are walking
Adverse Anesthetic Reactions
1. Occur with the use of halothane and succinylcholine: a. Malignant hyperthermia b. Acute hyperkalemia in absence of hyperthermia c. Acute cardiac failure (cardiomyopathy)
Systemic Involvement in DMD
1. Cardiac: a. Fibrosis of the ventricular wall b. Greatly enlarged R waves across the precordium c. Q waves in limb, body and precordial leads d. Decreased rate of relaxation in diastole e. Mitral valve prolapse f. Intra atrial conduction defects g. Infranodal conduction defects h. Arrhythmias are most common during infections i. Echocardiography: 1) Diminished contractility of the posterolateral ventricular wall and left ventricle 2) Rarely congestive heart failure may occur prior to respiratory involvement
Becker’s Muscular Dystrophy (BMD)
A. General features: 1. Allelic disorder to DMD 2. Mutations or deletions maintain the reading frame which results in the production of some functional dystrophin a. Longer or shorter dystrophin 3. Dystrophin reduced to tibialis anterior and peroneal muscles > shoulder girdle b. Early calf muscle pseudohypertrophy c. Neck flexors are affected later in the course 1) Differential point between DMD and other dystrophinopathies d. Fewer contractures; develop in wheelchair stage e. Scoliosis develops after patients are wheelchair bound f. Slow progression into age 30–40’s g. Cardiomyopathy occurs; its severity may not correlate with degree of muscle weakness: 1) EKG abnormalities not as frequent as in DMD h. pes Cavus is noted in 15–70% of patients i. Cardiac involvement: 1) RBBB 2) T wave changes 3) May precede muscle involvement by several years j. Intellectual function: 1) Minority of patients are mentally retarded 2) Cognitive impairment may be the presenting symptom k. Cryptorchidism; hypogenitalism; testicular atrophy have been reported 1) Fertility is approximately 70% of unaffected brothers l. EMG 1) Myopathic; short duration small amplitude polyphasic potentials 2) Rare fibrillation potentials m. Patients survive to 30–60 years of age n. Cause of death: 1) Respiratory insufficiency 2) Cardiomyopathy 3) Cor pulmonale
Intermediate Phenotype (“Outliers”)
1. Mild DMD or severe BMD: a. Ambulatory greater than 12 years of age b. Wheelchair bound less than 16 years of age c. Preservation of ability to flex their neck against gravity d. Cardiomyopathy e. Cognitive impairment
Isolated X-Linked Dilated Cardiomyopathy
1. General characteristics and clinical features: a. Progressive and fatal heart disease b. Presents in the second or third decade
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c. Congestive heart failure patients without skeletal muscle weakness d. Muscle isoenzyme of CK elevated 2. Genetics: a. Specific mutations in the dystrophin gene: 1) Selective absence of dystrophin in heart muscle 2) Mutations of the 5th exon of the gene result in a more severe cardiomyopathy than those in the spectrin-like region (exons 48–49) 3) Exclusive cardiac involvement is related to a difference in RNA splicing regulation between heart and skeletal muscle
Isolated Quadriceps Myopathy
A. Clinical characteristics: 1. Mild slowly progressive 2. Limited to the quadriceps muscles 3. Some patients have concomitant cardiomyopathy 4. Mutation of the dystrophin gene is causative 5. Some patients with calf hypertrophy
Muscle Cramps with Myoglobinuria
A. Genetics: 1. Exon 40–44 and 45–57 of the dystrophin gene is important 2. X-linked B. Clinical presentations: 1. Exercise induced myalgias and cramps without skeletal weakness 2. May have normal or borderline elevated CK; no pathology on muscle biopsy 3. Family with cardiomyopathy and muscle cramps without clinical weakness has been reported 4. Association of myoglobinuria without weakness seen in patients with: a. Exercise induced cramps b. Exercise induced myalgias c. Cardiomyopathy and exertional cramps C. Differential point: Need to rule out metabolic myopathy without fixed weakness Isolated Elevation of Muscle Enzymes: 1. Possible mutation of the rod domain of the dystrophin gene Female Relatives of Boys with DMD/BMD: 1. Heterozygous carriers with mutated dystrophin gene: a. Random “X” inactivation b. Inversions 2. Clinically evident weakness in 2.5–10% of carriers (proximal muscles) 3. 70% of carries have elevated CK
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SECTION XII. Muscle Disease
4. Mosaic of fibers with either normal or absent dystrophin 5. May have calf hypertrophy Differential Diagnosis: 1. Limb girdle muscular dystrophies: a. Absence of cognitive deficit b. Less frequent cardiomyopathy c. Less marked calf hypertrophy d. Autosomal receive or autosomal dominant inheritance (the later rules out dystrophinopathy) 2. Limb girdle clinical presentation in a girl: a. Rule out DMD or BMD with 45 XO b. Non-random X chromosome inactivation 3. Acid maltase deficiency: a. Childhood proximal muscle weakness b. Rare calf hypertrophy c. Irritative EMG d. Subsarcolemmal vacuoles on muscle biopsy 4. Spinal muscular atrophy: a. May have prominent proximal muscle weakness in childhood b. CK is minimally elevated c. EMG is neuropathic 5. Emery–Dreifuss muscular dystrophy: a. AD not X-linked b. No pseudohypertrophy c. Early elbow and heel contractions d. Mild CK elevation e. Prominent cardiac abnormalities 6. Unexplained persistent elevation of liver enzymes (ALT) alanine aminotransferase and aspartate aminotransferase (AST) a. Present in muscle tissue b. May represent dystrinopathy in: 1) women who later become symptomatic (DMD/BMD) 2) asymptomatic carriers c. Other muscular dystrophies d. CK is elevated if the other enzymes elevations are from muscle 7. Isolated dilated cardiomyopathy a. Need to rule out dystrinopathy
Laboratory Evaluation of Dystrinopathy
1. Genetic testing for DMD/BMD 2. Muscle enzymes: a. Less than 5 years of age, CK levels are 20–100 times normal in BMD b. Less than 5 years of age: CK levels are 50–100 times normal in DMD c. CK levels decline with age (20% per year) d. 70% of carriers have elevated enzymes 1) Decline with age e. CK is the most specific muscle enzyme:
1) AST is least organ specific 2) ALT more liver specific 3) Aldolase is elevated in BMD/DMD Electromyographic Evaluation of BMD/DMD
1. Myopathic in proximal muscles (early): a. May demonstrate fibrillation potentials and increased insertional activity b. Late changes: 1) CMAP decreases 2) Insertional activity decreases 3) Very small muscle action potentials 4) Disappearance of fibrillation potentials Muscle Biopsy Evaluation of BMD/DMD
1. Histopathologic findings: a. Degeneration b. Regeneration c. Isolated opaque fibers d. Replacement of muscle by fat and connective tissue e. Increased variability of muscle fiber size: 1) Larger than normal in younger patients 2) Smaller than normal fibers with disease progression f. Internal nuclei in 2–4% of fibers g. Type I fiber predominance h. Inflammatory cells in the perimysium, endomysium and perivascular spaces 1) Monocytes and macrophages i. Gomori trichome stain: 1) Striking endomysial and perimysial increase of connective tissue 2. Dystrophin immunostaining: a. DMD patients: 1) No detectable dystrophin of the sarcolemma 2) 80% of DMD patients: a) Dystrophin expression is noted cardiac signs c. Cardiac onset with sudden death 2. Myopathy with contractures a. Onset in childhood b. Contractures involve elbow extension, neck flexion and ankle dorsiflexion; occur in all patients with muscle weakness c. Proximal weakness: 1) Equinovarus position (rare) 2) Muscle weakness in upper arms noted early (rare) d. Flexion contraction at 4–6 years of age 1) No concomitant muscle weakness e. Contractures exacerbate during growth f. Flexion contracture of the wrist in adults g. Contracture of lower back muscle causes rigid spine h. Wasting is severe in the posterior leg compartment and the biceps 1) Hypertrophy of the extensor digitorum brevis i. Weakness of elbow flexion and finger extension > hip girdle and pelvic musculature weakness C. Rare muscular involvement: 1. Orbicularis ores and oculi 2. A severe phenotype with inability to walk by adolescence 3. Hyperextension of the neck and thorax D. EDMD/carriers 1. No musculoskeletal symptoms
1. Presents between second to fourth decades in EDMD1; 3rd to 4th decades in EDMD2 2. Atrial paralysis: a. Seminal in EDMDI 3. Atrial paralysis and dilated cardiomyopathy occur in EDMD2 4. EDMDI: a. Sudden death frequent between 25–49 years of age b. Few patients demonstrate syncope or dizziness c. Cardiac disease occurs in female carriers 5. Isolated cardiac involvement is more frequent in EDMD2 a. Defects in LMNA genes are associated with: 1) Adult onset dilated cardiomyopathy 2) Conduction defects 3) No weakness or contracture 6. Cardiac pathology a. Replacement of muscle by fat and fibrosis 7. Differential diagnosis of EDMDI vs. EDMD2 a. EDMDI: 1) Musculoskeletal weakness and early joint contracture 2) Late cardiac conduction defects 3) Maintain ambulation b. EDMD2: 1) Heterozygotes may be asymptomatic 2) Rarely aggressive from causes loss of ambulation 3) Isolated dilated cardiomyopathy 8. Laboratory Diagnosis of EDMD a. Elevation of CK to 10x normal in younger patients 9. EMG: a. Myopathic b. NCVs are normal 10. Muscle Biopsy a. Myopathic: 1) Variation of fiber size 2) Endomysial fibrosis 3) Type I fiber atrophy or fibrosis 11. Emerin is absent in the nuclei of 95% of patients (EDMDI) a. Emerin may be detectable in missense or promotor mutations 12. EDMD2 a. Perinuclear LMNA and emerin is present 13. EKG findings in young patients with early cardiac involvement: a. Low amplitude P waves b. Prolongation of the P-R interval c. Atrial fibrillation and atrial flutter occur with progression of the disease d. Sentinel pattern: 1) Functional escape rhythm at 40–50 beats/minute 2) No P wave due to atrial standstill 3) No electrical or mechanical activity of the atria 4) Inability to pace the atria
Associated Findings
1. Scoliosis is not usually severe 2. Hyperextension of the neck and thoracic spine lordoscoliosis, is rare 3. Decreased cognitive function (rare) 4. No correlation of cardiomyopathy and skeletal myopathy
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14. Molecular diagnosis of EDMDI: a. Western blot and immunohistochemistry b. Absent emerin in muscle, skin and buccal smears in male patients 1) Reduction of protein and mosaic expression in female carriers
c. Early flexion contractures of elbows, ankles and last four fingers d. No cardiac involvement (one patient described with septal hypertrophy) e. May cause progressive respiratory compromise (rare) f. Some patients over 50 are wheelchair bound
EDMD2 CMD with Rigid Spine Syndrome
a. AD and AR forms 1) Emerin is normal and genetic analysis is necessary
Emerin Mutations (EDMD1):
1. Non-sense frame shift or splice mutations a. Result in absence of the protein 2. In-frame deletions and missense mutations: a. May be associated with residual or normal expression of the protein
LMNA Gene Mutations (EDMD2):
a. Non-sense and missense mutations 1) Rod domain mutations a) Isolated cardiomyopathy with A-V block
Differential Diagnosis of the Rigid Spine Syndrome
1. 2. 3. 4.
X-linked Emery–Dreifuss muscular dystrophy Bethlehem myopathy Congential muscular dystrophy with rigid spine (CMDRS) Scapuloperoneal syndrome of Thomas
Bethlehem Myopathy
A. Genetics 1. AD 2. Chromosome 21q22: a. Decrease in beta laminin expression 3. Mutations in collagen type VI genes: a. Collage IV deficiency in the extracellular matrix B. Clinical Presentation: 1. Decreased fetal movements 2. Weakness or contractures during the first two years of life 3. Neonatal hypotonia; torticollis at birth (rare) 4. Contractures change during childhood 5. Pattern of muscle involvement: a. Pelvic weakness in early childhood b. Slow progression
A. Genetics: 1. Chromosome 1p 35–36; rigid spine (RSDMD) locus; sporadic cases are noted 2. Families with rigid spine and CMD that have been excluded from RSMDI have been identified 3. Merosin positive congenital muscular dystrophy (CMD) with rigid spine ARC B. Clinical presentation: 1. Majority of patients are male 2. Delay in reaching motor milestones; wobbly gait 3. Proximal muscle weakness noted by age 8 4. Weak sternocleidomastoid muscles 5. Non-painful progressive limitation of flexion of the neck and trunk 6. Progressive scoliosis 7. The neck is hyperextended, the trunk is tilted forward, flexion only occurs at the hips 8. Contractions of the elbows and knees 9. Decreased deep tendon reflexes 10. The heart may be involved: a. Complete heart block c. Cardiomyopathy b. Ventricular hypertrophy C. Laboratory evaluation: 1. CK is moderately elevated 2. EMG-myopathic 3. X-ray of the spine is normal D. Muscle biopsy: 1. Fiber size variation 2. Regeneration and degeneration 3. Increased endomysial and perimysial connective tissue (particularly axial muscle) 4. Type I fiber disproportion (not universal)
Scapuloperoneal Syndrome of Thomas
1. Clinical features a. Proximal muscle weakness of the upper limbs and distal muscles of the lower limbs b. Contractures of the elbows c. Pes cavus (as the disease progresses) d. Scoliosis and flexion contraction of the neck is rare e. Cardiomyopathy in adult life f. Color blindness
Chapter 1. Inherited Myopathies Autosomal Dominant Muscular Dystrophies
A. Myotonic Dystrophy Type I 1. Epidemiology: a. Incidence of 13/100,000 live births b. Prevalence 3–5/100,000 population B. Genetics: 1. CTG repeat in the gene in chromosome 19 2. Enlarged section of a CAMP-dependent kinase gene due to CTG repeats 3. CTG expansion interferes with a neighboring homeobox gene 4. Several genes may be rendered dysfunctional 5. Abnormal RNA produced has detrimental effect on RNA homeostasis 6. Anticipation is noted with age at onset from teens to old age: a. Normal 5–35 repeats b. Mild and late onset greater than 50 repeats c. Congenital severely involved patients have 1000– 2000 repeats 7. Severity worse with maternal inheritance a. Greater CTG length 8. Variable penetrance, anticipation and somatic gene variability: a. Mutation size varies over time in the same tissue of an individual b. Varies between tissues in a single individual at a single time c. Best correlation of repeat length: 1) Strength 3) Intelligence 2) Age at onset d. Variations in age of onset correlate with repeat length for short repeats only C. Clinical Presentation 1. General onset: a. Usually in early adult life; there is an infantile from b. Heterogeneity among family members is common c. Anticipation with succeeding generations 1) Maternal imprinting; greater increase in repeat length when disease is inherited from the mother
Muscle Weakness
1. Weakness of facial muscles and ptosis is often present prior to the diagnosis 2. Jaw muscle weakness and wasting is characteristic; temporalis and masseter weakness is associated with TMJ dysfunction 3. Sternocleidomastoid weakness and wasting is prominent; relatively well preserved posterior neck and shoulder girdle muscles (differential point from FSH dystrophy)
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4. Distal greater than proximal limb muscle weakness; dorsal and volar interossei, intrinsic foot muscle weakness; wrist extensors are prominently involved; quadriceps and proximal pelvic girdle strength allow patients to walk 5. Long finger flexors; weakness of mouth closure and lower facial musculature; differential involvement of lateral fingers (similar finger and forearm involvement to inclusion body myositis) 6. Rare muscle hypertrophy a. Similar to that noted with myotonia congenita Facial Dysmorphism
1. Long; “hatchet” like 2. Transverse smile 3. Slight backward head tilt (looking under ptotic lids) Muscle Pain
1. Deep ache; different from discomfort of myotonia but coexistent with it Myotonia
1. Primary symptom is “stiffness” of muscle 2. Aggravated by cold 3. Generalized myotonia is rare; often the hand and tongue are most easily noted. Generalized myotonia is common in myotonia congenita. 4. Grip myotonia is the predominant myotonic symptom 5. Percussion myotonia is easily induced in tongue, extensor forearm and thenar muscles 6. EMG: a. Electrical myotonia highly penetrant feature in adults b. Diffuse fibrillation potentials and occasional fasciculations may be seen during myotonic runs 7. Molecular basis for myotonia: a. Increased muscle fiber expression of a calcium activated potassium channel 1) Apamin receptor b. Possible alteration of chloride channel conductance Cardiac Disease
1. Often causes death 2. EKG abnormalities: a. First degree heart block is most common b. Atrial flutter c. His bundle recordings demonstrate conduction defects 1) Intraventricular d. Does not correlate with disease severity or repeat length 3. Hypotension 4. Sudden death 5. Anesthetics (quinidine, procainamide) may exacerbate conduction defects 6. Rare: congestive heart failure, mitral valve prolapse and cardiomyopathy 7. Rare posterior wall myocardial infarction
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SECTION XII. Muscle Disease
Respiratory Involvement
1. Diaphragm weakness a. Myotonia may be causative 2. Alveolar hypoventilation 3. Aspiration pneumonia and bronchitis 4. Post anesthetic respiratory failure Smooth Muscle Dysfunction
1. Swallowing disturbance with aspiration: a. Delayed relaxation of hyoid musculature b. Abnormal esophageal peristalsis 2. Colonic dysfunction: a. Abdominal pain b. Reduced colonic motility c. Dysfunction of internal and external anal sphincter d. Obstipation 3. Ureter a. Rare dilatation 4. Uterus a. Uncoordinated contractions during labor 5. Gallbladder a. Delayed emptying b. Increased incidence of gallstones 6. Eye a. Dysfunction of ciliary muscle which is responsible for low intraocular pressure Ocular Abnormalities
1. Posterior subcapsular cataracts (“stellate”) in almost all adult patients 2. Retinal degeneration: a. Peripheral pigmentary b. Macular involvement 3. Enophthalmos 4. Low intraocular pressure 5. Corneal lesions 6. Blepharitis 7. Ptosis 8. Slow saccades 9. Ophthalmoplegia is rare Central Nervous System
1. Proportion of patients with low IQ: a. 2/3 are normal b. Possible early memory deficit 2. Deficits on behavioral and psychometric testing 3. Hypersomnia: a. Some related to alveolar hypoventilation b. Centrally mediated hypoventilation 4. Imaging abnormalities a. CT: 1) Ventricular dilatation 2) Progressive atrophy b. MRI 1) T2 non-specific abnormalities
Endocrine System Dysfunction
1. Hyperinsulinism; flat glucose tolerance curve; rare to have overt diabetes 2. Testicular atrophy: a. Primary tubular degeneration b. Leydig cells are intact c. Oligospermia d. High LSH levels e. Low serum testosterone 3. Women: a. High rate of fetal loss b. Severe complications of pregnancy 4. Pituitary a. Increased FSH levels b. Slightly increased LH levels c. Increased luteinizing hormone releasing response 5. Hypothyroidism (rare) 6. Hyperresponsiveness to exogenous growth hormone (rare) 7. Pituitary adenoma (rare) 8. Abnormal adrenocortical function 9. Some indications of abnormal parathyroid function
Miscellaneous Abnormalities
1. Hair a. Early male frontal balding 2. Calcified epitheliomata and pilomatrixomata 3. Hypogammaglobulinemia a. Lower levels of IgG and IgM 4. Liver involvement a. Increased serum transaminase b. γ -glutamyltransferase elevation in some patients 5. Putative relationship with neoplasia
Myotonic Dystrophy Type 2 and Proximal Myotonic Myopathy
A. General features: 1. 10 cm region on chromosome 3q (MD2) a. CCTG finger 9 gene b. Toxic RNA repeat expansions 2. Gene for proximal myotonic myopathy (PROMM) also maps to DM2 locus 3. DM2 locus a. Disease linked to this locus 4. PROMM a. Multisystemic myotonic disorder that is not due to DM1 locus and have not been mapped to DM2 locus B. Clinical features: 1. DM2 has muscle pain similar to DM1 2. Muscle weakness: a. Less severe than DM1 patients
Chapter 1. Inherited Myopathies
b. Neck flexors, long finger flexors, hip girdle musculature; lower extremity proximal weakness c. DM2 same facial weakness as DM1 3. Electrical and clinical myotonia: a. Less severe myotonia than DM1 b. Same pattern of myotonia in muscle as DM1 c. Occasional brief high-frequency 250–300 Hz discharges in DM2 (possibly specific to PROMM and DM2) 4. Eye findings: a. Ptosis b. Cataracts 5. Cardiac: a. Conduction defects and fatal arrhythmias 1) Atrioventricular defects less common than in DM1 b. Rare cardiomyopathy and congestive heart failure 6. Endocrine: a. Hyperinsulinemia, hyperglycemia, flat glucose tolerance curve, insulin insensitivity 1) Rare frank diabetes b. Hypothyroidism (rare) c. Testicular failure 7. Central nervous system: a. DM2 with mental retardation b. MRI and PET abnormalities have been reported in some PROMM families
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2. Bulbar involvement with consequent feeding and respiratory difficulty 3. No clinical or electrical myotonia 4. Severe facial diplegia (85% of patients) 5. “Tented” upper lip 6. Skeletal abnormalities: a. Talipes b. Congenital hip dislocation C. Clinical progression: 1. Delayed muscle tone a. Children can walk 2. Mental retardation 3. Myotonia develops 4. Distal weakness D. Laboratory evaluation: 1. CPK is mild to moderately elevated 2. EMG: a. Spontaneous trains of motor unit firing that vary in amplitude and frequency (myotonic discharges) E. Muscle biopsy: 1. Variation of fiber size 2. Internal nuclei 3. Type I fiber atrophy 4. Sarcoplasmic masses 5. Ring fibers (ringbinden) 6. Fibrosis 7. Prominent fiber splitting
Miscellaneous System Dysfunction Differential Diagnosis of Myotonic Dystrophy
1. DM1 has frontal balding 2. Hypogammaglobulinemia a. Decreased IgG and IgM 3. Liver dysfunction possible in DM2
1. Myotonia congenita 3. Schwartz–Jampel syndrome 2. Paramyotonia 4. Drug induced myotonia
Fascioscapulohumeral Muscular Dystrophy Muscle Biopsy Evaluation of DM1 and DM2
1. 2. 3. 4. 5. 6. 7.
Atrophic and hypertrophic fibers Scattered severely atrophic fibers Nuclear bags Scattered necrotic fibers Split and ring fibers (ringbinden) Eosinophilic cytoplasmic inclusions in DM1 Type 1 fiber predominance in DM1 and DM2
Congenital Myotonia
A. General features: 1. Mother the most often affected parent 2. Poor fetal movements; hypohydremias B. Clinical features: 1. Hypotonia at birth
A. General characteristics: 1. Third most common dystrophy a. MD > DMD > FSHD b. Prevalence of 1/20,000 population c. Incidence .4–5/1000 population B. Genetics: 1. Gene on chromosome 4q 35: a. Deletion of variable size in a 3.3-kilobase repetitive element D4Z4 repeats b. D4Z4 repeat alter chromosomal structure: 1) Influences the expression of more centromerically located genes a) Position effect variegation c. Size of the deletion determines disease severity d. Possible deleterious gain of function from mutations within D4Z4 C. Clinical features:
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SECTION XII. Muscle Disease
1. Age at onset (7–27 years of age; infantile from has been noted rarely) a. Perhaps 30% of patients may be asymptomatic 2. Facial muscle weakness occurs first: a. Orbicularis oculi c. Orbicularis oris b. Zygomaticus 3. Facial involvement may be asymmetrical 4. Ocular, masseters, temporalis, pharyngeal muscles are spared 5. Patients may sleep with their eyes slightly open 6. Early in the course patients cannot whistle or drink from a straw 7. Descending sequence of muscle involvement 8. Initial weakness of the scapular muscles and shoulder fixators: a. Latissimus dorsi b. Lower fibers of the trapezius c. Rhomboids d. Serratus anterior D. This pattern of weakness causes the clavicle to assume a more horizontal location and to angle downward: 1. Winging of the scapula with abduction 2. Sternocostal head of the pectoralis muscle is weak and atrophic which causes an upward slope of the axillary fold; flattening of the anterior chest wall; pectus excavatum in severely affected patients 3. First, 25 degrees of arm abduction is affected by the supraspinatus muscle; 25 degrees to the horizontal is accomplished by the deltoid; over the head position of the arm requires scapular rotation and fixation to the chest wall which fails in FSHD. 4. Coincident with shoulder girdle weakness: a. Significant weakness of the anterior tibialis > peronei muscles b. Foot drop is often noted c. Posterior leg muscles are spared d. Proximal hip girdle muscle may be significantly involved early in some patients e. Differential involvement of lower abdominal musculature that produces a positive Beevor’s sign; exaggerated lordosis f. Relative sparing of neck flexors 5. Progression of weakness: Facial musculature > shoulder girdle > biceps and triceps > ankle dorsiflexors > pelvic girdle 6. Slow progression is the rule: periods of accelerated weakness occur 7. Wheelchair confinement is rare: life expectancy is normal. Mean age at death for males is 64 years of age and for females 70 years of age. 8. Associated clinical features: a. Ptosis b. Sensorineural hearing loss: (1) Largely asymptomatic; may be severe in the infantile presentations
(2) High frequency hearing loss c. Retinal telangiectasis: (1) Usually is asymptomatic (2) Rarely cause an exudative retinal detachment d. Lordosis and kyphosis e. Depressed deep tendon reflexes f. Cardiac involvement: (1) 60% of patients demonstrate EKG abnormalities involving: (a) Atrial (b) Atrioventricular-node (c) Infranodal arrhythmias (d) Inducible atrial flutter or fibrillation (2) Approximately 5% of patients have significant cardiac abnormalities E. Laboratory Evaluation: 1. Molecular diagnosis: a. Highly specific and sensitive b. Performed on DNA of leukocytes 2. CK is elevated (70 years) 6. AR: double GCG polymorphism B. Clinical Features: 1. Geographic areas of occurrence a. Quebec, Southern California, Northern New Mexico and Arizona 2. Manifests in general 5th to 6th decade a. Dominant GCG, allele: 1) 21% ( liquids early b. Impaired gag reflex; decreased palatal mobility c. Palatal and laryngeal weakness with dysphonia d. Weakness and atrophy of the tongue (primarily Hispanic-Americans) 7. Weakness of facial, temporal and masseter muscles 8. Proximal leg weakness 9. Decreased upgaze 61% 10. Decreased deep tendon reflexes in some patients 11. Weakness and atrophy of the neck, shoulders, hip and arms occur in the late stage of disease 12. Muscle cramps in some patients 13. Early onset dominant OPMD is severe (5–10% of patients): a. Ptosis/dysphagia < 45 years of age b. Leg weakness < 60 years of age c. Allele GCG d. Severe case cluster in families C. Laboratory Evaluation: 1. DNA testing (99% specificity and sensitivity) 2. EMG: a. Facial, limbs and pharyngeal muscles are myopathic b. May have abnormalities in the extremities c. Sensory and motor conduction velocities are normal or occasionally slightly decreased 3. Serum CK and aldolase are often normal; CK may be 2–3 x normal in some patients 4. Manometric and video fluoroscopy studies: a. Weak prolonged and repetitive pharyngeal contractions b. Normal upper esophageal sphincter c. Sphincter relaxation is late and incomplete 5. A few patients demonstrate bundle branch block on EKG 6. Muscle biopsy: a. intra nuclear filamentous inclusions (INIs) b. Rimmed vacuoles D. Differential Diagnosis: 1. Myotonic muscular dystrophy: a. Predominant systemic manifestations b. Cardiac involvement c. Myotonia 2. AD distal myopathy: a. Welander b. Marksberry/Gregg’s/Udd c. Noneka d. Specific distal leg compartment atrophy e. Less swallowing abnormality f. No ophthalmoplegia 3. MG: a. Fluctuating symptoms b. Pattern of weakness c. Severe ocular involvement that fluctuates
4. Mitochondrial myopathy with or without external ophthalmoplegia: a. Severe cardiac involvement b. Fatigue with exercise c. VIIIth nerve deficits d. Kearns–Sayre syndrome: 1) Dysphagia 2) Cardiac involvement (heart block) 3) Ptosis and ophthalmoplegia predominant e. Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): 1) Pseudo gastrointestinal obstruction 2) Pes cavus 5. Polymyositis and progressive bulbar palsy a. No ptosis 6. Late onset familial ptosis: a. onset in the sixties b. No dysphagia 7. Recessive OPMD: a. Late onset ptosis and dysphagia 1) Requires DNA testing
Distal Myopathies
A. General Features: 1. Exclusive or predominant involvement of distal muscles 2. Primarily inherited muscular dystrophies a. Some inflammatory and metabolic myopathies have a distal phenotype 3. Compatible with normal life span and function
Hereditary Distal Myopathies
A. Late Adult Onset Type I: Welander Distal Myopathy a. Large Kindred from Southern Sweden b. Genetics: 1) AD; chromosome 2p13 a) 80% penetrance in males and 70% in females b) Same locus for Miyoshi distal myopathy and LGMD Type 2B c) Putative dysferlin gene B. Clinical Features: 1. Age at onset is greater than 40 years; mean is 47 years, a few patients have presented greater than 70 years of age; recorded in patients less than 30 years of age 2. Site of onset: a. Finger and wrist extensors b. Later evolution to toe and ankle dorsiflexors 3. Proximal involvement has been noted in some families 4. No neck weakness 5. Slow progression; compatible with a normal active life C. Laboratory Evaluation:
Chapter 1. Inherited Myopathies
1. CK: normal or mildly increased 2. EMG: a. Myopathic pattern b. Rare neuropathic features c. Some spontaneous activity and fibrillation potentials may be noted 3. Muscle biopsy: a. Ringed vacuoles b. Tubulo filamentous inclusions: 1) 15–18 mm cytoplasmic and nuclear filaments c. Split fibers Unusual Features
1. Loss of reflexes (primarily ankle jerks) late in the course of the disease 2. Autonomic dysregulation with cold hands and feet in 90% of patients 3. Weakness of toe and finger flexors early in the illness 4. Some progress subacutely rather than the usual insidious pattern
Type 2: Late Adult Onset (Marksberry/Gregg’s/Udd)
A. Genetics: 1. English, French; Finnish patients 2. AD; 2q 31 B. Clinical features: 1. Age at onset is greater than 40 years 2. Site of onset: a. Anterior leg important; ankle and toe dorsiflexors 3. Proximal weakness: a. Limb girdle pattern in some families b. Occurs late in the course of the illness c. Weakness is usually confined to the legs 4. No neck weakness 5. Late distal finger and wrist extensor weakness C. Laboratory Evaluation: 1. Serum Creatine Kinase: is normal or mildly increased (2–5x normal) 2. EMG: a. Myopathic pattern b. Spontaneous activity: fibrillations and positive sharp waves 3. Muscle biopsy: a. Rimmed vacuoles (more prominent than Welander’s) b. Tubule-filamentous inclusions 4. Infantile from (AD; foot drop; no progression after childhood) 5. Juvenile onset (AD: Biemond variant; onset at 5–15 years of age)
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Early Adult Onset (Type I) Nonaka
A. Genetics: 1. Patients reported from Japan, Italy; North and South America 2. Chromosome 9p1-q1 (also sharing this locus is: familial inclusion body myopathy, quadriceps sparing myopathy) B. Clinical features: 1. Site of involvement: a. Ankle, dorsiflexors and toe extensors 2. Foot drop and steppage gait 3. Mild distal upper extremity involvement 4. Late onset proximal weakness in some patients 5. Quadriceps is strong in the face of proximal weakness 6. Neck flexor weakness C. Laboratory Evaluation: 1. Muscle Enzymes: a. Serum CK elevated (less than 5 times normal) 2. EMG: a. Myopathic; some fibrillation potentials 3. Muscle biopsy: a. Prominent rimmed vacuoles b. Dystrophic features c. Nuclear or cytoplasmic 15–18 mm filaments associated with the vacuoles
Type 2: Miyoshi Distal Myopathy
A. Genetics: 1. AR or sporadic; families linked to chromosome 10 2. Chromosome 2p18; LGMD-2B (same locus) 3. Dysferlin is the gene product 4. Japanese, Dutch, Hispanic and other ethnic groups 5. Dysferlin: a. Muscle membrane bound protein B. Clinical features: 1. Presents between 15–30 years of age 2. Initial site of weakness is posterior leg compartment: a. Gastrocnemius atrophy b. Difficulty standing on their toes c. Pain in the calves d. Loss of ankle jerks e. Later progression of weakness to the anterior leg compartment f. Leg involvement may be unilateral g. Late stages of the diseases: 1) May have proximal weakness h. Weakness is related to duration of illness C. Laboratory Involvement: 1. CK markedly elevated (20 to 150x, normal) 2. EMG: a. Myopathic features in partially affected muscle b. Weak and atrophic muscles:
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SECTION XII. Muscle Disease
1) Long duration poly phasic motor unit potentials 3. Muscle biopsy: a. Myopathic features: 1) Rare rimmed vacuoles 2) Two patients demonstrated inflammatory features
Type B: Laing Distal Myopathy
A. Genetics: 1. Chromosome 14q 11; AD 2. Sites of involvement: a. Patients between 4–25 years of age b. Weakness of the anterior compartment and neck flexors > finger extensors > shoulder girdle B. Laboratory evaluation: 1. Slight increase of CK C. Muscle biopsy: 1. Myopathic changes 2. No vacuoles
Distal Myopathy with Vocal Cord and Pharyngeal Weakness
A. Genetics: 1. Autosomal dominant; 5q31 B. Clinical features: 1. Onset 4th to 6th decades 2. Site of involvement: a. Anterior leg compartment is usually first; finger extensor weakness may be initial site; may be asymmetric initially 3. Vocal cord and pharyngeal involvement occurs after extremity weakness C. Laboratory evaluation: 1. CK is normal or moderately elevated 2. EMG: a. Myopathic in vocal cord and pharyngeal muscles b. Extremity muscles may have neuropathic features 3. Muscle biopsy: a. Myopathic c. No neurofilaments b. Rimmed vacuoles
Myofibrillar Myopathy with Desmin
A. Genetics: 1. AD primarily; desmin gene 2. X-linked and sporadic cases noted 3. Chromosome 2q 35 4. Gene mutation on 11q 21–23; primary family with scapuloperoneal phenotype noted with mutation on chromosome 12 B. Clinical features:
1. Onset 25–45 years of age; cases occurring in infancy and late life have been reported 2. Site of involvement varies in different pedigrees: a. Hands b. Distal lower extremities 1) Anterior compartment of the leg c. Scapuloperoneal distribution 3. Cardiomyopathy: a. Arrhythmia b. Congestive heart failure c. Heart block d. May precede muscle weakness 4. Proximal muscle involvement occurs in later stages 5. Rare respiratory insufficiency C. Laboratory evaluation: 1. Elevated CK ( distal weakness c. Slowly progressive d. Thin muscles by adolescence e. Facial muscle involvement Central core: a. Kyphoscoliosis, short stature, contractures of fingers b. Cardiomyopathy occurs c. Proximal weakness; legs > arms Centronuclear (AD variant): a. Limb girdle weakness b. Distal muscles may be affected c. May have facial and neck flexor weakness Childhood onset distal myopathy a. Infantile onset (less than two years) b. Juvenile onset
Neurogenic Causes of Distal Muscular Atrophy
1. Hereditary sensory motor neuropathy Type II (axonal form) 2. Distal spinal muscular atrophy 3. Scapuloperoneal syndromes (neurogenic variants) 4. Acute intermitted porphyria 5. Multifocal motor neuropathy with conduction block
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Chapter 2 Congenital Myopathies A. General Features: 1. Genetic defects 2. Often specific muscle histopathology 3. Specific patterns of involvement and dysmorphisms 4. Starts in early childhood; slowly progressive 5. Compatible with a normal life in many instances: a. Rarely display an aggressive course b. Some demonstrate mild improvement over time c. May only become symptomatic in adolescence or adulthood 6. Congenital muscular dystrophies: a. Divided into those with and without brain involvement b. Merosin: positive or negative 7. Usually have proximal muscle weakness and decreased deep tendon reflexes: a. Many were floppy infants b. Adolescents have difficulty in gym B. EMG: 1. Myopathic 2. CK (mildly elevated)
Central Core Disease (Shy-Magee Disease)
A. Genetics: 1. AD; gene located 19q 13.1: a. Gene codes: ryanodine receptor of the calcium release channel of skeletal muscle sarcoplasmic reticulum; allelic with malignant hyperthermic locus 2. Gene coding for beta-myosin heavy chain (MYH7); patients demonstrate: 1) Hypertrophic cardiomyopathy 2) Central core changes in skeletal muscle B. Clinical features: 1. Dysmorphisms: a. Kyphoscoliosis b. Pes cavus c. Dislocated hips d. Short stature e. Contractures (flexion deformities of the fingers) 2. Delayed acquisition of milestones; hypotonic only in infancy or childhood 3. Cardiac abnormalities: a. Cardiomyopathy c. Mitral valve prolapse b. Arrhythmia 4. Proximal symmetrical motor weakness; legs > arms; rare facial and sternocleidomastoid weakness 5. High risk for malignant hyperthermia a. RYRI receptor involved in calcium release from endoplasmic reticulum
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SECTION XII. Muscle Disease
6. Muscle cramps and myalgias occur in adults; stiffness after exercise C. Muscle biopsy: 1. Cores occur in the center of Type I fibers: a. Demonstrated with NADH-TR (nicotinamide adenine dinucleotide-tetrazolium reductase histochemical stain) b. Type I fiber predominance c. May have associated nemaline rods D. Laboratory: 1. EMG: a. Myopathic, no fasciculations b. Some polyphasic potentials of long duration 2. Muscle biopsy: a. Round or oval cores that lack oxidative enzyme activity b. Absent mitochondria (in the cores) c. Type I fiber predominance 3. CK, minimally elevated
Nemaline Myopathy
A. Genetics: 1. AD from; NEMI; chromosome 1q 22–q23 a. TMP3 gene (tropomyosin–3) 2. AR; NEM2; chromosome 1q421.1 (α-actin gene) 3. NEM2 also caused by: a. Mutation in gene coding for nebulin; 2q22 B. Clinical features: 1. Congential form causes a rapidly fatal myopathy 2. Congenital progressive or slowly progressive form: a. Non-progressive or exacerbation at adolescence; mild myopathy b. Progression may only be apparent in middle or late life c. Weakness and flaccidity in infancy; proximal > distal muscles d. Facial and muscles of mastication may be involved e. Slender muscle; decreased or absent deep tendon reflexes f. Dysmorphic features: 1) Elongated face 2) High arched narrow palate 3) Kyphosis, lordosis, pes cavus, talipes equinovarus D. Asymptomatic variant: 1. Asymptomatic relatives 2. Muscle biopsy: rod bodies or Type I fiber predominance E. Adult-onset variant: 1. Lacks dysmorphic features 2. Sporadic inheritance 3. Usually proximal weakness in adult life a few patients have distal weakness at onset (usually leg muscles)
4. Bulbar musculature is not involved 5. Cardiomyopathy has been described; rod bodies in the contractile and conducting system of the heart F. Laboratory features: 1. EMG: myopathic 2. CK: rarely elevated 3. Muscle biopsy (adult from): a. Rod bodies seen in atrophic fibers b. Predominance of Type I and 2C fibers in the congenital forms c. Rod bodies emanate from the z discs within the cytoplasm; reddish purple granules on Gomori trichrome stain; 27 μm in length that are subsarcolemmal membrane in Type I muscle fibers; rod bodies are composed of d-actinin. 4. Several late onset forms have had an elevated sed rate; some with associated monoclonal gammopathy 5. Rod bodies may be seen in: a. Chloroquine myopathy (treatment of SLE) b. Schizophrenia c. Polymyositis d. Hypothyroidism e. Asymptomatic relatives of nemaline patients
HIV Associated Adult Onset Nemaline Myopathy (HAONM)
1. Clinical features: a. Neck, face and respiratory muscle may be involved b. Similar skeletal abnormalities to central core disease 2. Pathology a. Rods noted in myofibrils
Centronuclear Myopathy
A. Genetics: 1. Congenital sex-linked recessive form: a. Xq28; mutation in the myotubular gene (MTMI); product is a tyrosine phosphatase 2. Congenital AR a. Late infancy and childhood presentations 3. AD variant: a. In one family the gene maps to 11q22 b. Adult variants 4. Non-hereditary late onset variant B. Clinical features: 1. General characteristics: a. Early childhood onset b. Weakness of extraocular, facial, neck and limb musculature c. Slowly progressive
Chapter 2. Congenital Myopathies Congenital AR Variant
A. Clinical Features: 1. Respiratory weakness at birth 2. High arched palate; elongated face 3. Ptosis, strabismus, facial weakness, sternocleidomastoid weakness 4. Delayed motor milestones 5. Muscle weakness; proximal > distal 6. Talipes equinovarus 7. Depressed or absent deep tendon reflexes 8. Adolescence or early adult life: patients are unable to walk 9. At approximately age 12, patients develop scoliosis, accentuated lordosis, scapular winging
Congenital Sex-Linked Recessive Variant (Myotubular Myopathy)
Clinical features
1. Respiratory distress at birth; death 2. Weak suck, cry, cough; weak swallowing and neck muscles at birth 3. Bilateral ptosis, facial diplegia, poor extraocular movements 4. Depressed or absent deep tendon reflexes 5. Cardiomyopathy: a. Extensive fibrosis b. Right ventricular hypertrophy secondary to chronic pulmonary hypertension due to weak respiratory muscles c. Autosomal dominant variant: 1) Limb girdle weakness; distal muscles may be affected; may have onset in oculo- cranial musculature 2) Some patients: facial and neck flexor weakness 3) Weakness is evident by the third decade; slowly progressive; some patients become wheelchair bound
Sporadic Adult Onset Variant
1. Onset in adulthood 2. Slowly progressive weakness of both proximal and distal musculature 3. Facial and bulbar musculature are spared 4. One patient described with pseudohypertrophy; one patient with extraocular muscle involvement Laboratory evaluation
1. EMG: myopathic; may have fibrillations and myotonic discharges
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2. CK and aldolase are usually normal: occasionally they are slightly elevated 3. Muscle biopsy: a. Central position of muscle nuclei (surrounded by vacuoles containing glycogen granules) b. Increase of perimysial connective tissue c. Small Type I fibers; normal Type II fibers d. Type I fiber predominance; central nuclei may be restricted to Type I fibers or may be seen in both Type I and Type II fibers
Congenital Fiber Type Disproportion
A. Genetics: 1. Most patients are sporadic 2. AD; possible location on chromosome 10 or 17 B. Clinical features: 1. Infants are hypotonic and weak 2. Dysmorphisms: a. Kyphoscoliosis b. High arched palate c. Dislocated hips d. Pes cavus e. Contractures of elbows and knees 3. Mental retardation (some patients) 4. Hyperinsulinemia; peripheral insulin resistance 5. Relation to rigid spine syndrome 6. Non-progressive; some patients have improved 7. Respiratory muscle weakness C. Laboratory evaluation: 1. EMG: normal or myopathic 2. CK: mildly elevated 3. Muscle biopsy: a. Type I fiber predominance; small size (12–15% smaller than Type II fibers)
Reducing Body Myopathy
A. Genetics: 1. AR (putatively related to LGMD) 2. Not established for most patients B. Clinical features: 1. Weak hypotonic infants 2. Proximal > distal weakness 3. Respiratory weakness 4. Hyporeflexia 5. Occasional facial weakness and ptosis C. Laboratory Evaluation: 1. CK: usually normal 2. EMG: myopathic 3. Muscle biopsy: a. Reducing bodies stain for glycogen, RNA and sulfhydryl groups
SECTION XII. Muscle Disease
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1) Round to ovoid masses (10–70 um) 2) EM composed of osmophilic granular and fibrillar material b. Variation of fiber size, Type I fiber predominance, some degeneration c. Strong staining with α-glycerophosphate dehydrogenase (enendione linked); autophagic vacuoles filled with filamentous material
Multicore Myopathy (minicore disease)
A. Genetics: 1. Most patients are sporadic or AR 2. AD from: mutation at 12q a. Codes for acyl-CoA dehydrogenase B. Clinical features: 1. Onset in infancy 2. Hypotonia, slow to pass motor milestones; slowly progressive 3. Proximal > distal weakness; rarely upper extremities weaker than lower; ptosis and weakness of extraocular muscles (rare) 4. Dysmorphisms: a. Scoliosis b. Multiple joint contractures c. Dolichocephaly d. High arched palate e. Club foot 5. Cardiac involvement: a. Atrial and ventricular septal defects b. Cardiomyopathy c. Heart attack 6. Respiratory involvement 7. Associated with malignant hyperthermia 8. Patients with microcephaly and mental retardation a. Adult onset variety has slowly progressive weakness C. Laboratory evaluation: 1. CK: usually normal 2. EMG: myopathic 3. Muscle biopsy: a. Multiple fusiform areas of Z-disk streaming (minicores) 1) Small Type I myofibers b. Presence or absence of Type I fiber hypotrophy c. Variations of muscle fiber size d. Fiber splitting e. Multicores found in both Type I and II fibers 1) Absent mitochondrial enzyme activity in the cores
Finger Print Body Myopathy
A. Genetics:
1. Sporadic: AD; and X-linked; inheritance pattern has not been definitively identified B. Clinical features: 1. Weakness and hypotonia of the arms and legs 2. Slowly progressive or at times non-progressive muscle weakness 3. Proximal weakness atrophy and hypotonia since infancy 4. Cranial musculature spared 5. Kyphoscoliosis in some patient 6. Depressed or absent deep tendon reflexes 7. Mental retardation and febrile seizures have been noted C. Laboratory evaluation: 1. CK: normal 2. EMG: a. Myopathic b. Normal nerve conduction velocities 3. Muscle biopsy: a. Ill defined ovoid inclusions: 1) Beneath the sarcoplasmic membrane 2) Predominantly in Type I fibers 3) 1–10 μm in diameter b. EM of fingerprint bodies: 1) Parallel osmophilic lamellae that resembles fingerprints; each lamellae has a serrated margin c. Similar inclusions noted in: 1) Oculopharyngeal muscular dystrophy 2) Myotonic dystrophy (rare) 3) Inflammatory myopathies (rare)
Cytoplasmic Body Myopathy (Myofibrillar or Desmin Myopathy)
A. Genetics: 1. AD; some families are AR or sex linked 2. AD patients: a. Mutations in the desmin gene; 2q 35 B. Clinical features: 1. Congential onset 2. Adult onset 3. Weakness may be noted in second decade or later 4. Severe from of the disease: a. Axial and intercostal weakness b. Death from respiratory insufficiency and right heart failure c. Cardiomyopathy may present as an isolated form of the disease 5. Feeding and bulbar dysfunction during infancy presentation 6. Delayed motor milestones C. Adult presentation: 1. Facial weakness 2. Nasal speech 3. Dysphagia
Chapter 2. Congenital Myopathies
4. Tongue weakness 5. Proximal > distal weakness 6. Rare pseudohypertrophic calves 7. Neck flexor weakness 8. Occasional joint contractures 9. Chest muscle weakness and scoliosis 10. Cramps or pain after exercise (rare) 11. One family: thenar and flexor hand muscle weakness D. Laboratory evaluation: 1. CK: slight to moderate elevation 2. EMG: myopathic primarily; myotonic pattern and denervation in some patients 3. EKG changes: a. Bundle branch block b. Depressed ST segments 4. Muscle biopsy: a. 25% of muscle fibers contain cytoplasmic bodies b. May be seen in Type I or II fibers c. Core of cytoplasmic body: filaments intermixed with dense amorphous material d. EM of dense core: 1) Cytoplasmic bodies may arise from the Z disk: a) Desmin and myofibrillar protein have been demonstrated b) Desmin is a motor intermediate protein of skeletal and cardiac muscle (1) Links Z band with the sarcolemma and the myonuclei e. Non-specific cytoplasmic bodies found in Type II fibers f. Differential Diagnosis of cytoplasmic bodies: 1) Denervation atrophy 2) Inflammatory myopathy 3) Myotonic dystrophy 4) Periodic paralysis 5) Acropathic psoriasis 6) Menkes Kinky Hair Disease 7) Mitochondrial myopathy
Myopathy with Tubular Aggregates
A. Genetics: 1. AD; AR forms 2. Familial variants B. Clinical features: Four clinical variants: 1. Myopathy with myasthenic features 2. Myopathy with pain and stiffening after exercise; or cramps 3. AD slowly progressive myopathy 4. AR limb girdle pattern
Myopathy with Myasthenic Features
1. Slowly progressive myopathy since infancy
2. 3. 4. 5. 6.
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Cardiomyopathy EMG response similar as to that seen with MG Response to acetylcholinesterase Hypoplasia of Type I fibers; tubular aggregates Relationship to congenital prolonged open channel MG not established
Myopathy with Exercise Induced Cramps, Pain and Stiffness
1. Adult onset 2. Pain and stiffness of lower extremities; with time it spreads to the upper extremities 3. Weakness is minimal; no atrophy or fasciculations 4. CK: normal or mildly increased 5. EMG: normal 6. Tubular aggregates: Type II fibers only
Autosomal Dominant Myopathy with Tubular Aggregates
A. Genetics: AD B. Clinical features: 1. Insidious onset of a very slowly progressive myopathy 2. Pectoral and pelvic girdle involvement initially 3. CK: a. Normal 4. EMG: a. Myopathic 5. Muscle biopsy: a. Tubular aggregates in 50% of muscle fibers
Autosomal Recessive Myopathy with Tubular Aggregates
A. Genetics: AR B. Clinical features: 1. Onset in childhood and adolescence 2. Slowly progressive weakness of proximal limb muscles C. Laboratory evaluation: 1. CK: slightly elevated 2. EMG: myopathic 3. Tubular aggregates in both Type I and II fibers D. Pathology: 1. Tubular aggregates: a. Double walled parallel tubules b. 60–80 mm in diameter c. Arranged in hexagonal arrays d. Continuity of the sarcoplasmic reticulum with the tubular aggregates
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SECTION XII. Muscle Disease
Differential Diagnosis of Disease in Which Tubular Aggregates are Noted: a. Hypokalemic, normokalemic and hyperkalemic periodic paralysis b. Myotonia congenita c. Paramyotonia d. Congential myasthenic syndromes e. Acromegaly f. Hyperaldosteronism g. Myotonic dystrophy h. Hyperornithemia i. Denervation atrophy of muscle In general: 1. Patients with periodic paralysis and myalgic syndromes, the tubular aggregates are in Type II fibers. 2. Genetic myopathies: Tubular aggregates are found in both Type I and II fibers
Sarcotubular Myopathy
A. Genetics: possibly X-linked recessive B. Clinical features: 1. Decreased intrauterine movements 2. Mild proximal weakness of both upper and lower extremities 3. Weakness of neck flexors, facial and intercostal muscles C. Laboratory evaluation: 1. CK: slightly elevated 2. EMG: myopathic 3. Muscle biopsy: a. Vacuolar myopathy of Type II fibers; vacuole origin may be membranes of the sarcoplasmic reticulum
Trilaminar Myopathy
A. Genetics: not determined B. Clinical features: 1. Rigidity to passive movement at birth 2. High pitched weak cry 3. Decreased bulbar function 4. Decreased range of motion of the neck, shoulders and hips C. Laboratory evaluation: 1. CK: elevated 2. EMG: normal 3. Muscle biopsy: a. Trilaminar bodies b. Prominent filaments, mitochondria, vesicles, triads and glycogen particles
Familial Myopathy with Lysis of Myofibrils in Type I Fibers
A. Genetics: not determined B. Clinical features: 1. Inactive, weakness and hypotonic at birth 2. Delayed motor milestones 3. Increased lumbar lordosis 4. Symmetric proximal myopathy 5. An adult documented with scapuloperoneal weakness C. Muscle biopsy: 1. Absence of myofibrils in the periphery of Type I fibers 2. Normal Type II fibers
Type I: Myofiber Predominance
A. Genetics: 1. Possibly autosomal recessive B. Clinical features: 1. Non-progressive weakness and hypotonia C. Laboratory evaluation: 1. Muscle biopsy: a. Type I fiber predominance b. Weakness in many congenital myopathies may be correlated with the degree of Type I fiber predominance
Spheroid Body Myopathy
A. Genetics: Autosomal dominant B. Clinical features: 1. Onset is adolescence; some late onset patients > 40 years of age 2. Slowly progressive proximal myopathy 3. Respiratory insufficiency in adult life C. Laboratory evaluation: 1. CK; normal 2. Muscle biopsy: a. Spheroid bodies within Type I muscle fibers b. Spheroid bodies contain: 1) Alpha-B-crystallin 2) Ubiquitin 3) Desmin 4) Compacted and degraded myofibrillar elements
Differential Diagnosis of Myopathy with Abnormal Foci of Desmin Positivity
1. 2. 3. 4.
Mallory body myopathy Myopathy with granular filamentous inclusions Desmin storage myopathy Intermediate filament myopathy
Chapter 2. Congenital Myopathies The Congenital Muscular Dystrophies
A. General features: 1. Most are AR 2. Hypotonia and weakness are noted in the first year of life 3. All have muscle weakness and deformities from intrauterine decreased movements: a. Arthrogryposis b. Pes cavus 4. Lamina in chain is: a. Extracellular protein b. Connects the extracellular matrix and the dystrophinassociated glycoprotein complex of the muscle cytoskeleton B. Genetics: 1. Merosin deficient CMD a. Deletion or mutation of the laminin 2 gene (LAMA2): chromosome 6q22-q23 C. Clinical features of Merosin-negative CMD: 1. Hypotonia at birth 2. Some patients have multiple joint contractions 3. Generalized muscle weakness 4. Proximal weakness > distal 5. Face, neck, intercostals muscle involvement 6. Extraocular muscles are spared 7. Deep tendon reflexes depressed or absent 8. Mental development is often normal 9. Usually a delay in passing motor milestones 10. Some patients with respiratory deficits 11. Intra family muscle weakness similar between family members 12. May be rapidly progressive D. Laboratory evaluation: 1. CK and aldolase are normal or mildly increased; tend to return to normal with age 2. EMG: myopathic; rare fibrillation potentials 3. Muscle biopsy: variation of fiber size, rounded rather than polygonal; increase of endomysial and perimysial connective tissue 4. MRI evaluation: a. Leukoencephalopathy is generalized
Clinical Features of Merosin-Positive CMD
1. Non-progressive or slowly progressive proximal > distal weakness 2. Usually no cognitive impairment 3. 90% of patients can walk by four years of age
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1. Chromosome 9q31: a. 461 amino acid protein is deficient b. 87% founder effect; ancient retrotransposal integration of a 3Kb in the non-coding region of the Fuji gene c. probably allelic to Walker–Warburg Muscular Dystrophy d. Missense and nonsense mutations B. Clinical features: 1. 30% of mothers of patients with FCMD have had spontaneous abortions 2. Infants have poor fetal movements; at birth weak suck and cry 3. Pectus excavatum in 30% of infants 4. Hypotonic generalized muscle weakness; proximal greater than distal 5. Mild contractures of knees and elbows are present at birth or develop 6. Deep tendon reflexes are decreased or absent 7. Convulsions (major motor) in 5i0% of patients; occasional status epilepticus 8. Severely retarded motor and intellectual development 9. Contractures of knees, elbows and hips develop 10. Death usually by age ten C. Laboratory evaluation: 1. CK: 10–15 times normal (after age six, enzymes decline) myoglobin is in the urine during the period of extremely high CK. LDH, SGOT, Aldolase are elevated. 2. EMG: myopathic 3. Serum cholesterol is elevated in approximately 50% of patients 4. Muscle biopsy: a. Focal fibrosis in cardiac muscle b. Variation of fiber size central nuclei; rounded fibers c. Massive endomysial and perimysial fibrosis 5. EEG: a. Diffuse and marked decrease in frequency, bihemispheric sharp waves b. 50–75% of patients have focal paroxysmal discharge with spikes in the frontoparietal cortex 6. MRI evaluation: a. Poor cortical gyral development particularly in the temporal and occipital lobes b. Prominent sylvian fissures: dilated lateral ventricle (aqueductal stenosis in some); T2 abnormalities of periventricular white matter; polymicrogyria of the cerebellum c. Pachygria and polymicrogyria; lissencephaly in some patients
Congenital Muscular Dystrophy with Clinical Cerebral Involvement Fukuyama Congenital Muscular Dystrophy (FCMD)
Walker–Warburg Disease
A. Genetics:
A. Genetics: chromosome 9q31; allelic to Fukuyama CMD
SECTION XII. Muscle Disease
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B. Clinical features: 1. Severely affected at birth 2. Usually die in infancy 3. Brain abnormalities: 1) Cephalocele 4. Lissencephaly Type II 5. Hemispheric fusion 6. Agnesis of the corpus callosum
Ocular Findings Present in FCMD, WWS and MEBD (Muscle Eye Brain Disease)
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Myopia Microphthalmia Corneal opacities Congenital cataracts Retinal dysplasia and non-attachment Pre-retinal membrane Gliosis of the retina Mottling of retinal pigment epithelium Persistent hyperplastic primary vitreous Optic nerve atrophy Degree of ocular pathology a. WWS > MEBD > FCMD
Limb Girdle Muscular Dystrophy
Limb girdle muscular dystrophies are being rapidly characterized by molecular genetic techniques. The present classification rests on the basis of the 1994 criterion. The disease may have its initial presentation in the pelvic or shoulder girdle musculature concomitantly or seriatim. The initial symptoms relate to weakness of these muscle groups. Early contractures may be noted in some of the AD forms, but not often in the AR varieties. Calf hypertrophy is frequent and often demonstrates intrafamilial variability. Exclusion criteria are onset of weakness in distal, facial or extraocular muscles. Onset of the disease may occur at any age. In recessive forms the process generally starts prior to 20 years of age. Later onset usually occurs in dominant disease. The classification continues to be modified according to each entities specific genetic defect. Single gene mutations may cause specific phenotypic expression. Both Miyoshi distal myopathy and LGMD 2B may result from mutation of the dysferlin gene on chromosome 2p13. LGMD 2G and LGMD 2H involve distal lower extremity muscle compartments. LGMD 2H may have early facial involvement which usually is an exclusion criterion for LGMD.
Autosomal Dominant Limb Girdle Muscular Dystrophy Muscle-Eye Brain Disease LGMD-1A
A. Genetics: chromosome 1p34-p32 B. Clinical features: 1. Congenital hypotonia 2. Severe myopia 3. Mental retardation 4. Neuronal migration disorder 5. Hypomyelination 6. Leptomeningeal glial mesodermal proliferation 7. Pyramidal tract hypoplasia C. Ocular Abnormalities: a. Optic atrophy c. Congenital glaucoma b. Retinal hypoplasia d. Severe myopia D. Laboratory evaluation: 1. CK: increased 3. EMG: myopathic 4. Muscle biopsy: a. Dystrophic features b. Deficient laminin in central nervous system, eye and muscle 5. MRI evaluation: a. Convoluted agyric pattern of the occipital lobe b. Cobblestone cortex c. Lissencephaly d. Cytoarchitectural disorganization
A. Genetics: 1. Chromosome 5q22-q31.3 2. Gene product is myocilin: a. Protein localizes to the I band or the Z line of the sarcomere B. Clinical features: 1. Onset is third decade (18–35 years of age) 2. Lower extremity limb girdle weakness > upper extremity 3. Facial muscles spared (several patients have weakness) 4. Dysarthric speech pattern 5. Absent ankle deep tendon reflexes 6. Frequent heel cord contractures 7. Anticipation may occur; a differential point from FSH dystrophy a. In FSH facial involvement and ptosis are prominent at presentation C. Laboratory evaluation: 1. Serum CK is elevated (mild) 2. EMG: myopathic 3. Muscle biopsy a. Dystrophic
Chapter 2. Congenital Myopathies LGMD-1b
A. Genetics: chromosome 1q11–12 (AD) B. Clinical features: 1. Slowly progressive 2. Symmetric proximal myopathy 3. Childhood presentation in 50% of patients: a. Waddling gait c. Difficulty running b. Hyperlordosis 4. Middle age patients demonstrate: a. Mild symmetric wasting and weakness of proximal upper extremity muscles. The biceps are particularly affected b. A few patients demonstrate mild symmetric facial involvement and calf hypertrophy c. Cardiac abnormalities: 1) Sudden death (young to middle age) 2) Dilated cardiomyopathy 3) Atrial fibrillation 4) Frequent supraventricular premature beats C. Laboratory evaluation: a. Serum CK: slightly elevated b. EMG: myopathic
LGMD-1C (Caveolaopathy)
A. Genetics: 1. AD 2. Chromosome 3p25 3. Caveola 3 gene (CAV3): a. There are three isoform of the membrane incorporated protein; caveola 3 is expressed in skeletal and cardiac muscle b. Cevalin 3-MOS-α1−syntropin-dystrophin B. Clinical features: 1. Onset at age five; initial motor milestones were achieved 2. Slow progression of proximal weakness 3. Cramps after exercise 4. Gower’s sign in adults 5. Calf hypertrophy C. Laboratory evaluation: 1. CK: 4–25 times normal 2. EMG: myopathic
LGMD-1D
A. Genetics: 1. AD 2. Chromosome 6q 23B B. Clinical features: 1. Adult onset 2. Proximal weakness without contractures 3. Facial musculature is normal 4. Mild weakness; ambulatory for life
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Limb Girdle Muscular Dystrophies (autosomnal dominant)
1. LGMD-2A (calpainopathy): a. Genetics: AD; chromosome 15q 15.1–q 21.1; gene is calpain3; protein is located in the myofibril and the nucleus: 1) Calpain 3 transcribed; a Ca++ dependent protease involved in catabolism and transcription regulation 2) Approximately 10% of heterogenous LGMD have calpain III mutations 3) Not associated with disruption of the dystrophin complex 4) Worldwide distribution b. Clinical features: 1) Onset 3–30 years of age; the earlier the onset the more severely affected 2) Slowly progressive course; earliest muscles involved: a) Gluteus maximus and thigh adductors; cause difficult with walking. Less involvement of gluteus medius b) Minimal involvement of quadriceps c) Abdominal muscles greater involvement than spinal muscles d) Upper extremity, limb girdle weakness and atrophy e) Rare calf muscle hypertrophy f) Late stage: 1) Atrophy of quadriceps and other leg muscles 2) Atrophy of distal lower extremity muscles 3) Sparing of face and intrinsic hand muscles 4) Contractures of hips, knees and elbows g) Intellect, heart, and pharyngeal muscles are spared c. Laboratory evaluation: 1) CK: 10 times normal 2) EMG: myopathic 3) Muscle biopsy: variation in fiber size, interstitial fibrosis, dystrophic changes
Limb Girdle Muscular Dystrophy-2B (Dysferlinopathy)
A. Genetics: chromosome 2p12–13; dysferlin gene: 1. Localization of the protein is the cell membrane 2. Allelic to Miyoshi distal myopathy 3. AR B. Clinical features: 1. Age at onset is 13–35 years 2. Lower extremities involved earlier than upper extremities 3. 15% of patients have calf hypertrophy 4. 70% of patients are unable to walk on their toes
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SECTION XII. Muscle Disease
5. Great phenotypic variability is noted within and between families 6. Late stages of the disease: a. Atrophy of the anterior compartment of the lower extremities b. Scapular muscle and distal upper extremity weakness and atrophy 7. Families may demonstrate members with myiosis and LGMD phenotype C. Laboratory evaluation: 1. CK: 10–150 times normal 2. EMG: myopathic 3. Muscle biopsy: dystrophic changes
LGMD-2E
LGMD-2C
LGMD-2G
A. Genetics: Chromosome 13q12: 1. Disruption of the dystrophin complex 2. Deficit of alpha and β sarcoglycan B. Clinical features: 1. Childhood onset; adult onset has been reported 2. Severe weakness of pelvic and pectoral girdle; usually symmetric 3. Lower extremity involved first; difficulty climbing stairs and standing up from the floor 4. Muscle pain and cramps 5. Affected muscles become atrophic 6. Hypertrophy of the calves may be seen early 7. Joint contractures may occur; particularly of the ankles 8. Rare facial muscular involvement (early) 9. Rare cardiac involvement: a. Cardiomegaly b. Cardiac conduction defects c. Partial right or left bundle block
A. Genetics: chromosome 17q11–12: 1. Telethionin gene: a. Encodes a sarcomeric protein b. Binding rite for other sarcomeric proteins c. Important in the assembly of the sarcomere B. Clinical features: 1. Childhood onset (mean age of 12.5) 2. Difficulty climbing stairs, walking and running 3. Weakness of ankle, dorsiflex on and consequent foot drop 4. Proximal muscle weakness and atrophy in the arms 5. Distal and proximal involvement of the legs 6. Absent deep tendon reflexes 7. Patients are wheelchair bound in their thirties C. Laboratory evaluation: 1. CK: early stages is increased 3 to 17 times normal; late stages it may return to normal 2. EMG: myopathic 3. Muscle biopsy: variation in fiber size, rounded fibers, necrotic and regenerating fibers and central nuclei; rimmed vacuoles may be seen
LGMD-2D (alpha sarcoglycan)
LGMD-2H
A. Genetics: chromosome 17q21; AR: 1. Double null mutation causes a severe myopathy 2. Degree of sarcoglycan expression correlates with clinical severity 3. There is an associated dystrophin deficit 4. Ten missense mutations have been described 5. Located (alpha sarcoglycan) at the cell membrane B. Clinical features: 1. Symmetric involvement of trunk and limb muscles; similar to Duchenne Muscular Dystrophy 2. Calf hypertrophy 3. Absence of cardiac involvement
A. Genetics: chromosome 9q31-q33 1. Gene localized to Hutterite patients in North America (ancestors migrated from Switzerland) B. Clinical features: 1. Age of onset is the first decade 2. Early involvement of the pelvic girdle and quadriceps: a. Waddling gait b. Difficulty arising from a squat 3. Facial muscles involved 4. Some patients noted to have brachioradialis and anterior tibialis weakness C. Laboratory evaluation: 1. CK; markedly elevated 3. Muscle biopsy: dystrophic 2. EMG: myopathic
A. Genetics: chromosome 4q12 (B-sarcoglycan) 1. B sarcoglycan deficit 2. Located in the cell membrane B. Clinical features: 1. Similar to DMD LGMD-2F
A. Genetics: chromosome 5q33–34 (gamma sarcoglycan) 1. Protein in the cell membrane B. Clinical features: 1. Similar to DMD
Chapter 3. Myotonic Disorders of Muscle
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LGMD-2I
The Non-Progressive Myotonias
A. Genetics: 19q 13.3 B. Clinical features: 1. Variable age at onset 2. Proximal limb muscle weakness and wasting; pelvic girdle affected most severely C. Laboratory evaluation: 1. CK: elevated in younger patients 2. EMG: myopathic 3. Muscle biopsy: dystrophic changes: a. Normal expression of dystrophin and: 1) AP complex that include: SG subunits, DG, and sarcospan
The non-progressive myotonias are differentiated from the progressive dystrophies by lack of systemic features such as cataracts, cardiac defects, endocrine, pulmonary and dysmorphic features and smooth muscle involvement.
Differential Diagnosis of Limb Girdle Dystrophy
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
Multicore disease (rare in adult life) Sarcotubular myopathy Reducing body myopathy Mitochondrial myopathy with primary limb girdle weakness Finger print myopathy Acid maltase deficiency (adult onset) Debrancher enzyme deficiency (adult onset) McArdle disease (adult type) Carnitine deficiency of muscle (adult onset) Myopathy with tubular aggregates (adult onset) Congenital fiber type disproportion (detected in adulthood) Myopathy with cytoplasmic bodies (early adult onset) Centronuclear myopathy (adult onset is rare) Central core disease (may be first detected in adulthood) Adult nemaline disease Scapuloperoneal myopathy FSHD DMD Becker Muscular Dystrophy Manifesting carrier of DMD Chronic spinal muscular atrophy Polymyositis/dermatomyositis complex
Chapter 3 Myotonic Disorders of Muscle
General 1. Myotonic Dystrophy DMD
Chloride Channel Disorders
A. Myotonia congenital (Thomsen’s Disease) 1. Genetics: chromosome 7q a. AD b. Chloride channel dysfunction; reduced conductance 2. Clinical features: a. Onset in infancy b. Affected girls may present in late childhood c. Prevalence is 4/100,000 people d. Stiffness with the initiation of movement that decreases with exercise e. Presents in hands, legs and eyelids; variation between family members f. Cold is an aggravating factor g. May affect chewing, speech and swallowing; occasionally causes diplopia h. Weakness is minimal i. Pain is slight j. Myotonia may increase with pregnancy k. Percussion elicits myotonia in any muscle l. Muscle hypertrophy is common 2. EMG: a. True myotonia; no myopathic features 3. Muscle biopsy: a. Absence of Type II B fibers b. Fiber hypertrophy
Recessive Myotonia
A. Genetics: 1. AR; Becker’s variant 2. 7q (chloride channel) 3. More common than AD from 4. Reduced chloride conductance B. Clinical features: 1. Onset 1–2nd decade; rarely in infancy 2. Prevalence: 2/100,000 people 3. Symptoms are progressive during childhood; usually presentation is in the legs 4. Myotonia may be severe 5. Generalized episodes with falling or emotional upset may induce a transient rigid state 6. Prominent muscle atrophy may occur; usually in distal muscles of the lower extremities 7. Muscle hypertrophy of the legs and gluteal muscles; upper extremities may be underdeveloped
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SECTION XII. Muscle Disease
8. Stiffness is most severe with muscle contractures after rest and improves with exercise 9. No cardiac or smooth muscle involvement 10. No cataract 11. No deterioration through adult life 12. May have depressed reflexes 13. Aggravated by cold in some patients 14. Men more severely affected than women C. Laboratory evaluation: 1. CK: usually normal; may be slightly elevated 2. EMG: clear myotonia 3. Muscle biopsy: normal; a few severe AR patients demonstrate mild dystrophic features and increased internal nuclei; decreased 2B muscle fibers 4. EMG: True myotonia: a. High frequency repetitive discharges b. Vary in frequency and amplitude c. Dive bomber sound d. Produced by: a) Voluntary movement c) Needle movement b) Percussion d) Repetitive stimulation
Characteristics of Pseudomyotonic
1. 2. 3. 4. 5.
Complex repetitive discharge Repetitive discharge with constant frequency Variation in amplitude Short duration High frequency not noted with voluntary movement but requires percussion or needle movement
Differential Diagnosis of Pseudomyotonia
1. 2. 3. 4. 5.
Polymyositis Acid maltase deficiency Debrancher deficiency Progressive muscular atrophy True myotonia
Sodium Channel Disorder
General Overview: Patients with sodium channel disorders may present with episodic weakness, myotonia, stiffness, spasm and mild pain. Those with primary myotonia do not experience true weakness, may vary in day to day symptomatology and may be provoked by a potassium load. Hyperkalemic periodic paralysis and paramyotonia congenital suffer periodic weakness exacerbated or provoked by cold. Hyperkalemic periodic paralysis patients may have clinically symptomatic stiffness and myotonia. There is phenotypic variation of weakness, myotonia and stiffness within families. There are rare families with hyperkalemic periodic paralysis without myotonia. There is persistence of Na+ conduction with failure of channel inactivation.
Sodium Channel Myotonia
All are associated with mutations of the α-subunit of the skeletal muscle voltage gated sodium channel gene (SCN4A). They present in childhood or adolescence with stiffness and are aggravated by potassium. The myotonia and stiffness may be painful. Patients are neither weak nor cold sensitive. Myotonia Fluctuans
A. Genetics: 1. AD; chromosome 17q; SCN4A gene B. Clinical features: 1. Presents in adolescence 2. Proximal > distal myotonia 3. Myotonia fluctuates in frequency and severity 4. Myotonia may be painful; may be delayed in onset after exercise (several minutes) 5. Warming up relieves symptoms 6. Cooling does not trigger or worsen myotonia 7. Involvement of extraocular muscles and trunk (distinctive) 8. Bulbar, facial and distal muscles may be severely affected 9. Well developed musculature without hypertrophy 10. Grip and pathologic lid retraction myotonia is present Myotonia Permanens
A. Genetics: chromosome 17q; AD; SCNA4 gene B. Clinical features: 1. Childhood presentation 2. Severe generalized myotonia a. May affect thoracic muscles with respiratory involvement 3. Symptoms provoked and exacerbated by potassium Acetazolamide Responsive Myotonia
A. Genetics: 1. Chromosome 7 2. SCNA4 gene B. Clinical features: 1. Childhood onset 2. Axial and proximal muscles are affected more than distal muscles a. Associated with severe spasms and acute lordosis during exacerbations 3. May respond to mexiletine as well as acetazolamide C. Laboratory evaluation: 1. EMG: true myotonia; cold induced response is electrically silent 2. Muscle biopsy: variation is fiber size; abnormalities of terminal innervation 3. Unclear differentiation between Type I and II fiber types
Chapter 3. Myotonic Disorders of Muscle Paramyotonia Congenita (Von Eulenburg’s Disease)
A. Genetics: AD, chromosome 17q23; SCNA4 mutation 1. Complete penetrance in both genders 2. Sodium channel mutation alters fast inactivation B. Clinical features: 1. Onset at birth (bulbar facial neck and hands are affected) 2. Paradoxical increase of myotonia with exercise (reverse of the warm up phenomenon in other myotonic disorders) 3. Myotonia induced by cold and exercise 4. May be associated with weakness; flaccid paralysis occurs rarely 5. Can last for hours after rewarming 6. Muscle hypertrophy is present 7. Overlap with hyperkalemic periodic paralysis and sodium myotonias (different mutation) that may present as: a. Periodic paralysis not associated with cold b. Fixed weakness between attacks c. A variant in which weakness may occur at room temperature 8. Diamox may trigger an attack 9. Percussion and electrical myotonia 10. Spontaneous weakness without stiffness in some families C. Laboratory evaluation: 1. EMG: myotonia; cold induced reaction is electrically silent 2. Muscle biopsy: variation in fiber size; poor differentiation into Type I and Type II fibers; changes noted in terminal twig innervation
Differential Diagnosis of Myotonia Congenita
The differential is limited to those neuromuscular diseases in which myotonia is a prominent symptom. These include the dystrophic myotonias, myotonic dystrophy 1 and 2, the sodium channel myotonias, paramyotonia-congenita, hyperkalemic periodic paralysis and the Schwartz–Jampel Syndrome. There are no dystrophic features in congential myotonias such as frontal balding, cardiac, and endocrine, cataract and smooth muscle abnormalities that are noted in DMD 1 and 2. The recessive from (Becker’s variant) is more common than the AD (Thomsen’s variant), is more severe and may be associated with minor progressive weakness (particularly of the lower extremities) and may have periodic weakness initiated by movement after rest. The sodium channel myotonias are characterized by: 1) worsening of symptoms with a potassium load; 2) exercise induced delayed onset myotonia (opposite to relief of myotonia with exercise noted in the chloride channel disorders);
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3) myotonia may be painful; 4) a fluctuating course (myotonia fluctuans) may occasionally be seen with chloride channel disease. Myotonia congenita and paramyotonia both have generalized stiffness and myotonia as well as muscle hypertrophy. Some may also worsen with cold. Differential points are that in patients with paramyotonia congenita: 1) patients have extreme cold sensitivity; 2) stiffness followed by true weakness (not seen in the true congenital myotonias) and AD and AR recessive myotonias demonstrate a warm up phenomena whereby the myotonia is relieved by exercise. Attacks of weakness in AR generalized myotonia occur during movement and after rest rather than cold. Hypokalemic periodic paralysis and Anderson’s Syndrome both suffer attacks of periodic weakness and may show some features of AR generalized myotonia with weakness. In hypo PP, the attacks of weakness are longer, provoking factors are high carbohydrate intake after exercise, extraocular and pharyngeal muscle are not affected and there is proximal muscle predominance. The weakness may last for several weeks after attacks. Anderson’s cardiac variant of hypo PP is easily distinguished by the dysmorphic features of short stature, scoliosis, micrognathia and hyperthecosis. There is an associated long QT interval with cardiac arrhythmia. Schwartz–Jampal Syndrome has the characteristic dysmorphisms of short stature, bony dysplasia with metaphysical enlargement, arachnodactyly, kyphoscoliosis, and pectus carinatum. There are prominent facial abnormalities. Proximal upper and lower extremity hypertrophy with distal weakness is characteristic. The major differential points between sodium channel myotonia and chloride channel myotonia are: 1) exacerbation of symptoms with potassium in the sodium channel disorders; 2) painful myotonia in sodium channel and not with chloride channel disease; (3) myotonia fluctuans (Na channel dysfunction) causes exercise delayed onset myotonia; 4) acetazolamide responsiveness is clear in this variant of sodium channel myotonia. Fluctuations may be seen in both disorders. Paramyotonia congenita demonstrates more severe cold sensitivity associated with true weakness which is not seen in the sodium channel myotonias. The worsening of myotonia with exercise is immediate in paramyotonia congenita as opposed to the delay noted in myotonia fluctuans. Sodium channel myotonias do not suffer periodic paralysis. The dysmorphism and extra muscular manifestation separate the sodium channel myotonias from the dystrophic myotonias and the Schwartz–Jampel Syndrome.
Schwartz–Jampel Syndrome
1. Genetics: linked to chromosome 1q34–36 or 1p34–36 in different families 2. AR transmission 3. Clinical features:
SECTION XII. Muscle Disease
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4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
a. Dysmorphic features: 1) Dwarfism 2) Bowing and shortening of long bones 3) Metaphyseal enlargement 4) Arachnodactyly 5) Hip dysplasia 6) Kyphoscoliosis 7) Pectus carinatum 8) Micrognathia and pursed lips 9) Upward slanting eyes 10) Blepharophimosis 11) Exotropia 12) Hypoplastic larynx 13) Short neck 14) Hypertrichosis 15) Joint contractures (particularly elbows) Proximal upper and lower extremity hypertrophy Distal predominant weakness and atrophy 20% of patients are cognitively impaired Clinical phenotype varies within family members Susceptible to malignant hyperthermia Carpal tunnel syndrome frequently associated Develop visual impairment due to blepharophimosis, lens abnormalities, small corneas Gait abnormalities develop due to hip dysplasia Nasal speech Laboratory evaluation: a. Serum CK: mildly to moderately elevated 3. EMG: myotonic discharges; complex repetitive discharges; spontaneous action potentials from individual muscle fibers (primary hyperexcitability from the sarcolemmal membrane 4. Muscle biopsy: A few patients have myopathic changes of excessive variability of fiber size and central nuclei; may be normal 5. Electron microscopy: 1) Subsarcolemma membrane abnormalities 2) Changes in intracellular organelles 3) Abnormal distribution of isoform of contractile and structural proteins
Three Major Clinical Presentations
1. Type 1A: a. Onset in childhood d. Dysmorphic facial features b. Bone dysplasia e. Myotonia c. Muscle hypertrophy 2. Type 1B: a. Similar to Type 1A c. More prominent bone dysplasia b. Onset at birth 3. Type 2: a. Manifests at birth b. Contractures c. Severe long bone bowing (camptomelia) d. Dysplasia of bone
e. Severe dysplasias f. Myotonia g. Infantile death Differential Diagnosis
1. Skeletal anomalies distinguish the illness from myotonic dystrophy 2. Marden–Walker Syndrome has similar skeletal abnormalities but no myotonia or proximal muscle hypertrophy 3. Stuve–Wiedmann Syndrome is similar
Rippling Muscle Disease
A. Genetics: heterogeneous; one family maps to 1q41 (family from Oregon) 1. Autoimmune from associated with myasthenia gravis B. Clinical features: 1. Presents in childhoods or adolescence 2. Intermittent pain and cramps induced by exercise 3. Some patients present in adulthood 4. Mechanical percussion or contraction of muscle induces: a. “Rippling” or rolling waves of contraction that begins proximally and spread laterally across the affected muscle b. Biceps and quadriceps most often affected c. Mounding of muscle (may be painful) d. Rapid muscle contraction e. Prolonged muscle contraction similar to percussion myotonia 5. EMG silence during contractions 6. Muscle hypertrophy of the calves 7. One family with mild proximal muscle and facial weakness 8. Variable penetrance 9. Men may be more affected than women 10. Mounding and muscle contraction more common than the rippling phenomena 11. One family; cardiac arrhythmia 12. One family; pigmenturia with exercise
Drug Induced Myotonia
1. Hypocholesterolemic drugs: a. 10/25 diazacholesterol 1) Decreased chloride conductance b. 2–4 dichlorophenoxyacetic acid c. 1) Decreased chloride conductance 2. Clofibrate 3. 3-Hydroxy-3methylglutaryl coenzyme A reductase inhibitors (statins) 4. Inderal/beta blockers
Chapter 4. Periodic Paralysis
5. 6. 7. 8. 9.
Fenoterol Terbutaline Colchicine Penicillamine Cyclosporine
Muscle Disorders with Myotonia
1. 2. 3. 4.
Acid maltase deficiency Polymyositis/dermatomyositis complex Myotubular myopathy (centronuclear myopathy) Malignant hyperthermia
Myotonia with Myokymia, hyperhydrosis and Muscular Wasting
A. Genetics: not determined B. Clinical features: 1. Benign 2. Myotonia of all muscle groups 3. Distal wasting and weakness 4. Widespread fasciculations 5. Hyperhidrosis C. Laboratory evaluation: 1. EMG: myotonia on needle movement
Chapter 4 Periodic Paralysis Hyperkalemic Periodic Paralysis (Hyper PP)
A. Genetics: chromosome 7q23: 1. Mutations of the α-subunit of the muscle voltage gated sodium channel gene (SCN4A); Thr704met mutation is common 2. Complete penetrance in both genders is usual 3. Two families with clinical hyper PP without myotonia: a. Mutation in a potassium channel 4. Most common mutations are Thr704met and met1592 Val 5. Dysfunction of slow inactivation of sodium channels 6. Potassium channel variant a. Mutation in the KCNE3 gene B. Clinical features: 1. Onset first or second decade (usual is 1–10 years) 2. Attacks of generalized weakness (flaccid paralysis) 3. Vary in frequency; intermittent to daily 4. Usually lasts for 20 minutes to one hour 5. Most often occur in the morning; may occur at any time; legs to arms to neck (ocular extremely rare)
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6. Attacks decrease during middle age 7. Premonition of oncoming attacks by a sense of muscle discomfort 8. Provoked by increased potassium, cold, fasting, and exercise 9. Most commonly associated with myotonia, pathologic lid retraction; tongue myotonia 10. May have associated paresthesias 11. Potassium is usually (4.5–8) during attacks; a few patients it may be normal during attacks of weakness 12. Attacks may develop during rest after exercise 13. Attacks may be aborted by mild exercise (“walking off attacks”) 14. Paralysis, areflexia, myotonia and Chvostek’s sign may be seen concomitantly 15. May have variants in which myotonia is consistently absent 16. Cranial nerves and respiratory muscles are usually spared; permanent weakness may develop 17. During attacks moving the extremities and calcium gluconate may be effective 18. Precipitating factors: exercise followed by rest, cold, hunger, stress, ice water. 19. Diamox, hydrochlorothiazide and frequent meals are preventative C. Laboratory evaluation: 1. Potassium: may be normal; usually 4–8 mm; severe attacks may develop at potassium levels of 6 mm or less (would not affect a normal patient) 2. Calcium may be depressed (Chvostek’s sign) 3. EKG: Hyperkalemic charges 4. EMG: a. May demonstrate myotonia; high frequency discharges, occasional fibrillation potentials 1) CMAP amplitude may decline in proportion to the degree of weakness b. Myopathic MUAPs may be noted in some patients between attacks c. Myotonic discharge decrease as weakness progresses d. Increase in CMAP early in the prolonged exercise test which decline over 20–40 minutes e. There is no decrement of the CMAP with the short exercise test or with cooling 5. CK: May be slightly elevated during an attack 6. Muscle biopsy: a. Vacuolar myopathy (vacuoles are in the center of the fibers) b. Tubular aggregates may be seen 7. DNA testing may be definitive
Hypokalemic Periodic Paralysis
A. Genetics:
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SECTION XII. Muscle Disease
1. Hypo PP (type I): a. Chromosome 1q31–32 b. CACNAIS c. Encodes an L-hyper dihydropyridine sensitive calcium channel 2. Hypo PP (Type II) a. Point mutations of α-subunit of the sodium channel skeletal muscle gene cause phenotypic Hypo PP B. Clinical features: 1. Most common of the periodic paralysis 2. Onset in teens; 7–21 years of age 3. Attacks may occur daily or only two in a lifetime 4. Attacks last hours to days 5. Provoking factors: a. Sleep (attacks in the morning) b. High carbohydrate and sodium ingestion c. Following exercise d. Insulin e. Glucose f. Stress g. Menses h. Alcohol i. Chinese food 6. Serum potassium usually 2–3 meq/dl during attacks 7. Proximal greater than distal weakness; flaccid 8. Paresthesias are common; patients may complain that gastrocnemius muscles feel tight 9. Cranial nerves and respiratory muscles are spared 10. After multiple attacks proximal muscle weakness is permanent 11. May have rare clinical myotonia between attacks 12. Patterns of a characteristic attack: a. Legs > arms > trunk > neck b. Cranial nerves and respiratory muscles are unaffected (rarely they are during a severe attack) c. Proximal greater than distal weakness d. Rarely: there is thirst, constipation and oliguria e. Recovery occurs in the reverse order of onset; may be accompanied by diuresis and sweating f. Examination: 1) Flaccid paralysis 2) Muscles feel swollen and tight (particularly the gastrocnemius) 3) No elicitable myotactic reflex 4) Absent deep tendon reflexes 13. Focal limb weakness may be seen 14. Potassium levels between 2–3 mEq/liter may be associated with: a. Sinus or brady arrhythmias b. May not correlate with expected EKG patterns 15. Attacks occur more frequently in men than woman 16. Only eyelid myotonia may be present 17. Proximal weakness develops in adulthood irrespective of frequency of attacks C. Laboratory evaluation:
1. EMG: during an attack no response to electrical stimuli; no myotonia 2. Muscle biopsy: a. Dilatation of the sarcoplasmic reticulum b. T-system may be PAS+ and can contain Ca++ c. Occurs in both Type I or Type II fibers d. Tubular aggregates are seen in Type II fibers
Differential Diagnosis of the Periodic Paralysis
Structural lesions of the neck particularly C1-C2 dislocation with cord compression. The cardinal features are an appropriate segmental or dropped sensory level. Patients suffer complete or partial quadriparesis. If the process is epidural, pain is the predominate part of the presentation. Bowel and bladder are involved. Prior to paralysis, ataxia may be noted as the outside lateral components of the spinal cord are the dorsal and ventral spinocerebellar pathways. Reflexes may be increased due to disinhibition of the anterior horn cells or decreased or absent due to spinal shock. Babinski sign is present. If the problem is intramedullary such as a syrinx, there is disassociated sensory loss (pain and temperature greater than lemniscal properties or the reverse if the syrinx is lateral and compromises the lateral cervical nucleus). There is segmental atrophy and weakness hyperactive lower extremities reflexes and decreased or absent reflexes at the level of the syrinx. Dural AVMs most commonly are accompanied by a more apoplectic onset than the periodic paralysis, are dorsally at thoracic levels and are accompanied by bowel and bladder dysfunction. Depending on the size and extradural spread, patients may have hyperactive reflexes and Babinski signs or spinal shock. A sensory and motor level is present. Spinal cord tumors and hemangiomas as well as intraparenchymal metastases have a different and more indolent tempo of symptoms and signs. Transverse myelitides, either autoimmune or viral are frequently accompanied by a band-like segmental level of pain or pressure (often at T4–T6 in multiple sclerosis), motor and sensory level, Babinski sign and Beevor’s sign. Myasthenia gravis is dominated by cranial nerve abnormalities, particularly ocular, without sensory loss and with maintained reflexes. Babinski signs are absent. Depressed level of consciousness occurs in patients with respiratory compromise and CO2 narcosis. Arrhythmias are common under these circumstances. Guillain-Barré syndrome usually starts with an ascending paralysis that compromises respiration. Paralysis and loss of reflexes predominate. If cranial nerves are involved during complete paralysis there will be a bilateral peripheral facial paralysis. The recurrent variety of chronic inflammatory demyelinating polyneuropathy has frequent mild sensory findings (particularly perioral at the onset of an exacerbation) with loss of reflexes. Attacks last for weeks.
Chapter 4. Periodic Paralysis
The primary differential diagnosis for Hyperkalemic periodic paralysis is the hypo PP from, secondary forms of hyper PP and Anderson’s syndrome. Hypokalemic attacks are precipitated by sleep, high carbohydrate and sodium meals, and rest after exercise and will last for hours. Hyperkalemic attacks start earlier in life, last for 20 minutes to an hour, are complicated by myotonia. Potassium relieves or prevents attacks of Hypo PP. Cold and rest after exercise induces attacks in both types of periodic paralysis. Southeast Asians have a high incidence of Hypo PP. Hypertelorism, short stature, broad base of the nose and cardiac arrhythmias (predominately long QT interval) distinguish Andersen’s Syndrome. Hyper PP and AR myotonia may suffer the combination of myotonia and periodic weakness. The later condition demonstrates a greater degree of myotonia as well as distal weakness. Hyper PP demonstrates a progressive decline in the CMAP over 20–40 minutes which is not seen in the congenital myotonias. Secondary causes of Hyper PP occur at a later age, often have an atypical presentation with no family history. Hypo PP is differentiated from Hyper PP by an onset in adolescence rather than childhood. As noted earlier Hypo PP is precipitated by carbohydrate ingestion particularly after exercise and symptoms may be abated by potassium ingestion. Hyper PP frequently follows potassium ingestion and is helped by carbohydrate ingestion. Cold affects Hyper PP more than Hypo PP, but rest after exercise may provoke attacks. Potassium levels are generally high during attacks of Hyper PP and low during Hypo PP. Severely low or high potassium may not always correlate with expected EKG manifestations. Myotonic discharges on EMG rules out Hypo PP. The prolonged exercise test produces a decremental response in both. A subset of Hypo PP patients never suffer periodic attacks and present with adult onset proximal myopathy suggestive of polymyositis. Inclusion body myositis frequently presents at a similar age, but is distinctive for steroid resistance and forearm contractures and quadriceps involvement. Muscle biopsy of Hypo PP reveals central vacuoles whereas rimmed vacuoles are noted in IBM. Hypo PP is AD, which may be helpful in discovering women with proximal weakness but without periodic attacks. Secondary causes of Hypo PP occur with later age at onset, no family history or an atypical presentation. Secondary hyperkalemic periodic paralysis that may have concomitant myotonia: 1. Renal failure 4. Metabolic acidosis 2. Adrenal failure 5. Potassium sparing diuretics 3. Hypoaldosteronism The medical conditions underlying these entities are usually clear. The potassium most often is greater than 6 mEq/dl and EKG changes more closely follow the potassium level. Thyrotoxic Periodic Paralysis
A. Genetics: highest incidents in patients of Southeast Asian ancestry
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1. Possibly AD B. Clinical presentation: 1. Older age at presentation (20–40 years of age) 2. Provoked by high carbohydrate ingestion 3. More prevalent in men than women 4. Sodium channel inactivation secondary to sarcolemmal depolarization; loss of membrane excitability 5. Responds to normalization of thyroid function
Secondary Hypokalemic Periodic Paralysis
1. Hypo PP with hyperthyroidism 2. Renal tubular acidosis: a. Low potassium triggers attacks of flaccid paralysis b. Seizures secondary to concomitant hypocalcemia 3. Hyperaldosteronism (secreting adenoma): a. Primary (Conn’s disease): 1) Abnormally high aldosterone secretion rate 2) Increased plasma and urinary aldosterone 3) Abnormally low plasma rennin activity b. May be seen with adrenal hyperplasia or morphologically normal adrenal glands 4. Barter’s syndrome 5. Villous adenoma of the intestine or colon 6. Alcoholism 7. Diuretics 8. Licorice ingestion (glyceric acid) 9. Amphotericin B 10. Long standing corticosteroid use 11. Lithium 12. EMG: a. Prolonged exercise test causes a progressive decline in the CMAP
Primary Normokalemic Periodic Paralysis
1. Least common of the periodic paralysis 2. Clinical presentation: a. Resembles Hyperkalemic periodic paralysis b. Serum potassium is not elevated even during the most severe attacks c. Paralysis induced or exacerbated by potassium d. Attacks can be improved by sodium
Differential Diagnosis of Hypokalemic Periodic Paralysis Hypokalemic PP (1qCACN14A)
1. 2. 3. 4. 5.
Hypo PP Renal tubular acidosis Barter’s syndrome Villous adenoma Alcoholism
SECTION XII. Muscle Disease
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6. 7. 8. 9. 10. 11. 12.
Diuretic (potassium wasting) Licorice ingestion (glyceric acid) Amphotericin B Prolonged corticosteroid ingestion Thyrotoxicosis (primary) Barium salt intoxication Thallium poisoning
Differential Diagnosis of Hyperkalemic Periodic Paralysis
1. 2. 3. 4. 5.
Addison’s disease Induced aldosterone deficiency Chronic heparin therapy Rhabdomyolysis Drugs: a. Triamterene c. Potassium supplements b. Spironolactone 6. Geophagia Differential Diagnosis of Normokalemic Periodic Paralysis
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Guanidine Myasthenia High cervical cord structural lesions Sleep paralysis (narcolepsy) Seizures (atonic) Multiple sclerosis Autoimmune recurrent neuropathies Recurrent neuropathies Eaton-Lambert Syndrome Metabolic abnormalities (usually with decreased level of consciousness): a. Hypoglycemia b. Hepatic insufficiency c. Urea cycle enzyme defects d. Mitochondrial defects (Leigh’s disease) e. Acute intermittent porphyria f. Variegate porphyria g. Coproporphyrinuria 11. Intermittent intoxications Differential Diagnosis of Disease Clinically Similar to the Myotonias
Chapter 5 Disorders with Continuous Motor Unit Activity (CMUA) 1. General features of this heterogeneous group of diseases
a. Myotonia b. Muscle stiffness c. Pain (sensitization of deep muscle pain afferents) d. Contracture e. Cramps f. Fasciculations 2. Origin: a. Spinal cord (stiff-man syndrome) b. Peripheral nerve (neuromyotonia) c. Muscle (myotonias) 3. EMG: a. Muscular myotonias: 1) Series of muscle fiber action potentials; positive sharp waves 2) brief spikes b. Continuous motor unit activity: 1) Continuous motor unit action potentials 2) Decrementing 3) High amplitude
Stiff-man Syndrome
1. Onset: sporadic disease of adult life 2. May be immune mediated 3. Insufficiency or dysfunction of GABA spinal cord inhibitory neurons 4. Clinical presentation: 1. Involuntary painful extremity spasms 2. Exacerbated by movement and stress 3. Axial predominance (hyperlordosis); truncal musculature more involved than appendicular muscles 5. Associated diseases: 1. Idiopathic diabetes mellitus 2. Hypothyroidism 3. Paraneoplastic 6. Antibodies to glutamic acid decarboxylase (GAD-67) 7. May occur following DDT poisoning
Chondrocyte Trophic Myotonia (Schwartz–Janpel Syndrome)
A. Genetics: AD from B. Clinical presentation: 1. Short stature 2. Skeletal abnormalities: a. Kyphoscoliosis c. Basilar compression b. Short neck d. Dislocation of the hips 3. Facial dysmorphisms a. Blepharophimosis b. Pursing of the mouth 4. 20% of patients are mentally retarded 5. Stiffness of gait 6. Exercise intolerance C. EMG: 1. Continuous motor unit activity 2. Some myotonia
Chapter 6. Ryanodine-Receptor/Calcium Channel Disease Isaac’s Syndrome (Neuromyotonia)
A. General Features: 1. Most common in adults; rare descriptions in infants 2. Antibody to potassium channels B. Clinical Presentations: 1. Insidious onset 2. Persistent muscle contractions 3. Distal > proximal muscle involvement 4. Trunk and facial muscles may be involved 5. Hyperhidrosis (often severe) 6. Erythema of the skin 7. Persistent contraction after exercise; rippling of the contracting muscles 8. Muscles may be painful with contractions 9. Dystonic flexed hand posture 10. Hypertrophy of continuously contracting muscle C. EMG: 1. Myokymic discharge of contracting muscle 2. Occasional superimposed neuromyotonic discharges
Morvan’s Syndrome
A. Clinical Features: 1. Clinical muscle features are similar to Isaac’s syndrome 2. Additional signs and symptoms are: a. Encephalopathy c. Insomnia b. Hallucinations d. Confusion
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5) Thymoma 6) Paraproteinemia 7) Paraneoplastic processes 8) Lymphoma 9) CTS (rare); carpal tunnel syndrome 10) Radiculopathy (rare) B. Specific Associations: a. Brainstem MS 1) Orbicularis oculi (myokymia) b. Pontine glioma 1) Facial myokymia (VII) c. Timber rattle snake envenomation 1) Generalized myokymia and neuromyotonia d. X-RT 1) Focal to the site of treatment (orbicularis oculi neuromyotonia following pituitary X-RT) episodic diplopia C. EMG: 1. Myokymic discharges are bursts of single motor unit action potentials at 5–150 Hz a. Pattern of firing is doublets, triplets or in multiples b. Regular bursts or slightly irregular 2. Neuromyotonic discharge: a. 150–300 Hz b. Begin and end abruptly c. Duration of a few seconds d. May wax and wane in amplitude and frequency e. Initiated by mechanical perturbation of the nerve f. Occur with myokymic discharges
Differential Diagnosis of Morvan’s and Isaac’s Syndrome Neuromyotonia and Myokymia
A. General Features (definitions): 1. Myokymia is a spontaneous continuous undulating vermicular (“worm” like) movement of muscles that does not displace a joint. It may be focal. 2. Neuromyotonia is a generalized continuous contraction of muscle that causes stiffness, but also does not move joints 3. Both processes are channelopathies 4. Hereditary myokymia has been described a. The locus for episodic ataxia and myokymia 5. Episodic ataxia and myokymia are on chromosome 12p13 (K+ channelopathy) 6. Isaac’s and Morvan’s syndrome are secondary to antibodies directed at potassium channels. 7. Acquired neuromyotonia in >50% of patients is secondary to voltage gated potassium channel antibodies 8. Associated illnesses: 1) MG 2) Penicillamine treatment 3) CIDP 4) Graft vs host disease
1. 2. 3. 4.
5. 6. 7. 8.
Snake envenomation (North American timber rattle snake) Hypocalcemia (tetany) CIDP (prominent sensory loss; depressed reflexes) Myotonic disorders (dysmorphisms and systemic involvement in dystrophic froms; hypertrophy of muscle with percussion myotonia in the benign froms) Stiff person syndrome (axial > appendicular involvement) SCA type 8 (vertigo and ataxia) Denervation with intense fasciculation Amyloidosis
Chapter 6 Ryanodine-Receptor/Calcium Channel Disease Central Core Disease
1. Genetics: AD; chromosome 1q 2. Clinical presentation: a. Onset in infancy
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SECTION XII. Muscle Disease
b. c. d. e. f.
Hypotonia Congential hip dislocation Spares extraocular muscles, face and swallowing Weakness slowly progressive into adulthood Some children are severely affected and develop kyphoscoliosis 1) Patients at risk for malignant hyperthermia 3. Pathology a. Cores of degenerating myofibrils at the center of Type I fibers
b. c.
Malignant Hyperthermia
1. Genetics: mutations of several genes: usually AD a. RYRI gene nystagmus (malignant hyperthermia I; MHI): 1) chromosome 19q 13.1 2) most common genetic mutation b. MH2 1) Chromosome 17q 11.6-q24 c. MH3: 1) 7q 21-q22 2) α2/8 subunit of L-Type dihydropteridine (DHP) receptor d. MH4 1) 3q 13.1 e. MH5: 1) 1 q31-q32 2) Mutation of the α, subunit of the DHP calcium channel c-receptor (CACNL-1A3) f. MH6 1) 5P mutation
Mechanism of Attacks
1. Increased release of calcium causes severe prolonged muscle contraction a. RYRI receptor is activated at lower than normal calcium concentration; located in the sarcoplasmic reticulum (SR) b. Succinylcholine increases membrane depolarization c. DHP-receptor is located in the T-tubule system and is the voltage sensor for the RYRI receptor 1) Opening of DHP receptor causes the RYRI channel to release calcium 2. Ether and halothane trigger the process in susceptible individuals 3. Prevalence: a. Occur in one of every 50,000 adults undergoing anesthesia 4. Clinical presentation: a. Muscle spasm
5.
6.
1) Often masseter muscle rigidity and spasms occur initially and is noted by the anesthetist; increase of end-tidal CO2 2) Generalized rigidity Rapid rise in temperature greater than 105◦ Fahrenheit 1) Usually temperature falls during anesthesia Hypermetabolism: 1) Increased oxygen consumption 2) Acidosis; respiratory or metabolic 3) Hypoxemia; increased end-tidal CO2 greater than 60 4) Cardiac arrhythmia; tachycardia 5) Muscle necrosis: a) Elevated CK; greater than 10,000 units/liter b) Potassium increases c) Lactic acidosis d) Myoglobinuria greater than 60 μg/liter: (1) If unrecognized may lead to renal failure (2) Serum myoglobin greater than 170 μg/liter 6) Labile blood pressure 7) Mottled cyanotic hot sweating skin Attacks may be triggered by exercise and stress; rare attacks may be observed 24 hours after surgery; this includes minimally invasive procedures in susceptible patients Diseases associated with a MH-like syndrome: a. Congential myopathies: 1) Central core disease (calcium release mechanism) 2) Multicore disease 3) Evans myopathy 4) King–Denborough Syndrome b. Muscular dystrophies: 1) Dystrophinopathy 2) Myotomic dystrophies c. Periodic paralysis d. Metabolic myopathies: 1) Phosphorylase deficiency 2) Carnitine palmityl transferase deficiency e. Miscellaneous diseases: 1) Hyper CK-emia 3) Myotonia congenita 2) Brodie’s disease
Differential Diagnosis of Malignant Hyperthermia
The differential diagnosis is clear in susceptible individuals who have a full blown syndrome during anesthesia. Several similar appearing attacks during anesthesia occur in some myopathies due to increased muscle membrane depolarization, but not calcium release mechanisms. These myopathies are noted above. Central core disease is allelic to MH and the attacks are similar. Exercise and stress may induce MH with consequent myoglobinuria. The cramps are more severe, exercise tolerance is more limited in the metabolic myopathies where this occurs. Hyperthermia is not seen with
Chapter 7. Inflammatory Myopathy
the metabolic myopathies. Anesthetic clearance should include a family history of unexplained death during minimally invasive procedures (or unexplained problems with minor surgery), a history of congenital myopathy or unexplained CK-emia. Diagnosis: Established by the caffeine or halothane induced contracture test of biopsied muscle Possible triggering agents include: Catecholamines Ketamine Phenothiazines MAO inhibitors
Triggering Agents in Susceptible Patients
1. Depolarizing blockers: a. Succinylcholine c. Suxamethonium b. Decamethonium 2. Inhalational anesthetics: a. Enflurane d. Sevoflurane b. Halothane e. Isoflurane c. Desflurane
Chapter 7 Inflammatory Myopathy The three major categories of inflammatory myopathy are polymyositis, dermatomyositis, and inclusion body myositis. There are many conditions both myopathic and neuropathic that affect muscle in a similar pattern. Collagen vascular diseases frequently affects proximal musculature similar to and polymyositis and dermatomyositis but have extra muscular involvement that distinguishes them.
Polymyositis
1. Genetics: sporadic a. Possible increase incidence of HLA-B8 and B12 antigen 2. Clinical presentation: a. Onset subacute over weeks to months 1) Children 5–14 years of age 2) 45–64 years of age in adults b. Incidence: 1) 1 per 100,000 people 2) Females greater than males, 2:1; black women patients 3) Weakness of neck flexor musculature 4) Symmetrical proximal girdle weakness
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a) Rarely anterior tibialis and brachioradialis may be affected 5) Dysphagia occurs in 20–30% of patients: a) Involvement of the striated posterior pharyngeal and cricopharyngeus muscles 6) Rare respiratory muscle involvement: a) Does occur in severely patients affected late in their course b) Rare mild facial muscle involvement c) Extraocular muscles are not involved 7) Extra muscular involvement: a) Interstitial lung disease: (1) Positive anti-Jo-1 antibody (anti aminoacyl transfer ribonucleic acid (+ RNA) synthetase (2) Occurrence possibly 5–10% b) Cardiac involvement includes: (1) Congestive heart failure (2) Pericarditis (rare) (3) Valvular disease (rare) 3. EKG abnormalities are common: a. Non-specific ST-T wave abnormalities b. Heart block c. Bundle branch block 4. Association with malignancy: a. Rare (perhaps 3% of older patients) b. Any type of malignancy c. Sites are age related d. Negative associations with malignancy: 1) Accompanying connective tissue disease 2) Pulmonary fibrosis 3) Myositis specific antibody 5. Myositis specific autoantibodies: a. Antisynthetase (anti-Jo-1) 1) Possibly 20% of PM 2) Acute onset in spring 3) Associated with interstitial lung disease 4) Nonerosive arthritis (associated) 5) Seen with relapse during prednisone taper b. Anti-signal recognition particle (SRP) 1) 5% of PM 2) Onset in autumn 3) Associated with myocarditis 4) Severe weakness with myalgia 5) Poor response to prednisone 6) 25% five year survival Polymyositis (PM) Associated with Connective Tissue Disease
General Features
1. Polymyositis occurs in approximately 20% of associated connective tissue diseases 2. Higher incidence of arthralgia and arteritis 3. Milder muscle disease 4. More responsive to immune suppressive therapy
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SECTION XII. Muscle Disease
PM with Scleroderma
1. Proximal muscle weakness similar to PM 2. Associated with other features of scleroderma: a. Raynaud’s phenomena b. Kidney disease c. Hypertension d. Tendon sheath involvement e. Vth nerve sensory involvement f. Rare stroke 3. Focal from of scleroderma (morphea): a. Primarily affects children b. Girls 3 : 1 over boys c. Frequently affects the forehead; appears as a “sabre scar”
2) Raynaud’s 5) Telangiectasia 3) Esophageal dysfunction e. Anti-Ky antibody 2. CK and aldolase: minimally elevated; may not be elevated 3. EMG: myopathic 4. Muscle biopsy: a. Variation of fiber size b. Occasional necrosis of single muscle fibers c. Great increase of endomysial and perimysial connective tissue d. Decreased capillaries in skeletal muscle e. Increased thickness in the walls of intramuscular blood vessels; endothelial hyperplasia f. Tubular aggregates in intramuscular capillary endothelial cells g. T-cells predominate in the inflammatory infiltrate
Laboratory Evaluation of Polymyositis PM Associated with Systemic Lupus Erythematosus
1. Muscle enzymes: a. Elevated 5 to 50 times normal 2. Sed Rate: a. May be normal; increased in associated connective tissue disease or malignancy 3. EMG: a. Membrane irritability b. Myopathic motor unit potentials 4. Muscle biopsy: a. Inflammatory cells in the perimysium and endomysium b. Prominent single fiber necrosis c. Non-necrotic fibers are focally involved d. Inflammatory aggregates contain a high percentage of activated T8 cells; small percentage of B cells e. No perifascicular atrophy f. No tubular aggregates in the cytoplasm of endothelial cells g. Pathology confined to the skin, subcutaneous tissue and underlying muscle h. Skin lesions are multiple or single; 0.5 to 15 cm in diameter i. No symmetric proximal weakness 5. Anti PM-Scleroderma associated antibody: a. 50% have scleroderma b. May be seen in other autoimmune diseases c. May occur in scleroderma without myositis
Laboratory Evaluation
1. Antibodies: a. Anti PM-Scl-myositis b. SCL–70 c. Anti-nucleolar antibody d. Anticentromere antibody with CREST that consists of: 1) Calcinosis cutis 4) Sclerodactyly
1. 2. 3. 4. 5. 6. 7.
Females 9 : 1 more affected than males Presents second to fifth decade Pericarditis, pleuritis, serosal surface involvement Arthritis Cerebral arteritis (generalized) Peripheral nerve involvement Muscle involvement same distribution as PM often less severe
Laboratory Evaluation: 1. IgG antibodies to double stranded DNA are most specific 2. CK and aldolase: mildly elevated 3. EMG: myopathic 4. Muscle biopsy: a. Vasculitis of small blood vessels b. Muscle changes similar to dermatomyositis c. Immunoglobulin deposits and complement found in muscle d. Multiple central vacuoles in some patients
Polymyositis with Rheumatoid Arteritis
1. 2. 3. 4.
0.7% have onset between 3–7th decade Severe joint involvement Pattern of weakness similar to PM Associated neuropathy; often severe intrinsic hand muscle weakness and atrophy 5. C1–C2 dislocation; pannus formation at C2; destruction of the cruciate ligament 6. Laboratory Evaluation: a. Rheumatoid arteritis antigens b. EMG: myopathic; evidence of sensorimotor neuropathy in some patients c. Muscle biopsy:
Chapter 7. Inflammatory Myopathy
1) Nodular vasculitis in the muscle 2) Necrotizing arteriolitis with fibrin deposits in the small blood vessels of muscles 3) Type II muscle atrophy 4) Immune complexes containing immunoglobulin and complement in blood vessel walls
a. Anti RO-SSA, anti-LA-SSB antibodies (anti nuclear) b. Serum antibodies against RNA, and antigens in the lacrimal, thyroid and salivary glands c. Elevated smooth muscle and mitochondrial antibodies d. EMG: myopathic e. Muscle biopsy: 1) Changes in muscle similar to those of rheumatoid arthritis 2) Degeneration and regeneration of isolated muscle fibers 3) Inflammatory cells within the perimysium combined with a vasculitis 4) Immunoglobulins and C3 may be deposited within the walls and capillaries of the venules of skin and muscle
Mixed Connective Tissue Disease
1. General features: a. Associated with anti-fibronuclear protein (RNP) 1) Not specific b. The antibody is to a rilsonuclease selective antigen component of extratractable nuclear antigen 2. Clinical presentation of MCTD; which has feature of: a. SLE b. Scleroderma c. Dermatomyositis d. SLE like rash e. Fever, hepatomegaly, serositis, leukopenia 3. Raynaud’s phenomena 4. Sclerodermatous hand findings 5. Decreased esophageal motility 6. Proximal muscle weakness and pain 7. Laboratory evaluation: a. EMG: myopathic b. High aldolase and CDK c. Muscle biopsy: a. Muscle findings similar to those of dermatomyositis b. Hyalinization of blood vessel walls
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Variants of Polymyositis
Antisynthetase Syndrome
1. Seen in 20% of PM and DM patients 2. The anti-Jo-1 autoantibody is present 3. Clinical features: a. Acute myositis b. Occurs in the spring c. Associated with non-erosive small joint arthritis d. Low grade fever e. Raynaud’s phenomena f. Relapses with steroid taper g. Interstitial lung disease (70% of patients) h. Small number of patients have other features of the syndrome without the myositis
Sjögren’s Syndrome
1. General features: a. Proximal and symmetric myopathy b. Dryness of eyes, mouth and mucosal membranes c. Arthritis d. Multiple organ system involvement: 1) Vasculitis 4) Interstitial nephritis 2) Pancreatitis 5) Thyroid abnormalities 3) Hepatobiliary disease e. PNS/CNS involvement: 1) Vth nerve involvement 2) Dorsal column dysfunction 3) Associated with higher incidence of primary progressive MS 2. Sensory ataxia (dorsal root ganglionitis; large neurons) 3. Sjögren’s associated with: a. Polyarteritis b. Chronic active hepatitis c. Interstitial pulmonary fibrosis d. Lymphoproliferative neoplasia 4. Laboratory evaluation:
Anti-SRP Auto Antibody Syndrome
Clinical Presentation
1. 2. 3. 4. 5.
Severe polymyositis with myalgia Present in the autumn Myocarditis Resistance to treatment (immunotherapies) Poor prognosis
Dermatomyositis
1. Clinical presentation: a. Childhood variant: age 5–14 b. Adult: 45–64 years of age c. No specific precipitative events; insidious onset with fatigue and weight loss 2. Onset over weeks to months 3. Rash may precede the onset of weakness by weeks to months
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SECTION XII. Muscle Disease
4. Weakness is proximal, symmetrical and involves neck flexors 5. Dysphagia occurs in approximately 30% of patients 6. Muscle tenderness less than 50%; arms greater than legs 7. Skin manifestations: a. Acute stage: 1) Erythema and edema of subcutaneous tissue 2) Periorbital, perioral, malar, anterior neck and chest distribution: a) Heliotrope suffusion primarily in children. Purplish discoloration of the eyelid and infraorbital skin b) Groton’s sign-erythematous symmetrical scaling lesions over bony prominences; knuckles and interphalangeal joints. SLE may affect areas between the joints c) Dilatation and inflammation of capillaries at the base of the nail; SLE causes periungual telangiectasia b. Chronic stage: 1) Scaling of the skin 2) Hyperpigmentation 3) Zones of brown induration (poikiloderma) in the extensor surfaces and back 4) Calcification of the skin in children 8. Increased reflexes in the lower extremities (irritation of intrafusal) muscle fibers 9. Systemic involvement: a. Cardiac manifestation (5–10% of patients): 1) Atrial arrhythmias 2) Atrioventricular conduction defects 3) Bundle branch block 4) Congestive heart failure b. Primary lung disease: 1) Interstitial pneumonitis: a) Presenting manifestation or occurs late in the course of the disease b) 5–10% of patients 2) Secondary lung disease: a) Weakness of intercostals muscles b) Chronic aspiration c) Pyogenic or atypical lung infection (immunosuppressant treatment) d) Methotrexate c. Raynaud’s phenomena d. Arthritis 20–50% of PM greater than that which occurs in dermatomyositis
Dermatomyositis Associated with Malignancy
Associated malignancy in DM possibly as high as 40% in patients older than 40. PM only 3.4% malignancy at greater than 40 years of age. Earlier studies demonstrated approximately 10% of elderly patients develop malignancy. Probably now
closer to 5%. Malignancy occurs with IBM (inclusion body myopathy). 1. Malignancy may precede or follow the onset of myopathy by months or years; usually occurs within two years of the diagnosis 2. Any tumor type may be associated. Small cell squamous carcinoma of the lung in men and ovarian cancer in women appear most common. Stomach cancer has a greater incidence than colorectal malignancy. 3. Less likely to have malignancy with myositis associated with connective tissue disease, pulmonary fibrosis or myositis specific antibody syndrome 4. A few patients have had an explosive onset with malignancy 5. Removal of the tumor may benefit the myopathy; recurrence of the myopathy may be the initial manifestation of tumor recurrence. 6. Laboratory Evaluation: a. CK and aldolase elevation occurs in the great majority of patients: exceptions are very early in the disease when only the rash is present and in very late illness. Usually 3–5 times normal. Antinuclear helicase antibody (anti-Mi-2) is detected in 5–10% of patients. b. EMG: 1) Myopathic 2) Increased insertional activity, positive sharp waves; fibrillations particularly noted in paraspinal muscles c. Long standing disease: 1) Signs of reinnervation with high amplitudes, long duration polyphasic MUAP 7. Muscle biopsy: a. Perivascular inflammatory cells in the perimysium that extend into the endomysium. b. High percentage of B-cells and helper T cells in the infiltrate c. Rare single fiber necrosis d. Occasional necrotic or non-neurotic fibers surrounded by inflammatory cells e. Tubular aggregates noted in the cytoplasms of endothelial cells of arterioles and capillaries f. Capillary necrosis and degeneration
Pathology of PM/DM Associated with Malignancy
1. Muscle pathology is similar to polymyositis 2. Dermatomyositis: a. Changes in muscle resemble dermatomyositis b. Tubular aggregates are prominent within the endothelial cytoplasm of intramuscular arterioles, capillaries and vessels
Pathology of Dermatomyositis of Childhood
1. Muscle pathology similar to that of the adult
Chapter 7. Inflammatory Myopathy
2. 3. 4. 5.
Perivascular collections of inflammatory cells Internal hyperplasia of the arteries and veins Small vessels occluded by fibrin thrombi Deposition of IgG, IgM, and C3 within the walls of intramuscular arteries and veins 6. Deposition of complement membrane attack complexes in the walls of small intramuscular arteries Childhood Dermatomyositis
1. Affects children and young adults 2. Clinical features: a. Erythematous skin lesions over the extensor surface of joints b. Malar rash c. Aberrant skin calcifications d. No precipitating cause e. Muscle weakness and rash are associated f. Duration of disease is variable; months to years g. May have rapid course; respiratory failure is rare h. Vasculitis of the gastrointestinal tract with perforation and hemorrhage are feared complications 2. Skin rash may precede weakness, stiffness and painful muscles 3. Muscle weakness is generalized; proximal shoulder and pelvic girdle muscles predominate: a. Abductors of the legs greater than adductors b. Extensors greater than flexors c. Tip toe gait (children) due to gastrocnemius flexion contraction d. May lose deep tendon reflexes with severe weakness e. Severely affected children: 1) Incomplete muscle recovery 2) Progressive to bulbar musculature, phonation and respiration 3) Flexion contractions of elbows, hips, knees, and ankles 4) Brown erythematous skin thickening 5) Subcutaneous calcification with skin ulceration 6) Areas of hyperpigmentation and depigmentation 7) Groton papules in the knuckles Inclusion Body Myositis
1. General features: a. Incidence is increasing; may be the second most common from of inflammatory myopathy b. Most common inflammatory myopathy over age 50 2. Clinical presentation: a. Male predominance b. Age of onset 60–70 years of age c. Duration of symptoms prior to biopsy (mean of 7 years) d. More common in white than black patients e. Flexion contraction of forearm muscles and quadriceps f. Swallowing abnormalities
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Differential Diagnosis
PM/DM Complex Criteria for Diagnosis of Definitive Polymyositis
1. Presence of symmetrical weakness of limb girdle and neck flexor muscles 2. Abnormal neck flexor muscles 3. Increased CK 4. Abnormal EMG with evidence of an irritative myopathy 5. Chronic rash (DM) a. 25–30% of patients fulfill the definitive criteria for PM
Less Restrictive Diagnostic Criteria for PM/DM Complex
Subacute Chronic Myopathy
1. Course: rapid progression over weeks or months with reversibility 2. Distribution: dysphagia, neck (flexor) and proximal limb weakness 3. Myalgia and muscle tenderness 4. Laboratory features: a. Myopathic EMG b. Elevated CK and aldolase c. Impaired esophageal motility d. Myopathic biopsy with presence of inflammatory cells
Evidence of Systemic Disease
A. Clinical features: 1. Raynaud’s 5. Fever 2. Arthralgia 6. Weight loss 3. Cardiac dysfunction 7. Esophageal dysmotility 4. Interstitial lung disease B. Laboratory: 1. Elevated sedimentation rate 2. Polyclonal hypergammaglobulinemia C. Exclusion of other disease: 1. Absence of family history (r/o dystrophies) 2. No cranial muscle weakness or cholinergic drug response (r/o MG) 3. Lack of endocrine disorder (r/o thyroid, Addison’s disease, hyperparathyroidism) 4. No specific biochemical disorder on muscle biopsy a. Rules out: 1) Carnitine deficiency 2) Acid maltase deficiency 3) Phosphorylase deficiency 4) Phosphofructokinase deficiency
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SECTION XII. Muscle Disease
Differential Diagnosis of Polymyositis
Criteria for Diagnosis of Polymyositis
1. Myopathy similar to myopathy of dermatomyositis: a. Course: rapid progression (weeks or months); reversibility b. Distribution: dysphagia; neck and proximal limb weakness c. Myalgia and tenderness (less than 50% of patients) d. Laboratory evaluation: 1) Myopathic EMG 2) Myopathic biopsy: inflammatory cells (mononuclear endomysial infiltrates precuneate); variation of fiber size, muscle fiber degeneration and regeneration scattered throughout the fascicle) 3) Increased serum muscle enzymes 4) Impaired esophageal motility in 40% of patients 2. Evidence of systemic disease: a. Clinical; arthralgia, Raynaud’s phenomenon, fever, weight loss b. Laboratory evaluation; sedimentation rate elevation, hypergammaglobinemia 3. Absence of other diseases: a. No family history (dystrophies) b. No rash, calcinosis, heliotrope suffusion (PM) c. No endocrine dysfunction d. No biochemical abnormality on muscle biopsy: which rules out carnitine, phosphorylase, acid maltase, PFK A. Connective Tissue Diseases in which Polymyositis in Associated: 1. SLE 2. Scleroderma 3. Vasculitis 4. Sjögren 5. Rheumatoid arthritis 6. Mixed connective tissue disease B. Infectious causes of Polymyositis: 1. Toxoplasmosis 8. Influenza 2. Tania sodium 9. Hepatitis-B virus 3. Schistosomiasis 10. Coxsackie virus 4. Cysticercosis 11. ECHO 5. Chagas disease 12. HIV 6. Legionnaire’s disease 13. Mycoplasma 7. Candidiasis C. Drugs: 1. Ethanol 7. Chloroquine 2. Penicillamine 8. Aminocaproic acid 3. Clofibrate 9. Rifampicin 4. Statins 10. Diuretics 5. Emetine 11. Zidovudine D. Intramuscular Injectable Drugs: 1. Meperidine (Demerol) 2. Pentazocine (Talwin) E. Systemic Diseases:
1. Carcinoma (paraneoplastic) 2. Thymoma (paraneoplastic) 3. Sarcoid 4. Celiac Disease 5. Vitamin D deficiency states F. Endocrine diseases: 1. Hyperthyroidism 2. Hypothyroidism 3. Hyperadrenocorticism 4. Hyperparathyroidism 5. Hashimoto’s thyroiditis G. Metabolic Diseases: 1. Protein malnutrition 2. Malabsorption 3. Hypocalcemia 4. Parenteral nutrition (phosphate depection) 5. Osteomalacia 6. Chronic renal disease 7. Hypokalemia 8. Carnitine deficiency 9. Acid maltase deficiency 10. Phosphorylase deficiency 11. Phosphofructokinase deficiency H. Hereditary Disorders: 1. Limb girdle dystrophies 2. Becker’s muscular dystrophy 3. Mitochondrial myopathies 4. Fascioscapulohumeral dystrophy 4. Inclusion in Body Myositis: a. Steadily progressive; more slowly than PM/DM b. Legs more affected than arms in many patients c. Wasting of forearm, finger flexor muscles; weakness of wrist flexors, knee extensors, ankle dorsiflexors d. May have generalized muscle weakness e. Weakness is more often asymmetrical than symmetrical f. Dysphagia is common g. Scapular cervical and facial muscle may be involved; frequent falls from quadriceps weakness h. Extraocular muscles are spared i. Spinal, respiratory and abdominal muscles are rarely affected j. Transient myalgias occur at the beginning or during the course of the illness k. No sensory abnormalities l. Deep tendon reflexes are normal or are slightly hyperactive; decreased knee jerks are seen with severe quadriceps atrophy m. Higher incidence of peripheral neuropathy with sensory loss and decreased AJ 5. Same relationship to other autoimmune diseases: a. Scleroderma b. Sjögren’s c. SLE d. Monoclonal gammopathies e. Antibodies to epitopes of myonuclei
Chapter 7. Inflammatory Myopathy
6. Steroids are minimally or not effective. IVIG is minimally to moderately effective 7. Lack of steroid responsiveness in a patient appearing to have PM suggest s the diagnosis 8. Laboratory Evaluation: 1. CK elevation: 3–5 times normal; anti 2. Antinuclear helicase auto antibody (anti-M1-2) found in 5–10% of patients 3. EMG: a. Short duration motor unit potentials b. Increased polyphasic potentials c. Fibrillation potentials; positive sharp waves are common d. Normal nerve conduction velocities 4. Muscle biopsy: a. Necrosis and regeneration scattered throughout the fascicle b. Vacuoles in 5–10% of fibers; single or multiple c. Fibrosis d. Inflammatory changes are endomysial 5. Electron Microscopy: a. Abnormal filamentous inclusions in the nucleus and cytoplasm b. Neurofilaments are 15–18 mm in diameter c. Membrane lined sarcoplasmic vacuoles 1) Contain membranous walls 2) Rimmed vacuoles with hematoxyphilic material
Differential Diagnosis of IBM
1. Chronic polymyositis (rarely distal predominant, but usually affects the brachioradialis rather than finger flexors) 2. Chronic spinal muscular atrophy 3. Vacuolar myopathies (pathologic muscle biopsy differential) a. Chloroquine myopathy b. Colchicine myopathy c. Vincristine myopathy d. Acid maltase deficiency e. Primary hypokalemic periodic paralysis f. Juvenile Batten disease (lipocercoid fusionis) g. Muscular dystrophy (rapidly progressive) h. Oculopharyngeal dystrophy (AD) i. Distal myopathy (sporadic or familial): 1) Rimmed vacuoles 2) Filamentous inclusions
Unusual Inflammatory Myopathies (Eosinophilic Polymyositis)
Hypereosinophilic Syndrome (HES)
1. Heterogenous disorder 2. Eosinophilia (often greater than 30,000 mm3 )
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3. Diagnostic criteria: a. Persistent eosinophilia greater than 1500 eosinophlis/ mm3 b. Duration of greater than six months c. No evidence of parasitic or other causes of eosinophilia d. Organ system involvement 5. Clinical features: a. Insidious onset of proximal muscle b. Skin involvement c. Raynaud’s phenomenon d. Splinter hemorrhages of nail beds f. Occasional ocular muscle involvement g. Polymyositis may occur in the setting of hypereosinophilic syndrome (HES) 5. Associated organ system involvement a. Lung e. Eosinophilia b. Heart f. Hypergammaglobulinemic c. Skin g. Peripheral neuropathy d. Anemia 6. Laboratory evaluation: a. Elevated CK (serum) b. Positive rheumatoid factor c. EMG: 1) Myopathic d. Rare EKG abnormalities: 1) Heart block 2) Arrhythmias e. Chest X-ray: 1) Pulmonary infiltrates f. Muscle biopsy: 1) Single fiber necrosis 2) Eosinophilic infiltration 3) Perivascular and interfascicular distribution of eosinophilic infiltration 7. Differential diagnosis: a. PAN b. Hypersensitivity vasculitis c. Allergic granulomatosis d. Allergic eosinophilic gastroenteritis e. Parasitic infection
Diffuse fascitis with Eosinophilia
A. Clinical features: 1. Onset 30–60 years of age 2. Men greater than women 3. Onset may occur after unusual exertion; may occur without a precipitating event 4. Rapid evolution 5. Some patients have a prodromal period consisting of: a. Low grade fever d. Cramps b. Myalgias e. Fatigue c. Arthralgias 6. Thickening of subcutaneous tissue:
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SECTION XII. Muscle Disease
a. Edema of arms and legs b. Trunk may demonstrate mild edema c. Face is spared 7. Restriction of movement of small joints of the hands, elbows, wrists, knees, and shoulders 8. Rare Raynaud’s phenomenon 9. Visceral involvement is unusual 10. Proximal greater than distal muscle weakness 11. Spontaneous remission is common 12. Rapidly responsive to corticosteroids 13. Aplastic anemia may occur during the illness or following remission of the fascitis B. Laboratory evaluation: 1. Eosinophilia in the blood: a. May be intermittent b. Usually present (86% of patients) 2. Hypergammaglobulinemia occurs in approximately 75% of patients 3. 25% of patients have a positive ANA; occasional elevation of the rheumatoid factor; rare antimicrosomal and antithyroid antibodies 4. Elevation of circulating immune complexes 5. Elevated sedimentation rate 6. EMG: a. Myopathic 7. Muscle biopsy: a. Muscle tissue close to the fascia demonstrates endo and perimysial inflammation b. Single fiber necrosis c. Perifascicular atrophy d. Deposits of IgG and C3 complement in deep muscle fascia
Focal Myositis
A. Clinical features: 1. Asymmetric inflammatory myopathy 2. Weakness and wasting confined to a single limb muscle or one side of the body 3. Weakness may generalize 4. Weakness may remain confined for 1–20 years B. Laboratory evaluation: 1. Elevated serum CK 2. EMG of affected muscle: a. Small motor unit potentials of brief duration b. Fibrillation potentials 3. Muscle biopsy of the involved limb: a. Perimysial inflammatory infiltrate of monocytes b. Single muscle fiber necrosis
Proliferative Focal Myositis
A. Clinical features:
1. 2. 3. 4.
Benign pseudosarcomatous mesenchymal lesions Solitary discrete mass within muscle Freely moveable Painless focal swelling; rarely a dull or lancinating pain 5. Mass most frequently occurs in the shoulder, thorax or thigh 6. Grows rapidly; may double in size within days 7. No precipitating factor 8. No recurrence following excision B. Muscle biopsy: 1. Epimysium, perimysium and endomysium are thickened 2. Proliferation of fibroblasts and histiocytes 3. Myocytes, myotubes, and muscle giant cells are noted 4. Some patients: a. Single fiber necrosis b. Regeneration c. Aggregation of lymphocytes, plasma cells and histiocytes in the endomyserium and perimysium
Localized Nodular Myositis
A. General Clinical Features: 1. Primarily in men 2. Painful. nodular myopathy localized to an extremity 3. Evolves into diffuse myositis 4. Nodules disappear during the transition 5. Dysphagia occurs B. Muscle biopsy: 1. Nodules: a. Large zones of necrotic muscle fibers b. Inflammation in the zones c. Similar pathology to infarction b. Diffuse stages of the disease: 1) Histology is similar to PM/DM
Localized Myositis Ossificans
A. Clinical features: 1. Swelling within muscle 2. Occurs in an area of injury; arm and thigh most frequently involved 3. Area is doughy; evolves into a firm and hard mass 4. Bone can be visualized greater than one month after disease onset B. Pathology: 1. Core of mass contains histiocytes and fibroblasts, giant cells and fibrin 2. Surrounding the core are compact layers of connective tissue 3. Periphery of the core is formed bone
Chapter 7. Inflammatory Myopathy Myositis Ossificans Progressiva
A. Clinical features: 1. AD inheritance 2. Onset in first decade 3. Progressive widespread ossification of many muscles a. Often starts in paraspinal muscles 4. Associated congenital defects: a. Mono phalangeal digit of the great toe and thumb b. Microdactyly c. Wide separation of the great toe and first digit d. Broad neck of the femur e. Absence of two upper incisors f. Hypogenitalism g. Absence of the ear lobes h. Deafness 5. Primary sign is subcutaneous masses of the posterior neck and shoulders: a. Initially masses are warm and tender b. Shrink and become bony hard c. Masses may appear and then disappear B. X-Ray evaluation: 1. Configuration of bone resembles the shape of the muscle 2. Restriction of hip movement by age 20 3. Progressive involvement of muscles of the extremities, abdominal wall, chest and vertebral column 4. Most patients are wheelchair bound by the age of 30 5. Calcification occurs between muscle groups and across joints 6. Bone replaces tendons, fascia, ligaments and muscle 7. Occasional patients may display only skeletal alterations C. Pathology: 1. Primary changes are in connective tissue, dermis and fascia 2. Hemorrhage, inflammation and proliferation of collagen occurs 3. New cartilage and bone formation occur in the altered tissue
2.
3.
4.
5.
Muscle Involvement in Vasculitis
1. Polyarteritis nodosa (PAN): a. Muscle weakness may be symmetrical or asymmetrical 1) Affects approximately 40% of patients b. Associated organ system involvement: 1) PNS – 60%; mononeuritis multiplex, GBS picture, sensorineural neuropathy 2) CNS – rare stroke of large vessels 3) Kidneys – 70%; severe hypertension particularly virulent from in young black patients 4) GI – tract involvement in 30% of patients; hepatic lobe infarction
6.
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5) Skin involvement in 50%; palpable vessel enlargement (often on quadriceps) 6) Testis – 5–30% may suffer infarction 7) Heart-myocardial infarction in approximately 15%; secondary to prolonged hypertension in some Laboratory evaluation: a. Sedimentation rate increased in greater than 90% of patients b. Increased rheumatoid factor in 50% c. Decreased complement in approximately 25% d. Hepatitis-B antigen positive in 30% e. Hepatitis-C positive antigen in 5–20% f. ANCA + in 70% g. Persistent eosinophilia in 77% h. Arteriogram positive 1) Aneurysmal dilatation of medullary kidney arteries Pathology: a. Involvement of small and medium sized arteries and adjacent veins b. The inflammatory cells is the neutrophilic leukocyte c. Splitting and fragmentation of the internal elastic membrane of vessels d. Arterial walls are thickened and nodular e. Aneurysmal dilatation of arterioles; seen on renal arteriograms in the medullary arteries f. Fibrinoid necrosis of arteries Microscopic Polyangiitis: a. 20% of patients suffer a mild symmetric limb girdle weakness b. Associated organ involvement: 1) Glomerulonephritis in 100% of patients 2) Lung involvement (intersitial) 40–50% of patients 3) Skin involvement in 40% of patients 4) Eye – 30% of patients 5) Spleen – 30% of patients 6) CNS – small vessel stroke 7) PNS – mononeuritis multiplex; sensorimotor neuropathy Allergic Arteritis/Granulomatosis: a. Muscle involvement is proximal b. Most frequently occurs in asthmatics c. Clinical evolution is rapid d. Preceding infection is common e. Fever f. Eosinophilia g. Prominent lung involvement h. Subcutaneous nodules i. Non-thrombocytopenic purpura Pathology: a. Disseminated necrotizing arteritis with involvement of: 1) Medium and small arteries 2) Veins and arterioles b. Acute and chronic lesions c. Necrotizing extravascular granulomata d. Lung, heart, skin and muscle involvement
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SECTION XII. Muscle Disease
Wegener’s Granulomatosis
Clinical features
1. Onset after 40 years of age 2. Sinus and upper respiratory tract involvement in 79% of patients 3. Lung diffusely involved (85%) 4. Eye and skin involvement in 50% 5. Glomerulonephritis in 70% of patients 6. PNS-cranial nerve involvement; mononeuritis multiplex, sensorimotor neuropathy – 45% 7. CNS, stroke; occurs conducting vessels in 4–8% of patients 8. Muscle-direct extension of the vasculitis Laboratory evaluation: 1. ANCA: 50–90% of patients 2. RF: 60% of patients Pathology: 1. Small arteries, arterioles, venules and capillaries are involved 2. Fibrinoid necrosis of small arteries and veins 3. Granulomata are interspersed among acute lesions; they are intramural and perivascular 4. Muscle: a. Involved by spread from adjacent tissue b. Necrotizing granulomata in vascular and extravascular distributions
Rheumatoid Vasculitis
A. Clinical features: 1. Muscle involvement occurs in long standing patients: a. Intrinsic hand muscle wasting is prominent (may have associated neuropathy) b. Symmetrical proximal weakness 1) Steroid causes Type II muscle atrophy 2. Associated organ involvement a. Skin: 70% b. Muscle: 55% c. Lungs: 25% d. Kidneys: 25% e. GI: 10% f. Serositis: 10% g. PNS, sensorimotor neuropathy; mononeuritis multiplex: 40–50% h. CNS: 10–15%; medium sized vessel stroke; thickened meninges; occasional seizure from cortical encroachment of meninges B. Laboratory evaluation: 1. RF: 90–95% 2. Increased sedimentation rate: 85% 3. Decreased complement: 45% 4. ANCA: 40%
5. ANA: elevated 50% 6. Eosinophilia: 5–10% C. Pathology: 1. Necrotizing vasculitis 2. Internal hyperplasia of small vessels
Hypersensitivity Vasculitis
1. Criteria: a. Lesions are of one age b. Involvement of small blood vessels c. Non-granulomatous reaction 2. Components of hypersensitivity vasculitis are seen in: a. Rheumatoid arteritis c. Cryoglobulinemia b. SLE 3. Clinical features: a. Skin lesions predominate: 1) Purpura, urticaria, ecchymosis, papules, vesicles, necrotic ulceration 2) Lesions are symmetrical 3) Legs, ankles and feet are primarily involved b. Renal disease is common c. Myalgia and arthralgia may be prominent 4. Pathological features: a. Small blood vessels, arterioles, venules and capillaries are involved b. Non-granulomatous inflammation c. Muscle biopsy: 1) Inflammatory reaction occurs in one stage 2) Involvement of blood vessels, perimysium and endomysium 3) Immune complexes are seen in the walls of blood vessels 5. Laboratory evaluation: a. Increased sedimentation rate: 40–70% b. RF: 15% c. ANA elevated: 15% d. Decreased complement (rare)
Sjögren’s
A. Clinical features: 1. Muscle involvement occurs in approximately 50% of patients 2. Autoimmune dysfunction of salivary and sweat glands; dry mouth, eyes and vagina 3. PNS involvement in 35% of patients; characteristic Vth nerve involvement; sensorimotor neuropathy; sensory neuropathy, mononeuritis multiplex 4. CNS (rare stroke) 5. GI: 50% 6. Glomerulonephritis: 50% 7. Lungs, spleen: involvement is rare
Chapter 7. Inflammatory Myopathy
B. Laboratory evaluation: 1. ANA positive in 90% of patients 2. SSA/RO: 60–70% of patients 3. SSB/LA: 40–60% of patients 4. RF: 60–90% of patients 5. Decreased complement: noted in greater than 50% of patients 6. Cryoglobulins: 15% of patients 7. ANCA: 10% of patients
Systemic Lupus Erythematosus
A. Clinical features: 1. Proximal myopathy occurs in the setting of active generalized disease 2. CNS manifestations: a. Seizures b. Psychosis c. Small vessel strokes d. Chorea e. Migraine f. Emboli from verrucous endocarditis 3. PNS and systemic manifestations a. Generalized vasculitis neuropathy; legs greater than arms b. Mononeuritis multiplex c. Rare cranial neuropathy; CN-II > III > VI d. Skin: malar rash; interphalangeal rash; discoid lesions e. Arthritis and arthralgia of small joints: 85% f. Kidney involvement: 50% g. Pleuritic involvement: 35% i. h Raynaud’s: 30% h. Pericarditis with effusion: 20% B. Laboratory evaluation of antibody prevalence: 1. ANA+ > 90% 2. ds DNA: 60–70% 3. SM: 30–40% 4. RO: 25–40% 5. RF: 40% 6. ANCA: 15%
Giant Cell Arteritis
A. Clinical features: 1. Occurs in patients older than 50 years of age 2. Male = female in incidence 3. Muscle involvement: a. 50% of patients have polymyalgia rheumatica b. Inflammatory reaction of vessels extends into muscle and adjacent connective tissue 4. Intermittent claudication of mastication
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5. Visual loss: infarction of the optic nerve head (posterior ciliary arteries) 6. Perforation of the nasal septum 7. Tender palpable external carotid arteries (less than 30% of patients) 8. Head; burning scalp pain: 30–50% of patients 9. Involvement of other major arteries in 10% of patients: a. Carotid c. Brachial b. Subclavian d. Abdominal B. Laboratory evaluation: 1. Increased sedimentation rate: 70% of patients 2. ANCA rarely positive 3. Arteriogram of extend carotid system positive in 50% of patients C. Pathology: 1. Necrotizing vasculitis 2. Medium to large arteries are involved 3. Giant cells in about 50% of patients 4. Internal elastic membrane is fragmented early 5. Granulomatous infiltration of the involved artery (lymphocytes and eosinophiles)
Laboratory Differential Diagnosis of Vasculitis Affecting Muscle
1. PAN: a. Elevated sedimentation rate b. Leukocytosis c. Anemia d. Dilatation and aneurysmal formation of intramedullary renal arteries e. Aneurysmal dilatation of arteries in skin nodules 2. Allergic granulomatosis/arteritis: a. Peripheral eosinophilia 3. SLE: a. Circulating DNA (particularly when there is associated vasculitis) 4. Differential diagnosis of circulating DNA: a. Chronic hemodialysis b. Pulmonary embolism c. Neoplasms d. Circulating DNA seen primarily with associated vasculitis 5. Hepatitis-B antigen seen in: a. Small and medium vessel vasculitis b. Associated with immunoglobulin and complement and necrotizing small and medium vessel disease 6. ANCA+: Wegener’s disease 7. SSA/RO; SSB/2A-Sjogren’s disease
The Borderline of Muscle Vasculitis
A. Clinical features:
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SECTION XII. Muscle Disease
1. Follows infection with group A streptococcus 2. No muscle symptoms or myalgia B. Pathology: 1. Perimysial and epimysial connective tissue infiltration 2. Mononuclear and inflammatory cells, proliferation of collagen; Aschoff giant cells in perimysium and epimysium
3. Underlying muscle disease, trauma from exercise, hematogenous spread of infection are risk factors B. Clinical Presentation: 1. Localized pain and swelling 2. Increased CK 3. Fever and leukocytosis may be minimal 4. Multiple abscesses occur
Polymyalgia Rheumatica (PMR)
Bacterial Pyomyositis
Clinical Features
A. General Features: 1. Common in the tropics 2. Organisms: a. Staphylococcus aureus (90%) b. A and B hemolytic streptococci c. Escherichia coli d. Streptococcus pneumonia e. Yersinia f. Legionella g. Neisseria gonoccous h. Staphylococcus epidermitis i. Proteus mirabilis j. Pseudomonas k. Salmonella l. Bacteroides 3. Risk factors: a. Local trauma d. Steroids b. HIV infection e. Diabetes mellitus c. IV drug abuse B. Clinical Presentation: 1. Most common areas of involvement are the quadriceps, deltoids and gluteal muscles 2. Paraspinal involvement presents with back pain 3. Group A and B-hemolytic streptococci pyomyositis may be associated with septicemia; also abscess of muscle 4. Clostridial myositis: a. Most lethal b. Clostridium perfringens is most common organism c. Incubation period is 2–4 days d. Acute onset of edema and local tenderness; later a serosanguineous discharge, blebs and green-black cutaneous necrosis; crepitus of the involved tissue e. High fever followed by DIC in severe cases C. Laboratory Evaluation: 1. Neutrophilic pleocytosis 2. Elevated ESR 3. Serum CK is usually mildly elevated
1. Affects middle aged and elderly patients 2. Peak incidence 70–75 years of age 3. Diffuse aching and stiffness in the neck and shoulders initially 4. Later involvement of the pelvic girdle, torso and thighs 5. Minimal (secondary to pain) or no weakness 6. Associated temporal arteritis (16% of PMR patients) 7. Increased incidence of rheumatoid arthritis 8. Median duration of the disease is eleven months 9. Dramatically responsive to a small dose of steroids (5 mg of prednisone) Laboratory evaluation: 1. Sedimentation rate greater than 49 mm/h (during active disease) 2. Elevated immunoglobulin and fibrinogen levels Pathology: A. Muscle biopsy: 1. No significant pathological change B. Deep Abscesses: 1. Tropical climates 2. Young patients 3. Thighs most common site C. Intramuscular abscess: 1. From of tropical myositis 2. Small abscess with less swelling 3. Parasitic etiology 4. Nigeria (dracunculus medinensis) worm D. Burned patients 1. Pyomyositis: direct linear extension of suppuration from the surface to the muscle 2. Core of destruction contains degenerating neutrophiles surrounded by granulomatous tissue 3. Perivascular monocytes at the periphery of the lesion
Pyomyositis
A. General Features: 1. Affects patients in the late stage of immunosuppression 2. Median CD4 count of 50 mm3
Orbital Myositis (Orbital Pseudotumor)
A. Clinical presentation: 1. Inflammation of some or all of the orbital structures
Chapter 7. Inflammatory Myopathy
2. 3. 4. 5.
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Acute onset of unilateral periorbital pain Diplopia Swelling of the eyelid Chemosis and conjunctival infection adjacent to the insertion of the extraocular muscles 6. Ptosis 7. Both orbits are involved seriatim; involvement may be weeks apart 8. Patients may have symptomatic complaints: a. Headache d. Anorexia b. Fever e. Pharyngitis c. Vomiting f. Abdominal pain g. Lethargy 9. Iritis is common (severe photophobia) 10. Papilledema in approximately 40% of patients 11. Precipitating event: a. Upper respiratory illness b. Streptococcal pharyngitis 12. Excellent response to steroids B. Laboratory Evaluation: 1. CT or MRI findings of enlargement of a single or multiple muscles 2. Specific radiologic characteristics: a. Involvement of the tendon (insertion on the globe) b. Enhancement of the sclera and Tenon’s capsule c. Irregular enlargement of the muscle d. Extension of the inflammation to the orbital fat e. No bone involvement f. ESR elevated during the acute stage g. Eosinophilia and antinuclear antibodies are occasionally noted C. Pathology: 1. Lymphocytes, plasma cells and eosinophils are the muscular inflammatory infiltrate D. Differential Diagnosis: 1. Grave’s Disease 2. Tumor infiltration 3. Orbital myositis 4. Carotid cavernous fistula 5. AVM 6. Parasellar mass (compresses venous outflow from the orbit)
3. Metastatic: a. Breast cancer; scirrhous from pulls the eye in b. Small cell cancer of the lung c. Melanoma 4. Usually a separate lesion that compresses or enlarges the muscle
Grave’s Disease
Wegener’s Granulomatosis
1. Inferior rectus may enlarge first; collier’s sign (pathologic lid retraction; early) a. May be unilateral
1. Acute orbital pain 2. Ocular pareses 3. Destruction of the sinuses and the nasopharynx
Tumor Infiltration
Pseudothrombophlebitis Syndrome Affecting Muscle
1. Lymphoma-superior rectus muscle involved first 2. Rhabdomyosarcoma (underlying tuberous sclerosis)
1. Mimics signs and symptoms of deep vein thrombophlebitis
Carotid Cavernous Fistula
1. Traumatic precipitating cause 2. Arterialized con junctural veins that reach the iris (in an infection, veins do not reach the iris) 3. Bruit over the orbit 4. Enlargement of the superior or inferior ophthalmic vein on MRV
AVM
1. Chemosis 3. Partial ophthalmoplegia 2. Proptosis 4. Arterialized venous blood on the sclera
Parasellar Mass
1. Cranial nerve involvement (III or IV) 2. May involve optic nerve and chiasm
Infection (Bacteria, Fungi, Parasites)
1. Bacteria: a. Gain access to the orbit through the lamina papyracea of the medial wall of the ethmoid sinus b. Severe orbital and periorbital edema and pain 2. Fungus: a. Mucormycosis (Rhizopus): 1) Immunosuppressed patient 2) Ophthalmoparesis 3) Venous sinus occlusion (black palate-occlusion of sigmoid and jugular sinuses)
SECTION XII. Muscle Disease
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2. Clinical features: a. Swelling; warmth and tenderness of the calf b. Positive Homan’s sign c. Pedal edema d. Popliteal mass 3. Etiology is popliteal synovial cyst: a. Ruptured or has dissected into the calf b. Associated with inflammatory joint disease c. Rupture precipitated by exercise or knee injury d. Rule out localized polymyositis
Chapter 8 Metabolic Muscle Disease
Metabolic muscle disease presents as exercise intolerance, cramps and myoglobinuria with or after strenuous exercise or as progressive weakness. The type and duration of specific exercise offers insight into the metabolic deficiency causing specific clinical symptoms. Burst muscle activity such as sprinting utilizes anaerobic metabolism and Type II muscle fibers. Prolonged less than maximal intensity exercise (measured by oxygen utilization) requires glucose derived from glycogen stores as the primary energy source. Prolonged exercise, such as distance running, free fatty acids (FFA) are utilized for ATP production. Many mitochondrial myopathies suffer weakness and exercise intolerance with minimal activity. Exhaustion of glycogen is correlated with fatigue and myoglobinuria which is seen with energy failure and muscle breakdown from any cause of failure to produce adequate ATP.
General Categories of Defects in Metabolic Muscle Disease
Disorders of Glycogen Metabolism
Type II – Acid maltase deficiency Type III – Amylase 1, 6 glycosidase deficiency (debrancher) Type IV – Amylase 1, 4 to 1, 6 transglycosylase deficiency (brancher) Type V – Myophosphorylase deficiency (McArdle’s disease) Type VII – Phosphofructose kinase deficiency (PFK) Type IX – Phosphoglycerate kinase deficiency (PGK) Type X – Phosphoglycerate mutase deficiency (PGM) Type XI – Lactate dehydrogenase deficiency (LDH) Disorders of Lipid Metabolism
1. Carnitine deficiency 2. Carnitine palmityl transferase deficiency (CPT) 3. Lipid storage myopathies Disorders of Adenine Nucleotide Metabolism
1. Adenylate deaminase deficiency (AMPD) Mitochondrial Dysfunction
Exercise intolerance: 1. Luft’s disease 2. NADH-CO Q reductase deficiency 3. Cytochrome b deficiency Mitochondrial dysfunction with progressive weakness: 1. Kearns–Sayre syndrome 2. ATPase deficiency 3. Cytochrome-c-Oxidase deficiency 4. MERRF (mitochondrial encephalomyopathy with ragged red fibers) 5. MELAS (mitochondrial encephalomyopathy with lactic acid and stroke) 6. PEO (progressive external ophthalmoplegia)
Free Fatty Acids (FFA)
Metabolic Disorders of Muscle
Phosphorylase Deficiency (Type V McArdle’s Disease)
A. General Features: 1. Exercise intolerance 2. Cramps with exercise 3. Myoglobinuria with exercise 4. Second wind phenomena (same entities) B. Weakness of muscle: 1. Episodic: a. Phosphorylase deficiency b. Phospho fructose kinase deficiency c. Carnitine palmityl transferase deficiency d. Acid maltase deficiency e. Debrancher deficiency f. Brancher deficiency
A. Genetics: 1. AR; male to female 2.39 : 1 2. Chromosome 11 3. 16 different mutations; most common is a cytosine to thymine substitution codon in 49 of exon 1; may be analyzed in leukocytes 4. Stored glycogen accumulates at the subsarcolemma areas of muscle fibers (subsarcolemmal vacuoles) B. Clinical Presentation: 1. Exercise intolerance: a. Myalgia and early fatigue; weakness of the exercised muscle; easy fatigability in childhood; isometric exercise and sustained dynamic exercise precipitate symptoms
Chapter 8. Metabolic Muscle Disease
b. Relieved by rest c. Any muscle may be affected; includes masseters and throat muscles d. Exercise (isometric or sustained) may precipitate symptoms; the amount of exercise required for symptoms may vary day to day e. Second wind phenomenon: 1) Rest at first sign of myalgia; then patients are capable of further exercise f. Painful cramps with muscle swelling if exercise tolerance is exceeded; true cramps g. Muscle necrosis and myoglobinuria after severe exercise h. Few patients recognize impending myoglobinuria attacks i. Renal failure occurs in 25% of patients with myoglobinuria j. Muscle pain; stiffness, weakness with exercise relieved by rest as the patient enters adulthood 2. Permanent weakness: a. Usually mild b. Proximal greater than distal muscles in 1/3 of patients c. Weakness increases with age d. Wasting is uncommon; when it is severe it occurs in older patients e. Exercise intolerance occurs in childhood f. Increase of seizures greater than in the general population C. Heterogeneity: 1. Excessive tiredness or fatigue rather than cramps or myoglobinuria as the major complaint 2. Progressive weakness rather than cramps or myalgia 3. Several elderly patients have demonstrated proximal weakness wasting and ptosis 4. Late onset myopathy with weakness 5. A few children have weakness at or soon after birth; respiratory insufficiency; death in infancy 6. Recurrent myoglobinuria in adults 7. Late onset asymmetric arm weakness (one patient) D. Laboratory Evaluation: 1. CK variably increased (92%) 2. EMG (abnormal in 40%): a. Normal between attacks of myoglobinuria b. Increased insertional activity c. Increased polyphasic potentials d. Increased muscle irritability-fibrillation, myotonic discharges and positive sharp waves e. No electrical activity during the cramp 3. EKG: a. Minor abnormalities that are non-specific have been reported in a few patients; abnormal increase of heart rate with exercise 4. EEG:
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a. Spike and slow waves are noted in some patients with seizures 5. Positive forearm ischemic exercise test: a. No rise of lactate and pyruvate with exercise b. In normal patients there is usually a 3–5 fold increase of pyruvate and lactate at 1 and 3 minutes after exercise 6. Pathology: a. Subsarcolemmal deposits of PAS positive glycogen, and vacuoles
Phospho Fructose Kinase Deficiency (Tarui’s Disease) Glycogenosis Type VII
1. Genetics: a. AR: 1) Chromosome 1 – encodes muscle (M) subunit 2) Chromosome 2 – encodes the liver (L) subunit 3) Chromosome 10 – encodes platelet enzyme 2. Group I: a. M subunit of muscle is defective b. Major symptom complex is myopathy and hemolysis c. Clinical features: 1) Adults at diagnosis, noted exercise intolerance in childhood 2) Exercise intolerance or cramps: a) Isometric exercise induces cramps b) Phasic activity induces cramp and myoglobinuria c) Intermittent degrees of exercise intolerance d) Process starts in childhood e) Patients are nauseated with exercise that induces cramps f) Permanent weakness may occur after a childhood illness g) Glucose decreases exercise capacity h) Fixed weakness in later life in a few patients 3) Myoglobinuria: a) Myoglobinuria and renal failure are less common than in myophosphorylase deficiency 4) Second wind phenomena occurs 5) Rare seizure 6) Gout 7) Exercise of moderate intensity is better tolerated d. Laboratory evaluation: 1) CK is increased 2) Ischemic exercise test is positive 3) Decreased RBC, PFK in 50% of patients 4) Hemolysis with elevated reticulocyte count: a) Some patients are mildly jaundiced b) Cholecystectomy for gall stones is necessary in some adolescent patients 5) High serum urate 6) Muscle biopsy:
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SECTION XII. Muscle Disease
a) PAS positive vacuoles 3. Group II Patients: a. Hemolysis without myopathy b. L-subunit disorder; unstable unit c. PFK is normal in muscle; 60% of normal in RBCs d. No muscle symptoms e. Clinical characteristics: 1) Jaundice 2) Hemolysis 4. Group III-infantile myopathy: a. PFK-M normal b. Delayed motor development c. No hemolysis d. Congenital joint deformities 5. Laboratory evaluation: a. Normal or myopathies features b. Muscle irritability; fibrillation potentials, pseudomyotonia, positive sharp waves c. No EMG activity during a cramp 6. Ischemic Exercise Test: a. No rise in venous lactate b. MR spectroscopy, no increase in lactate 7. Muscle biopsy: a. Same pattern as noted in phosphorylase deficiency
Physiology
1. Abnormal Polysaccharide in 2–10% of muscle fibers instead of glycogen 2. High levels of adenosine diphosphate 3. Increased production of ammonia and myogenically induced uric acid 4. Exaggerated sympathetic neural response to exercise: a. Enhanced mobilization of extra muscular substrate b. Increased heart rate c. Increased cardiac output and blood flow in relation to muscle oxygen consumption 5. Glucose diminishes exercise tolerance: a. lowers the level of circulating FFA and ketones (the alternate substrate for metabolism) b. opposite of myophosphorylase
6. Myoglobinuria 7. Prolonged exercise of modulate intensity can be accomplished C. Hemizygous males: 1. Severe hemolytic anemia after births; hemolytic crisis precipitated by infections 2. Mental retardation, delayed language acquisition, behavioral aberrations and seizures D. Laboratory evaluation: 1. Anemia 2. Severe reticulocytosis 3. Erythroid hyperplasia of the bone marrow 4. Residual muscle enzyme activity of 5% due to mutant enzyme
Phosphoglycerate Mutase Deficiency (Glycogenosis X)
A. Genetics: 1. AR; chromosome 7 2. Muscle specific M subunits; brain specific B subunits B. Clinical manifestations (PGAM): 1. Myalgia 2. Cramps 3. Myoglobinuria (recurrent) 4. Intense exercise is the precipitant 5. Childhood onset C. Laboratory evaluation: 1. Ischemic exercise test: a. Positive lactate elevation greater than two times above pre-exercise level b. Elevated CK c. EMG/NCV - normal 2. Muscle biopsy: a. Increased PAS positive granules b. Subsarcolemmal pools of glycogen c. Tubular aggregates in type II B muscle fibers d. Decrease in the activity of PGAM to 5–6% of normal activity
Lactate Dehydrogenase Deficiency (glycogenosis Type XI) Phosphoglycerate Kinase Deficiency (Glycogenosis Type IX)
A. Genetics: 1. X-linked recessive; X q 13 B. Clinical characteristics: 1. Nonspherocytic hemolytic anemia 2. CNS dysfunction; one child with myopathy and mental retardation 3. Exercise intolerance 4. Cramps 5. Primary myopathy
A. Genetics: muscle component gene on chromosome II B. LDH: tetrameric enzyme composed of a: 1. Muscle specific subunit (LDH-A); encoded by gene or chromosome II 2. Cardiac subunit (LDH-B) C. Clinical features: 1. Pigmenturia following intense exercise 2. A few patients have had dystonia during childbirth 3. Dermatologic abnormalities D. Laboratory evaluation: 1. Decreased rise in lactate; abnormal rise in pyruvate
Chapter 8. Metabolic Muscle Disease
2. High CK 3. The amount of residual enzyme activity in muscle is approximately 5% of normal 4. Muscle: a. 5% of normal enzyme activity in muscle
Differential Diagnosis of Myophosphorylase Deficiency
The major myopathies that comprise the differential diagnosis are other metabolic myopathies terminal glycogenases. These include: • PFK (phospho fructokinase) • PGK (phospho glycerokinase) • PGAM (phosphoglyceromutase) • LDH (lactate dehydrogenase) Patients with PFK differ from those with McArdle’s disease (myophosphorylase deficiency) in that they have: • Less of a second wind phenomena; glucose may be deleterious for them • Severe nausea and vomiting occurs during exercise induced cramps • Less myoglobinuria • Increased bilirubin in the serum • An increased reticulocyte count Patients with terminal glycogenosis, PGAM, PGK, and LDH, have an abnormally low lactate rise during the ischemic exercise test, but it is not absent. LDH deficiency demonstrates a low lactate and high pyruvate under ischemic stress. Carnitine palmityl transferase deficiency Type II is the most common cause of recurrent adult myoglobinuria. This occurs not only with exercise, but also with fasting without exertion. The ischemic exercise test is negative in CPT II deficiency. In myophosphorylase deficiency the myoglobinuria occurs with and following intense exercise. Exercise induced myoglobinuria may also occur with DMD, BMD and malignant hyperthermia. The AR recessive genetics pattern, interval CK and clinical presentation rule out the dystrophinopathies. Malignant hyperthermia is AD and there is often a family history of death or unexpected anesthetic complication. Undue fatigue with exercise and without myoglobinuria occurs with terminal glycogenoses as well as with adenylate deaminase deficiency (AMPD). In this myopathy the ischemic exercise test demonstrates a normal rise in lactate, but no increase in ammonia.
B. Clinical features: 1. Infantile, childhood and adult variants C. The spectrum of disease: 1. The onset can be in infancy but the patient may survive into the second decade 2. May present during the first few years of life and the patient succumbs near the end of the second decade 3. May present in the 7th decade
Infantile Acid Maltase Deficiency (Pompe’s Disease; Glycogenosis Type II)
A. Genetics: 1. AR 2. Long arm of chromosome 17 B. Clinical features: 1. Onset is in the first few months of life; the clinical course is rapidly progressive 2. Progressive weakness and hypotonia 3. Respiratory failure 4. Feeding difficulties 5. Cardiorespiratory failure by age 2; cardiomegaly 6. Macrogenesis C. Laboratory evaluation: 1. Response of blood glucose to epinephrine or glycogen is normal 2. EMG; myopathic; irritatives features 3. EKG: a. Short PR interval b. Thickening of the interventricular septum c. High QRS voltage d. Left ventricular hypertrophy 4. CK – increased 5. Chest X-ray: congestive heart failure; massive heart enlargement D. Pathology: 1. Glycogen accumulates in the liver, heart and skeletal muscle 2. Microscopic examination reveals glycogen in: a. Smooth muscle b. Endothelial cells c. Lymphocytes d. Cellular components of the eye e. Neurons of the brain and spinal cord; anterior horn cells and brainstem nuclei f. Schwamm cells of peripheral nerves
Acid Maltase Deficiency Childhood Acid Maltase Deficiency
A. Genetics: 1. AR; chromosome 7 2. Acid maltase: a. Lysosomal L-glucosidase b. Releases glucose from maltase, oligosaccharides and glycogen
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A. Genetics: AR B. Compound heterozygosis C. Clinical features: 1. Onset in infancy or early childhood 2. Primarily myopathic; no cardiomegaly
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SECTION XII. Muscle Disease
3. 4. 5. 6. 7.
Delay of motor milestones Weakness is proximal greater than distal Respiratory muscles are affected early Calf enlargement occurs Death from respiratory failure is usual; rarely there is survival past the second decade 8. Enlargement of the liver, heart and tongue is rare D. Laboratory evaluation: 1. Serum CK: increased E. EMG: 1. Myopathic with irritative features F. Pathology: 1. Less marked glycogen in muscle than in the infantile from 2. Acid maltase in muscle 3. Little glycogen in heart, liver, skin and the nervous system
Acid Maltase Deficiency in Adulthood (Glycogenosis Type II)
A. Genetics: AR; chromosome 17 mutations B. Clinical features: 1. Slowly progressive myopathy; proximal greater than distal; lower extremity greater than the upper extremity; usually starts in 3rd or 4th decade; some patients onset in sixth or seventh decade 2. Respiratory failure occurs 3. Weakness affects the torso; may involve individual muscles or parts of muscles selectively 4. Loss of reflexes occurs late in the illness 5. 1/3 of patients present with respiratory failure 6. Atrophy is proportionate to weakness 7. Cardiac dysfunction is rare in adults 8. Massive headaches and exertional dyspnea (CO2 retention and diaphragm involvement) 9. No visceromegaly; glycogen in cerebral vessels may cause aneurysms C. Laboratory evaluation: 1. Serum CK: may be normal or slightly elevated 2. EMG: a. Myopathic b. Increased muscle irritability c. Myotonic discharges (paraspinal and abdominal muscles) d. Fibrillations, positive sharp waves, repetitive discharges at rest and myotonia 3. Urine: a. Decreased acid maltase 4. Pulmonary function studies demonstrates restrictive ventilatory deficit with respiratory muscle fatigue 5. Acid and neutral maltase activity in lymphocytes is decreased D. Pathology:
1. Vacuolar myopathy: a. All fibers are affected in severe patients b. Vacuoles contain glycogen; acid phosphatase positive c. Longitudinal fiber splitting in adult patients d. Lysosomal and sarcoplasmic glycogen deposits: Type I > II fibers e. Decreased acid maltase in muscle; biopsy from clinically unaffected muscles may be normal
Differential Diagnosis of Acid Maltase Deficiency
The infantile from of the disease presents with severe weakness and hypotonia. The differential diagnosis includes Werdnig Hoffmann’s disease (SMAI) and the other congenital metabolic or myopathic diseases. The major differential feature is severe congestive heart failure and macroglossia. Mitochondrial disorders such as COX deficiency may involve proximal muscles and the heart, but not to the same degree. Macroglossia is not a feature of mitochondrial disease. Debrancher deficiency presents with massive hepatomegaly and hypoglycemia. There is no rise of blood glucose to epinephrine or glycogen. Phosphorylase kinase deficiency may present with severe cardiomegaly in infancy, but lacks muscle weakness. Duchenne dystrophy has clear X-linked genetics more prominent calf hypertrophy and the EMG does not demonstrate irritative features. Carnitine deficiency does not have the same degree of cardiac dysfunction or macroglossia. Congential myopathies occasionally present with similar body habitus and include myotubular myopathy, central core disease and nemaline myopathy. Thinness, high arched palate, long facies are characteristic of nemaline myopathy while bilateral symmetrical ptosis is present in myotubular myopathy. Muscle biopsy clearly differentiates these congenital myopathies. Adult acid maltase deficiency is frequently misdiagnosed as limb girdle muscular dystrophy or polymyositis. The early respiratory muscle involvement as well as paraspinal myotonic discharges and complex repetitive action potentials differentiate the entities. Two adult variants of autophagic vacuolar myopathy occur with a similar phenotype. One with cardiomyopathy and mental retardation due to a mutation of the gene for lysosome associated membrane protein-2 (LAMP-2 gene) and the other with myopathy and multiorgan involvement. Muscle biopsy differentiates the vacuoles from PFK and acid maltase in the urine and the irritative EMG establishes in the diagnosis of AMD. Glycogen positive acid phosphatase containing vacuoles in AMD (acid maltase disease) distinguishes this entity from chloroquine vacuolar myopathy. This entity may have concomitant macular retinopathy.
Chapter 8. Metabolic Muscle Disease Debrancher Enzyme Deficiency (Cori–Forbes Disease): Glycogen Storage Disease Type III
A. Genetics: AR; chromosome 1p21 B. Debranching enzyme catalyses two reactions: 1. Oligo-11,4-1,4-glucantrousferase 2. Amylo-1,6-glucosidase C. Biochemical variants of the disease: 1. Type IIIa – common deficiency of both enzyme activities in muscle and liver 2. Type IIIb – less common; mutations in exon 3 3. Type IIId – rare; deficiency of oligo-1,4-1,4-glucantransferase D. Clinical features – infantile form: 1. Hepatomegaly 2. Hypoglycemia 3. Hypotonia (floppy baby) 4. Enlarged tongue with fibrillations 5. Congestive heart failure 6. Growth failure 7. Hypotonia and myopathy increase with age 8. Disease may improve after puberty 9. No exercise intolerance 10. Muscle weakness occurs after disappearance of liver symptoms E. Clinical features – adult from: 1. Usually had been less active than normal children 2. Onset of weakness in the third or fourth decade 3. Myopathy may be more distal than proximal 4. Wasting of leg muscles and intrinsic hand muscles 5. No exercise intolerance and myoglobinuria 6. Some patients have a preference for a high protein and low carbohydrate diet F. Laboratory evaluation: 1. Elevated CK 2. EMG: a. Mixed myopathic and neuropathic picture b. Some patients have slowed nerve conduction velocities 3. No or minimal increase of lactate in the ischemic exercise test 4. Muscle biopsy: a. Subsarcolemmal collection of glycogen b. Increased glycogen between and within fibrils c. No glycogen excess in muscle d. No glucose rise after epinephrine or glycogen stimulation e. Subsarcolemmal PAS positive deposits f. Vacuoles in Type II fibers
Brancher Enzyme Deficiency (GSD IV; Anderson’s Disease)
A. Genetics:
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1. AR; gene is on chromosome 3; primarily Jewish patients 2. Spectrum of clinical phenotypes 3. Defect can be silent; alternatively there may be dysfunction in the liver, heart, brain or skeletal muscles 4. Brancher deficiency reported only in Ashkenazi Jewish patients B. Clinical features – infantile from: 1. Failure to thrive 2. Hypotonia 3. Muscle atrophy 4. In a few older children the predominant problem is cardiomyopathy 5. Progressive cirrhosis with chronic hepatic failure C. Clinical features – adult from: 1. Distal muscle wasting (intrinsic hand muscles) 2. Enlarged liver 3. Cardiac myopathy 4. Brain involvement (adult polyglucosan body disease) late onset upper and lower motor neuron death, sensory loss, sphincter problems and dementia D. Laboratory evaluation: 1. Serum CK is normal 2. Flat ischemic exercise test 3. EMG is myopathic 4. Muscle biopsy: a. Increased glycogen on EM b. Type II fibers contain PAS + vacuoles c. Subsarcolemma deposition is amylopectin
Aldolase A Deficiency (Glycogenosis Type XII)
1. Genetics: enzyme is in erythrocytes and skeletal muscle 2. Clinical features: a. May have isolated non-spherocytic hemolytic anemia b. Proximal myopathy c. Exercise intolerance and weakness after febrile illness
Carnitine Deficiency and Lipid Storage Myopathy
Carnitine Deficiency State
1. There is insufficient intracellular carnitine for: a. Transport of long-chain fatty acids into mitochondria b. Modulation of intramitochondrial coenzyme A (CoAacyl CoA) 2. Most carnitine deficiencies syndrome: a. Secondary to inborn errors of metabolism b. Suffer metabolic crisis triggered by the carnitine deficiency c. Lipid storage myopathies: 1) Definition: a) Abnormal amounts of lipid accumulate in muscle
SECTION XII. Muscle Disease
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b) The abnormal lipid accumulation is the predominant pathological process 2) Lipid accumulation correlates with the oxidative capacity of muscle fibers a) Type I > 2A > 2B fibers b) Mitochondrial abnormalities may occur concomitantly: (1) Increase in the number and size of mitochondria (2) Intra mitochondrial inclusions (3) Altered morphology of mitochondrial cristae c) Abnormal lipid deposits are primarily triglycerides
General Characteristics of Lipid Storage Syndrome
1. Some defects of lipid metabolism, principally carnitine palmityl transferase, do not have lipid storage myopathy 2. Muscle fiber lipid content can vary: a. From patient to patient with the same disorder b. In different lipid metabolic disorders c. During the course of the disease 3. Defects in other metabolic pathways: a. Fatty acid oxidation b. Utilization of long chain fatty acids 4. Ischemia and obesity increase lipid muscle fiber content
Systemic Carnitine Deficiency
A. Genetics: AR; chromosome 5 q: 1. Encodes organic cation transporter in kidney intestine, muscle, heart and fibroblasts 2. No gender difference 3. 50% of described patients have had siblings who died suddenly or who had cardiomyopathy B. Clinical features: 1. Onset one month to seven years of age 2. Heterogeneity of clinical presentation 3. Progressive cardiomyopathy is most common: a. Dilated cardiomyopathy b. Peaked T waves c. Ventricular hypertrophy d. Poor response to diuretics or digitalis e. Endomyocardial biopsy demonstrates massive lipid storage f. Carnitine concentration is less than 5% in the myocardium 4. Infant presentation: a. Acute encephalopathy b. Hypoketotic hypoglycemia c. Hepatomegaly d. Myopathy is associated with cardiomyopathy or encephalopathy
e. Motor delay and hypotonia f. Crisis resemble those of Reye’s syndrome in greater than 75% of patients 5. Adolescent and adult presentation a. Low levels of free carnitine in plasma, liver and other tissues C. Clinical presentation: 1. Myopathic weakness may follow an episode of recurrent hepatic encephalopathy. They have preceded or have been noted concomitantly with attacks 2. Hepatic encephalopathy attacks characterized by: a. Nausea and vomiting b. Somnolence c. Mental confusion d. Hepatomegaly e. Increased liver enzymes f. Increased serum ammonia g. Hypoglycemia (some patients) h. Metabolic acidosis i. Increased urinary excretion of dicarboxylic acids 3. Encephalopathy triggered by: a. Fasting b. Intermittent infection 1) May remit spontaneously c. Death due to cardiorespiratory failure d. Weakness: 1) Proximal greater than distal 2) Eyelids, face and neck may be involved 3) Begins abruptly 4) Fluctuates 5) May rapidly progress during pregnancy or post partum 6) After anesthesia 7) Prolonged fast j. Heart and peripheral nerves are affected in some patients D. Laboratory evaluation: 1. Serum: a. Increased CK b. Serum carnitine is decreased in most patients c. All patients have decreased liver, muscle and heart carnitine 2. EMG: a. Myopathic 6. Pathology: a. Lipid accumulation in muscle and liver greater than heart and kidney
Primary Muscle Carnitine Deficiency
1. Free carnitine levels less that 25% of normal in muscles; normal or slightly low in other tissues or plasma 2. Clinical presentation:
Chapter 8. Metabolic Muscle Disease
a. Slowly progressive myopathy in childhood or adolescence b. Late onset patients well documented c. Weakness; usual onset 2nd – 3rd decade: 1) Proximal greater than distal muscles 2) Trunks is involved 3) Rarely face, pharyngeal and neck muscle involvement d. Weakness may fluctuate or progress rapidly e. Exercise intolerance may develop prior to weakness f. Cardiomyopathy is rare 3. Laboratory evaluation: a. Serum: decreased muscle carnitine (less than 20% of normal) with normal serum carnitine b. Pathology: accumulations of triglycerides in Type I fibers greater than Type II fibers
Mixed Carnitine Deficiency
1. Clinical features of an overlap syndrome: a. Signs and symptoms of systemic carnitine deficiency b. Normal serum carnitine 2. Clinical picture of myopathic carnitine deficiency: a. Normal liver function b. Decreased serum carnitine Carnitine deficiency is noted in: 1. Chronic hemodialysis 2. Cirrhosis and cachexia 3. Severe and chronic myopathies (muscle) 4. Kwashiorkor (serum) 5. Idiopathic Reye’s Syndrome 6. Myxedema 7. Hypopituitarism 8. Adrenal insufficiency 9. Pregnancy 10. Pyruvate treatment 11. Renal Fanconi syndrome 12. Diphtheria 13. Total parenteral nutrition in infants
Metabolic Defects in Association with Carnitine Deficiency
1. Acyl-CoA dehydrogenase defects 2. Coupling of acyl-CoA dehydrogenase to the respiratory chain 3. Defects in enzymes of organic acid metabolism 4. Defects in the respiratory chain 5. Defects in oxidative-phosphorylation coupling 6. Folate metabolism defects 7. Renal Fanconi syndrome 8. Medium chain carnitine acyltransferase defects
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Secondary Carnitine Deficiency Syndrome
1. Acyl-CoA dehydrogenase deficiencies: a. Short chain acyl-CoA enzyme synthetase dehydrogenase deficiency 1) substrate is butyl CoA b. Medium chain acyl-CoA synthetase dehydrogenase deficiency 1) Substrate is C6-C10 acyl CoA c. Long chain-acyl CoA – synthetase – dehydrogenase deficiency 1) Substrate is C14-C22 acyl Ca A 2. Short-chain Acyl Coenzyme A Synthetase Dehydrogenase Deficiency (SCAD) a. Clinical presentation: 1) Onset in infancy 2) Poor feeding, vomiting, failure to thrive 3) Seizures 4) Psychomotor retardation 5) Hyperactivity b. Childhood from: (1 patient) 1) Myopathy a) Congenital muscles affected: neck and facial muscles b) Later axial limb and respiratory muscle involvement c) Ptosis and progressive external ophthalmoplegia d) Cataracts e) Proximal asymmetric muscle weakness c. Laboratory evaluation: 1) Normal CK 2) Lactic acidemia with minimal exercise d. 36 hour fast: 1) No hypoglycemia 2) Increased ketone body formation e. Muscle biopsy: 1) Type I fiber predominance 2) Hypotrophy; multicores 3) Muscle carnitine 30% of normal f. Urinary excretion of methylmalonic acid (30x normal) increased excretion of methyl succinic acid 3. Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCAD): a. Genetics: 1) Chromosome 1p31; K304E mutation is present in more than 90% of patients b. Clinical presentation: 1) Onset in some patients 5–25 months; others later in childhood 2) An episodic illness resembling Reye’s syndrome 3) Less severe than long chain acyl-CoA dehydrogenase deficiency 4) Causes hypoketotic-hypoglycemic coma: a) Precipitants: (1) Fasting (3) Viral illness (2) Stress
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5) Lethargy and vomiting followed by altered consciousness or coma 6) Mild hyper ammonemia during attacks 7) Muscle weakness appears or worsens during attacks: a) Resolves slowly b) Proximal greater than distal distribution c) Patients are easily fatigued between attacks: (1) Seizures (3) Cardiac arrest (2) Apnea (4) Sudden death c. Laboratory evaluation: 1) Serum: a) Mild hyperammonemia during attacks b) Increased liver enzymes c) Mild hypo prothrombinemia d) Moderate increase of CK e) Decreased serum carnitine between attacks f) Fractions of serum carnitine may increase during crisis or fasting 2) Urine: a) Increased excretion of dicarboxylic acids in the urine; increases during the crisis: (1) Increased excretion of hexanoyl glycine and sulfur glycine during attacks is characteristic (2) Octanol carnitine is always present in the urine 3) Muscle biopsy: a) Increased lipid storage in muscle 4. Long chain Acyl-CoA Dehydrogenase Deficiency (LCACD): a. Genetics: probable AR b. Clinical presentation 1) Onset neonatal or first three months of life 2) Failure to thrive 3) Post prandial vomiting with or without diarrhea 4) A ketotic hypoglycemic encephalopathic crisis 5) Hepatomegaly 6) Hypertrophic cardiomyopathy 7) Hypotonia c. Laboratory evaluation: 1) Urine: Dicarboxylic aciduria during fasting or crisis 2) Serum: low total serum carnitine 3) Muscle: LC-Acyl-CoA dehydrogenase 10% of normal
Multiple Acyl-CoA Dehydrogenase Deficiency (Glutaric Aciduria Type II); MUL-ACD
1. Electron transfer flavoprotein deficiency (ETF) and ETF CoQ10 oxidoreductase deficiency result in multiple acylCoA dehydrogenase deficiencies that cause: a. An inability of reducing equivalents from the acyl-CoA dehydrogenase to be accepted by an electron transferring flavoprotein (ETF)
b. Failure of oxidized ETF: ubiquinone oxidoreductase (complex I of the mitochondrial chain) c. Flavin adenine dinucleotide (FAD) is a cofactor for: 1) Three acyl-CoA dehydrogenase enzymes 2) ETF 3) ETF: Q10
Clinical Presentations of MUL-ACD Deficiency
Congenital from: a. Premature birth b. Polycystic kidneys, facial dysmorphism, abdominal wall and genital anomalies c. Hypoglycemia and acidosis d. Death during the first weak e. Lipid storage in muscle, heart, and kidney Similar congenital from: a. No associated anomalies b. Cardiomyopathy (some patients) Late onset variant: a. AR b. Onset: first few months of life to the second decade c. Clinical Characteristics: 1. Intermittent episodes: a) Vomiting b) Hypoglycemia c) Acidosis d) Mild hyperammonia e) Increased liver enzymes f) Protein intolerance d. Precipitating features: 1. Fasting 3. Infection 2. Pregnancy e. MUL-ACD: may become symptomatic in heterozygotes during pregnancy f. Carnitine deficiency occurs: increased levels of esterified to free carnitine in the serum g. A riboflavin responsive from of glutaric aciduria Type II occurs in adults: 1) Improvement of wasting and weakness within weeks of treatment
Organic Acidurias with secondary Carnitine Deficiency
Enzyme Deficiencies
1. 2. 3. 4.
Isovaleric Co-A dehydrogenase Propionyl Co-A carboxylase Methylmalonic Co-A mutase B-hydroxy-G-Methyl glutaric Co-A hydrolase
Chapter 9. Mitochondrial Myopathies Clinical Characteristics
1. 2. 3. 4. 5.
Hypoglycemia Ketoacidosis Hyperammonia Encephalopathic crisis muscle weakness between attacks; excretion of methylmalonic acids
General Characteristics of Defects in the Mitochondrial Respiratory Chain or in Oxidative Phosphorylation
1. NADH – ubiquinone reductase and succinyl cytochrome c-reductase 2. Maternal transmission 3. Clinical features: a. Fatigue of muscle on exertion b. Lactic academia c. Marked lipid deposition in muscle (rare) d. Muscle weakness is proximal greater than distal e. Carnitine depletion in muscle f. Associated neurological deficits depend on the specific entity
Chapter 9 Mitochondrial Myopathies 1. 2. 3. 4.
Cytochrome and oxidase deficiency Multiple cytochrome deficiency Pyruvate carboxylase deficiency Pyruvate decarboxylase deficiency
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Idiopathic Reye Syndrome
1. Clinical characteristics: a. Associated with ketoacidosis b. LC-ACD and M-ACD deficiencies are noted c. Intermittent encephalopathy d. Carnitine levels are normal between attacks
Valproate Therapy
1. Decrease free serum carnitine: occurs primarily in children 2. Increase serum ammonia: dose dependent 3. Four to six day gradual increase of lethargy, vomiting, anorexia, jaundice and edema 4. Hypo carnitinemia
Renal Fanconi Syndrome
1. Increased fractional excretion of free carnitine and acylcarnitine 2. Clinical characteristics: a. Nephropathic calcinosis b. Oculocerebrorenal syndrome c. Hypoglycemia and hyperammonia d. Decreased serum carnitine f. A few patients have had muscle weakness and lipid storage myopathy
Chronic Renal Failure Treated by Hemodialysis
a. Fall of serum carnitine during dialysis b. Increase of free fatty acids in serum
Carnitine Octanol Transferase Deficiency
Clinical Characteristics
1. 2. 3. 4. 5.
Recurrent encephalopathy Cardiomyopathy Dicarboxylic aciduria Hypotonia Decreased muscle carnitine
Methylene Tetrahydrofolate Reductase Deficiency
1. Defect causes decrease of S-adenosylmethionine for carnitine synthesis 2. Clinical features: a. Progressive leukoencephalopathy b. Flaccid paralysis c. Homocystinuria and homocystinemia d. Decreased muscle carnitine e. Lipid storage in muscle
Diagnosis of Carnitine Deficiency
1. Carnitine deficiency syndrome should be considered in a patient with a lipid storage myopathy 2. Recurrent encephalopathy resembling Reye’s syndrome is characteristic 3. Recurrent hypoglycemia with or without ketoacidosis precipitated by: a. Caloric deprivation c. Infection b. Exercise d. Pregnancy 4. Myalgia, increased fatigue 5. Lactic academia induced by exercise 6. Cardiomyopathy: a. High precordial T waves b. Left axis deviation 7. Unexplained hepatomegaly 8. Hypertrophic cardiomyopathy with or without family history of sudden death 9. Established organic aciduria
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SECTION XII. Muscle Disease
Differential Diagnosis
Chanarin Disease
1. 2. 3. 4. 5. 6. 7.
A. Genetics: AR B. Inability of cells to degrade endogenously synthesized triglycerides; cells can utilize exogenous phospholipids and triglycerides C. Clinical features: 1. Congenital ichthyosis 2. Age of onset: second decade in most patients 3. Ichthyosis: a. Lamellar ichthyosis b. Accentuated over the flexor creases c. Mild erythema in affected area d. Ectropion (eyelid) 4. Steatorrhea 5. Muscle weakness (when demonstrated): a. Proximal greater than distal b. Cranial muscles spared c. Moderate severity 6. Ataxia, nystagmus, neurosensory, hearing loss are associated D. Laboratory evaluation: a. Increased liver enzymes b. EMG: myopathic c. Increased CK d. Stored lipid is triglyceride e. No ketone bodies formed during a fast f. Sudanophilic droplets in granulocytes g. Pathologic features: triglyceride storage in all tissues
Chanarin disease Lipid storage myopathy Polymyositis Debrancher enzyme deficiency Infantile acid maltase Urea cycle defects (intermittent encephalopathy) Fructose-1, 6-diphosphate deficiency (intermittent encephalopathy) 8. Phosphoenolpyruvate carboxykinase deficiency
Seminal points of the Differential Diagnosis
1. Sporadic myopathic carnitine deficiency vs polymyositis: a. Proximal weakness b. Increased CK c. Absence of fibrillation potentials in carnitine myopathy and muscle biopsy findings excludes an inflammatory myopathy 2. Carnitine deficiency vs debrancher enzyme deficiency: a. Intermittent episodes of hypoglycemia b. Abnormal liver function tests c. Liver and heart enlargement d. Lactic academia e. Hyperuricemia Above occur in both entities: 1. Glycogen stored rather than lipid in debrancher enzyme deficiency 2. EMG has more irritability in debrancher deficiency 3. Distal weakness in debrancher deficiency 3. Infantile acid maltase deficiency vs carnitine deficiency in maltase deficiency: a. Enlarged tongue with fibrillation potentials b. Progressive weakness not associated with episodic metabolic crisis c. Cardiomyopathy (often congestive heart failure) d. Irritative EMG with pseudomyotonic discharges and abnormal electrical irritability e. Glycogen rather than lipid excess in muscle 4. Systemic carnitine deficiency with intermittent encephalopathy vs urea cycle defects: a. Metabolic acidosis does not occur in urea cycle defects b. Patients with MUL-ACD and branched chain aminoacidurias may also suffer protein intolerance c. Secondary carnitine deficiencies: 1) No oroticaciduria 2) Plasma levels of ureidosuccinic acid; arginine and citrulline are normal (elevated in urea cycle defects) 5. Fructose 1–6 diphosphatase deficiency and phosphoenolpyruvate carboxykinase deficiency: a. Impair gluconeogenesis d. Ketoacidosis b. Episodes of hypoglycemia e. Hypotonia c. Fatty liver
Differential Diagnosis of Lipid Storage Myopathy
Lipid Storage Myopathy Presenting at Birth
1. Clinically heterogeneous group: a. Onset in infancy b. Non-progressive proximal myopathy c. Benign course d. Easily fatigued 2. Fatal congenital variants: a. Weakness at birth b. Death from respiratory failure c. Possible mitochondrial respiratory chain defects
Heterogenous Adult Onset Lipid Storage Myopathy
1. Clinical features of a 21 year old patient: a. Attacks of muscle weakness b. Duration of weeks to years c. Proximal > distal muscles; cervical muscle affected 2. Lipid accumulation in muscle 3. Mitochondrial defect 4. Similar clinical pattern in an adult patient: responded to prednisone
Chapter 9. Mitochondrial Myopathies
5. Identical twin sisters: a. Lipid excess in muscle without weakness b. Cramping pain after exercise, fasting, ingestion of high fat diet c. Attacks of Myoglobinuria d. Formed no ketone bodies during fasting or after ingestion of long chain fatty acids e. Ketone bodies after ingestion of medium chain fatty acids
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b. Clinical features: 1) Muscle weakness 2) Intolerance to fatty foods c. Muscle biopsy: 1) Type I fiber predominance 2) Lipid and lipofuscin excess 3) Abnormal mitochondria 4) Medium chain triglyceride treatment a) Clinical improvement
Carnitine Palmitoyltransferase Deficiency (CPT) Lipid Storage Myopathy in Association with Other Diseases
1. Type I glycogenosis (Von Gierke disease) a. Mild muscle weakness and atrophy 2. Pyruvate decarboxylase deficiency a. No muscle weakness b. No exercise intolerance c. Intermittent ataxic attacks 3. Familial B-hyperlipoproteinemia a. Moderate myopathy 4. Arthrogryposis multiplex congenita a. Lipid storage in muscle (this from is rare) 5. Scapuloperoneal muscular atrophy 6. Patient with autonomic dysfunction: a. Hepatitis B surface antigen positive hepatitis b. Myalgia c. Tachycardia d. EKG abnormalities e. Steroid responsiveness
Genetic Defects of Long Chain Fatty Acid Oxidation
1. Autosomal recessive lipid storage myopathy: a. AR b. Onset in infancy c. Clinical features: 1) Slowly progressive weakness 2) Muscle aching and cramping during and after exercise 3) Lipid droplets in leucocytes (Jordan’s anomaly) 4) EMG: electrical but not clinical myotonia 5) Delay of ketogenesis on fasting 6) Treatment with carnitine and medium chain triglyceride: a) Improved the myopathy b) One patient abolished the myotonia 7) Defect in utilization of long chain fatty acids 8) Muscle biopsy: lipid storage myopathy Type I fiber predominance 2. Autosomal dominant lipid storage myopathy with systemic abnormality of fat metabolism a. AD
A. General clinical features and differential points: 1. AR possible X-linked recessive 2. Myoglobinuria is major clinical feature of CPT 3. Frequency of myoglobinuria greater than that of glycogenoses 4. No painful cramps on exercise 5. Precipitating factors for myoglobinuria in CPT a. Exercise (several hours) d. Cold b. Prolonged fasting e. Sleep deprivation c. Viral illness 6. No “second wind” phenomenon in CPT; noted in both phosphorylase and phosphofructokinase deficiency 7. Patients describe tightness and pain prior to pigmenturia a. Aching of jaw muscles after chewing b. Aching of facial muscles after speech 8. Myalgia and weakness: a. After exercise b. Limb or trunk muscles most commonly affected 9. Respiratory muscles affected 10. Myoglobinuria earlier than in phosphorylase or phosphofructokinase deficiency; first attacks in adolescence 11. Renal failure less than 25% of patients 12. Permanent weakness in CPT is rare 13. Women less myoglobinuria than men B. Laboratory evaluation: 1. CK normal at rest or between attacks 2. Some patients have elevated triglycerides and cholesterol 3. EMG: normal in general; occasionally abnormal between attacks 4. Prolonged fasting (30–72 hours): a. Delayed or decreased rise of blood ketone bodies (50%) b. Increased CK (50%) C. Pathology: 1. Muscle biopsy interictally is normal in 80% of patients 2. Lipid storage when present is less severe than in carnitine deficiency 3. CPT I and II decreased in muscle
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SECTION XII. Muscle Disease
Myoadenylate Deaminase Deficiency (AMPD)
A. Genetics: AR (unique to skeletal muscle)/AMPD-1 gene (Q12X) B. Most common of known enzyme defects of skeletal muscle C. Clinical features: 1. Onset: early adulthood or middle age; some patients are asymptomatic 2. Post exertional fatigue or weakness 3. Soreness and muscle cramps 4. Fatigue and soreness increase during exertion and throughout the day 5. Extremity muscles most commonly involved greater than chest and back muscles; face and extraocular eye muscles spared 6. Some patients: 1) Fixed weakness 2) Periodic paralysis 3) Repeated childhood infections 7. No second wind phenomenon 8. No post exertional myoglobinuria 9. 50% of patients: a. Mild to moderate muscle weakness b. Atrophy and muscle tenderness c. Early muscle fatigue with exercise 10. Higher incidence of malignant hyperthermia 11. AMPD-1 gene Q12X may be expressed in common with McArdle disease V and Tarui’s VII glycogenoses D. Laboratory evaluation: 1. CK mildly elevated; may become markedly elevated with exercise 2. EMG: myopathic 3. Normal AMP deaminase in RBC’s, lymphocytes and neutrophiles 4. Lactate ammonia exercise test (LAER) is positive 5. Some patients elevated uric acid levels 6. Normal patient in LAER test: a. Increase ammonia of 1.5% of lactate generated b. 1 + test < 0.4% 7. Muscle biopsy: a. Adenylate deaminase deficient b. 50% of AMP deaminase deficiencies in association with collagen vascular disease, muscular dystrophy, trichinosis and diabetes E. Differential Diagnosis: 1. Polymyositis 2. Benign congenital hypotonia (children)
The Mitochondrial Myopathies
General Features of Mitochondrial Disorders
1. Mitochondrial oxidation of substrates: most of the energy of most cell types
2. Disorders of oxidative metabolism due to defects of: a. Substrate transport or utilization: 1) TCA cycle 2) Beta-oxidation of fatty acids 3) Defects in the respiratory chain b. Tissues most reliant on oxidative metabolism: 1) Brain 3) Cardiac muscle 2) Skeletal muscle c. Most patients with these disorders present with symptoms and signs of: 1) Myopathy 2) Encephalopathy The respiratory chain: a. Final pathway for all substrates of oxidative metabolism b. Consists of 5 complexes (I–V) 1) Subunits coded from both mitochondrial and nuclear DNA 2) Succinic dehydrogenase (complex II) is completely nuclearly encoded
Features of Mitochondrial DNA
1. A double stranded circular molecule of 16,569 nucleotides 2. 2–10 DNA copies in each mitochondrion: a. Multiple mitochondria in each cell b. Normal and mutant mt DNA can coexist in different proportions within each cell or tissue 3. Mitochondrial DNA: a. Contains 37 genes b. Encodes 13 protein subunits of complexes I, III, IV and V of the respiratory chain c. 2 ribosomal RNAs and 22 transfer RNAs are required for intramitochondrial translation d. No introns; therefore all mutations change coding sequences e. No repair enzymes f. No protective histones g. Exposed to oxygen free radicals derived from oxidative phosphorylation h. Maternal inheritance i. No recombination j. High replication and mutation rate 4. Mitochondrial heteroplasia: a. mt DNA is randomly distributed to daughter cells b. Replicative segregation c. Mixed mutant and normal genomes in tissues that explains the differential clinical expression of mitochondrial dysfunction in different tissues d. Variable prototypes of identical mitochondrial genetic defects e. A shift in proportion of mutant to normal mt DNA can occur in daughter cells f. Threshold effect: 1) The proportion of mutant mt DNA to express symptoms:
Chapter 9. Mitochondrial Myopathies
a) Varies among persons, organ systems and tissues b) Depends on the balance between energy supply and demand c) Results in intermittent symptoms d) Brain retina, heart and muscle have the lowest threshold
Clinical Features of Mitochondrial Disorders
Systemic Signs and Symptoms
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Short stature Diabetes mellitus Pigmentary retinopathy Cardiac conduction defects Cardiomyopathy (dilated) Cataracts Liver disease Psychiatric manifestations (depression) Hypoparathyroidism Exocrine pancreatic dysfunction Episodic nausea and vomiting Lactic acidosis Pancytopenia GI pseudo obstruction Glomerulopathy Fanconi syndrome
Neurologic Manifestations
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
Myopathy (limb girdle) Exercise intolerance Ataxia Seizures Myoclonus Migraine headache Dystonia Ophthalmoplegia Optic atrophy VIII nerve deficits (sensorineural hearing loss) Stroke in the young Posterior leukoencephalopathy MRI basal ganglia defects Mental retardation Optic atrophy Peripheral neuropathy Dysarthria Somnolence Choreoathetotic movements Cortical blindness Salt craving Specific patterns of myopathy: a. Limb girdle c. FSH b. Distal d. Ophthalmoplegia
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Laboratory evaluation: 1. High resting lactate in serum and CSF 2. EMG: myopathic; axonal and demyelinating peripheral nerve deficits 3. EKG: conduction block 4. MRI: a. Basal ganglia calcification and signal change b. Focal stroke like changes c. Posterior leukoencephalopathy 5. Muscle Biopsy: a. Ragged red fibers (RRF); (Gomori tricome strain) are the muscle morphological marker of these diseases: 1) Large peripheral and intermyofibrillar collections of abnormal mitochondria 2) Intense staining for intramitochondrial enzyme succinic dehydrogenase (SDH) 3) Affected fibers contain increased lipid droplets 4) Some excess peripheral fiber glycogen 5) RRF may fail to stain with cytochrome C oxidase a) May be associated with by Type I paracrystalline mitochondrial inclusions b. Electron microscopic abnormalities in RRF negative patients: a. Increased collections of subsarcolemma mitochondria b. Abnormal mitochondrial structure; increased, distorted and abnormally arranged cristae c. Abnormal mitochondria may be seen in: a. Normal muscle c. Acid maltase deficiency b. Denervated muscle d. Polymyositis d. Brain neuropathology in mitochondrial disorders: 1) Spongiform degeneration 3) Neuronal loss 2) Cavitation 4) Demyelination
General Principles of Genetic Organization of Mitochondrial Encephalomyopathy
1. All mitochondrial clinical syndromes: a. May have several different underlying genetic defects b. Severity varies among patients c. A specific genetic defect may cause different phenotypes 2. Clinical manifestations are influenced by: a. Nuclear genes c. Heteroplasmia b. Tissue threshold effects 3. Defects of mitochondrial DNA: a. Point mutations (maternal inheritance): 1) mt DNA that code gene mutations: a) Leber’s hereditary optic neuropathy (LHON) b) LHON with dystonia c) Maternally inherited Leigh syndrome d) Neuropathy, ataxia, retinitis polyneuropathy (NARP) b. Mitochondrial (t) RNA gene mutations:
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SECTION XII. Muscle Disease
1) Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS) 2) Mitochondrial encephalomyopathy with ragged red fibers (MERRF) 3) Chronic progressive ophthalmoplegia (CPEO) 4) Diabetes mellitus and deafness 5) Maternally inherited cardiomyopathy 6) Maternally inherited deafness 7) Isolated mitochondrial myopathy 8) Acute rhabdomyolysis c. Mitochondrial ribosomal (rRNA) gene mutations: 1) Maternally inherited deafness with aminoglycoside sensitivity d. Deletions and duplications (sporadic inheritance): 1) CPEO 2) Kearns–Sayre syndrome 3) Pearson syndrome 4) Diabetes mellitus and deafness 5) Mitochondrial myopathy 4. Defects of nuclear DNA (Mendelian inheritance): a. Defects in nuclear genes that encode mitochondrial proteins: 1) Structural proteins – Leigh’s disease or Krebs cycle enzymes 2) tRNA gene mutations that affect multiple proteins b. Defects of mitochondrial protein transport c. Defects of nuclear encoded factors: 1) Multiple mt DNA deletions: a) AD or AR CPEO b) MNGIE (mitochondrial neurogastrointestinal encephalopathy) c) SANDO (sensory ataxic neuropathy, dysarthria and ophthalmoplegia) d) Acute rhabdomyolysis e) ARCO f) IBM g) Peripheral neuropathy and lipomatosis d. mt DNA depletion: 1) Hepatic dysfunction 3) Encephalopathy 2) Myopathy
2. Defects of substrate utilization: a. Pyruvate: 1) Pyruvate decarboxylase deficiency 2) Dihydrolipoyl transacetylase deficiency 3) Dihydrolipoyl dehydrogenase deficiency 4) Pyruvate dehydrogenase phosphatase deficiency 5) Pyruvate carboxylase deficiency 6) Carnitine acetyltransferase deficiency b. Free fatty acids 1) Defects of Beta Oxidation 3. Defects of the respiratory chain: a. Defects of NADH-CoQ reductase complex: 1) With normal carnitine levels 2) With carnitine deficiency b. Defects of the CoQ-cytochrome reductase complex: 1) CoQ10 deficiency 2) Deficiency of Fe-S proteins 3) Cytochrome b deficiency 4) Combined deficiency of cytochromes c. Cytochrome aa3 deficiency d. Deficiency of cytochromes a 3 and b 4. Defects of energy conservation and transduction: a. Loose coupling with hypermetabolism (Luft’s disease) b. Loose coupling without hypermetabolism c. Mitochondrial ATPase deficiency d. Deficiency of the adenine nucleotide translocase
Defects of Mitochondrial Substrate Transport
1. Mitochondrial outer membrane: a. Permeable to small molecules and ions 2. Mitochondrial inner membrane a. Acts as barrier to most hydrophilic and ionized metabolites b. Specific transmembrane translocaters move these molecules into the mitochondrial matrix c. Translocaters are within the mitochondrial inner membrane d. Pyruvate, fatty acyl-CoA, ketone bodies: 1) Major mitochondrial substrates for ATP production 2) Require carrier mediated entry
Biochemical and Physiological Classification of Mitochondrial Defects Defects of Pyruvate Transport
1. Defects of mitochondrial substrate transport: a. Mono carboxylate translocase deficiency b. Defects of the carnitine acylcarnitine carrier: 1) Primary muscle carnitine deficiency 2) Primary systemic carnitine deficiency 3) Mixed forms of carnitine deficiency 4) Secondary carnitine deficiencies 5) Carnitine palmityl transferase deficiencies (CPT 1 and 2) 6) Combined deficiency of carnitine and CPT
1. Possible primary pyruvate translocase deficiency in 2 patients: a. Clinical features: 1) Progressive external ophthalmoplegia 2) Paracrystalline mitochondrial inclusions on muscle biopsy 2. Mitochondrial pyruvate and ketone body transport are defective in: a. Phenylketonuria b. Maple syrup urine disease
Chapter 9. Mitochondrial Myopathies Fatty Acid Transport
1. L-carnitine: a. Obligate carrier molecule for medium and long chain free fatty acids (FFA) b. Synthesized in the liver c. Transported to tissues in the blood d. Active uptake mechanism into cardiac and skeletal muscle
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4. Carnitine transporter defect: a. not a mitochondrial disease b. AR c. Onset in infancy d. Clinical presentation: 1) Encephalopathy 2) Lipid storage proximal myopathy 3) Cardiomyopathy e. Laboratory evaluation: decreased uptake of labeled carnitine into fibroblasts
Defects of the Carnitine Acylcarnitine Carrier System Defects of Substrate Transport
1. Primary defect in muscle: a. Deficient transport of fatty acyl-CoA derivatives through the inner membrane into the mitochondrial matrix b. Neutral lipid accumulates within muscle fibers
Mixed Carnitine Deficiency
1. Clinical features of primary or systemic carnitine deficiency: a. Associated with the biochemical parameter of the other b. Some patients: recurrent hepatic encephalopathy with normal plasma carnitine c. Other patterns: low plasma carnitine with systemic clinical disease d. One family cardiomyopathy secondary to endocardial fibroelastosis 2. CPT-1 deficiency: a. Genetics: gene on 11 q b. Starts in infancy c. Clinical presentation: 1) Encephalopathy 2) Hypotonia 3) Non-ketotic hypoglycemic coma 4) Hyperammonia 5) Hepatic dysfunction 6) Renal tubular acidosis 7) Cardiomyopathy 8) Seizures 9) Induced by fasting 3. CPT-II deficiency: a. Infantile forms: 1) Lethal neonatal from 2) Hypoketotic hypoglycemia 3) Generalized steatosis 4) Multiple malformations b. Infantile hepatomuscle forms: 1) Hypoketotic hypoglycemia 2) Lethargy seizures 3) Cardiomegaly and hepatomegaly 4) Cardiac arrhythmia
1. Carnitine palmitoyltransferase deficiency (CPT II): a. AR; onset in late adolescents and young adults; male > female b. The enzyme that facilitates the entry of long chain fatty acid into the mitochondrial matrix c. CPT I is attached to the outside of the inner mitochondrial membrane; loads carnitine; palmityl CoA methylated to polymethyl carnitine 1) encoded by gene on 11 q d. CPT II is attached to the inner surface of the inner mitochondrial membrane; releases carnitine from palmityl carnitine; on 1p32 e. Carnitine acylcarnitine translocase: 1) Exchanges acylcarnitine and carnitine across the inner mitochondrial membrane f. Clinical manifestations of CPT II: 1) Severity of the disease depends on residual enzyme activity 2) Pain and muscle tenderness with cramps initiated by: a) Sustained exercise; not necessarily strenuous b) Excessive ingestion of fat c) Starvation d) Cold exposure e) Lack of sleep f) Infection 3) Muscle damage with recurrent myoglobinuria 4) Generalized muscle weakness 5) Severe episode may cause respiratory failure 6) Between episodes: g) No weakness h) Normal CK between attacks i) Some children develop a fixed myopathy j) Myoglobinuria not accomplanied by painful cramps g. Laboratory evaluation: 1) Delayed production of ketone bodies in blood and urine after a fast 2) Increased CK with myoglobinuria after sustained aerobic exercise h. Muscle biopsy:
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SECTION XII. Muscle Disease
1) Lipid droplets 2) May be normal 3) Enzyme measurement in muscle, fibroblasts or platelets for definitive diagnosis
Defects of Mitochondrial Substrate Utilization and Gluconeogenesis
1. Pyruvate carboxylase deficiency: a. AR b. Onset in infancy: 1) Metabolic acidosis 4) Hypotonia 2) Lactic academia 5) Death in childhood 3) Developmental delay c. French phenotype: 1) Greater severity than North American phenotype 2) Hepatomegaly 3) Hyperammonemia, lysinemia, citrullinemia 4) Clinical manifestations other wise similar to North America phenotype 2. Pyruvate dehydrogenase (PDH) complex deficiency a. Pyruvate: 1) Metabolized in the matrix of the mitochondrion 2) Decarboxylated to acetyl-CoA 3) Carbonized by intramitochondrial enzymes: collectively known as the pyruvate dehydrogenase complex (PDHC) 3. Components of the complex: a. Pyruvate decarboxylase (E1) b. Dihydrolipoyl transacetylase (E2) c. Dihydrolipoyl dehydrogenase (E3) d. Two regulatory enzymes of the complex 1) Pyruvate dehydrogenase kinase 2) Pyruvate dehydrogenase phosphatase 4. General clinical manifestations of PDHC deficiency: a. Fatal congenital lactic acidosis b. Intermittent ataxias c. Intermittent movement disorders d. Clinical manifestations depend on the severity of the deficit and not the particular enzyme that is deficient Clinical Features of PDHC: a. Presentation at birth b. M > F; may be X-linked c. Progressive encephalopathy: 1. Psychomotor retardation 2. Seizures 3. Generalized hypotonia 4. Metabolic and lactic acidosis 5. Rapid respiration 6. Infantile or neonatal onset 7. Facial dysmorphism 8. Ataxia d. Increased serum lactate, pyruvate and alanine; spill over into the urine
e. If decreased dihydrolipoyl dehydrogenases (E3) 1. Increased blood levels of branched chain amino acids and a-ketoglutarate
Leigh’s Syndrome (Subacute Necrotizing Encephalopathy; SNE)
1. 2. 3. 4.
Composed of different genetic and biochemical defects Genetics: AR; X-linked Some phenotype results from different genetic defects Pathology: a. Hemorrhagic lesions of the brainstem, thalamus, basal ganglia and cerebellum b. Spares the mammillary bodies
Specific Causes of Leigh’s Syndrome
1. PDH-complex deficiency: E1 Subunit a. Genetics: 1) Gene point mutation 3) AR 2) X-chromosome b. Variant: 1) Mutation impairing the affinity of binding of E1 to thiamine pyrophosphate (TPP) 2) Thiamine responsive PDH-complex deficiency E3 deficiency: a. AR b. Decreased lipoamide dehydrogenase c. Causes combination of both PDH and alpha-ketoglutarate dehydrogenase dysfunction (both contain E3 subunit) 2. Complex IV deficiency: a. AR b. Nuclear encoded subunits 3. ATP synthase (complex 5) subunit 6 gene: a. NARP (mt DNA 8993 or 9176 point mutations) b. Early onset; rapid progression 4. Complex I deficiency
Clinical Features of Leigh’s Syndrome
1. Earlier the onset the more rapid and severe the illness with death in infancy 2. Onset one year (60%) and 2 years (20%); rare after infancy (20%) 3. COX deficiency patients develop symptoms after the first year: a. Diarrhea, vomiting c. Slower progression b. Failure to thrive d. Exacerbation with infections 4. Adult onset rare: a. Ataxia c. Polyneuropathy b. Seizures d. Central hypoventilation
Chapter 9. Mitochondrial Myopathies
5. Usual symptom complex: a. Hypotonia d. Central hypoventilation b. Seizures e. Ophthalmoplegia c. Cheyne-Stokes breathing f. Nystagmus 6. Laboratory evaluation: a. Both lactate and pyruvate elevated at rest b. MRI: 1) BG lesions 3) Necrosis of GP 2) Adjacent to III ventricle c. Enzyme and mt DNA analysis are definitive
Differential Diagnosis
Alpers Disease (Progressive Infantile Poliodystrophy)
1. Sporadic cases putative causes: a. Anoxia b. Prion or slow virus disease 2. Clinical manifestations: a. Some familial cases now thought to be mitochondrial myopathy: 1) Pyruvate carboxylase deficiency 2) Complex I and IV deficiency b. Onset in early childhood c. Seizures (may present with status epilepticus) d. Psychomotor regression e. Blindness f. Progressive degeneration of cerebral gray matter g. Carbohydrate load increases clinical symptomatology and lactate levels
Menkes Syndrome (Trichopoliodystrophy)
1. Defect in intestinal copper transport 2. Secondary deficiency of copper-dependent enzymes; particularly COX 3. Clinical features: a. Onset by three months b. Lethargy c. Myoclonic seizures d. Developmental regression e. Vegetative state by 18 months f. Sparse poorly pigmental wiry hair g. X-ray evidence of osteogenesis imperfecta h. Low copper plasma levels
Multiple Carboxylase and Biotinidase Deficiencies
1. Genetics: AR 2. Clinical features: a. Present in infancy b. Immunodeficient state c. Dermatopathy
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d. Alopecia e. Breathing irregularities f. Lactic and metabolic acidosis 3. Laboratory evaluation: definite diagnosis made by enzyme analysis in fibroblasts
Beta-Oxidation Defects (see above)
A. Genetics: AR B. Clinical features: 1. Onset from neonatal life to early childhood 2. Symptoms and signs depend on size of fatty acid involved
Acyl CoA Dehydrogenases Deficiencies
1. Medium chain fatty acid: a. Sudden infant death syndrome b. Reye’s type encephalopathy c. Hypoglycemia d. Hyperuricemia 2. Short chain fatty acid: a. Recurrent vomiting b. Failure to thrive 3. Long chain fatty acid: a. encephalopathy c. hypoglycemia b. cardiomyopathy 4. Multiple defects: a. Metabolic acidosis d. Encephalopathy b. Hypoglycemia e. Facial dysmorphism c. Hyperammonia f. Polycystic kidneys 5. Late onset variant: a. Metabolic acidosis c. Vomiting b. Hypoglycemia d. Polyneuropathy
Defects of the Carnitine Acylcarnitine Carrier System
1. Primary defect in muscle: a. Deficient transport of fatty acyl-CoA derivatives through the inner membrane into the mitochondrial matrix b. Neutral lipid accumulates within muscle fibers 2. Krebs Cycle Defects: a. Biochemical reactions take place in the semifluid state of the mitochondrial matrix b. Reactions lead to oxidative decarboxylation of acetylCoA utilizing: 1) Pyruvate 3) Amino acids 2) Fatty acids c. All TCA cycle enzymes are nuclearly encoded 3. Deficiencies: a. a-ketoglutarate dehydrogenase (a-KGDH): chromosome 7q and 14 q
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SECTION XII. Muscle Disease
b. a-KGDH plus PDH complex: 1) AR; chromosome 7 q 2) deficiency of E3 subunit of the PDH complex (respiratory chain) 3) recurrent myoglobinuria c. Fumarase: 1) AR 2) chromosome 1 q d. SDH (succinic dehydrogenase): 1) Complex II of the respiratory chain 2) AR; chromosome 5 q e. SDH plus aconitase deficiency: 1) Mutation in common iron sulfur subunit 2) Chromosome 1 q 4. General clinical characteristics: a. Encephalopathy c. Cardiomyopathy (some patients) b. Myopathy
Defects of Oxidative-Phosphorylation Coupling
Luft’s Disease
A. General features: 1. Sustained and high respiratory rate 2. Recycling of Ca++ between the mitochondrial matrix and the cytosol 3. Energy production dissipated as heat rather than production of ATP B. Clinical presentation: 1) Onset in adolescence 7) Polyphagia 2) Fever 8) Polydysphasia 3) Heat intolerance 9) Tachycardia 4) Profuse sweating 10) Death in middle age 5) Exercise intolerance 11) Generalized weakness 6) Hypermetabolic state C. Laboratory evaluation: 1. Muscle biopsy: a. Peripheral aggregations of abnormal mitochondria: 1) Over abundant tightly packed disorganized cristae of the mitochondrion 2) Small electron dense osmiophilic bodies in the mitochondrion 3) Occasional para crystalline inclusions 2. Basal metabolic rate: dramatically increased D. Loose oxidative phosphorylation coupling without hypermetabolism: 1. Loss of normal state 3/state 4 transition with a normal PO ratio 2. Possible AD or mitochondrial pattern of inheritance: a. Mitochondrial myopathy b. No features of a hypermetabolic state c. Non-progressive or slowly progressive weakness in infancy, childhood or early adult life d. Associated features in some families: 1) Diabetes mellitus 3) Lactic acidemia 2) Cerebellar ataxia
Defects of the Mitochondrial Respiratory Chain
1. Complex I (NADH-CoQ reductase) deficiency: a. Genetic: mutation in the gene that encodes subunit 4 of complex I b. Fatal infantile multisystem disorder c. Congenital lactic acidosis d. Mental retardation e. hypotonia f. death in infancy from cardiorespiratory failure 2. Myopathy: Carnitine deficient patient: a. Onset in childhood or adult life b. Clinical features: 1) Exercise intolerance 3) Progressive weakness 2) Muscle pain 4) Female affected relative c. EMG: 1) Normal d. Laboratory evaluation: 1) Low plasma and muscle carnitine 2) Muscle biopsy: a) Lipid storage myopathy b) Ragged red fibers (COX-positive) Patients with Normal Carnitine Levels
A. General features: 1. Age at onset: 16–46 years of age 2. Females have affected relatives B. Clinical characteristics: 1. Exercise intolerance 2. Muscle pain 3. Weakness and fatigue 4. Remittent paralysis (rare) associated with lactic acidosis 5. Heart failure (rare) 6. Dementia, dystonia, blindness (one patient) C. Laboratory Features: 1. Metabolic acidosis 3. Lactic academia 2. Hypoglycemia 4. Increased serum CK level D. EMG: 1. Normal Complex II Succinic Reductase Deficiency
1. Nuclear encoded enzyme possible involvement of the Fe-S subunit 2. AR 3. May present in adult life 4. Clinical features: a. May present in adulthood b. Optic atrophy c. Growth retardation d. Spasticity e. Pulmonary edema f. KSS like presentation
Chapter 9. Mitochondrial Myopathies Coenzyme Q10 (CoQ) Deficiency
Complex V (ATP Synthetase) Deficiency
1. Onset may present in midlife: a. Encoded by nuclear genome b. Transfers electron from complex I and II to complex III c. Final acceptor of electrons from B-oxidation 2. Clinical features: a. Mental retardation b. Seizures c. Ataxia d. Progressive proximal weakness e. Recurrent myoglobinuria (exercised induced) f. Some bilateral ptosis in childhood g. Exercise intolerance
Mutation in Subunit 6 (mt DNA-8993)
Complex III
1. Three major presentations: a. Genetics: mutations of the cytochrome b gene b. Encephalopathy c. Myopathy d. Cardiomyopathy 2. Encephalopathy: a. Infant presentation (fatal) b. Childhood or adult life: 1) Pigmentary retinopathy 2) Sensory neuropathy 3. Myopathy: a. Exercise intolerance b. Fixed proximal weakness c. May respond to vit K3 (menadione) 4. Cardiomyopathy: a. Histiocytoid cardiomyopathy of infancy
Complex IV (Cytochrome C Oxidase Deficiency)
1. Myopathic phenotype: a. Fatal infantile from: 1) Lactic acidosis 3) Renal failure 2) Respiratory distress 4) Death in first year b. Benign from: 1) Patients improve and are normal by age three 2) Return of COX to muscle 3) Subunit VII, z, b and II involved c. Adolescent: 1) Exercise induced myoglobinuria 2) Normal exam between attacks 3) Mild myopathy 4) No multisystem involvement 5) Premature fatigue and myalgia
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A: Genetics: mt DNA mutation-8993 B: Onset: childhood: 1. Mild progressive muscle weakness 2. Fatigue on exertion 3. Growth retardation 4. Sensorineural hearing loss 5. Recurrent vomiting 6. Pigmentary retinopathy 7. Dementia 8. Peripheral sensory neuropathy 9. Cerebellar ataxia 10. Multisystem disorder C: Laboratory Evaluation 1. Muscle biopsy: a. Para crystalline deposits inner mitochondrial membrane b. Lipid myopathy (secondary carnitine deficiency) 2. MRI: a. BG calcification
Steps in Mitochondrial Importation
1. Transport of nuclearly encoded proteins from the cytoplasm into mitochondria a. Targeted to different intramitochondrial compartments 2. Defects of translocation steps: a. Address signals: amino terminal leader peptides b. Cytoplasmic heat shock proteins: peptide transport protection c. Leader peptide-receptor interaction at the mitochondrial membrane d. Energy dependent translocation through the mitochondrial membrane e. Intramitochondrial cleavage of leader peptides by peptidases f. Intramitochondrial protein assembly
Defects of Mitochondrial Importation
1. Heat shock protein 60: a. Deficits of multiple mitochondrial enzymes b. Infantile encephalopathy c. Lactic acidosis 2. Methylmalonic academia: a. Mutation in the leader peptide of methylmalonic Co-A mutase b. Inability to enter the mitochondria 3. Frataxin (Friedreich’s ataxia): a. Trinucleotide expansion (CGG intron9) chromosome 6
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SECTION XII. Muscle Disease
b. Loss of regulation of iron transport into the mitochondria c. Dysfunction of all enzymes that contain iron sulfur subunits: 1) Aconitase 2) Complex I, II, III d. Paraplegia: 1) Chromosome 16q 2) AR hereditary spastic paraplegia 3) Regulator of metalloproteinase a chaperone of respiratory chain assembly e. Putative defect of translocation 1) Reye’s syndrome associated with multiple mitochondrial enzyme dysfunction
Defects of Ingenomic Interaction
1. Mitochondrial genome dependent on: a. Products of nuclear encoded genes that are important for: 1) mtDNA replication 3) Translation 2) Transcription b. Transmitted by Mendelian inheritance 2. Multiple mtDNA deletions noted in: a. AD chronic progressive ophthalmoplegia (ADCPEO) b. AR CPEO c. MENGIE syndrome d. ARCO: 1) AR 3) Ophthalmoplegia 2) Cardiomyopathy e. Recurrent myoglobinuria f. Peripheral neuropathy and lipomatosis g. Inclusion body myositis 3. Depletion of mtDNA: a. 1) Severity relates to degree of depletion 2) AR inheritance 3) Defect in nuclear genes required for mt DNA replication b. Fatal infantile hepatopathy 1) Intractable hepatic failure during the first year of life c. Congenital myopathy: 1) Similar to COX deficiency myopathy 2) Some patients have concomitant renal dysfunction d. Infantile or childhood myopathy: 1) Onset after first year 2) Progressive proximal weakness 3) Muscle biopsy: a) Ragged red fibers b) Depleted mt DNA c) No mt DNA encoded proteins e. AZT treatment in AIDS treatment: 1) AZT incorporated into mt DNA by polymerase gamma 2) Inhibits mt DNA replication 3) Myopathy reversible after discontinuation of AZT therapy
Myopathic Syndromes with mtDNA Defects
1. Kernes-Sayre Syndrome (KSS): a. Sporadic large scale mitochondrial rearrangements b. Single mtDNA deletions c. Defects of several respiratory chain complexes: COX dysfunction most detrimental d. Onset by age 20 years e. Male and females affected equally f. Clinical characteristics: 1) Chronic progressive external ophthalmoplegia 2) Ptosis; hearing loss 3) Retinitis pigmentosa 4) Cerebellar ataxia 5) Some patients with mental retardation 6) Rare seizure 7) Rare stroke 8) Cardiac conduction defects common 9) May present with syncope 10) Cerebral spinal fluid greater than 100 mg/dl 11) Frequent sensorineural hearing loss 12) Associated: DM, hypoparathyroidism, growth hormone deficit, irregular menses 13) Fanconi syndrome 14) Barter cilia syndrome 15) Lowe-like syndrome 16) Chorea 17) Anhydrosis g. Parson’s syndrome: 1) Same mtDNA defect 2) Clinical features: a) Sideroblastic anemia b) Pancreatic insufficiency h. Imaging: 1) BG calcification 2) Pontine and cerebral atrophy 3) BG decencies
Chronic Progressive External Ophthalmoplegia (CPEO)
1. AD-CPEO: a. Sporadic multiple mtDNA deletions: 1) One deletion affects the heavy strand promoter – HSP region 2) Chromosome 3p b. Clinical features: 1) Progressive external ophthalmoplegia 2) Severe ptosis (symmetrical) 3) No diplopia 4) Proximal myopathy 5) Cataracts 6) Tremor 7) Ataxia 8) Peripheral neuropathy
Chapter 9. Mitochondrial Myopathies
9) Onset from childhood to adult life 10) Weakness of the face, neck, trunk, respiratory muscles 2. AR-CPEO: a. AR; multiple mtDNA deletions; smaller proportion of DNA deleted 10% compared to AD-CPEO (30%) mtDNA deletions b. Both sporadic and familial AD/AR patients multiple tRNA genes are affected c. Regulator metalloproteinase (chaperone) at respiratory chain assembly are deficient 3. Putative defect of translocation: a. Reye’s syndrome associated with multiple mitochondrial enzyme dysfunction
Differential Diagnosis of CPEO
1. Oculopharyngeal muscular dystrophy (OPMD) with poly alanine repeats 2. KSS (Kearne–Sayre-Syndrome): a. Heart block with syncope c. Ophthalmoplegia b. Retinopathy 3. MNGIE (mitochondrial neurogastrointestinal encephalopathy) a. GI dysmotility 4. Myasthenia: a. Fluctuation of cranial nerve signs b. Asymmetrical muscle weakness c. Diplopia d. Bilateral ptosis 5. Progressive supranuclear palsy: a. Dramatic vertical gaze defects b. Falls c. Parkinsonian features d. Cognitive decline e. Head held in extension 6. SCA ataxia (Type III): a. AD b. Cerebellar degeneration most prominent feature c. Amyotrophy of the extremities
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1) 3251; 3271; 3291; 5824; 1642 nucleotides 2) few patients have a 9957 mutation: a) gene for subunit 3 of COX d. Clinical features: 1) Normal early development 2) Onset prior to age 40 3) Stroke-like episodes; not in a vascular territory; maybe severe 4) Migraine headaches; preceded by nausea and vomiting 5) Encephalopathy: a) Seizures c) Hemiparesis b) Progressive dementia d) Hemianopia 6) Myopathy: a) Proximal greater than distal b) Exercise intolerance 7) Short stature 8) Less than 50% of patients: a) Cardiomyopathy c) Ataxia b) Myoclonus 9) Oligosymptomatic maternal relatives are common 10) Lesions may affect the temporal lobe 11) Unusual to have full syndrome in more than one member of the pedigree 12) Optic atrophy 13) Congestive heart failure 14) Pigmentary retinopathy 15) Wolff–Parkinson–White Syndrome 16) PEO 17) DM e. Pathology: 1) Spongiform encephalopathy: a) Cortex primarily involved b) Focal lesions: occipital lobes cerebellum, pons, inferior olives c) Basal ganglia calcification 2) Muscle biopsy: a) Ragged red fibers 3) Lactic acidosis
Myoclonic Epilepsy with Ragged Red Fibers (MERRF) MELAS (Mitochondrial Encephalopathy, Lactic Acidosis and Stroke)
1. Genetics: a. 80–90% of patients have a mtDNA 3243 point mutation in: 1) tRNA Leu gene b. Same mtDNA 3243 gene defect causes: 1) PEO 2) maternally inherited DM and deafness c. Other mutations within tRNA Leu gene that cause MELAS are:
A. General features: 1. 80% of cases are familial: a. Severity of presentation variable among family members b. Oligosymptomatic maternal relatives c. Many relatives within the pedigree have full syndrome B. Genetics: 1. 90% of patients have 8344 mtDNA mutation 2. 5–10% have the 8356 mt DNA mutation 3. tRNA Lys gene 4. 8363 mutation in Japanese patients
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SECTION XII. Muscle Disease
5. Mutation of tRNA genes: a. Decreased protein synthesis b. Multiple enzyme deficiencies c. COX deficiency most profound C. Clinical features: 1. Onset in childhood; first manifestations may be in adults 2. Hearing loss 3. Optic atrophy 4. Sensory neuropathy 5. Short stature 6. Myoclonic epilepsy 7. Proximal myopathy 8. Encephalopathy 9. Ataxia a. Degeneration of posterior columns and cerebellum 10. Exercise intolerance 11. Lactic acidosis 12. Large lipomas in patients and relatives 13. Pes Cavus 14. Impaired sensation D. Pathology: 1. Neuronal loss in the dentate, inferior olive 2. Diffuse gliosis in cerebellar white matter and brain
Differential Diagnosis of MERRF
1. Unverricht-Lundborg disease (Baltic myoclonus): a. AR-chromosome 21q 2. Lafora Disease: a. AR chromosome 6q b. PAS +/− inclusion bodies 3. Juvenile ceroid lipofuscinosis (Batten’s disease) 4. Sialidosis 5. Gaucher Type III a. Glucosylceramide lipidosis 6. Ramsey Hunt syndrome Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) 1. Genetics: a. Maternal transmission b. mtDNA point mutation 8993 in the ATP synthetasesubunit 6 gene 1) Same defect noted in some patients with Leigh’s disease 2. Clinical features: a. Ataxia b. Peripheral neuropath (sensory) c. Retinitis pigmentosa d. Dementia e. Seizures f. Spasticity g. Myopathy (proximal) h. Onset in young adults i. Symptoms may be subtle in young adults
Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)
1. Genetics: a. Autosomal recessive b. Chromosome 22q 13.32-qter c. Thymidine phosphorylase gene 1) Loss of function mutation 2. Clinical features: a. PEO b. Gastrointestinal dysmotility with pseudoobstruction c. Peripheral neuropathy: 1) Pes cavus 2) axonal and demyelinating neuropathy d. Cachexia: 1) Particularly during the later stage of the disease 2) Generally thin throughout the illness e. Diffuse leukoencephalopathy 4. Laboratory evaluation: a. Lactic acidosis at rest b. EMG: 1) Axonal and demyelinating features on EMG 4. Muscle biopsy: a. COX negative RRFs b. Neurogenic atrophy c. Abnormal mitochondria in Schwann cells d. Multiple deletions of muscle mtDNA
Infantile Myopathy with Cytochrome C Oxidase Deficiency
Fatal From
A. General features: 1. Genetics: a. Probably AR b. Absent mitochondrial subunits of nDNA-encoded subunit VII ab: 1) Subunit II is present c. COX deficiency is in skeletal muscle; but spares the heart, brain and liver B. Clinical presentation: 1. Generalized muscle weakness during infancy 2. Lactic acidosis 3. Death by respiratory insufficiency at one year of age 4. Some patients have de Toni-Fanconi Debre Syndrome
Reversible Infantile Myopathy
A. General features: 1. Genetics: a. AR absent b. Subunit VI of nDNA encoded subunit VII ab
Chapter 9. Mitochondrial Myopathies
B. Clinical presentation: 1. Severe myopathy with lactic acidosis after birth a. May dramatically improve by age 2–3 2. Lactic acidosis and muscle histology resolves Progressive External Ophthalmoplegia
1. Genetics: AD 2. Clinical features: a. Age at onset is 24–30; death in middle age b. PEO c. Facial and limb weakness d. Cataracts e. Exercise intolerance f. Dysphagic g. Dysphonia h. Febrile illness may cause respiratory failure i. Depression and psychomotor retardation in some patients 3. Laboratory Evaluation: a. Serum 1) Resting lactic acidosis b. Muscle biopsy: 1) RRFs 2) Multiple mitochondrial deletions in skeletal muscle; not in lymphocytes or fibre blasts Mitochondrial DNA Depletion Syndrome
1. Heterogenous clinical features between different variants and within families 2. Genetics: a. Some AR b. Mechanism not known for failure of mitochondrial replication 4. Clinical variants: a. Severe congenital myopathy b. Intractable liver failure with death in the first year c. Infantile myopathy: 1) Associated seizures (multifactorial) 2) Associated peripheral neuropathy (some patients) Autosomal Recessive Cardiomyopathy and Ophthalmoplegia
A. General features: 1. Genetics: a. mtDNA deletions b. AR inheritance; male equals female in incidence B. Clinical presentation: 1. Childhood onset 2. Proximal myopathy 3. PEO 4. Hypertrophic cardiomyopathy
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Azidothymidine (AZT)
1. Nucleoside lacks 3-hydroxyl group: a. Incorporated into replicating HIV virus DNA 1) Premature termination of the elongating DNA chain 2) Incorporating enzyme is a polymerase gamma 2. Pathology (muscle biopsy): a. RRF b. Decreased amounts of mtDNA in muscle 3. Clinical features: a. Subacute onset b. Proximal myopathy
Differential Diagnosis of Mitochondrial Myopathy
Any patient that presents with easy fatigueability, bilateral symmetrical ptosis or ophthalmoplegia, diabetes, short stature and sensorineural, hearing loss and migraine should alert the clinician to the possibility that he is dealing with a mitochondrial myopathy. There are few problems that demonstrate bilateral ptosis and ophthalmoplegia in concert with heart block. Syncope may be the presenting feature of Kearns–Sayre’s syndrome. Congenital myasthenic syndromes and myasthenia gravis have no cardiac symptomatology. Interstitial myocarditis may be seen in adult patients with myasthenia and thymoma. Niemann Pick Type C has failure of upgaze and a supranuclear palsy, but AR inheritance, ptosis and heart conduction defects are not seen. Oculopharyngeal muscular dystrophy may demonstrate the same pattern of weakness as KSS, but begins in the fourth to sixth decade, whereas, KSS starts prior to age 20. No cardiac conduction defects are noted with OPMD. AD-PEO with multiple mtDNA deletions has prominent ptosis and prominent face, neck flexor and proximal weakness, but no other manifestations of KSS. AR-PEO has ocular manifestations, but an associated hypertrophic cardiomyopathy cataracts, and early death. MNGIE’s most dominant feature is gastrointestinal dysmotility and peripheral neuropathy, whereas, ARCO is dominated by a severe cardiomyopathy rather than conduction defects. Mitochondrial point mutations such as the A3243G MELAS mutation is the most common cause of maternally inherited PEO. The sentinel features of MERRF are the myoclonic seizures, dementia and lipomatosis. Hypoparathyroidism may be seen as well with KSS. Dementia is prominent in MELAS, MERFF, and KSS. Ptosis and PEO are most prominent in PEO, MNGIE, and ARCO. Occasionally, it is noted in MELAS. The stroke-like episodes and posterior leukoencephalopathy and migraine differentiate this entity. Pigmentary retinopathy is seen in KSS, MELAS and MERFF. Optic atrophy may be noted in MERFF. Peripheral neuropathy is seen in NARP and MNGIE, but the pseudoobstruction dominates the latter illness.
SECTION XII. Muscle Disease
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Chapter 10 Malignant Hyperthermia 1. Genetics: (3 syndromes): a. Syndrome I: 1) Mutation of the RYR1 gene 2) Located on chromosome 19q 13.1 3) Linkage to this location occurs most commonly in patients b. Syndrome II: 1) 17q 11.6–q24 (mutation) 2) Mutation is close to a subunit of the sodium channel c. Syndrome III: 1) 7q21–q22 (disease locus) 2) CACNL2A (mutation locus): a) L-Type dihydropteridine (DHP) receptor voltage gated calcium channel d. Syndrome IV: 1) 3 q 13.1 (disease mutation locus) e. Syndrome V: 1) Chromosome 1q31–q32 (mutation) 2) Mutation is in a subunit of the DHP calcium channel receptor (CACNL1A3) f. Syndrome VI: 1) Mutation is on chromosome 5 2. Central core disease: a. Allelic to MH b. Attacks are similar to the genetic forms of the disease c. Pathogenesis is the same 3. MH-like attacks are reported in different myopathies: a. Clinical features of these attacks: 1) Muscle rigidity during anesthesia due to excessive muscular depolarization 2) Increased cytosolic calcium levels b. Specific myopathies that are associated with MH-like episodes: 1) Myotonia congenita 2) Dystrophinopathies 3) Myotonic dystrophy 4) Brodie’s disease 5) Phosphorylase deficiency 6) Multicore disease 7) Periodic paralysis 8) Carnitine palmityl transferase deficiency 9) King–Denborough syndrome: a) Short stature b) Undescended testicle c) High-arched palate d) Kyphosis, lordosis, scoliosis e) Pectus carinatum f) Small chin, low set ears 10) Evans myopathy: a) Proximal muscle weakness and wasting
4.
5.
6.
7.
b) Sporadic muscle hypertrophy (individual muscles) c) Ptosis d) Elevated CK e) Non-specific muscle biopsy findings Clinical features of malignant hyperthermia: a. Triggered by any volatile agent: 1) Halothane 2) Succinylcholine (onset more abrupt) b. Body temperature rises quickly with anesthesia: 1) May exceed 109 degrees Fahrenheit c. Temperature usually drops 1–2 degrees at the start of anesthesia in normal persons d. Arterial blood carbon dioxide tension greater than 100 mm Hg; severe cyanosis e. Arterial blood pH may fall to a pH of less than seven f. Tachycardia g. 75% of patients demonstrate muscle rigidity during acute MH: 1) Contractures not contractions occur 2) May progress to rigor and death 3) Increased permeability of muscle with: a) Increased serum K+ b) Increased ionized calcium c) Increased CK (to 100,000 units) d) Total calcium may be increased e) Myoglobulin release with myoglobinuria f) Marked muscle edema g) CK returns to normal in approximately two weeks h. Rarely an attack may begin post operatively Muscle biopsy of susceptible patients: a. Normal in some patients b. Non-specific findings: 1) Internal nuclei 2) Moth eaten fibers 3) Super contracted myofibrils 4) Target fibers 5) Necrosis and regeneration 6) Mitochondrial alternations 7) Inclusion bodies Contracture of prepared skeletal muscle to: a. Halothane b. Caffeine c. Release of ionized calcium from the endoplasmic reticulum triggered by ryanodine receptors Associated clinical findings: a. Cardiac involvement during MH: 1) Tachycardia, dysrhythmia 2) Hypotension 3) Decline of cardiac output 4) Cardiac arrest 5) Five fold increase in myocardial O2 utilization; 8 fold decrease of myocardial efficiency; sympathetically mediated
Chapter 10. Malignant Hyperthermia
6) Other cardiac manifestations: a) Sudden death b) Cardiomyopathy (non-specific) c) Abnormal thallium cardiac scans b. Central nervous symptoms: 1) Secondary to: a) Increased temperature c) Hyperkalemia b) Acidosis d) Hypoxia 2) Coma 3) Areflexia 4) Cerebral edema 5) Sympathetic nervous system role in maintenance or initiation of MH is controversial
Pharmacologic Agents that Initiate MH
Depolarizing agents
1. Succinylcholine increases: a. Temperature b. O2 Consumption c. Lactate production d. In conjunction with volatile anesthetic provokes fulminant MH 2. Clinical features: a. Exaggerated fasciculations b. Muscle rigidity c. Trismus early (not always present) d. Muscle rigidity may occur
Alternate Responses to Succinylcholine
1. Muscle contracture (asymptomatic) 2. Change in muscle membrane permeability with contracture causes: a. Myoglobinuria b. Increased CK release c. May occur in non-susceptible patients d. Increased by halothane e. Decreased by d-tubocurarine
Non-Depolarizing Muscle Relaxants
1. Non-depolarizing relaxants a. Delay or attenuate the effects of halothane 2. Effects are reversed by cholinergic agonists
Dantrolene
1. Decreases sarcoplasmic calcium release 2. Decreases abnormal contracture responses in isolated muscle
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3. Controls metabolic imbalances (acidosis, increased ion fluxes, sympathetic overactivity) 4. High doses produces muscle weakness 5. Prolonged use may cause hepatic dysfunction
Hyperthermic Episodes Unrelated to Anesthesia
1. In humans MH is overwhelming triggered by anesthetic agents 2. Associated conditions unrelated to anesthesia: a. Unexplained sudden death in susceptible families b. Susceptible patients may develop nonspecific cardiomyopathy c. Febrile episodes for years d. Stress e. Exercise
Differential Diagnosis of Malignant Hyperthermia
The diagnosis of malignant hyperthermia is relatively straight forward. A volatile anesthetic agent or succinylcholine used during induction of anesthesia causes an elevation rather than depression of temperature, tachycardia, masseter rigidity, increase in end tidal CO2 and acidosis. Suspicion of malignant hyperthermia should be raised if a family member of the patient has died or had a major complication during uncomplicated anesthesia. An increased resting CK in a patient with an affected family member is also a clue that the individual is at risk. Baseline CK may be normal in MH patients. The congenital myopathies, muscular dystrophies, phosphorylase deficiency, carnitine palmityl transferase deficiency and periodic paralysis have all been implicated in MH or a MH-like syndrome. Rarely familial malignant hyperthermia occurs.
Differential Diagnosis of Uncontrolled Metabolic State of Abrupt Onset
1. Rhabdomyolysis: a. Anesthetic agents b. Drug induced 2. Exercise 3. Acute intermittent porphyria 4. Ketamine induced catatonia 5. Thyroid storm: a. Precipitated by surgery b. Anesthetics 6. Hyperkalemia following succinylcholine 7. Agents and illnesses that have produced MH responses in humans: a. Ketamine e. MAO inhibitors b. Phencyclidine f. Tranquilizers c. Viral infections g. Tricyclic antidepressants d. Lymphoma
SECTION XII. Muscle Disease
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8. Malignant neuroleptic syndrome a. Higher doses of neuroleptics trigger the illness; occasionally it is idiosyncratic b. Clinical syndrome: 1) High fever 3) Coma 2) Rigidity 4) Tachycardia
Chapter 11 Rhabdomyolysis and Myoglobinuria 1. General features: Rhabdomyolysis is the lysis of skeletal muscle whose major clinical features are myalgias of the affected muscle, pigmenturia and elevated serum creatine kinase. Acute renal failure, cardiac arrest, and nerve damage from compartment syndromes are the major systemic complications. In general, muscle enzymes are elevated to five times normal and serum and urinary myoglobin is present. The balance of extracellular and intracellular calcium across the muscle membrane is maintained by: 1. Sodium-potassium pumps regulated by sodium/potassiumactivated adenosine triphosphatase 2. Calcium channels 3. Specific calcium-ATPase 4. Sodium-calcium exchangers Disruption of the muscle and sarcoplasmic reticular membrane occurs (possible osmotic mechanism due to failure of Na pump mechanisms) and calcium homeostasis is lost that causes a dramatic rise in intracellular calcium. This calcium overload activates phospholipase-A2 and neutral proteases which further destroy muscle membranes. The elevated cytoplasmic calcium induces myofibrillar hyper contractures from enhanced action of myosin filament interaction. Rhabdomyolysis causes myoglobinemia and myoglobinuria. The latter at levels above 300 μg/liter causes renal failure (at levels of 1000 μg/liter greater than 82% of patients). The clearance of myoglobin through the kidneys is rapid as well as its conversion to bilirubin so serum values return to normal after an attack between 1–4 hours. Myoglobin levels in serum precede a CK increase. Myoglobin is detected by a positive toluidine blue test, pigmented casts in the urine, absence of RBC and a normal haptoglobin. The most sensitive test for rhabdomyolysis is a five time normal elevation of serum CK. Approximately 200 grams of muscle is involved to effect a rise in serum CK. The CK isoenzyme CK mm is most prominent although CK-MB (cardiac greater than skeletal muscle) is also elevated. CK-BB is found in brain tissue. Serum CK rises 2–12 hours after the onset of rhabdomyolysis, peaks in 1–3 days and decreases 3–5 days after the muscle damage. Immunologic measurement of carbonic amylase II is a very specific marker of skeletal muscle injury and is not present in cardiac tissue.
Rhabdomyolysis is associated with hyperkalemia, hypocalcemia and hyperphosphatemia. Approximately 150 grams of muscle destruction release 15 millimols of potassium which may elevate plasma levels acutely and contribute to or cause cardiac arrhythmia. Hypocalcemia seen in early rhabdomyolysis has been attributed to deposition of calcium in affected muscle. Hypocalcemia may also be secondary to a decrease of 1,25-dihydroxycholecalciferol due to hyperphosphatemia. In later stages of rhabdomyolysis, hypercalcemia may be seen as calcium is mobilized from necrotic tissue. Rhabdomyolysis is also associated with elevated aldolase, lactate dehydrogenase, amino transferases, creatine and uric acid. Muscle signs and symptoms are generally similar for all causes of rhabdomyolysis. Patients suffer muscle pain and edema, they have thin shiny skin, weakness, stiffness and later contractures. Patients may present without significant muscle weakness. The most commonly affected muscles are the quadrates lumborum (paraspinal muscles), the quadriceps and major muscles of the upper extremity. Rarely, muscles of the chest, abdomen, throat and masseter muscles are affected. All striated muscles may be affected focally or diffusely depending on specific etiology.
Myoglobinuria
1. Clinical features: a. Associated with rhabdomyolysis b. Swelling of affected muscles c. Pigmenturia with myalgia d. Weakness of the involved muscle group e. Pain free episodes may be associated with: 1) Pigmenturia 2) Leakage of muscle enzymes 2. Myoglobinuria may develop with: a. Severe and excessive stress upon fuel reserves of working muscle 3. During moderate exercise muscles utilize: a. High energy phosphate to generate ATP b. Muscle glycogen for the first 5–10 minutes c. 15–90 minutes of exercise: 1) Blood glucose is derived from liver glycogen 2) Requires insulin for uptake d. Greater than 90 minutes of exercise the metabolites utilized are: 1) Glucose 2) Free fatty acids 4. Myoglobin: facilitates rapid diffusion of 02 from capillaries to mitochondria in exercising muscles 5. Myoglobinuria with serum levels greater than 300 ug/liter may cause renal failure: a. Levels greater than 100 ug/liter renal failure is common b. Cleared rapidly through the kidneys: 1) May return to normal 1–6 hours after muscle injury 2) Concomitantly metabolized to bilirubin
Chapter 11. Rhabdomyolysis and Myoglobinuria
c. Myoglobin detection: 1) Positive toluidine blue test 4) RIA 2) Colorless serum 5) ELISA assays 3) Normal haptoglobin
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Phosphofructokinase Deficiency (Tarui’s Disease)
1. 2. 3. 4.
Lifetime intolerance to severe exercise Rhabdomyolysis with myoglobinuria relatively rare Pain and stiffness of exercised muscle Older onset of proximal myopathy in a subset of patients
Hereditary Causes of Rhabdomyolysis and Myoglobinuria
1. General features: a. Defects of glycolysis b. Dysfunction of lipid metabolism c. Genetic causes: 1) Idiopathic rhabdomyolysis 2) AD myoglobinuria 3) Malignant hyperthermia 4) Myoadenylate deaminase deficiency 5) Mono carboxylate transporter defect 6) Neuroleptic malignant syndrome 7) Dystrophinopathies
Genetic Metabolic Defects of Muscle with Myoglobinuria and Rhabdomyolysis
Glycolytic Defects
1. 2. 3. 4. 5. 6.
Myophosphorylase (McArdle’s Disease) Phosphofructokinase Phosphoglycerate mutase Phosphoglycerate kinase Lactic dehydrogenase Phosphorylase kinase
Clinical Features of Glycolytic Defects
1. Onset in childhood 2. Intense exercise causes: a. Pain c. Cramps b. Weakness d. Myoglobinuria 3. “Second wind” phenomena 4. Serum CK persistently increased (5–10x normal) 5. Pain may develop asymmetrically in any working muscle 6. Acute tubular necrosis described only in patients with gross pigmenturia
Myophosphorylase Deficiency (McArdle Disease)
1. Exercise intolerance most severe the first few minutes 2. Approximately 60% of patients: a. Clear myoglobinuria b. Elevated CK c. At least 2 attacks d. Exercise intolerance may occur without myoglobinuria
Phosphoglycerate mutase (PGAM) and Lactate Dehydrogenase Deficiency (LDH)
1. Defect of terminal glycolysis: a. Exercise intolerance, cramps, recurrent rhabdomyolysis b. No permanent weakness
Phosphoglycerate Kinase (PGK); X-linked recessive
1. Enzyme defect occurs in: a. Erythrocytes c. Muscle b. Fibroblasts 2. Associated features: a. Hemolytic anemia c. Mental retardation b. Seizures
Lipid Metabolic Defects with Myoglobinuria and Rhabdomyolysis
1. Carnitine – palmityl transferase deficiency Type I and II: a. Most common hereditary disorder of recurrent rhabdomyolysis and myoglobinuria 1) Transport of long chain fatty acids across mitochondrial membrane b. Attacks associated with: 1) Prolonged exercise without food 2) Stress 3) Attacks can be blocked if carbohydrate intake is maintained during exercise c. Much greater incidence of rhabdomyolysis with CPT than occurs than is seen in systemic carnitine deficiency, acid maltase or mitochondrial myopathies d. Carnitine deficiency associated with lipid storage in muscle
Long-Chain 3-Hydroxyacyl-Coenzyme A Dehydrogenase (LCHAD) Deficiency
1. Defect in mitochondrial fatty acid beta-oxidation 2. Clinical features: a. May be manifest in infancy d. Hypocarnitinemia b. Hypoglycemic coma e. cardiomyopathy c. Hepatic steatosis
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SECTION XII. Muscle Disease
3. Unusual features: a. Peripheral neuropathy b. Chorioretinopathy c. Female carriers of LCHAD deficiency: 1) Pre-eclampsia 4. Diagnosis: a. 3-hydroxylated acylcarnitine derivatives in the blood
L-3-Hydroxyacyl-Coenzyme A Dehydrogenase Deficiency
1. Clinical features: a. Juvenile onset b. Recurrent myoglobinuria c. Hypoketotic hypoglycemic encephalopathy d. Hypertrophic or dilated cardiomyopathy
AD Myoglobinuria
1. Clinical features: a. Swiss family b. Both genders affected c. Precipitated by febrile illness d. Acute renal failure 2. Posited mechanism: a. Nuclear encoded genetic defect of the respiratory chain
Myoadenylate Deaminase (MAD) Deficiency
1. Clinical features: a. Cramping and fatigue with strenuous exercise b. Few patients have exertional rhabdomyolysis 2. Catalyzes the deamination of adenosine monophosphate to inosine hypophosphate with ammonia formation
d. Muscle rigidity and myoglobinuria e. Elevated CK f. Probably CNS disorder rather than the sarcolemmal ryanodine receptor and pyridine interaction of MH
Toxic Myopathy
1. General Features: a. Muscles may be damaged by direct toxic effects or secondarily from immune mechanisms, electrolyte imbalance, ischemia or sustained contraction b. Major categories of toxic compounds: 1) Alcohol 2) Corticosteroids 3) Amphiphilic agents 4) Anti HIV compounds 5) Anti microtubular drugs: a) Vincristine and colchicine are the two primary agents of this class b) Disruption of the microtubule cytoskeletal network in muscle is major pathology: (1) Possible dysfunctional movement or localization of lysosomes 6) Anesthetics 2. Clinical Presentation: a. Pain and myoglobinuria b. Generalized or focal weakness c. Associated neurologic features specific to the toxin d. Wasting of affected muscles e. Cramps 3. Categories: a. Acute alcoholic myonecrosis or rhabdomyolysis b. Hypokalemia with alcoholic myopathy c. Chronic alcoholic myopathy d. Asymptomatic or subclinical myopathy e. Alcoholic cardiomyopathy
Mono Carboxylate Transporter 1 Mutation Rhabdomyolysis from Drug Use
1. Clinical features: a. Muscle breakdown with heat and exercise 2. Muscle lactate transporter deficient; also expressed in RBC
Neuroleptic Malignant Syndrome
1. Clinical features: a. Moderate hyperthermia of gradual onset b. Triggered by: 1) Neuroleptic medications 2) Synthetic narcotics 3) Tricyclic anti-depressants c. Autonomic signs and symptoms
Opioids
A. General Presentation: 1. IV injection of heroin: a. Generalized severe muscle tenderness b. Edema and weakness c. Clinical symptoms may occur hours after injection of heroin and adulterants d. Lower limbs affected to a greater degree than upper limbs e. Proximal greater than distal muscle involvement f. Associated transverse myelitis (occasionally) g. Pulmonary edema h. Local rhabdomyolysis from IM or SC injection
Chapter 11. Rhabdomyolysis and Myoglobinuria
B. Laboratory evaluation: 1. Elevated CK 2. Myoglobinuria C. Pathology (muscle biopsy): a. Necrosis of muscle fibers b. Edema and focal hemorrhage of rare fibers
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Chloroquine
A. Clinical Presentation: 1. Rarely cause myonecrosis and myoglobinuria following one large oral dose 2. SC injection may cause focal swelling and muscle necrosis 3. In barbiturate coma: a. Associated bullous skin lesions
1. Clinical aspects of toxic reaction: a. Doses of 250–500 mg daily for months b. Slow progressive muscle weakness c. Legs affected prior to arms d. Proximal greater than distal muscle weakness e. Face may be affected f. Reduced or absent deep tendon reflexes g. Heart may be affected 2. Pathology: a. Type I greater than Type II fibers affected b. Vacuolar myopathy c. EM demonstrates curvilinear mitochondrial bodies in muscles
Amphetamines
Emetine hydrochloride
1. Thin patients 2. Agitated; attention and concentration problems
1. Dilated pupils 2. Depressed patients
1. Clinical features: a. Generalized muscle weakness, pain and tenderness b. Stiffness 2. Pathology: a. Generalized atrophy b. Type II greater than I fiber involvement
Diazepam
Vincristine
Phencyclidine
1. Severe nystagmus 2. Self mutilating behavior 3. Acute dystonic reaction
1. Clinical features: a. Minimal muscle involvement b. Proximal muscles demonstrate slight fascicular necrosis
Antibiotics
Colchicine
Beta-Blockers
1. Rare muscle involvement 2. Weakness and atrophy of all muscle groups of the lower extremities
Barbiturates
Meprobamate
Clofibrate
1. Generalized cramps, weakness and muscle tenderness 2. Increased CK 3. Increased risk in chronic renal failure B-HMG-CoA Reductase Inhibitors (Statins)
Neuroleptics
1. Possibly compounded by heat related effects
Phenformin/Fenfluramine
Succinylcholine
1. 2. 3. 4. 5.
1. Associated malignant hyperthermia
Acute rhabdomyolysis Rapidly progressive weakness of all muscles Elevated CK and LDH Right heart valve lesions Pulmonary hypertension
Strychnine
1. Severe muscle contractions; patients are conscious in extreme extensor postures
Hypokalemic-Induced Myonecrosis and Myoglobinuria
1. Occurs most frequently in patients utilizing purgatives and diuretics 2. Acute potassium loss from: a. Amphotericin B b. Licorice and carbenoxalone c. Azathioprine
B-HMG-CoA Reductase Inhibitors
1. Primarily associated with muscle pain and cramps Zidovudine
1. Associated with proximal myopathy
SECTION XII. Muscle Disease
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Antihistamines Theophylline Cocaine Plasmoid (Quinoline Derivative) Epsilon Amino Caproic Acid 51 -Azacytidine Drugs that Cause Rhabdomyolysis and Myoglobinuria
1. 2. 3. 4.
Amphetamines Meprobamate Diazepam Phencyclidine: a. Secondary to acute dystonic reaction 5. Phenformin and Fenfluramine: a. Causes acute rhabdomyolysis b. Rapidly progressive weakness of all muscles c. Elevated CK and LDH
Drugs Causing Myalgia, Muscle Cramps, Myokymia and Weakness
1. 2. 3. 4.
Isoetharine Albuterol Cimetidine Danazol
5. 6. 7. 8.
Metolazone Bumetanide 5-azacytidine Ipecac
Most Often Implicated Drugs in Focal Myopathy
1. 2. 3. 4.
Pentazocine Meperidine Penicillin Streptomycin
5. Chloromycetin 6. Paraldehyde 7. Colistimethate
Chronic Alcoholic Myopathy
A. General Features: 1. Controversy as to whether the clinical picture is secondary to neuropathy or myopathy B. Clinical Presentation: 1. Chronic proximal muscle weakness and wasting 2. Apparently dose-dependent C. Pathology (muscle biopsy): 1. Fiber size variability 3. Occasional vacuoles 2. Myopathic type grouping
Alcoholic Cardiomyopathy
A. General Features:
1. Dilated cardiomyopathy secondary to ethanol 2. Cobalt poisoning (beer drinkers) 3. Beriberi: a. Deficiency of thiamine B. Clinical Presentation: 1. Peripheral vasodilatation from alcohol 2. CHF of the high output type 3. Chronic alcoholic cardiomyopathy: a. Dilated cardiomyopathy b. EKG changes of left ventricular hypertrophy c. Conduction defects
Toxic Myopathy with Myoglobinuria and Rhabdomyolysis
1. Grape seed oil ingestion (toxic oil syndrome): a. Clinical features: 1) Initial symptoms of respiratory illness 2) Myalgia and numbness of the extremities 3) Muscle weakness and atrophy (3rd–4th week) b. Severely affected patients: 1) Sclerodermal features 2) Hypertension 3) Respiratory failure 4) Carpal tunnel syndrome c. Pathology 1) Monocellular inflammatory infiltrate of the perimysium and sheaths of intramuscular nerves 2. Penicillamine a. Autoimmune induced myositis 3. Acute alcoholic myopathy (myonecrosis or rhabdomyolysis) a. Incidence varies: approximately 5–10% of severely intoxicated alcoholics b. Clinical features: 1) Alcoholics of long duration 2) Previous clinical attacks of pain and swelling of muscles c. Acute attacks occurs during: 1) Bouts of heavy drinking 2) Withdrawal phenomenon 3) Sustained heavy drinking 4. Abrupt onset 5. Severe muscle cramps, pain and swelling 6. Rarely progressive 7. Pain and tenderness may occur without cramps: a. Usual cramps last 20–30 seconds; some may last for hours 8. Process may affect single muscle groups (gluteus, quadriceps, scalenus and gastrocnemius); rarely trunk muscles (rectus abdominus) 9. Occasionally one or most of one extremity is involved 10. Course: a. Usually benign b. Cramps cease within 48 hours
Chapter 11. Rhabdomyolysis and Myoglobinuria
c. Pain tenderness and swelling last 1–2 weeks d. Weakness lasts 10–14 days 11. Myoglobinuria and rhabdomyolysis cause acute renal failure in severe cases 12. One attack increases susceptibility to future attacks 13. Laboratory Evaluation: a. Elevated CK, SGOT, SGPT, LDH; may be a lag of CK elevation b. Muscle biopsy: 1) Necrosis of individual muscle fibers 2) Segmental (rarely the entire fiber is involved)
Asymptomatic Alcoholic Myopathy
1. Only increase of CK is seen 2. May have serum and urinary myoglobin
Acute Hypokalemia in Alcoholics Patients
A. General Features: 1. Occurs during chronic alcoholism B. Clinical Presentation: 1. Long history of severe alcoholism 2. Evolves over two to several days 3. Painless, weakness of proximal muscle 4. Serum potassium is 1.4–2.3 meq/l 5. Elevated CK and aldolase 6. Repletion of K+ with recovery in two weeks C. Muscle biopsy during the acute phase of the illness: 1. Necrosis of individual fibers 2. Vacuolar myopathy both Type I or II fibers 3. Dilatation of the sarcoplasmic reticulum and T cells
Severe Hypokalemia with Myoglobinuria Occurs at a Level of .6-2.3 mEq/l with:
1. 2. 3. 4. 5. 6. 7. 8.
Renal tubular acidosis Amphotericin B therapy Primary aldosteronism Regional enteritis Nasogastric suction and hyperalimentation Laxative abuse Hypernatremia Water intoxication
Rare Toxins Causing Myoglobinuria and Rhabdomyolysis
1. Licorice ingestion: a. Glycorrheic acid is the active precursor of carboxylase b. Clinical features: 1) Licorice abuse (fad eating)
2.
3. 4. 5. 6.
585
2) Muscle pain 3) Neck weakness 4) Quadriplegia 5) Depressed, but maintained reflexes Cicuta (water hemlock): a. Seizures c. Renal failure b. Myoglobinuria Toluene (leukoencephalopathy, dorsal column disease) Clozapine (basal ganglion) Gasoline vapors (leukoencephalopathy) Carbon monoxide (cortex, BG, cerebellar)
Direct Effect on Muscle Membranes with Myoglobinuria and Rhabdomyolysis (Envenomations)
1. Direct toxicity of sarcolemmal membranes: a. Sea snake (Enhydrina schistosa) b. Australian tiger snake (Pseudechis) c. North and South American rattlesnakes (crotalus virilis viridis) 1) Myotoxin a) Phospholipases A 2. Hornet sting a. Alteration of the sarcoplasmic reticulum 3. Spider a. Damage to the endoplasmic reticulum 4. Scorpion a. Damage to the endoplasmic reticulum
Heat and Exercise
1. Leakage of myoglobin and CK a. Type I and Type II A fibers when stressed produce excess lactate and lose sarcolemmal integrity 2. Exertional myoglobinuria: a. Specific exercise (squat jump) b. Military recruits c. Long distance runners d. Determining factors: 1) State of fitness of the individual 2) Ability to terminate the exercise if severe cramps or pain develop 3) Core temperature 4) Ambient temperature 5) Ischemia of specific muscles in particular positions e. Normal serum myoglobin: 1) 10 ng/ml 2) Greater than 200 ng/ml may induce renal complications 3. Myoglobinuria during violent muscle contractions: a. Status epilepticus b. Electroshock therapy c. Delirium tremors
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4.
5. 6. 7.
SECTION XII. Muscle Disease
d. Prolonged myoclonus e. Tetanus f. Prolonged dystonic spasms g. Status asthmaticus h. Sit ups i. Cross country skiers j. Anterior tibial syndrome k. Wrestling High body temperature and excessive muscle work: a. Exercise in hot humid climate b. Malignant hyperthermia c. Neuroleptic malignant syndrome d. Strychnine poisoning e. Amphetamine intoxication Heat stroke with myoglobinuria Typhoid vaccination fever and myoglobinuria Toxic shock syndrome with myoglobinuria (staphylococcus toxin)
Myoglobinuria and Rhabdomyolysis after Surgery
1. Contributing factors: a. Renal dialysis b. Opioids c. Anesthetics d. Compression of specific muscle groups e. Prolonged exposure to cold
Crush Injury and Ischemia
1. Extensive muscle necrosis from crush injury: a. Myoglobinuria b. Acute tubular necrosis c. Skin and nerve ischemia d. Bullae on the skin (often with barbiturate overdose) 2. Comatose patients: a. Narcotized greater than 12 hours; immobilized b. Compression of limbs or torso c. Impaired muscle metabolism from: 1) Sedatives 5) Alcohol 2) Hypnotics 6) Hypotension 3) Tranquilizers 7) Acidosis 4) Carbon monoxide 3. Crush injury with myxedema coma 4. Specific common compartment syndromes: a. Anterior tibial c. Forearm flexor b. Posterior tibial 5. Myoglobinuria following muscle infarction: a. Embolic arterial occlusion b. Thrombin of vessels from trauma c. Venous thrombosis d. Secondary features: 1) Hyperkalemia 2) Hypocalcemia 3) Hyperphosphatemia 4) Myoglobinuria may occur only when the circulation is restored
Enzyme Deficiencies Associated with Myoglobinuria Ingestion Causing Myoglobinuria
1. Hoff’s disease: a. East Prussia, Sweden, Russia b. Ingestion of fish c. Myalgia d. Stiffness of muscles 2. Hellebore (veratrum alkaloid) a. Ingestion of quail 3. Heat stroke with Myoglobinuria and Rhabdomyolysis: a. Association conditions: 1) Following several days of severe heat 2) Elderly individuals 3) Sickle cell trait 4) Amphetamine abuse b. Concomitant medical conditions: 1) Encephalopathy 2) DIC (platelets are activated) 3) Hyperthermia frequently greater than 106–109 degrees Fahrenheit 4) Renal failure (cortex degenerate) 5) Heart failure
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Myophosphorylase Phosphofructokinase Phosphoglycerate kinase (PGK) Phosphoglycerate mutase (PGM) Adenylate deaminase (AMPD) Lactate dehydrogenase Carnitine palmityl transferase I/II (CPT) Very long chain acylcoenzyme A dehydrogenase Medium chain acylcoenzyme A dehydrogenase Succinic dehydrogenase aconitase Trifunctional enzyme deficiency (mitochondrial) Coenzymes Q10 COX (cytochrome oxidase, subunit defects) mtDNA (multiple deletions) tRNA (phenylalanine) mtDNA defect
Muscle Disease with Prominent Myoglobinuria
1. Acute polymyositis 2. Acute dermatomyositis 3. Duchenne muscular dystrophy (rapid deterioration)
Chapter 12. Myopathy Caused by Nutritional Deficiency Infections with Myoglobinuria
1. Mechanisms: a. Excessive endogenous heat (high fever) b. Effect of bacterial toxins c. Viral destruction of muscle 2. Bacterial infections with septicemia and myoglobinuria: a. Shigella d. Legionnaire’s disease b. Salmonella e. Leptospirosis c. Escherichia coli f. Clostridium perfringens 3. Virus infections: a. Influenza e. Coxsackie virus b. Herpes Simplex f. Adenoviruses c. Herpes Zoster g. Enteroviruses (ECHO 9, 21, 24) d. Epstein Barr 4. Cysticercosis Focal Myopathy Secondary to Intramuscular Injection
1. Local effects: a. Connective and fatty tissue replaced by granulation tissue b. Fibroblastic reaction separates adjacent muscle from the inflammatory site 2. Clinical features: a. Pain, swelling and hemorrhage at the injection site 3. Drugs most likely to cause a local reaction: a. Tetracycline d. Ceftriaxone b. Paraldehyde e. Talwin (pentazocine) c. Colistimethate Chronic Infection Focal Myopathy
1. Clinical features: a. Frequent IM injections b. Localized induration c. Fibrosis of overlying connective tissue and skin 2. Most often implicated drugs: a. Penicillin d. Meperidine b. Streptomycin e. Pethidine c. Chloromycetin f. Pentazocine 3. Clinical features: a. Quadriceps and deltoids most often affected b. Segments of muscle replaced by hard indurated bands c. Fixed contracture of the affected extremities
Chapter 12 Myopathy Caused by Nutritional Deficiency Vitamin E A. General Features:
587
1. Difficult to achieve pure vitamin E deficiency nutritionally 2. α-tocopherol transporter deficiency B. Clinical features: a. Cerebellar degeneration b. Posterior column sensory loss c. Peripheral large fiber neuropathy d. Proximal myopathy e. Rare extraocular muscle involvement f. May be seen in cholestatic syndrome (if acquired) Vitamin D Deficiency A. Clinical features: 1. Proximal muscle weakness of the extremities 2. Legs greater than arms; waddling gait 3. Wasting, pain, and tenderness of muscle 4. Weak neck muscles 5. Bulbar and ocular muscles are normal B. Laboratory evaluation: 1. Increased alkaline phosphatase 2. Normal CK C. Pathology (muscle biopsy): 1. Normal muscle biopsy
Osteomalacic Myopathy
A. General Features: 1. Approximately 1/3 of patients with osteomalacic have weakness or myalgia 2. Myopathy occurs in: a. Dietary deficiency or malabsorption of vitamin D b. Dilantin c. Renal tubular acidosis d. Boys with X-linked Type I hypophosphatemic rickets: 1) No weakness 2) Vitamin D metabolism is normal 3) No renal response to vitamin D with phosphate wasting B. Clinical presentation: 1. Insidious onset 2. Proximal weakness 3. Myalgia 4. Myopathy may precede bony changes C. Laboratory evaluation: 1. Parathyroid levels are normal or increased 2. Normal CK 3. Decreased bone density 4. Increased urinary creatine excretion 5. Increased serum calcium, phosphate and alkaline phosphatase (not invariable) D. EMG: 1. Myopathic in 80% of patients 2. Slightly slowed NCVs in some patients
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SECTION XII. Muscle Disease
E. Pathology (muscle biopsy): 1. Type II fiber atrophy 4. Interstitial fibrosis 2. Fatty infiltration 5. Proliferation of nuclei 3. Variation of fiber size
Primary Hypophosphatemic Osteomalacia
1. 2. 3. 4.
Sporadic presentation in adult life No dwarfism or previous rickets Persistent hypophosphatemia Normal plasma and urinary calcium
Hypermagnesemia
A. General Features: 1. Usual clinical settings: a. Treatment of eclampsia b. Antacid and cathartic abuse 2. Magnesium inhibits calcium at the nerve terminal thus blocking the release of Ach B. Clinical Presentation: 1. Serum concentration of 3–5 mEq/dl: a. Smooth muscle paralysis b. Dysautonomia c. Dry mouth d. Cutaneous flushing e. Hypotension f. Nausea and vomiting 2. Serum concentration of 5–6 mEq/dl: a. Depressed tendon reflexes b. Muscle weakness (7–8 mEq/dl) c. Heart block (7–8 mEq/dl); cardiac arrest d. Serum levels of 8–10 mEq/dl: confusion to coma 5) Magnesium may exacerbate MG C. EMG: a. Low motor amplitudes on NCV studies b. Incremental response with repetitives stimulation (facilitates Ach release) D. Pathology (muscle biopsy): a. Mitochondrial myopathic features have been reported in two patients
Amphiphilic Drug Myopathy
A. General features: 1. Cationic amphiphiles (as exemplified by chloroquine and congers): a. Contain a hydrophilic region and a primary or substituted amino group 2. Hydrophobic region partitions in muscle membrane that then allows the drug to react with anionic groups of phospholipids that causes:
a. Conformational and surface change of the plasma membrane b. Consequent abnormalities of permeability, transport, fusion and receptor properties c. Necrotizing myopathic change induced: 1) Repeated cycles of segmental necrosis 2) Myoblast regeneration and abnormal myotube fusion 3) Chlorphentermine, chlorcyclizine, Triparanol and iprindole are representative drugs for this phenomena 3. Lysosomal vacuolization: a. Produced by the non-porotomized forms of amphophile compounds b. Complexes are formed with polar lipids in lysosomes; change of pH in the lysosome leads to dysfunction of lysosomal enzymes that induce the formation of vacuoles that contain lipids and membranous material (vacuolization of non-necrotic myofibers) c. EM reveals autophagic vacuoles d. Vacuoles, myeloid bodies and necrosis is characteristic of amphophil myopathy
Chloroquine Hydroxychloroquine
A. Clinical presentation: 1. Doses of 200–500 mg taken daily for months are required for toxicity 2. A slowly progressive weakness 3. Legs affected prior to arms 4. Proximal greater than distal muscles 5. Face may be affected 6. Reduced or absent deep tendon reflexes 7. Associations: a. Macular retinopathy c. Axonal neuropathy b. Cardiomyopathy B. EMG: 1. Myopathic changes 2. Increased insertional activity and fibrillation potentials C. Laboratory Evaluation: 1. CK moderately elevated D. Pathology (muscle biopsy): 1. Type I > II fibers affected 2. Vacuolar myopathy 3. Curvilinear and mitochondrial bodies noted by EM
Amiodarone
A. Clinical presentation: 1. Peripheral neuropathy is the predominant neurological manifestations 2. Acute necrotizing vacuolar myopathy
Chapter 12. Myopathy Caused by Nutritional Deficiency
3. Myopathy may be secondary to hypothyroidism B. Pathology: 1. Peripheral nerve, muscle, heart, skin and multi organ involvement 2. Phospholipids-contain myeloid inclusions; may persist for months after discontinuation of the drug
Differential Diagnosis (Amphiphilic Myopathy)
1. Chloroquine toxicity versus exacerbation of inflammatory myopathy of the primary autoimmune disease: a. Muscle biopsy is the only method to differentiate the two 2. Perhexiline (associated neuropathy) 3. Amiodarone (associated neuropathy 4. Chlorpromazine (associated psychiatric problem) 5. Imipramine (associated neuropathy) 6. Quinacrine (yellow sclerae) 7. Doxorubicin (DRG; ganglioneuritis; large fiber sensory loss)
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Lipid-Lowering Drug Myopathy
Fibric Acid Derivatives
A. General Features: 1. Fibric acid derivatives 3. Clofibrate, bezafibrate and fenofibrate are primary examples 4. They are branched chain fatty acids 5. Mechanisms of action: a. Inhibit hepatic release of very low density lipoproteins b. Possibly cause alterations in the sarcolemmal membrane (myotonic discharges) 6. Gemfibrozil: a. Fibric acid derivative b. Risk of myopathy (0.4%) B. Clinical Presentation: a. Causes myopathy in conjunction with HMG Co Areductase inhibitors
Clofibrate Colchicine Myopathy
A. Clinical Presentation: 1. Primarily men over 50 with secondary gout 2. Usual dose 0.5–0.6 mg twice per day 3. Subacute onset of proximal muscle weakness over 1–6 months 4. May involve weakness and atrophy of all muscle groups of the lower extremities 5. Normal deep tendon reflexes 6. Rare clinical myotonia 7. Chronic renal insufficiency is a risk factor B. EMG: 1. Abnormal spontaneous activity in 60% of proximal muscles 2. Myotonic discharges 3. Sensory motor axonopathy present C. Pathology (muscle biopsy): 1. Large spindle shaped vacuoles 2. Subsarcolemma or central location of vacuoles 3. Acid phosphatase and lipid positive material (lysosomal in origin) 4. EM: Sphero membranous bodies in the lysosomes; perinuclear aggregates of densely packed filaments D. Differential diagnosis: 1. Polymyositis 2. Subacute myopathies with axonal neuropathy: a. Amiodarone d. Chloroquine b. Vincristine e. Uremia (no CK elevation) c. Alcohol
A. General Features: 1. More prevalent myopathy with concurrent renal insufficiency; low albumin (nephrotic syndrome) B. Clinical Presentation: a. Generalized cramps, weakness and muscle tenderness b. Occurs within 2–3 months of initially of drug c. Discontinuation of the drug leads to rapid improvement and decreased CK levels
3-Hydroxy-3-Methyl-Glutaryl Coenzyme A-Reductase Inhibitors (HMG-CoA)
A. General features: 1. Microsomal enzyme HMG-CoA-reductase catalyzes the conversion of HMG CoA to mevalonic acid 2. Statins: fluvastatin, lovastatin, atorvastatin, pravastatin, simvastatin; all decrease the synthesis of mevalonic acid 3. Mevalonic acid is a precursor for: a. Cholesterol c. Dolichol b. Ubiquinone 4. Pathology: a. Disruption of the sarcoplasmic membrane b. Toxicity more severe with lipophilic rather than hydrophilic agents B. Clinical presentation: 1. Transient myalgia (usual) 2. Mildly elevated CK (usual) 3. Necrotizing myopathy (severe): a. Acute or subacute muscle pain
SECTION XII. Muscle Disease
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b. c. d. e.
Proximal weakness Deep muscle hyperalgesia Rare myoglobinuria Concurrent drugs that may cause necrotizing myopathy with statins are: 1) Macrobid antibiotics 2) Mibefradil (calcium channel blocker) 3) Nefazodone 4) Nicotinic acid 5) Itraconazole (fungal agent) f. Mechanisms of drug interaction toxicity: 1) Increased HMG-CoA levels due to dysfunction of the enterohepatic circulation or decreased biliary excretion 2) Renal or liver failure
Differential Diagnosis of Drug Induced Necrotizing Myopathy
1. Ethanol 4. Procainamide 2. Zidovudine 5. Etretinate 3. Fibric acid derivatives
Zidovudine Myopathy (AZT)
A. General Features: 1. 3 azido-2 ,3 -dideoxythymide 2. Inhibits HIV replication 3. Dose dependent toxicity 4. A mitochondrial myopathy; causes dysfunction of DNA polymerase gamma 5. Decreased plasma and muscle carnitine B. Clinical Presentation: 1. Spectrum of myalgia and slight CK elevation to myopathy with weakness 2. Dose that induces myopathy: a. 250 gm b. Treatment period of greater than nine months 3. Insidious onset of muscle pain and proximal weakness 4. Minimal wasting of pelvic and shoulder girdles (exacerbated with HIV-wasting syndrome) C. EMG: 1. Myopathic; short duration, small amplitude polyphasic potentials; fibrillation potentials 2. Normal NCVs D. Pathology: a. Atrophic degenerating fibers b. Pseudoragged red fibers (outpouching from mitochondrial proliferation) c. COX negative fibers d. Interstitial lymphocytes e. Intermyofibrillar lipid droplets E. Differential diagnosis:
a. HIV related inflammatory myopathy (similar to polymyositis) b. HIV related muscle wasting syndrome c. Proximal root presentation of CIDP in HIV
Unusual Toxic Myopathies
1. Emetine hydrochloride: a. Ipecac (abused in bulimic patients) b. Painless proximal myopathy c. Associated cardiac abnormalities d. Elevated CK e. Muscle biopsy: 1) Areas of absent myofibular ATPase staining 2) Type II greater than Type I fiber damage 2. Epsilon-amino caproic acid: a. Causes necrotizing myopathy b. Rare myoglobinuria and renal failure c. Severe proximal weakness d. Usual toxic dose is 24 g/day for greater than four weeks; described with 10 gm/day for two weeks 3. Organophosphates and anticholinesterase compounds: a. Insecticide exposure b. Causes necrotizing myopathy
Toxin Associated Inflammatory Myopathy
1. 2. 3. 4.
Penicillamine Procainamide Tryptophane associated eosinophilia myalgia syndrome Toxic oil ingestion (Grape seed oil): a. Clinical features: 1) Initial symptoms of a respiratory illness 2) Myalgia and numbness of the extremities 3) During the third and fourth week patients experienced muscle weakness and atrophy 4) Unusual features: a) Sclerodermal skin features b) Hypertension c) Respiratory failure b. Pathology: 1) Inflammatory infiltrate of the perimysium and sheaths of intramuscular nerves 5. Snake venoms: a. Cause of amputation of limbs in children b. Severe compartment syndromes c. Venom contains: 1) Single-chain peptides 2) A2 phospholipases 3) Pathology: a) Vacuolization, lysis and necrosis of skeletal muscle
Chapter 12. Myopathy Caused by Nutritional Deficiency
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Myopathy of Infectious Disease
Acute Viral Myositis
Viral Myositis
A. General features: 1. May occur during epidemics 2. Adults are more severely affected than children 3. Myalgia is common during viral infection: a. Cytokines IL-1, IL-6 and TNF-α are increased B. Clinical presentation: 1. Acute onset 2. Myalgia 3. Fever 4. Myoglobinuria 5. Swelling 6. Associated findings in severe patients: a. Myocarditis c. Pneumonia b. Renal failure 7. Weakness recovers within 2–3 weeks 8. Epidemic benign myalgia of the neck (influenza) C. Laboratory Evaluation: 1. Elevated CK (highest with associated myoglobinuria) 2. 50% of patients have elevated ESR 3. Increased BUN and Creatinine occurs with the myoglobinuria D. Pathology (muscle biopsy): 1. Myositis with necrosis and perivascular and interstitial inflammation 2. Focal changes
A. General features: 1. Not immune mediated 2. Early cellular changes precede an inflammatory response 3. Immunosuppression does not prevent viral associated muscle damage Epidemic Pleurodynia (Bornholm disease) A. General Features: 1. Usually caused by group B coxsackie virus; rarely group A or echovirus B. Clinical Presentation: 1. Abrupt onset in 75% of patients 2. May have prodrome of headache, anorexia and muscle hyperalgesia for up to ten days 3. Deep breathing, valsalva maneuvers or cough causes chest pain 4. Headache, fever, anorexia, cough and nausea and vomiting are common 5. Lasts for 2 to 14 days 6. Associated sequelae: a. Orchitis b. Aseptic meningitis c. Pericarditis C. Laboratory evaluation: 1. Routine CBC, liver function tests are normal D. Pathology (muscle biopsy): 1. Rare inflammatory changes noted with muscle biopsy
Benign Acute Childhood Myositis
A. General Features: 1. Myositis in a small minority of affected children 2. Influenza B virus in greater than 50%; influenza A in 10%; small number of patients with parainfluenza and adenovirus 3. Adults rarely affected B. Clinical Presentation: 1. Occurs during epidemic of influenza 2. Young boys affected (mean nine years of age) 3. Initiated 4–5 days following upper respiratory infection 4. Severe calf tenderness and pain; duration of 4–10 days; slight swelling 5. Recurrent myositis may occur from a different strain C. Laboratory Evaluation: a. Normal sed rate b. Moderately elevated CK; severe patients may demonstrate SGOT and LDH elevation D. EMG: a. Myopathic MUAPs; calves most prominent, but upper extremities can be involved
Myopathy of HIV
A. General features: 1. Occurs primarily with late infection 2. Probably a cell mediated autoimmune response B. Clinical presentation: 1. Subacute or slowly progressive inflammatory myopathy throughout the course of the illness 2. Usually in late stage of HIV; may be seen with acute infection 3. Symmetrical proximal muscle weakness 4. Myalgia 5. Rarely an acute onset with myocardial and swallowing involvement 6. Associated with dementia and peripheral neuropathy C. Laboratory evaluation: 1. Elevated CK (10–15 times normal) 2. Myoglobinuria is rare 4. EMG: 1. Low amplitude and brief MUAPs; positive sharp waves; fibrillation potentials 5. Pathology (muscle biopsy): 1. Inflammatory macrophages and CD8+ cytotoxic infiltrates that are perimysial, endomysial and perivascular 2. Invasion of both necrotic and non-necrotic muscle fibers 3. Nemaline rods may be found in muscle fibers (usually with AZT myopathy)
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SECTION XII. Muscle Disease
Opportunistic Infections of Muscle in HIV Patients
1. 2. 3. 4.
Myobacterium tuberculosis Mycobacterium avium intracellular Cryptococcus Pyomyositis: a. Staphylococcus aureus most common b. Salmonella (10%) c. Streptococcus (4%)
5. Concomitant liver involvement with jaundice 6. Associated meningitis, liver, heart and renal involvement B. Laboratory evaluation: 1. Early stage has neutrophilia; rare thrombocytopenia 2. 50% of patients demonstrate an elevated sed rate 3. Elevated CPK 4. Leptospira excreted in the urine 5. Serologic tests are positive C. Pathology (muscle biopsy): 1. Swelling, vacuolation and hyalination
HTLV-1 Myositis
A. General Features: 1. Causes T-cell leukemia, polymyositis and tropical spastic paraparesis 2. Transmitted by blood products and sexual contact 3. Endemic in Kii peninsula of Japan, parts of South America, the Caribbean Islands and Central Africa 4. May coexist with HIV and causes spastic paraparesis 5. Less prevalent polymyositis than spastic paraparesis with HTLV–1 infection in Japan 6. Possible T-cell mediated inflammatory reaction; MHC-I restricted cytotoxic process B. Clinical Presentation: 1. May occur in isolation or with T-cell leukemia and spastic paraparesis 2. Slowly progressive proximal myopathy 3. Proximal muscle and neck flexor weakness C. Laboratory Evaluation: 1. CK elevated D. EMG: 1. Myopathic 2. Fibrillation potentials E. Pathology (muscle biopsy): 1. Inflammatory myopathic changes similar to HIV myopathy
Leptospirosis
A. General Features: 1. Leptospira interrogans is the major genus causing clinical disease; a gram negative rod 2. Reported in all regions of the USA 3. Infection in man is incidental; infected animal hosts (rats, skunks, opossum, domestic animals) shed leptospira in urine. Infection in man occurs due to contact with animals or through contaminated soil or water B. Clinical Presentation: 1. Occurs in all age groups; primarily a disease of children and young adults 2. Immersion in contaminated water is common source of infection 3. Hepatic, renal and muscle involvement 4. Myalgias of major muscles
Fungal Myositis
A. General Features: 1. Occurs in immunocompromised patients 2. Organisms: a. Candida (most common) b. Disseminated infection with muscle involvement from: 1) Cryptococcus 2) Aspergillus 3) Sporotrichia 4) Actinomyces 5) Histoplasma
Candida
A. Clinical Presentation: 1. Immunocompromised host or in the setting of prolonged use of broad spectrum antibiotics 2. High fever 3. Erythematous skin rash 4. Severe myalgia and muscle tenderness 5. Lower extremities are involved, more severely than upper extremities B. Muscle biopsy: 1. Hemorrhagic necrosis and budding yeast, pseudohyphae and inflammatory cells.
Tuberculous Myositis
A. General features: 1. Granulomatous myositis 2. Species involved: a. Mycobacterium tuberculosis b. M. Ulcerans c. M. fortuitum d. M. cholinate e. M. haemophilum f. M. xenopi B. Clinical presentation:
Chapter 12. Myopathy Caused by Nutritional Deficiency
1. 2. 3. 4. 5.
Immunocompromised patients Spreads from infected foci Single or multiple abscesses Hematogenous spread is rare Enlarged muscle masses; involvement of adjacent lymph nodes C. Pathology (muscle biopsy): 1. Granulomatous inflammation; histiocytes and macrophages surround an area of caseation 2. Acid fast bacilli noted in the lesions
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1. Associated rash (erythema marginatum); early flu-like symptoms followed by migratory arthritis, neurologic and cardiac involvement 2. Myalgia occurs in the chronic phase; orbital myositis is a rare manifestation C. Laboratory Evaluation: 1. PCR of CSF and blood most helpful after screen for serum antibodies D. Pathology (muscle biopsy): 1. Lymphocytic and mononuclear inflammatory cell invasion of muscle 2. Spirochetes seen in muscle fibers
Sarcoid
A. General features: 1. Incidence higher in black than white patients 2. Patients with sarcoid have up to 60% incidence of muscle involvement 3. Associated involvement of CNS (dura, posterior hypothalamus, pituitary, optic chiasm and parenchyma); lungs, heart, skin (erythema nodosa); uveitis B. Clinical presentation: 1. Muscle involvement is most often asymptomatic 2. Acute myositis is rare 3. Painful proximal muscle weakness; rare cramps and contracture 4. Rare dysphagia, ocular muscle involvement and respiratory compromise 5. Mass in a muscle 6. Chronic sarcoid myopathy evolves into proximal wasting and weakness 7. Usually an associated neuropathy C. Laboratory Evaluation: 1. Chest X-ray is positive in 90% of patients; demonstrates hilar adenopathy or an interstitial pattern 2. Elevated ACE levels (angiotensin converting enzyme) 3. MRI of muscle: a. Distinctive star-shaped pattern with peripheral gadolinium enhancement D. EMG: 1. Myopathic; often associated neuropathic features from the concomitant neuropathy E. Pathology (muscle biopsy): 1. Granulomatous inflammation of surrounding perifascicular connective tissue 2. Necrosis of individual muscle fibers is rare
Trichinosis
A. General Features: 1. Trichinella spiralis is the organism 2. Usually contracted by eating raw or inadequately cooked pork products 3. Pigs eat infected rats; humans eat pork muscle containing encysted larvae that encyst in the small intestine and develop into adults in its mucosa. Five days after infection, females deposit larvae that migrate through tissue to encyst. Larvae encystation in muscle may continue for two weeks. Larvae become calcified. 4. Bear or wolf meat may contain larvae B. Clinical Presentation: 1. Incubation period after eating pseudocysts is 2–12 days 2. Abdominal pain and diarrhea followed by fever and myalgia (primarily in proximal muscle) is concurrent with infestation 3. Periorbital swelling and edema is common 4. Acute proximal myopathy can occur; extraocular, intercostal and diaphragmatic muscles may be involved 5. Myocarditis and CNS involvement can be associated C. Laboratory evaluation: 1. Marked blood and CSF eosinophilia 2. CK is elevated 3. Serology for Trichinella antibodies is positive in 3–4 weeks D. EMG: 1. Myopathic MUAPs with fibrillations E. Pathology (muscle biopsy) 1. Pseudocysts with Trichinella larvae are seen
Lyme Disease Cysticercosis
A. General Features: 1. Organism is Borrelia burgdorferi (spirochete) 2. Deer tick is the usual transmitting host; carried also by dogs, but not cats B. Clinical Presentation:
A. General Features: 1. Organism is Taenia solium 2. Oral route from under washed meat or unwashed vegetables
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SECTION XII. Muscle Disease
3. Mature larvae penetrates the intestinal mucosa (released from the ova by gastric acid) and is disseminated by the lymphatics and hematogenously 4. Larvae mature in 2–3 months (5–6 mm in length and 8–10 mm in width) and grow rapidly in infested tissues B. Clinical Presentation: 1. CNS manifestations predominate: a. Seizures b. Focal neurologic deficits c. Racemose ventricular from with hydrocephalus d. Meningoencephalitis 3. Muscle involvement: a. Weakness b. Hypertrophy (symmetric in limb girdles) c. Pain d. Nodular muscle involvement e. Proptosis and ophthalmoparesis is seen C. Imaging Evaluation: 1. CT or MRI scanning demonstrate calcified cysts in brain and muscle D. Pathology: 1. Cysticerci are identified
1. Lobular cyst in the muscle (hydatid cyst); may grow and calcify; not painful C. Laboratory evaluation 1. Serology is positive
Rare Nematodes that can Infect Muscle
A. General Features: 1. Toxocara canis (T. coli) 2. Ancylostoma canium (cutaneous larva migrans) 3. Dracunculus medinensis (Africa, India and the Middle East) B. Clinical Presentation: 1. Toxocara usually causes visceral larvae migrans in children 2. Patients may be asymptomatic with eosinophilia alone 3. Myalgia in association with fever, hepatosplenomegaly, pneumonitis, ocular invasion and meningoencephalitis in severe cases C. Pathology (muscle biopsy) 1. Granulomatous inflammation
Protozoan Muscle Infection Cestodes (Tapeworms)
A. General Features: 1. Spirometra: cestodes that can involve muscle a. Tapeworms: 1) Spirometra 2) Echinococcus 3) Spirometra mansonoides is the dog and cat tapeworm; may accidentally infect humans 2. Infective stage: a. Second stage larvae (sparganum) gains access to the host by oral route or through open wounds b. Encysts in subcutaneous tissue and muscle; also less frequently in viscera or the eye B. Clinical presentation: 1. Slowly enlarging subcutaneous nodule in muscle or skin; may migrate distally C. Pathology (muscle biopsy): 1. Sparganum is detected in the nodule
Echinococcus
A. General features: 1. Clinically relevant species to man are Echinococcus granulosa and Echinococcus multilocularis 2. Cause infection in dogs and wolves; infection in human is hydatoids caused by ingestion of contaminated food B. Clinical presentation:
A. General features: 1. Usual organisms are toxoplasma, sarcocystis, and trypanosoma 2. Malaria (muscle necrosis and myoglobinuria)
Toxoplasmosis
A. General features: 1. Toxoplasma gondii is the organism 2. Immunocompromised patients 3. Transmission to humans occurs most commonly from cat feces or undercooked meat; placenta and blood products 4. Dissemination occurs from tachyzoites that penetrate leukocytes and are hematogenous B. Clinical Presentation: 1. Subacute polymyositis with associated fever and proximal weakness 2. Associated lymphadenopathy C. Laboratory Evaluation: 1. Elevated muscle enzymes 2. Increased immunoglobulin IgM (positive serology) 3. Isolation of toxoplasma from body fluid D. EMG: a. Myopathic MUAP; typical of inflammatory myopathy E. Pathology (muscle biopsy): a. Histiocytes and lymphocytes in the peri and endomysium; Toxoplasma cysts b. Giant cells in inflammatory aggregates
Chapter 13. Endocrine Myopathy
Chapter 13 Endocrine Myopathy
A. General features: 1. Glucocorticoids induce nuclear gene expression; the hormone receptor complex binds to glucocorticoidresponse elements that regulate transcription of steroid responsive genes 2. Primary action on muscle is the mobilization of amino acids from skeletal muscle for both oxidation and gluconeogenesis. They decrease protein synthesis and increase the rate of proteolysis. Their effect is primarily expressed in type II muscle fibers 3. Glucocorticoids specifically activate ATP dependent protease pathways which are active during disuse, sepsis and cachexia 4. May have direct effect on cellular membranes 5. 50–80% of patients with Cushing’s disease develop muscle weakness 6. 2.4–20% of patients with iatrogenic steroid use develop muscle weakness 7. Women develop myopathy more frequently than men at the same dose of glucocorticoid 8. All synthetic glucocorticoids cause atrophy; the incidence is higher in 9-alpha fluorinated compounds 9. Effects on muscle are less severe with an alternate day course; doses of 30 mg of Prednisone a day or equivalent of steroid are usually necessary to induce atrophy; 10 mg per day rarely cause significant disease B. Clinical presentation: 1. Onset is insidious 2. Quadriceps and iliopsoas are often the first muscles affected 3. Proximal greater than distal muscle weakness 4. Facial and neck muscles are spared C. Laboratory evaluation: 1. CK and aldolase are normal D. EMG: 1. Normal insertional activity b. Low amplitude short duration, polyphasic (MUAP) potentials E. Pathology: 1. Type II muscle fiber atrophy 2. EM: mitochondrial aggregation, swelling and vacuolation
Steroid Myopathy vs Exacerbation of Inflammatory Myopathy
1. Increased sed rate and CK (inflammation) 2. EMG: fibrillation potentials (inflammation)
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3. Biopsy: Active inflammation; white cell invasion of muscle fibers 4. May have normal enzymes with exacerbation of myopathy 5. Type II atrophy on muscle biopsy with steroids
Myopathy from ACTH
A. Clinical Presentation: 1. Proximal weakness 2. Wasting of muscle 3. Thoracic (“fish mouth”) vertebrae with prolonged use 4. Hyperpigmentation B. EMG: 1. Sharp waves or fibrillation potentials C. Muscle biopsy 1. Subsarcolemmal lipid deposits
Myopathy of Addison’s Disease
A. General features: 1. Adrenal insufficiency in the USA is primarily an autoimmune disease. It may also be caused by tuberculosis, pituitary failure, hemorrhage or congenital enzyme defects 2. Muscle weakness is caused by: a. Decreased muscle blood flow b. Impaired carbohydrate metabolism c. Electrolyte abnormalities 3. Enhanced sensitivity to insulin 4. Depletion of glycogen stores and inadequate stimulation by epinephrine of glycogen dephosphorylation in both muscle and liver 5. Adrenergic insensitivity is prominent 6. Addisonian patients suffer hyponatremia, hyperkalemia and hypovolemia B. Clinical presentation: 1. 25–50% of patients have generalized muscle weakness, cramping and severe fatigue 2. Isolated respiratory weakness occurs; may precipitate myasthenic crisis 3. Associated joint contraction (flexion posture) 4. Hyperkalemic paralysis occurs from: a. Prolonged sarcolemmal depolarization that causes sodium channel inactivation b. Intracellular potassium depletion c. Loss of membrane excitability d. Provoked by exercise and potassium load 5. Associated disorders: a. X-linked congenital adrenal hypoplasia: 1) Adrenal cortex affected 2) AX-1 gene (encodes a nuclear hormone receptor)
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SECTION XII. Muscle Disease
3) Associated with Duchenne muscular dystrophy and glycerol kinase deficiency 4) Boys present with salt wasting and hyperpigmentation neonatally; aldosterone loss occurs before cortisol b. Kearne-Sayre Syndrome: 1) Adrenal insufficiency occurs concomitantly with: a) DM b) Hypoparathyroidism c) GH deficiency C. Laboratory evaluation: 1. High serum potassium with loss of serum sodium 2. Eosinophilia 3. Decreased plasma cortisol 4. ACTH stimulation test is positive 5. CK and aldolase are normal D. EMG: 1. Normal
Differential Diagnosis of Flaccid Quadriparesis of Adrenal Insufficiency
1. Hyperkalemic periodic paralysis: a. Cold and potassium induced b. Usually short attacks 20–30 minutes c. Family history d. Myotonia is prominent and may be seen between attacks Adrenal insufficiency: 1) Attacks resolve with glucocorticoids 2. Paramyotonia congenita: a. Prominent cold induced weakness (rarely flaccid paralysis) b. Paradoxical myotonia (exercise increases myotonia)
Myopathy of Thyroid Disease
A. General Features: 1. Thyroid hormone regulates the transcription of muscle-specific genes that effect contractibility: a. Sodium-potassium ATPase b. Myosin heavy-chain isoform c. Sarcoplasmic reticulum-calcium ATPase 2. Increase skeletal muscle heat production, mitochondrial oxygen consumption, pyruvate and malate consumption 3. Stimulates glycolytic activity 4. Causes insulin resistance and increased degradation of skeletal muscle protein 2. Clinical Presentation: 1. Female predominance of 3 : 1 to 4 : 1; weakness occurs in 50% of patients
2. Mean age of onset is 50 3. Proximal weakness 4. Weakness out of proportion to wasting: a. Rhomboids and shoulder girdle muscles may be severely affected b. Distal weakness occurs c. Sphincters and bulbar muscles are spared; affected with concomitant MG d. Myalgia, fatigue and exercise intolerance is common e. Controversial: 1) Bulbar involvement and respiratory insufficiency in the absence of MG f. Rare inflammatory myopathy g. Weakness develops: 1) Minimal hyperthyroidism of long duration 2) Rapidly with severe disease (storm): a) Rhabdomyolysis c) Renal failure b) Myoglobinuria h. Tendon reflexes are normal to increased i. Myasthenia gravis: 1) 7.5% are hyperthyroid 2) 5.3% are hypothyroid; 2% have a non-toxic goitre j. Thyrotoxic periodic paralysis (hypokalemic): 1) Usually south eastern Asian patients 2) Attacks usually develop over several days 3) Precipitated by carbohydrates, muscle cooling or rest after exercise; maybe “walked off” (aborted by exercise) 4) Generalized attacks affect proximal > distal > bulbar and respiratory musculature (rare) 5) Hypokalemia of 1–3.5 meq/dl; associated hypophosphatemia and hypomagnesemia C. Laboratory Evaluation: 1. Decreased TSH with elevated T3, T4 2. CK, LDH, SGOT usually normal 3. Creatine may be elevated D. EMG: 1. Short duration MUAP; increased polyphasic potentials 2. Fibrillation and fasciculations are rare 3. Approximately 30% of patients with normal strength have an abnormal EMG E. Pathology (muscle biopsy): 1. Fatty infiltration between myofibrils 2. Isolated fiber necrosis with lymphocytic and macrophage infiltration 3. Atrophy of Type I/II fibers
Thyroid Ophthalmopathy
A. General features: 1. Chronic inflammatory condition of orbital tissue 2. Associated with immune thyroid disease
Chapter 13. Endocrine Myopathy
3. Ophthalmopathy occurs in 5% of patients with Grave’s disease; subclinical disease (ultrasound) occurs in 90% 4. Lymphocytes and macrophages that invade retroorbital tissue secrete cytokines that stimulate orbital fibroblasts which secrete glucosaminoglycans into the extracellular space B. Clinical presentation: a. Ocular findings may be noted prior to or concomitant with hyperthyroidism or may appear during treatment b. Conjunctival and lid swelling c. Proptosis d. Weakness and enlargement of extraocular muscles. Inferior and medial recti may be least involved. Fromerly thought that inferior rectus enlarges first. Impairment of elevation and abduction is most common functional deficit e. Corneal ulceration occurs with severe proptosis f. Optic nerve compression in the orbit occurs with concomitant scotoma g. Exophthalmos: a. Painful b. Diplopia occurs c. Associated with an increase of orbital contents and perimysial connective tissue d. Most often bilateral; is the most common cause of unilateral proptosis e. Compresses the vascular supply to the optic nerve f. Poor correlation between thyroid function and ophthalmopathy
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10. Rarely hypothyroidism is associated with proximal weakness and atrophy 11. Rare rhabdomyolysis C. Laboratory Evaluation: 1. Elevated CK in symptomatic patients 2. Serum myoglobin elevated in proportion to severity of the hypothyroidism 3. Creatine excretion is not elevated 4. Increased TSH with low free and total T4 5. Macrocytic anemia of around 10 grams/dl 6. Elevated antithyroglobulin antibodies in autoimmune thyroiditis 7. Secondary hypothyroidism; TSH and T4 are both low 8. Creatine excretion is not elevated D. EMG: 1. Normal or low amplitude polyphasic motor unit potentials 2. Rarely increased insertional activity and positive sharp waves are noted 3. Concomitant findings of sensorimotor neuropathy and CTS 4. Myoedema: a. Electrically silent muscle contraction b. Non-propagating contraction c. Initiated by a slight mechanical stimulus E. Pathology (muscle biopsy): 1. Atrophy, necrosis and hypertrophy of fibers 2. Increased ring fibers, glycogen accumulation and interstitial connective tissue 3. Inflammatory infiltrate and muscle fiber necrosis in patients with rhabdomyolysis
Hypothyroid Myopathy
A. General Features: 1. Decreased mitochondrial oxygen capacity, glucose uptake and muscle oxidative enzyme activity 2. Fasting hypoglycemia; insulin resistance and glycogen accumulation occurs in muscle 3. Decreased adrenergic receptors on muscle cells which causes diminished glycogenolysis B. Clinical Presentation: 1. Proximal muscle weakness 2. Difficulty initiating movements 3. Muscle fatigue and stiffness 4. Myalgia and myoedema 5. Pseudohypertrophy of muscle 6. Delayed relaxation phase of reflexes: a. Slowing of calcium sequestration by the sarcoplasmic reticulum 7. Painful cramps in adult thyroid myopathy 8. Myokymia (reduced sodium-potassium pump activity) 9. Hypothyroid myopathy without cramps (Kocher– Debre–Semelaigne syndrome)
Acromegalic Myopathy
A. General Features: 1. GH stimulates the formation of somatomedins which are insulin-like growth factors (IGF) 2. IGF–1 is the most important of these and is manufactured in the liver 3. GH accelerates fatty acid oxidation, decreases glucose utilization and induces insulin resistance 4. Muscle protein synthesis is increased and protein breakdown in muscle is decreased 5. Decreased force-generating ability in the face of increased fiber diameter 6. Associated cardiomyopathy, arthritis of large joints, spinal cord compression (hypertrophied ligaments) carpal and tarsal tunnel syndrome B. Clinical Presentation: 1. Initial increased bulk and strength 2. Insidious onset of proximal weakness, fatigue and exercise intolerance 3. Muscle weakness affects 50% of patients 4. Minimal muscle wasting
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SECTION XII. Muscle Disease
C. Laboratory Evaluation: a. GH and IGF-1 levels are increased b. Paradoxic GH response to thyrotrophin releasing hormone occurs in 2/3 of patients c. Lack of GH suppression during glucose tolerance test d. Slight elevation of CK and aldolase e. Creatine excretion is normal or slightly increased D. EMG: 1. 50% of patients have myopathic changes 2. Neuropathy in 50% of patients: a. Generalized hypertrophic neuropathy b. Entrapment neuropathy (CTS and TTs) 3. Neuropathy and myopathy occur independently and evolve separately 4. Pathology (muscle biopsy): a. Isolated fiber necrosis (primarily type II) b. Nuclear enlargement with prominently enlarged nucleoli c. Increased muscle glycogen
Hypopituitarism
A. General features: 1. Etiology: a. Pituitary tumors (primarily chronophobe adenoma) craniopharyngioma (15% intrasellar origin); meningioma, and rarely pituitary cancer b. Head trauma c. X-RT d. Thrombophlebitis e. Granuloma (sarcoid) f. Cysts g. Meningitis h. Lymphocytic adenohypophysitis 2. Muscle manifestations are due to: a. Decrease of thyroid hormone b. Growth hormone c. Rarely cortisol 3. Prepubertal panhypopituitarism: a. Secondary to craniopharyngioma; rarely idiopathic or GH receptor dysfunction b. Muscle wasting c. Dwarfism d. Alabaster white skin; no melanocyte stimulating hormone e. Lack of sexual development B. Clinical presentation: 1. Severe weakness 2. Fatigability (exercise intolerance) 3. Disproportionate preservation of muscle mass 4. Isolated decrease of GH secretion: a. AR b. Dwarfism c. Poor muscle development
d. Gross reduction of muscle number 5. Familial dwarfism: a. Resembles GH deficiency b. Elevated GH level c. Inability to produce somatomedins in response to GH insulin like growth factor (ILGF)
Primary Hyperparathyroidism
A. General features: 1. Parathyroid hormone directly affects mineral and ion transport of bone and kidney 2. Action on vitamin D synthesis 3. Stimulates protein degradation of muscle: a. Activation of sarcoplasmic reticulum calcium channels to increase intracellular calcium (cyclic AMP mediated) b. Increases mitochondrial calcium permeability c. Increased intracellular calcium activates intracellular proteases 4. Vitamin D deficiency: a. Dysfunctional excitation contraction coupling b. Inability to absorb calcium from the gut with decreased storage in mitochondria and the sarcoplasmic reticulum c. Depressed myofibrillar ATPase d. Decreased protein synthesis (wasting) e. Uremic myopathy (secondary hyperparathyroidism): 1) Inability to convert 25-OH-D3 to 1,25 (OH)2 D3 the active from of Vitamin D 2) Degradation of troponin I by calcium activated proteases B. Clinical presentation: 1. Proximal muscle weakness (25% of patients) 2. Wasting and cramps 3. Fatigability and exercise intolerance 4. Painful stiffness without myotonia 5. Bulbar musculature and sphincters are spared 6. May have increased tendon reflexes 7. A few patients have been described with bulbar involvement and fasciculations 8. Waddling gait and difficulty walking C. Laboratory evaluation 1. Elevated serum alkaline phosphatase and calcium (>14 mg/dl); decreased serum phophate ( proximal weakness; large fiber sensory loss; absent reflexes) 8. Severe cervical stenosis (decreased range of motion to all planes; inverted radial reflex; proximal muscle weakness) 9. Prolonged chemodenervated from Botox injection 10. Myotonic dystrophy (dysmorphism, myotonia, cataracts) 11. Nemaline (tall, thin, dysmorphism) 12. Mitochondrial myopathy (associated VIII nerve dysfunction, short stature, exercise intolerance, myoglobinuria) 13. FSH dystrophy (severe lower face; humeral involvement) 14. Carnitine deficiency (exercise intolerance myoglobinuria, cramps)
Rare Presentations
1. Dropped head: a. Parkinson’s Disease; akinetic rigid syndrome 2. Bent spine: a. ALS b. Hypothyroid myopathy c. DM/polymyositis complex
Differential Diagnosis of Skeletal Abnormalities that Simulates Bent Spine Syndrome
1. 2. 3. 4. 5. 6.
Torticollis Dystonia of chronic regional pain syndrome (CRPS) Ankylosing spondylitis Severe kyphosis/lordosis Ochronosis (homogentisic aciduria) Thoracic disc disease
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Section XIII CEREBELLAR DISEASE
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SECTION XIII. Cerebellar Disease Cerebellar Disease
A. General considerations: 1. The cerebellum is parcellated both anatomically and functionally into specific zones. a. The archicerebellum consists of the flocculonodular lobe; it has major connections with the vestibular system and is important for control of eye movements. b. The paleocerebellum is composed of the vermis of the anterior lobe (lobule I-V) as well as the pyramis, uvula and paraflocculus. Most of its afferents are from the spinal cord. Its major functional role involves muscle tone and control of axial and limb movements. c. The neocerebellum comprises the middle vermis and the hemispheres. d. The cerebellar cortex may be divided into longitudinal zones that project to specific nuclei. 1) The vermal zone projects to the fastigial nucleus 2) The intermediate zone projects to the nucleus globosus and emboliformis 3) The lateral zone projects to the dentate nucleus e. The somatotopic representation within each nucleus is: 1) Caudal body parts are anterior; rostral parts posterior, trunk is lateral; limbs medial. f. Functional anatomy of the nuclei: 1) Fastigial nucleus a) Upright posture, muscles of the trunk b) Important for sitting, standing and walking 2) The globosus and emboliform nuclei: a) Involved with segmental reflexes that control stability b) Important for the initiation of movements derived from somatosensory input (proprioception) c) Stabilizes proximal joints that facilitate pyramidal movements d) Lesions cause: 1) Delayed check 2) Truncal titubation 3) Oscillation of the extremities e) Facilitate control of oscillations during the last 1/3 of movement. 3) The dentate nucleus a) Important in the facility of fine movement by promoting their initiation, coordinating extensor and flexor musculature at multiple joints, controlling the spatial coordination of hard and finger movements. Lesions of the nucleus and its connections cause postural kinetic tremors (rubral tremor). This tremor is distinguished by increasing amplitude of oscillation that occurs at right angles to the line of movement
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The Afferent and Efferent Cerebellar Pathways of Clinical Relevance
Inferior Cerebellar Peduncle
This is known as the restiform body and is most often involved in vertebral artery and PICA strokes, as well as by compression from tumors, demyelinating disease and stroke. a. It is comprised of: 1) The dorsal spinal cerebellar tract which carries proprioceptive and exteroceptive information from the lower extremity and trunk. Cervical spondylosis and any spinal cord compressive disease, as well as the reviewed acquired and congenital diseases of the cervical cord affect this pathway. No patient with significant cervical stenosis from any cause can tandem walk. It originates from Clarke’s column of the spinal cord. 2) The cuneocerebellar tract that arises from the external arcuate nucleus and relays proprioceptive information from the arm and neck 3) The vestibulocerebellar tract projects bilaterally to the flocculonodular lobe. A cause of cervical induced nystagmus. 4) Reticulocerebellar tracts from the lateral and paramedian nuclei of the brainstem are important for tone and cerebellar influences on segmental reflexes 5) The arcuate cerebellar tract arising from the medullary arcuate nuclei 6) Trigeminocerebellar tract which originates in the spinal and main sensory nuclei of cranial nerve V. This nucleus is important for migraine, head pain, and facial reflexes (trigeminal reflexes, i.e., light causing cough) 7) Olivocerebellar tract is an afferent tract for somatic modalities from the contralateral inferior olivary nucleus. Efferent Tracts in the Inferior Cerebellar Peduncle
1. Fastigiobulbar tract (juxtarestiform body) and cerebellar reticular efferents) The Middle Cerebellar Peduncle (the Brachium Pontis)
Connects the cerebellum to the pons. Corticospinal fibers synapse in the pontine gray, project to the intermediate zone of the cerebellum and thence to the cerebellar zone of the thalamus in the ventrolateral nucleus. These afferents then project to area 3b of the somato sensory cortex and thence to area 4 of the primary motor cortex. Lesions of this distributed pathway cause specific symptom complexes at each level of involvement. Pontine grey lesions cause hemiparesis and ataxia of the contralateral side. Descending corticospinal fibers are responsible for the weakness and are the origin of the middle cere-
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SECTION XIII. Cerebellar Disease
bellar peduncle (MCP) which projects to the intermediate zone of the cerebellum and then to the thalamus and cortex. A cause of ataxic gait. The lateral zone of the cerebellum, if involved, causes greater ataxia of the arm then the leg as does involvement of the middle cerebellar peduncle. Thalamic lesions involving cerebellar radiations are notable for ataxia of stance. Disruption of cerebellar connections from 3 b of SI to M1 of area 4 cause Brunn’s frontal lobe ataxia. The Superior Cerebellar Peduncle (SCP)
The superior cerebellar peduncle is the primary connection of the cerebellum to the midbrain. It is the primary efferent pathway of the cerebellum. The clinically most important efferent pathways are the dentatorubral and dentothalamic tracts which are the anatomic basis of the postural kinetic and cerebellar outflow tremors, seen with midbrain and thalamic lesions.
Posterior Vermal Split Syndrome
A. General considerations: 1. Caused by surgical disruption of parallel fibers crossing the midline cerebellar cortex B. Clinical features: 1. Severe difficulty in performing tandem gait 2. Normal regular gait, standing and unilateral hopping Cerebellar Hemispheric Syndrome
A. General considerations: 1. Usually caused by metastases, abscesses and infarction 2. Muscles controlled by the precentral cortex are primarily affected B. Clinical features: 1. Poor fine finger movement and incoordination of the ipsilateral extremity 2. Dysarthria Pan Cerebellar Syndrome
Specific Anatomically Based Cerebellar Syndromes
Rostral Vermis Syndrome
A. General considerations: 1. Most often seen in alcoholic patients 2. Anterior and superior vermis are involved (the lingula, centralis, culmen) 3. Severe Purkinje cell loss B. Clinical features: 1. “Martonette” gait; broad based with predominance of truncal extensor tone 2. Minimal arm ataxia 3. Minimal or no dysarthria and extraocular muscle impairment 4. No heel to shin ataxia in recumbency Caudal Vermis Syndrome
A. General considerations: 1. Primary damage is to the floccular nodular lobe 2. Medulloblastoma in children 3. Posterior fossa cysts and hemorrhages, Chiari malformations are most common in adults B. Clinical features: 1. Titubation; inability to sit with the back straight 2. Minimal limb ataxia 3. Extraocular movements: a. Down-beat nystagmus accentuated in lateral gaze b. Rotary nystagmus c. Hypermetric saccades
A. General considerations: 1. Signs and symptoms of all cerebellar syndromes 2. Caused by autoimmune and infectious processes, hypoglycemia, paraneoplastic induced antigens (anti-Yo and anti-Hu), hyperthermia, solvents, toxins and hypothyroidism B. Clinical features: 1. Bilateral signs of cerebellar dysfunction that is appendicular and truncal 2. Extraocular movements are affected Vascular Disease of the Cerebellum
[See page (vascular disease section)]
Differential Diagnosis of Major Cerebellar Arterial Diseases
1. PICA The distinguishing features of a PICA infarction are nausea, vomiting, hoarseness, rotary nystagmus to the side of the lesion and inability to walk out of proportion to other aspects of the stroke. A pure medial branch occlusion may primarily involve the nucleus ambiguous. A pure lateral lesion may cause isolated vertigo and dysmetria without dysarthria and without vestibular signs. The sensory loss is to pain and temperature of the ipsilateral face and contralateral body. 2. The hallmark of an AICA occlusion is sudden hearing loss, a peripheral facial (a branch of the artery, supplies the VIIth nerve peripherally) and ataxia of the arm greater than the leg.
SECTION XIII. Cerebellar Disease
3. The superior cerebellar artery is frequently infarcted by an embolus to the top of the basilar artery. The occlusion is manifest by ataxia of all extremities and severe dysarthria. These features are often accompanied by midbrain, thalamic and parietal signs and symptoms. The interpeduncular artery from the top of the basilar feeds the decussation of the SCP at the level of the inferior colliculus (Windekink’s commissure) which can also cause ataxia of all extremities. Rarely, patients have a contralateral IVth nerve and hearing loss (crossed fibers of the lateral lemniscus).
Oculomotor Deficits of Superior Cerebellar Artery Occlusion
1. Contrapulsion of saccadic eye movements. These complex eye movements have three major components: a. Horizontal saccades away from the lesion (opposite side) on upgaze which causes an oblique trajectory of the nystagmus b. Hypermetria of the contralateral saccadic movement c. Hypometria of ipsilateral saccades 2. These eye movements are opposite to those seen with PICA infarction a. Lateral pulsion to the side of the lesion (torsional nystagmus on attempted upgaze) b. Hypometric saccades contralaterally. Lateral branch of the superior cerebellar artery signs and symptoms: 1. Ipsilateral extremity dysmetria 2. Axial lateral pulsion (ipsilaterally) 3. Contra pulsion of saccades 4. Dysarthria 5. Clumsy hand dysarthria syndrome
Medial Branch Cerebellar Artery Infarction
1. Dysarthria and gait abnormalities are the most prominent feature 2. Rarely ipsilateral appendicular dysmetria, extensor posturing of the trunk and all extremities.
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Friedreich’s Ataxia (classic phenotype)
A. General considerations: 1. Most common recessively inherited ataxia; most patients have a GAA repeat expansion of the first intron of frataxin gene a. Frataxin is a nuclear encoded mitochondrial protein 2. Prevalence of 2 per 100,000 people a. Long normal alleles (25–40 repeats) occur in Caucasian patients b. Chromosome 9q13; FRDA gene c. Associated medical abnormalities: 1) Hypertrophic cardiomyopathy (50%) 2) Repolarization defects on EKG 3) Diabetes mellitus 10% e. 95% of patients have homozygous GAA expansion in both alleles B. Clinical features: 1. Onset of less than 25 years of age 2. Mean age of onset is 11–12 years 3. Presentation of progressive gait ataxia 4. Rare presentations: a. Cardiac dysfunction b. Scoliosis 5. Loss of position and vibration sensibility of the lower extremities occur early 6. Dysarthria; pes cavus 7. Pes cavus 8. Bilateral Babinski signs 9. Square wave jerks noted with eye movement recording 10. Inability to walk occurs between 10–15 years of illness 11. Loss of muscle strength (late) 12. Flexor spasms 13. Dysphagia 14. Optic atrophy and VIIIth nerve deficits occur late C. Electrodiagnostic evaluation (EMG/NCV): 1. Early decrease of SNAP (sensory nerve action potential) 2. Central conduction defects occur late D. MRI evaluation: 1. Atrophy of the upper cervical cord greater than cerebellar atrophy
Atypical Phenotypes of Friedreich’s Ataxia The Autosomal Recessive Ataxias
Late Onset
A. General considerations: 1. Most are childhood onset 2. May have adult onset 3. Consaniquinity is higher than in the general population, but is not required 4. The parents are asymptomatic 5. In small families only one child may be affected
A. General considerations: 1. Onset later than age 25 years occurs in 7–17% of patients 2. Classic onset with preservation of ankle jerks a. 5–13% of patients b. Small number of patients have late onset with preserved reflexes
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SECTION XIII. Cerebellar Disease
3. Larger repeat size: a. Correlated with hypertrophic cardiomyopathy and DM (diabetes mellitus) 4. Somatic musacism may account for variability of presentation Early Onset
A. General considerations: 1. Two missense mutations located in the amino-terminal half of the frataxin gene 2. Loss of function mutation (D122Y and G130V) B. Clinical features: 1. Atypical and milder clinical presentation 2. Early onset of spastic gait 3. Slow disease progression 4. No dysarthria 5. Retained or brisk tendon reflexes 6. Minimal cerebellar ataxia 7. Optic disc pallor: a. Higher in compound heterozygotes than in expansion homozygotes
Intrafamilial Phenotypic Variability in Friedreich ataxia associated with a G130V mutation in the FRDA gene
A. General considerations: 1. GAA expansion on one allele and a point mutation on the other B. Clinical features: 1. Slow disease progression 2. Minimal or no ataxia 3. Increased deep tendon reflexes 4. Mild gait spasticity C. Neuropathology: 1. Loss of myelinated fibers in peripheral nerves 2. Decrease of large dorsal root ganglion cells 3. Demyelination of the dorsal columns 4. Distal degeneration of the corticospinal pathways (“dying back”) 5. Degeneration of the spinocerebellar pathways 6. Loss of neurons occurs in Purkinje cells, cranial nerve neurons and dentate nucleus 7. Cerebellum and brainstem are less affected
Ataxia Telangiectasis (A-T)
A. General considerations: 1. Second most common recessive ataxia 2. Frequency of 1 : 400,000 births in the USA 3. Most frequent in ethnic groups with high consanguinity; seen among all races 4. Lack ATM protein or ATM kinase activity; chromosome 11q22–23
5. Absence or dysfunction of the ATM gene; splicing and missense mutations 6. Ataxia telangiectasias variants: a. Nijmegan syndrome (NBS) or nibrin/Nbs1 deficiency 1) Mental retardation with microcephaly 2) No ataxia, apraxia or telangiectasias b. A-T (Fresno) 1) Features of both NBS and A-T a) Mutations in the A-T M gene 7. Cells from A-T are extremely sensitive to ionizing irradiation or other DNA damaging agents 8. ATM protein is involved in mobilizing the cellular response to DNA double stranded breaks B. Clinical features: 1. Early onset and progressive 2. Ataxia by age two 3. Wheelchair bound by 12 years of age 4. Oculocutaneous telangiectasia occur several years after onset 5. Oculomotor apraxia 6. Dysarthria 7. Immunodeficient patients with frequent sinopulmonary infection 8. Lymphoid cancer occurs in 1/3 of patients 9. Short stature and mental retardation are common 10. Choreoathetosis may be prominent C. MRI Evaluation: 1. Decreased volume of the cerebellum by age 10; progression of atrophy in the hemispheres from lateral and superior to inferior D. Laboratory Evaluation: 1. Elevated albumin to globulin 2. Deficiency of IgA, IgE, and IgG2 3. Low T cell levels with poor response to mitogin 4. Translocations and telomeric fusions; increased ratio of telomeric shortening 5. In vitro radiosensitivity of cells 6. Deficits in the activation of cell cycle check points 7. Decreased ATM protein 8. Deficient phosphorylation of p53, nibrin/Nbs1, Mdm2, Smc1, Mre11 Variability within the classical A-T Phenotype
1. Late development of ataxia (teens) 2. No telangiectasias (usually seen on bulbar conjunctive, but also bridge of the nose, pinna, antecubital fossae, knuckles and behind the knee 3. Cancer phenotype: a. β lineage lymphocytes b. T cell lineage in teenagers c. Non-lymphoid malignancies 4. No mental retardation; some patients with higher than normal IQ
SECTION XIII. Cerebellar Disease
5. Laboratory evaluation: a. 15% of patients have some ATM protein; some normal ATM (poor function) 6. ATM phosphorylates proteins involved in cell regulation (to various degrees)
A-T Variants
Nijmegen Breakage Syndrome
A. General considerations: 1. Similar cellular phenotype to A-T 2. Radiosensitivity and translocations of chromosome 7 and 14; immunodeficiency and predisposition to cancer 3. AT-V2 gene (Nijmegen; AT-V2 (Berlin gene for these diseases localized to 8q21) B. Clinical features: 1. Microcephaly 2. Mental retardation 3. No ataxia or telangiectasia Mutations of the Mre 11 Gene
A. General considerations: 1. Chromosome 11q21 B. Clinical features: 1. Early onset ataxia 2. Radiosensitivity Aicardi Syndrome (AOA2 Type II; ataxia with oculomotor apraxia)
A. General considerations: 1. ATM levels are normal 2. No radiosensitivity 3. Gene localized to 9q34 (creatoxin gene) 4. Increased serum alpha-fetoprotein 5. Found in Europe, North Africa and West Indies 6. Frequency of 8% of non-Friedreich’s ARCA B. Clinical features: 1. Later onset of ataxia (11–22 years of age) 2. Sensorim motor neuropathy (92%) 3. Choreic or dystonic movements (44%) 4. Oculomotor apraxia (56%) a. Increased horizontal saccade latencies b. Hypometria C. Laboratory evaluation: 1. Increased alpha-fetoprotein
B. Clinical features: 1. Spinocerebellar ataxia 2. Axonal neuropathy Ataxia – Oculomotor Apraxia 1 Gene (AOA 1)
A. General considerations: 1. AR; gene is on chromosome; 9p13; codes for aprataxin 2. In vitro cells do not have radioresistant DNA; they do have normal ability to phosphorylate targets of ATM B. Clinical features: 1. Early onset of ataxia 2. Oculomotor apraxia C. Laboratory evaluation: 1. Not radiosensitive by CSA; but are sensitive to hydrogen peroxide and agents that cause single strand DNA breaks 2. Normal AFP levels Ataxia with Vitamin E Deficiency
A. General considerations: 1. Decreased alpha-tocopherol levels 2. Chromosome 8q; point mutation in the gene that encodes the alpha-tocopherol transporter a. Childhood onset phenotype 1) Occurs with mutations that inactivate the transporter b. Adult onset phenotype: 1) Some residual transporter activity remains B. Clinical features: 1. Early onset of progressive ataxia 2. Severe proprioceptive loss 3. Areflexia 4. Retinal disease 5. Head trauma 6. Chorioretinitis 7. Rare cardiomyopathy Spastic Ataxia of Charlevoix-Saquenay
A. General considerations: 1. Chromosome 13q11; mutated protein SACS 2. Transcribed protein is sacsin B. Clinical features: 1. Seen amongst French Canadians of the CharlevoixSaquenay province of Quebec 2. Spasticity 3. Ataxia
Rare AR Cerebellar Ataxias
Mutations of TDP1
A. General considerations: 1. Tyrosyl-DNA phosphodiesterase (TDP1) repairs covalently bound topo isomerase 1-DNA complexes a. A step in the DNA repair process
609
Hypogonadotrophic hypogonadism (Holmes)
A. Clinical features: 1. Abnormal sexual development 2. Neurologic symptoms develop in the 3rd decade
610
B.
C.
D.
E.
F. G.
H. I. J. K. L.
SECTION XIII. Cerebellar Disease
3. Dysarthria, nystagmus, progressive gait and limb ataxia 4. Mental retardation, dementia, distal weakness, choreoathetosis, retinopathy, dorsal column defects Behr’s Syndrome 1. Clinical features: a. Scoliosis c. Optic atrophy b. Spasticity d. Learning disability Marinesco-Sjögren 1. Clinical features: a. Learning disability b. Short stature c. Myopathy d. Nail infections e. Delayed sexual development DIDMOAD (Wolfram’s Syndrome) 1. Clinical features: a. Diabetes insipidus b. Diabetes mellitus c. Optic atrophy d. Deafness e. Ataxia f. Short arm of chromosome 4 Autosomal recessive cerebellar ataxia syndrome with upward gaze palsy, neuropathy and seizures 1. Clinical features: a. Early onset ataxia b. Dysarthria c. Myoclonic and generalized tonic clonic seizures d. Upward gaze palsy e. Extensor plantar reflexes f. Sensory neuropathy g. Normal cognition Autosomal recessive late-onset ataxia Recessive ataxia with pigmentary retinopathy 1. Clinical features: a. Mental retardation b. Deafness c. Peripheral neuropathy d. Pigmentary retinopathy Early onset cerebellar ataxia with mental retardation Childhood onset deafness 1. Ataxia develops in midlife Congenital deafness 1. Ataxia develops in the third decade X-linked spastic ataxic syndromes Early onset cerebellar ataxia: 1. General considerations: a. Most patients have mutations in the frataxin gene b. Prognosis is better than for patients with Friedreich’s ataxia 2. Clinical features: a. Onset between 2–20 years of age b. Biceps, triceps and knee jerks are normal or increased
c. Absent ankle jerks d. No optic atrophy, dilated cardiomyopathy or scoliosis 3. MRI evaluation: a. More cerebellar atrophy than Friedreich’s ataxia 4. Neuropathology: a. Some patients have similar pathology to OPCA
Ramsay–Hunt Syndrome
A. General characteristics: 1. AR inheritance B. Clinical features: 1. Progressive cerebellar ataxia 2. Myoclonus 3. Dementia 4. Seizures
Unverricht–Lundborg (Baltic myoclonus)
A. General characteristics: 1. Chromosome 21 q; gene cystatin B B. Clinical features: 1. Stimulus sensitive myoclonus 2. Seizures 3. Ataxia and dysarthria 4. Pyramidal tract dysfunction
Differential Diagnosis of Progressive Myoclonic Ataxia
1. 2. 3. 4. 5. 6.
Mitochondrial encephalopathy Sialidosis Ramsay-Hunt Ceroid lipofuscinosis Coeliac disease Some patients with cystatin B mutations
Recessive Syndromes with Prominent Ataxia
1. 2. 3. 4. 5. 6. 7.
Cerebrotendinous xanthomatosis Partial hypoxanthine guanine phosphoribosyl deficiency Wilson’s disease Late onset hexosaminidase deficiency Refsum’s disease Adrenomyeloneuropathy Mitochondrial DNA mutations: a. 8344, 3243, 8993
SECTION XIII. Cerebellar Disease Autosomal Dominant Ataxias
A. General characteristics: 1. General onset from the third to fifth decades (may be from childhood to old age) 2. Offspring are at risk (50% inherit the mutation) 3. Rarely the disease is not apparent in a parent: a. Variable penetrance b. Due to anticipation, the child may demonstrate the disease prior to the parent c. Premature death of the parent d. Origin of a new mutation 4. Genetic heterogeneity is widespread 5. The progressive cerebellar ataxia in most instances is associated with: a. Ophthalmoplegia b. Optic atrophy c. Peripheral neuropathy d. Pyramidal and extrapyramidal signs e. Dementia is not an early feature f. Differential SCAs have clinically seminal features that are helpful in diagnosis
ADCA 1
A. General characteristics: 1. CAG repeats occur within SCA1, SCA2, SCA3, SCA6, SCA7, SCA12 and dentatorubral-pallidoluysian atrophy DRPLA 2. SCA12, the CAG is in the promoter region 3. Usual onset is a progressive gait disorder; loss of ability to walk occurs about 10 years after onset of the illness 4. Ocular signs include: a. Nystagmus b. Deficits of smooth pursuit c. Gaze palsies d. Ptosis e. Blepharospasm f. Ocular dysmetria 5. Cranial nerve deficits a. Facial atrophy b. Tongue fasciculation and atrophy c. Dysphagia d. Impaired cough 6. Peripheral nerve abnormalities a. Stocking and glove distal sensory loss b. Amyotrophy c. Fasciculations d. Usual is a dying back neuropathy 7. Upper motor signs include: a. Often appear early in the course of the disease b. Spasticity, Babinski response and increased reflexes
611
8. Basal ganglionic signs: a. Bradykinesia, rigidity, tremor, dystonia and choreoathetosis 9. Cortical signs include: a. Seizures, myoclonus, dementia 10. Retinal degeneration occurs B. Imaging evaluation: 1. SCA1, SCA2, SCA3 and SCA7 a. Pontocerebellar atrophy b. Loss of pontine fibers that constitute the MCP 2. SCA3 and SCA6 a. Isolated cerebellar atrophy with sparing of the brainstem SCA1
A. General characteristics: 1. Most common of the ADCAs 2. Chromosome 6p 22–23 B. Clinical features: 1. Onset from 15–65 years of age; symptoms usually occur in the third to fourth decade 2. Initial feature is progressive ataxia of gait 3. Arm involvement with associated dysarthria occurs later 4. Pure cerebellar syndrome early 5. Later associated features are: a. Ophthalmoplegia (supranuclear) b. Pyramidal tract dysfunction c. Familial pneumothorax d. Slow saccadic eye movements in Indian patients 6. Dementia 7. Parkinsonism, dystonia, chorea 8. Fasciculation of the face and tongue (rare) 9. Progressive loss of reflexes 10. Loss of vibration and proprioception C. EMG 1. Evidence of peripheral neuropathy D. MRI evaluation: 1. Cerebellar and brainstem atrophy SCA2
A. General characteristics: 1. Chromosome 12q 23–24; CAG repeat 2. High inter and intra family variability; anticipation is noted 3. Aggregation of ataxin protein in the cytoplasm of Purkunje cells 4. Slowing of saccades B. Clinical features: 1. Supranuclear gaze palsy 2. More frequent hyporeflexia than SCA1 C. MRI evaluation: 1. Greater cerebellar and brainstem atrophy than SCA 1
612
SECTION XIII. Cerebellar Disease
SCA/Machado Joseph Disease
SCA6
A. General characteristics: 1. Chromosome 14q 32.1 2. Initially reported in patients of Azorean or Portuguese descent B. Clinical features: 1. Bulging eyes 2. Extrapyramidal manifestations 3. CAG repeats > 62–80 the more parkinsonian features 4. Dopa-responsive parkinsonism; bradykinesia and rigidity respond initially 5. Peripheral neuropathy 6. Facial fasciculation and dystonia
A. General characteristics: 1. Chromosome 19 2. Aggregation of calcium channel protein in the cytoplasm B. Clinical features: 1. Onset in adulthood 2. Benign course 3. Intermittent ataxia 4. Migraine associated 5. Interictal vertigo 6. Calcium channelopathy
MJD/SCA3
SCA7 (DRPLA)
1. Type 1 a. Early onset b. Extrapyramidal/pyramidal signs c. Cerebellar ataxia 2. Type II a. Middle age onset b. Ataxia c. Pyramidal tract signs d. Extrapyramidal features 3. Type III a. Cerebellar ataxia b. Amyotrophy 4. Type IV a. Parkinsonism b. Peripheral neuropathy SCA1 # of CAG repeats MJD # of repeats Normal 19–36 12–40 Borderline 37–42 None Full mutation >41 >61
A. General characteristics: 1. Dentatorubral pallidal Luysian atrophy 2. Chromosome 3 p12–21.1 3. Prominent anticipation B. Clinical features: 1. Onset in childhood 2. Upper motor neuron signs 3. Retinal degeneration 4. Personality disruption 5. Parkinsonism and chorea 6. Myoclonus 7. Seizures and dementia may start prior to age 20
SCA4
A. General characteristics: 1. Chromosome 16q-ter B. Clinical features: 1. Similar to SCA1 2. Sensory axonal neuropathy 3. Generalized areflexia
SCA5
A. General characteristics: 1. Chromosome 11 centromeric B. Clinical features: 1. Relatively pure ataxia
SCA8
A. General characteristics: 1. Chromosome 13; CTG expansion (54–79 repeats) B. Clinical features: 1. May start in infancy 2. Ophthalmoplegia 3. VIIIth nerve involvement 4. Seizures 5. Hypotonia
SCA10
A. General characteristics: 1. Mexican kindreds 2. Chromosome 22; ATTCT expansion B. Clinical features: 1. Associated with seizures 2. Ataxia may precede or follow the onset of seizures 3. Seizures are partial or generalized
SECTION XIII. Cerebellar Disease Autosomal Dominant Ataxias Related to Point Mutations
SCA 14
a. Single Japanese family b. FGF 14 mutation c. Axial myoclonus SCA 15
a. Chromosome 3p24.3–3pter b. Pure cerebellar dysfunctions SCA 16
a. Chromosome 8q22.1–24.1 b. Head tremor SCA 18
a. Seizures b. Peripheral neuropathy SCA 20
a. Palatal tremor b. Hypermetric saccades c. Dentate nuclei calcification
613
4. Autosomal dominant congenital non progressive ataxia a. Linkage to chromosome 3 pter b. Overlaps SCA 15 locus c. Cognitive decline d. Dystonia e. Nystagmus f. Gait ataxia 5. Autosomal dominant cerebellar cortical atrophy a. Chromosome 16q 6. SCA a. Chromosome 19q 13.4 q ter b. Onset third and fourth decades c. No anticipation d. Overlaps SCA 14 locus e. No axial myoclonus
Episodic Ataxia (EA1)
A. General characteristics: 1. Chromosome 12; mutation of the potassium channel gene B. Clinical features: 1. Brief episodes of ataxia 2. No interictal signs 3. Associated skeletal muscle myokymia
SCA22
a. b. c. d.
Chromosome 1 p21–q23 Gait ataxia Dysarthria Hyporeflexia
SCA 23
a. Chromosome 20p 12.3–20 b. Late onset >40 years of age c. Pure cerebellar SCA 25
Episodic Ataxia Type II (EA2)
A. General characteristics: 1. Point mutation alpha-1A subunit of the calcium channel gene on chromosome 19 2. CAG expansion in the same gene causes SCA6 B. Clinical features: 1. Ataxia episodes last longer than in EA1 2. Permanent nystagmus 3. May develop permanent ataxia 4. Reduced penetrance in some families
a. Peripheral neuropathy Harding Clinical Features of Late Onset AD Ataxias
Not completely classified ADCA I
1. Cerebellar ataxia (AD) a. Chromosome 7q22–q32 b. Sensory motor neuropathy 2. Ataxia/pancytopenia (AD) a. No gene identified 3. Cerebellar ataxia (AD) a. Chromosome 19q (telomeric) b. Pure cerebellar symptoms c. Onset at 31 years (mean age) d. Mild to moderate dysarthria e. Saccadic substitution for smooth pursuit
1. 2. 3. 4. 5.
Optic atrophy Ophthalmoplegia Dementia Amyotrophy Inability to vomit
ADCA Type 1
A. General characteristics: 1. SCA 1, 2, 3, 12, 13, 17, 19; some patients in 4; 21
614
SECTION XIII. Cerebellar Disease
ADCA Type II
A. General characteristics: 1. Chromosome 3p 12–21.1 gene 2. Paternal transmission increases anticipation B. Clinical features: 1. Pigmentary maculopathy is the distinguishing feature a. Retinopathy involves the macula and leads to blindness b. Extends to peripheral fundus c. Early blue-yellow color discrimination deficit d. Supranuclear ophthalmoplegia e. Extrapyramidal features f. Patients are wheelchair bound by 15 years of age; onset may occur between 2–65 years of age g. Onset may be ataxia or visual loss h. Genetically homogeneous i. Adult onset cases usually have paternal transmission; there is reduced penetrance as obligate gene carries do not manifest disease although they live beyond 65 years of age j. Chorea k. Myoclonus and personality change C. Pathology: 1. Retinal atrophy 2. Cerebellar atrophy (cortex) 3. Atrophy of the spinocerebellar and the olivocerebellar tracts 4. Efferent cerebellar pathway atrophy
ADCA Type III
A. General characteristics (noted above): 1. SCA5 (Abraham Lincoln relative); chromosome 11 2. SCA6
Rare Dominant Ataxias
1. May be associated with: a. Cataract, deafness, peripheral neuropathy, Parkinsonism and essential tremor Episodic Ataxic Type I (ETA-1)
A. General characteristics: 1. Chromosome 12; potassium channel gene 2. Potassium channel mutation B. Clinical features: 1. Childhood or adolescent onset 2. Brief attacks (minute to hours) 3. Ataxia, dysarthria, vertigo and nystagmus 4. Myokymia 5. Acetazolamide may be effective Episodic Ataxia Type II (ETA2)
A. General characteristics: 1. Chromosome 19q; allelic to hemiplegic migraine; point mutations in a calcium channel gene a. Missense mutations cause familial hemiplegic migraine b. Truncating mutations cause episodic ataxia type II c. SCA 6 has CAG repeat in the 3’ region of the gene B. Clinical features: 1. Onset in childhood or adolescence 2. Longer attacks than ETA 1 3. Vertigo, nausea and vomiting 4. In childhood, attacks may be accompanied by headache, drowsiness and fever 5. Interictal nystagmus 6. Slowly progressive ataxia 7. Acetazolamide is effective Idiopathic Late-Onset Ataxias
ACDCA IV
1. DRPLA 2. SCA 14 a. Myoclonus and seizures b. Axial myoclonus (SCA 14)
ADCA V
1. Periodic dominant ataxia a. EAT 1 b. EAT 2 2. Clinical features: a. Essential tremor
A. General characteristics: 1. Approximately 2/3 of patients with ataxia after the age of 20 are singletons 2. Many of these patients in the past have been designated as olivopontocerebellar atrophies 3. Lose ability to walk independently, 5–20 years after onset 4. Those that evolve into MSA have a shortened life span 5. EMG/NCV of sensory neuropathy is present in 50% of patients 6. MRI evaluation: a. Cerebellar and brainstem atrophy b. Pure cerebellar atrophy c. “Maltese cross”-degeneration of the ponto cerebellar fibers is seen with OPCA
SECTION XIII. Cerebellar Disease
7. Brainstem involvement portends a poor prognosis 8. AD inheritance is suspected B. Clinical features of Déjérine-Thomas variant: 1. Onset 35–55: male > female 2. Ataxia associated with: a. Dementia b. Peripheral neuropathy (sensory loss and depressed reflexes) c. Rare supranuclear ophthalmoplegia d. Rare pigmentary retinopathy and optic atrophy 3. Approximately 15% of this group develop multiple systems atrophy in association with cerebellar ataxia a. Autonomic failure: 1) Postural hypotension 2) Fixed cardiac rate 3) Impotence 4) Bladder dysfunction
Differential Point Between MSA and Late Cerebellar Ataxia
1. Impotence or urinary urgency > for MSA 2. Narrow > broad based gait favors MSA (impairment of postural reflexes)
615
a. Cerebellar ataxia b. Dorsal column involvement 2. Fick–Hamacher Type II a. Prominent cranial nerve involvement b. Cerebellar ataxia 3. Type III a. AD b. Pure cerebellar ataxia 4. Type IV a. Retinitis pigmentosa b. Cerebellar ataxia Unusual Genetic Ataxia
Cerebrotendinous Xanthomatosis
A. General characteristics: 1. Sterol 27-hydroxylase (CYP27A1) deficiency 2. Slightly > female to male ratio 3. Treatable with chenodeoxycholic acid B. Clinical features: 1. Tendon xanthomas – 70% 2. Cataracts – 92% 3. Decreased cognitive function – 80% 4. Ataxia-approximately 100% C. Laboratory evaluation: 1. Elevated plasma cholestanol levels
Marie–Foix Alajouanine Syndrome Pelizaeus–Merzbacher Disease
A. General characteristics: 1. Midline cerebellar syndrome 2. Gait ataxia > appendicular 3. Minimal or absent dysarthria 4. Dementia can occur B. Pathology: 1. Vermian atrophy 2. Olivary atrophy; minimal long tract involvement 3. Pons spared 4. Minimal long tract involvement
Dyssynergia Cerebellaris Progressiva (Ramsay Hunt)
A. General characteristics: 1. Small number of late onset patients B. Clinical features: 1. Onset fifth and sixth decade 2. Prominent resting or postural kinetic tremor 3. Intention tremor
Variants of Olivopontocerebellar atrophy
Old Classification: 1. Type 1-Menzel variant
A. General characteristics: 1. X-linked; increased copies of the proteolipid protein gene (PLP1 gene) also arises from duplications, deletions and mutations 2. PLP 1-duplications usually have classical or transitional PMD 3. Defective CNS myelination B. Clinical features: 1. Usually childhood illness starting at 2.5 years of age; rare adolescent or adult onset patients. 2. Early nystagmus and hypotonia progressing to spasticity legs > arms 3. Cognitive deficiency 4. Expressive aphasia in some children Mitochondrial Ataxias
NARP
A. General characteristics: 1. 8993T > G NARP mutation in the ATPase 6 gene 2. Also causes a portion of Leigh’s syndrome B. Clinical features: 1. Neuropathy 2. Ataxia 3. Retinitis pigmentosa
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SECTION XIII. Cerebellar Disease
Leigh’s Disease
Chiari Malformation
A. General characteristics: 1. Defects of mitochondrial respiratory chain enzymes: a. Cytochrome oxidase (COX) complex I/II b. Deficiency of pyruvate dehydrogenase (PDH) complex c. SURF 1 mutation leads to COX deficiency; AR inheritance in Leigh’s syndrome d. Maternal inheritance noted in 20% of patients (mutation of the 8993 nucleotide of mitochondrial ATP 6 gene (encodes a component of complex V) B. Clinical features: 1. Infantile fatal form with necrotizing encephalopathy 2. Late childhood adolescent form: a. Optic atrophy b. Recurrent exacerbations c. Ataxia
A. General characteristics: 1. Chiari I a. Vermis of the cerebellum protrudes through the foramen manganum. The tonsils are usually pointed and fibrotic. 2. Chiari II a. Vermis herniation b. Downward displacement of the medulla with nuclear dysplasia c. Occurs with meningomyelocele d. Associated syringomyelia 3. Chiari III a. Cervical spina bifida b. Cerebellar encephalocele c. Elongated medulla d. “Beaked” collicular plate of the midbrain e. Widening of the angles of the petrous pyramid 4. Chiari IV a. Above Chiari malformations with additional absence of the cerebellum B. Clinical Features of Chiari 1 and 2 (adults): 1. Associated syringomyelia of Chiari II with expected signs and symptoms 2. Sudden ataxia after age of 30 3. Shallow posterior fossa; low hairline 4. Increased reflexes
Congenital Defects of the Cerebellum
A. General characteristics: 1. Extended ontogenesis; neuroblast migration from the external granular layer takes one year 2. Development occurs from 32 days of gestation to one year 3. Cerebellar cortex is susceptible to toxic effects of drugs, chemicals, viral infections, ischemia and hypoxia B. Clinical features: 1. Hypoplasia or aplasia of the vermis with intact lateral ventricles a. Associated with midline defects such as agenesis of the corpus callosum or holoprosencephaly b. Joubert’s syndrome 1) AR 2) Episodic hyperpnea 3) Abnormal eye movements 4) Ataxia 5) Mental retardation
Dandy–Walker
A. General characteristics: 1. Large posterior one half of the IVth ventricle associated with atretic foramen of Magendie 2. Heterotopia of the inferior olivary nuclei 3. Pachygria of the cerebral cortex 4. Hydrocephalus 5. Large posterior fossa B. Clinical features: 1. Spastic diplegia 2. Mental retardation
Selective Agenesis of the Cerebellar Hemispheres
A. General characteristics: 1. Less common than aplasia of the vermis alone
Global Cerebellar Hypoplasia
A. Differential Diagnosis: 1. Tay–Sachs disease 2. Menkes Kinky hair disease 3. Rare spinal muscular atrophy 4. Sporadic and genetic causes B. Clinical features of cerebellar hypoplasia: 1. Developmental delay 2. Muscular hypotonia 3. Truncal titubation and ataxia 4. Nystagmus and intention tremor
Focal Cerebellar Dysplasia
Differential Diagnosis a. Migrational disorder b. Exposure to cytotoxic drugs c. Viral infection
SECTION XIII. Cerebellar Disease Seminal Features of Some Named Cerebellar Syndromes
Metabolic Ataxias
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
Intermittent
13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
Marie Sanger Brown (cranial nerve) Marinesco–Sjögren (cataracts) Friedreich’s ataxia (scoliosis) dilated cardiomyopathy Marie’s (pure cerebellar cortical atrophy) Gordon Holmes (cortex-hypogonadism) Ramsay Hunt (progressive with myoclonus) Madame Lewy Barr (ataxia telangiectasias) Fahr’s disease (calcification dentate, BG) Menzel’s variant OPCA (posterior column) Fick Hamacher variant of OPCA (cranial nerve) Leigh’s disease (mt 8993); optic atrophy Gerstmann Straüssler Schenker (variant of CJ with late dementia) Pelizaeus Merzbacher (nystagmus) DRPLA (SCA 7) Russell’s syndrome (myoclonus; basal ganglia) Adult Krabbe’s (increased protein in CSF; peripheral neuropathy) Behr’s disease (optic atrophy) SCA/Machado Joseph (amyotrophy) Spastic ataxias – HSP 4; (spastin) Paine’s (X-linked recessive mental retardation, spasticity) Gillespie syndrome (congenital ataxia, mental retardation, aniridia) Granule cell hypoplasia (congenital ataxia and mental retardation) Tay-Sach’s (cherry red spot) Fabry’s (angiokeratoma diffusum universale) Wilson’s Disease (flapping postural kinetic tremor) Refsum (cataracts, hearing loss, ichthyosis) Bassen Kornsweig’s Disease (Abetalipoproteinemia and neuropathy) Hartnup’s Disease (rash on extensor surfaces) Joubert’s (episodic hyperpnea)
Chediak–Higashi Disease
A. General considerations: 1. AR; gene is CHS1; encodes a lysosomal transport protein 2. Increased infections (primarily bacterial) 3. Lymphoma like illness 4. 50% have neurologic symptoms B. Clinical features: 1. Cerebellar ataxia 2. Progressive motor sensory neuropathy 3. Parkinsonism 4. Mental retardation 5. Partial albinism
617
A. General considerations: 1. Onset in infancy or childhood 2. Urea cycle defects 3. Aminoacidurias 4. Pyruvate and lactate metabolic abnormalities 5. Most have AR inheritance Hyperammonia
A. General considerations: 1. Defects of urea cycle enzymes: a. Ornithine transcarbamylase (X-Linked) b. Arginosuccinate synthetase c. Arginase deficiency d. Hyperornithemia (not a urea acid cycle enzyme) B. Clinical features: 1. Intermittent ataxia 2. Dysarthria 3. Vomiting 4. Headache 5. Ptosis 6. Seizures 7. Confusion Intermittent episodes precipitated by: 1. Intercurrent illness 2. High protein diet Ornithine Transcarbamylase
A. General considerations: 1. X-linked; affected males die in the neonatal period 2. Clinical symptomatology varies widely in females Aminoacidurias with Intermittent Ataxia
A. General considerations: 1. Conditions to be considered are: a. Branch chain ketoaciduria b. Isovaleric acidemia c. Hartnup disease Hartnup Disease
A. General considerations: 1. AR 2. Defect of intestinal transport of monoaminomonocarboxylic acids B. Clinical features: 1. Intermittent ataxia 2. Rash on extensor surfaces (similar to pellagra) 3. Tremor 4. Chorea 5. Psychiatric symptomatology 6. Mental retardation
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SECTION XIII. Cerebellar Disease
Pyruvate Dehydrogenase Deficiency (PDH)
A. General considerations: 1. Mutation of the gene for the E1 α-subunit of the enzyme 2. X-chromosome; high frequency of manifesting heterozygotes a. Females have a variable deficit of the enzyme due to inactivation of the X-chromosome (Lyon hypothesis) 3. Infantile form: a. Lactic acidosis and death b. Less severe form that may reach adulthood which is more common in females B. Clinical features: 1. Episodic ataxia concomitant with increased lactic acid 2. Seizures mental retardation 3. Spasticity Multiple Biotin-Dependent Carboxylase Deficiencies
A. General considerations: 1. Autosomal recessive 2. Defects of humoral and cell mediated immunity B. Clinical features: 1. Generalized seizures 2. Myoclonus 3. Hypotonia 4. Nystagmus
Progressive Metabolic Ataxias
A. General considerations: 1. Ataxia a major feature of storage diseases 2. Enzyme deficiencies with ataxia: a. Develop in infancy or childhood b. May develop in adulthood 3. Include: a. Metachromatic leukodystrophy b. Adrenomyeloneuropathy c. Sphingomyelin lipidosis d. Krabbe’s disease (galactosylceramide) e. Hexosaminidase deficiency Hexosaminidase Deficiency
A. General considerations (see lysosomal storage disease): B. Clinical features: 1. Age of onset is less than 15 years of age 2. Intention tremor and dysarthria are presenting features 3. Limb and gait ataxia 4. Associated in some patients: a. Failure of upgaze b. Proximal neurogenic weakness and atrophy
C. Pathology: 1. Distension of neurons with lamellar bodies D. MRI evaluation: 1. Cerebellar and brainstem atrophy Niemann Pick Disease Type C
A. General considerations (see lysosomal storage disease): B. Clinical features: 1. Failure of upgaze 2. Ataxia C. Pathology: 1. Normal sphingomyelinase activity 2. Foamy bone marrow cells Cholestanolsis
1. Deficiency of mitochondrial sterol 27 hydroxylase Ramsay Hunt
1. Similar clinically to a. Neuronal ceroid lipofuscinosis b. Sialidosis Differential Diagnosis of Cerebellar Diseases
Acquired Cerebellar Deficits: 1. Anoxia 2. Heat 3. Uncontrolled seizures 4. Mercury 5. Lithium 6. Dilantin 7. Thallium 8. N-ethyl-toluene 9. Post dialysis ataxia 10. 5-flurouracil 11. Hypothyroidism 12. Hypnotic sedatives 13. Seasonal ataxia (Nigeria; thiamine deficiency) 14. Gamma-amino decarboxylase antibodies 15. Vitamin E deficiency 16. Adult opsoclonus myoclonus syndrome (paraneoplastic) 17. Anti malarial compounds 18. CSF leak causing caudal cerebellar tonsillar herniation 19. Deterioration of Chiari malformations 20. B12 deficiency 21. Acquired primary and secondary tremors 22. Vascular disease 23. Trauma 24. Hepatic encephalopathy 25. Pontine and extrapontine myelinolysis 26. Alcohol 27. Cyclosporin 28. Lithium 29. Tacrolimus
SECTION XIII. Cerebellar Disease
Differential diagnosis of the major acquired cerebellar syndromes can be divided into categories: 1. Drug effects 2. Toxins 3. Vascular disease 4. Endocrine disorders 5. Tumors 6. Paraneoplastic disease 7. metabolic deficiencies 8. Congenital defects that deteriorate in middle age
An Overview of Non-Vascular Cerebellar Disease
The major drug group that affects the cerebellum are the anticonvulsants. Characteristic of all in excess are lethargy, nystagmus (usually gaze evoked, but rarely spontaneous) due to interference with “hold neurons” of the visual system that foveate the target. Dilantin has been noted to cause ophthalmoplegia as well as a slowly progressive peripheral neuropathy usually limited to decreased ankle jerks. Phenobarbital in addition to nystagmus may cause severe dysarthria and reversible decortication and decerebration. 5-flurouracil is the usual anti-cancer agent encountered that causes a mild cortical cerebellar deficit. Notable is absent peripheral neuropathy which is characteristic of most of the other CNS toxic anti-neoplastic drugs. Cisplatinum affects the dorsal root ganglion with loss of large proprioceptive neurons and posterior column deficits. The intention tremor is throughout all thirds of movement and the patients are dramatically affected unless they have visual compensation. Cyclosporin and lithium have cerebellar features and render patients ataxic, but their seminal features are myoclonus, depressed cognition and hyperreflexia. Hypnotic sedatives cause ataxia both of gait and limb, but dysarthria, lethargy, depressed reflexes and psychiatric problems predominate. The primary deficiency states with cerebellar dysfunction as a core symptom are B12 and Vitamin E deficiency. The former is dominated by spasticity, an active peripheral neuropathy (paresthesias) an ebullient mental status, optic atrophy and cranial nerve I dysfunction. Trauma, Kallmann’s syndrome, Hencken’s syndrome, and Foster–Kennedy syndrome are also considered when cranial nerve I is involved. Vitamin E deficiency from either α-Tocopherol transporter or deficiency deficits has very prominent dorsal column dysfunction. Acute B12 deficiency involving all signs and symptoms may be induced by nitrous oxide anesthesia. Pantothenic acid deficiency is commonly associated with chronic alcoholism and may be partly responsible for its associated ataxia. Alcohol is by far the most serious toxin worldwide. Its pattern of expression is appendicular in the lower extremities with imbalance and an anterior vermian deterioration. The patients have a stiff legged gait (“Martinet” gait) without the usual cerebellar modulation of both the stance and swing
619
phase. There is minimal dysarthria, nystagmus or upper extremity dysmetria. The usual patterns of toxic involvement that affects the CNS are: 1. Optic neuritis (always occurs with methyl alcohol poisoning); centrocecal scotomata 2. Dorsal column dysfunction with acute vibratory and position sense impairment-longest fibers involved first 3. Spasticity as a late consequence 4. Frontal lose cognitive deficits This is seen with toluene n-ethyl toluene and paint solvents. Glue sniffing affects the frontal lobes and causes euphoria and lethargy. Huffer’s syndrome (gasoline sniffing) has prominent frontal lobe depression. Paint sniffing (silver paint, SW of the USA) causes cerebellar deficits that are overshadowed by pronounced mental status depression. Thallium is recognized by euphoria, ataxia and hair loss. Mercury poisoning is distinguished by mental changes, dystonia and choreoathetosis in addition to ataxia. Endocrine induced ataxia is usually secondary to hypothyroidism. This is minimal and is most often accompanied by VIIIth nerve deficits, proximal myopathy (pseudohypertrophy or Hoffmann’s syndrome) bilateral carpal or tarsal tunnel syndrome, and failure to make ear wax or sweat normally. Severe liver disease is associated with ataxia which is often due to degeneration of the anterior vermis (lingula, culmen and centralis) from alcohol abuse. The caudate and putamen may be hyperintense on T2 weighted images and the patients may demonstrate acquired hepatolenticular degeneration. This consists of subcortical dementia, severe dysarthria, extrapyramidal signs and falling backwards. In general, tumors of the cerebellum are age specific. Children and young adults may have an ependymoma of the fourth ventricle. This tumor is suggested by vertigo with change of head position, nystagmus and papilledema. Projectile vomiting (pressure on the vomit center) is common in the morning. Ataxia, headache and hydrocephalus are prominent. The origin of a medulloblastoma is the superior medullary velum of the IVth ventricle. The symptoms and signs are similar to those of an ependymoma but the spinal cord is seeded with this tumor. Cystic and solid astrocytomas may be hemispheric or vermian. In the later, axial symptoms are more prominent than appendicular. These tumors frequently distort the IVth ventricle and put pressure on the pons and medulla. Headache, vomiting, and bilateral VIth nerve palsy occurs if there is an acute change of pressure (trapped under the petroclinoid ligament in Dorello’s canal). Any mass in the IVth ventricle may cause down beat nystagmus accentuated by lateral gaze. Tumor’s involving the floccular nodular lobe cause hypermetric saccades and rotary nystagmus with a contralateral torsional component. Rarely, oligodendrogliomas are found in the cerebellum. Most of the tumor is benign, but there usually is one section that is malignant. Hemangioblastomas are most common in the hemisphere of an adult, but tend to be midline in younger patients. They bleed
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SECTION XIII. Cerebellar Disease
intermittently which is evident by new blood (4–8 days) noted as increased signal on T2 weighted images on MRI in the center of the lesion with a surrounding hemosiderin ring (old bleed). These cause symptoms by location. There are three major tumors of the cerebellopontine angle that often involve the cerebellum by pressure. A Schwannoma presents with tinnitus and hearing loss. Meningiomas often compress the Vth nerve and present with facial pain. Epidermoids have high signal on T2 weighted images (keratin) and may present with pain radiating to the inner ear, ataxia or cranial nerve involvement. A ganglioneuroma is benign and may present with vermian or hemispheric symptoms. It does not enhance strongly with gadolinium. The cerebellum is a major destination for metastatic lesions in adults. The hemispheres are more involved than the vermis. Squamous cell carcinoma of the lung is most common, followed by breast and the G.I. tract. Prostate metastasis reach the posterior fossa by means of the valveless paravertebral veins (Batson’s) plexus. This tumor may specifically metastasize to the petrous apex. Lymphomas in HIV patients are often necrotic and occasionally involve the cerebellum. Cholesterol granulomatosis (usually very bright T2 weighted image) at the petrous apex occasionally compress the cerebellum. Meningiomas of the tentorium (enlarged feeding artery from the meningohypophyseal trunk Bernasconi–Cassinari) produce headache, referred pain to the inner ear (IX nerve) and ataxia. Rarely a cerebrotendinous xanthoma and amyloidoma may be seen compressing the cerebellum from the tentorium. Paraneoplastic disease of the cerebellum is primarily associated with tumors of the female genitalia, primarily those of the ovary. Anti-Yo antibodies are sought. The ataxia may be of sudden onset rather than gradual as would be expected. Breast cancer that induces anti-Ri antibodies presents with the myoclonus opsoclonus syndrome of “dancing eyes”. The same clinical picture is caused by neuroblastoma (VMA should be sought in the urine) and rarely by lung tumors. Hyperosmolar syndromes from sodium excess (dehydration) or diabetes (glucose > 3000 mg/dl) may cause severe ataxia. Most often segmental myoclonus predominates. Too rapid correction of a low serum sodium (>12 mm/hr) may induce pontine and extrapontine myelinolysis. The ataxia occurs from destruction of the pontine crossing fibers that constitute the majority of the middle cerebellar peduncle. A recent case of hypernatremia has been reported as a cause of osmotic myelinolysis. Autoimmune induced cerebellar dysfunction is most prominent with demyelinating diseases such as MS. In general, it is accompanied by frontal lobe mental changes, intranuclear ophthalmoplegia, spasticity and optic nerve inflammation. A poor prognosis for patients has been suggested if there are infratentorial lesions early in the course of the illness (particularly the MCP). Acute disseminated encephalomyelitis frequently evolves into MS. A distinguishing
feature is that all lesions are of the same age. In acute hemorrhagic encephalomyelitis, all lesions are on the left side. Post viral and vaccination syndromes almost always have an autoimmune component that causes an acute hemispheric and vermian syndrome. It should be suspected 10–14 days following an infection or vaccination. There may be periventricular lesions in post viral patients and larger lesions in the centrum semiovale occur after vaccination. The latter may be accompanied by a transverse myelitis. The white matter lesions most suggestive of MS are in the corpus callosum, optic nerve and periventricular white matter (Dawson’s fingers). There is an overlap between central and peripheral myelin antigenic epitopes. There are many patients with GBS or CIDP that have central inflammatory white matter lesions due to this overlap. Anoxic lesions of the cerebellum are suggested by metronomic eye movements, oscillations in which the eyes remain at the end of their complete excursion prior to oscillating to the opposite extreme. Enzyme Defects with Major Cerebellar Symptoms
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Phenylketonuria (phenylalanine dehydrogenase) Tryptophane dehydrolase (Hartnup’s disease) Pyruvate dehydrogenase deficiency (complex IV) Multiple carboxylase deficiency Hyperornithinemia (transcarboxylase deficiency) Arginase deficiency Arginosuccinate deficiency Glucocerebrosidosis (Niemann Pick’s) Galactosyl cerebrosidoses (Fabry’s) Hexosaminidase A (Tay-Sach’s disease) Mannosidosis Fucosidosis 3-methyl-glucoconic aciduria Gamma-glutamyl-cysteine synthetase deficiency Triosephosphate isomerases deficiency
Progressive Treatable Ataxia
1. 2. 3. 4. 5. 6.
Vitamin E deficiency Wilson’s disease Galactosemia Coenzyme Q deficiency Refsum’ disease Thyroid failure
Episodic Ataxia
1. 2. 3. 4.
Episodic ataxia type I (ETA-1) Episodic ataxia Type II (ETA-2) Multiple carboxylase deficiency (biotin) Ornithine transcarboxylase deficiency (male heterozygote) 5. Krebs-Henseleit (liver cycle) enzyme defects
SECTION XIII. Cerebellar Disease Congenital Disorders
1. Congenital ataxia with episodic hyperpnea, abnormal eye movements and mental retardation (Joubert’s syndrome) 2. Congenital ataxia with mental retardation and spasticity (includes ponto-cerebellar hypoplasia type I and II) 3. Congenital ataxia and mental retardation (granule cell hypoplasia) 4. Congenital ataxia with mental retardation and partial aniridia (Gillespie syndrome) 5. Lhermitte Duclos (dysplastic gangliocytoma) 6. X-linked recessive ataxias with spasticity and mental retardation (Paine’s syndrome)
Ataxic Disorders with Known Metabolic or Other Causes
A. Metabolic disorders 1. With hyperammonia: a. Ornithine transcarbamylase deficiency b. Arginosuccinate synthetase deficiency c. Arginosuccinate deficiency d. Arginase deficiency e. Hyperornithinemia 2. Aminoacidurias without hyperammonemia: a. Intermittent branch chain ketoaciduria b. Isovaleric acidemia c. Hartnup disease 3. Disorders of Pyruvate and Lactate Metabolism a. Pyruvate dehydrogenase deficiency (Complex IV) b. Pyruvate decarboxylate deficiency (Complex IV) c. Leigh’s disease d. Multiple carboxylase deficiencies
Progressive Unremitting Ataxic Syndromes
1. 2. 3. 4. 5. 6.
Abetalipoproteinemia Hexosaminidase A deficiency Cholestanol (cerebrotendinous xanthomatosis) Mitochondrial diseases Glutamate dehydrogenase deficiency Partial hypoxanthine guanine phosphoribosyl transferase deficiency (Lesh Nyhan disease)
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Disorders Characterized by Defective DNA Repair and Ataxia
1. Ataxia telangiectasia 2. Xeroderma pigmentosa 3. Cockayne’s syndrome
Early Onset Cerebellar Ataxias (less than 20 years)
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.
Friedreich’s ataxia Early onset ataxia with retained reflexes With hypogonadism; deafness and/or dementia With myoclonus (Ramsay-Hunt) With pigmentary retinal degeneration; mental retardation and/or deafness With optic atrophy and mental retardation (Behr’s disease) With cataracts and mental retardation (Marinesco Sjögren) With childhood onset deafness and mental retardation With congenital deafness and mental retardation With extrapyramidal features X-linked recessive ataxias With ocular apraxia (EOA1) With ocular apraxia (EOA2)
Late Onset Cerebellar Ataxias (greater than 20 years)
1. ADCA1 (associated with optic atrophy, ophthalmoplegia, extrapyramidal features, and amyotrophy) 2. ADCA 2–pigmentary retinal degeneration, and ophthalmoplegia and/or extrapyramidal feature 3. ADCA 3 – pure primarily cerebellar hemispheric disease 4. ADCA 4 – ataxia with myoclonus and deafness 5. ADCA5 – ataxia with essential tremor
AD Cerebellar Ataxias
1. SCA 1–25
Autosomal Recessive Ataxias Metabolic Disorders in which Ataxia Occurs as a Minor Feature
1. 2. 3. 4. 5. 6. 7. 8.
Sphingomyelin disorders Metachromatic leukodystrophy Multiple sulphate deficiency Late onset globoid cell leukodystrophy (Krabbe’s disease) Adrenoleukodystrophy Adrenomyeloneuropathy Ceroid lipofuscinosis Sialidosis type I
1. Friedreich’s ataxia a. Variant with early onset and retained reflexes 2. Ataxia telangiectasia a. Njemien and Berlin variants 3. Cockayne’s syndrome 4. Vitamin E deficiency (alpha tocopherol transporter deficiency) 5. Holmes disease (hypogonadotrophic hypogonadism) 6. Ramsay Hunt (progressive myoclonus) 7. Infantile onset with spinocerebellar ataxia
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SECTION XIII. Cerebellar Disease
8. 9. 10. 11. 12.
Marinesco Sjögren (MR, cataracts, immune deficits) Behr’s disease (optic atrophy, seizures, scoliosis) Associated with childhood deafness Associated with extrapyramidal signs Wilson’s disease (dysarthria, flapping tremor, Kayser– Fleischer ring) 13. Refsum disease (cataract, deafness, intermittent neuropathy) 14. Batten–Kornsweig disease (abetalipoproteinemia, acanthocytosis, neuropathy)
6. GBS and other disimmune processes that affect large DRG cells with severe ataxia from (dorsal column demyelination) Richter’s variant 7. Tick paralysis: a. Ataxia out of proportion to weakness b. Tics are found on cold parts of the body c. Labyrinthitis like attacks d. Usually the lateral branch of PICA infarction
Acute Ataxia (associated symptoms and signs) Paraneoplastic Cerebellar Degeneration
1. Anti-Yo a. Gynecological breast cancer b. Cerebellar degeneration with ataxia c. Ab to cytoplasm of Purkinje cells (62 kD) 2. Anti-Ri a. Breast, gynecological, small cell lung cancer b. Cerebellar ataxia with opsoclonus c. Neuronal nuclei of CNS (55,80 kDa size) 3. Anti-Ta a. Hodgkin’s lymphoma b. Cerebellar degeneration c. Cytoplasm of neurons; Purkinje cell dendrites 4. Anti-Ma a. Testicular germ cell tumors primarily b. Limbic, brainstem encephalitis, and cerebellar degeneration c. Nuclear and cytoplasmic antigens (37, 40 kDa) 5. Anti-CV2 a. Encephalomyelitis; cerebellar degeneration b. Glial cells (66 kda antibody)
Differential Diagnosis of Acute Ataxia from Cerebellar Lesions
1. Vascular a. PICA infarct; inability to walk with cranial nerve IX, X involvement b. AICA; ataxia of arm > leg; VIIIth nerve deficit; peripheral VII (blood supply of the nerve is from this artery) c. Superior cerebellar artery; arm and leg ataxia with dysarthria is prominent 2. Hemorrhage a. Severe posterior headache; closure of one eye; head tilt to the side of the lesion; nystagmus, ataxia, quadriparesis not quadriplegia 3. Infarcts, if large, may have a pseudotumoral presentation; 4th day from swelling 4. Tumor (focal signs with headache) 5. Demyelinating disease (associated intranuclear opthalmoplegia) and APD (afferent pupillary defect)
1. Metabolic Hypoglycemias a. CSF sugar < 30–40 mg% (2/3 of serum sugar) b. Cognitive dysfunction c. Hyperhidrosis and piloerection d. Encephalopathy 2. Hyponatremia: a. Lethargy b. Absent reflexes c. Seizures if there is an acute drop of Na to black patients) c. Areflexia
Infections
Viral
1. Sudden onset of headache with stiff neck 2. Consciousness maintained much longer than with bacterial infection 3. Herpes simple; coxsackie, HZ are the most common infections 4. Post viral acute pancerebellitis 14 days after the acute infection
SECTION XIII. Cerebellar Disease Bacterial Infection
1. Dominated by rapidly decreasing level of consciousness and stiff neck
2.
Brainstem Encephalitis
3.
1. Delirium 2. Nystagmus 3. HZ, listeria monocytogenes, herpes simplex are the most common organisms 4. Anti-Hu antibody in association with limbic encephalitis
4. 5.
Toxins
1. 2. 3. 4.
Delirium Optic neuropathy Long tract dysfunction (dorsal column system) Toluene (associated with hallucinations and peripheral neuropathy)
Deterioration of Chiari Malformation
1. 2. 3. 4.
Tonsillar herniation Head tilt to the side of the lesion Acute gait ataxia Down beat nystagmus accentuated in lateral gaze
Early Spinal Compressive Lesions
6.
7. 8.
9. 10. 11. 12.
1. Gait ataxia and obstipation 2. Dominated shortly by bladder involvement, sensory level and weakness 13. Differential Diagnosis of Episodic Ataxia
1. AD episodic ataxia (Type I)
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a. Associated myokymia b. Antibodies to K+ channels AD episodic ataxia (Type II) a. Interictal nystagmus Paroxysmal kinesigenic choreoathetosis a. In association with initiation of movement b. Associated dystonia c. Attacks are short lived SCA 6 a. Associated nystagmus Familial hemiplegic migraine a. Associated CACN genes on chromosome 19 b. Most often hemiplegia rather than migraine headache c. Hemiplegia same side in all afflicted family members Basilar artery migraine (Bickerstaff’s) a. Disease of young women b. Associated paraesthesias of hands c. Dysarthria and dysphagia d. Brief loss of consciousness in some patients Post ictal ataxia a. Associated psychiatric phenomena Hartnup’s disease a. Most often noted in alcoholic patients b. Associated erythematous rash on extensor surfaces Hypoglycemia (see above) Hyperammonia (see above) Organic acidurias (see above) Refsum’s disease a. Cataracts b. Deafness c. Neuropathy d. Ichthyosis Acute intermittent porphyria a. Dominated by abdominal pain b. Psychosis c. Peripheral neuropathy
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Section XIV BASAL GANGLIA AND MOVEMENT DISORDERS
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SECTION XIV. Basal Ganglia and Movement Disorders Introduction
1. The basic approach to understanding and diagnosing movement disorders is an attempt to fit them into specific clinically useful major symptom complexes. 2. Earlier anatomic pathologic correlations have described a broad outline of specific areas of the brain associated with specific types of movement disorders. It is clear that movements are organized into distributed loops in many ways similar to language and behavioral neurology. a. The easiest classification is that in which a patient is moving too much, too little and at times hardly at all. 1) Conditions that are characterized by an excess of movement: a) Hyperkinesia c) Combinations b) Dyskinesia 2) Decrease of movement: a) Akinesia b) Bradykinesia c) Decreased automatic movement d) Not associated with weakness or spasticity 3) The planning of a movement is called an engram. Planning for simple movements have been associated with the pre-motor cortex and the supplementary motor cortex. The engram of tasks that require sequential movements are associated with the posterior parietal lobe. 4) Inability to sustain a sequence of movements “is impersistence persistence” which is right parietal. Inability to progress from one movement to the next to perform a specific task is perseveration and is most often seen with left frontal lesions. 5) Areas that require movement in emotional situations (fear, curiosity, joy) employ a distributed loop in which the caudate nucleus and anterior cingulate gyrus are pivotal. 6) Horizontal and vertical eye movements from the frontal eye fields are initiated, and have complicated connections to the midbrain ocular motor areas, brainstem nuclei, the medial longitudinal fasciculus, multiple areas of the reticular formation, the parapontine RF, the superior colliculus and vestibular nuclei. 7) Self paced internal movements (tapping a finger to a pre-set pattern) are associated with the supplementary motor area (SMA). 8) Overlearned movements such as walking, turning over in bed, and reflex defensive movements (nocifensor movements) are initiated and coordinated in the basal ganglia.
2.
3. 4.
5.
6. 7.
8. 9.
10.
11. Specific Correlation of Lesions and Movement Disorders
1. Cortex:
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a. Area 4: Pyramidal dysfunction b. Area 6: 1) Hemispheric syndrome of difficulty initiating specific movements or lack of facility with movements and slight weakness 2) Inhibitory strip of Marion Hines. Stimulating of this area inhibits area 4. c. Engrams, persistence, impersistence, apraxias, motor relapse phenomena (various grasp and avoidance phenomena) d. Parietal lesions with “loathness” to move (project to areas 4 and 6) e. Hand eye coordination area 5 of the superior parietal cortex projects to hand area and motor cortex. These connections are most important for the use of stereoscopic vision and fine finger movement f. Corticoreticular myoclonus Putamen: a. Dystonia b. Cortically initiated pyramidal movements (motor loop) Caudate nucleus (anteroventral lesions): a. Chorea b. Emotional aspects of movement Globus pallidus: a. Unilateral lesion causes contralateral dystonia, hemiparkinsonism or tremor b. Bilateral lesions cause flexed posture, rigidity, dystonia, abulia or akinesia Red nucleus: a. Fibers of passage from the dentate are involved with lesions in this area causing a “rubral” tremor: 1) The oscillation of the hand increases on the trajectory to the target 2) Associated postural kinetic tremor Substantia nigra: a. Parkinson’s disease STN (subthalamic nucleus): a. 85% destruction of the nucleus causes hemiballismus b. Proximal musculature more affected than distal Reticular formation: a. Myoclonus (nucleus gigantocellularis) Pallidal putaminal lesions: a. Sudden falling contralaterally while sitting, standing or walking: 1) Slower than falls from lack of tone that occurs with medial RF lesions 2) Lack of postural corrective reflexes Lesions of the putamen and internal capsule: a. Hemiplegic-Parkinsonism b. Medial reticular formation (tone) Locomotor centers (gait): a. Nucleus cuneiformis of the midbrain activated by the pedunculopontine nucleus and the globus pallidus. b. Other major components of this loop: 1) Posterior thalamic areas
SECTION XIV. Basal Ganglia and Movement Disorders
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2) Brainstem areas 3) Basic oscillatory circuits between flexor and extensor spinal cord neurons (step generators) 4) Cerebellum
due to fewer functioning cells in the substantia nigra pars compacta (SNpc) and therefore, there is more GABA ergic inhibition of the motor cortex.
Chapter 1 The Direct and Indirect Pathways
Bradykinetic Disorders 1. This hypothesis has made understanding of movement disorders much easier. 2. Problems with the hypothesisl: a. recurrent collaterals make separation into a direct and indirect loops impossible b. Earlier histological studies demonstrating distinct patch and matrix systems have a more complex physiology that cannot be easily compartmentalized. c. Results of surgical procedures do not support clinical findings in every instance.
The Direct System
The putamen and caudate receive excitatory input from the pars compacta of the substantia nigra (D2 receptors) and in turn inhibit the medial globus pallidus and pars reticularis of the substantia nigra (GABA erigic fibers). These neurons then project to VA and VL of the motor thalamus. They utilize GABA which inhibits firing of these thalamic motor neurons (which utilize glutamate) that prevents or lessens firing of cortical neurons. This causes bradykinesia and the inability to sustain movement. An easy way to remember these functional systems is to figure out the firing of the VA/VL neurons of the motor thalamus. They excite cortical motor neurons and utilize glutamate. If the GABA ergic neurons of the SNpr and GP: internus fire less, less GABA ergic inhibition of thalamic motor neurons occurs, they fire more readily, release glutamate and sustain cortical firing which relieves bradykinesia.
Parkinson’s Disease
A. General considerations: 1. Incidence of 4/1000 people over the age of 40 2. Affects both sexes approximately equally 3. Prevalence rates vary worldwide, possibly due to exposure to different environmental toxins 4. Prevalence rate increases exponentially with age; at 65, 1–3% of the population is affected 5. Risk factors: a. Age is the most important b. Rural living c. Herbicides (possibly); 2.8–3.1 greater frequency d. Well water (weak correlation) e. Industrial or chemical exposure: 1) MPTP 2) Carbon disulfide 3) Carbon monoxide 4) Manganese f. Smoking may reduce risk; 1.7–2.1 g. Family history of essential tremor, 2.1–2.4 h. Minor head trauma, 3.1–4.2 i. Coffee abstinence, 2.86 (univariate) j. Relative risk of PD in relatives: 1) Siblings – 6.7 2) Offspring – 3.2 3) Nieces and nephews – 2.7
The Indirect System Genetic Parkinson’s Disease
The putamen and caudate receive inhibitory projections (D1 receptors) from SNpc. They project inhibitory GABA ergic fibers to the lateral GPe. The GPe (lateral globus pallidus) projects inhibitory fibers to the STN (subthalamic nucleus). The STN utilizes glutamate which projects to and stimulates the GPi and the SNpr. Thus stimulating of GPi and SNpr (which is an inhibitory GABA ergic projection) blocks or lessens the firing of VL and decreases cortical motor firing. The important aspect of this system is that STN utilizes glutamate to stimulate inhibitory neurons of SNpr and GPi. Stimulation of these projection neurons that (utilize GABA) decreases firing of the motor cortex. In akinetic rigid syndromes there is less inhibition of the caudate and putamen
Mendelian PD Genes
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Park 1 – 4q21 - alpha synuclein gene; AD Park 2 – 6q 25.2–27-parkin-AR Park 3 – 2p13 – AD Park 5 – 4p14-UCHL-1-AD Park 6 – 1p35–36 PINK-1; AR Park 7 – 1p36-DJ-1; AR Park 8 – 12q12 – Durdarin/L RRK2; AD Park 9 – 1p36 – AR Park 10 – 1p32 – AR Park 11 – 2q36–37-AD
Chapter 1. Bradykinetic Disorders
Park 1 (alpha Synuclein) A. General considerations: 1. Chromosome 4q21; AD; alpha Synuclein 2. Point mutations; duplications; triplication 3. Contursi kindred a. A53T mutation B. Clinical features of A53T mutation: 1. Mean age of onset – 45.6 years 2. Cortical dementia approximately 20% 3. Rare tremor at rest 4. Triplication (100% over expression of alpha Synuclein) a. Age of onset is 34 years 5. Duplication (50% over expression) a. Age of onset 48 years (39–65) Park-2 A. General considerations: 1. Chromosome }AR; 6q25; gene is Parkin 2. Large gene with a wide variety of mutations 3. The gene product is a E3 ubiquitin ligase (possible substrates are syphilis -1 pae1-R a. Ubiquitin is pivotal in the ubiquitin proteosome pathway of protein degradation 4. The more mutations in the gene the earlier the onset of disease 5. The most common form of familial PD; world wide distribution B. Clinical features: 1. Onset less than 21 years or age; some greater than 40 years of age 2. Symmetrical presentation 3. Slow progression 4. Excellent response to levodopa 5. Earlier onset: a. Psychiatric features c. Early dyskinesia b. Increased reflexes Park-3 A. General considerations: 1. AD with reduced penetrance 2. North Germany-South Denmark families B. Clinical features: 1. Cognitive impairment 2. Excellent response to levodopa C. Pathology: 1. SNpc A9 degeneration 2. Positive Lewy body formation Park-5 (UCHL1) A. General considerations: 1. Ubiquitin carboxy-terminal hydrolase L1 (deubiquitin enzyme) involved in the ubiquitin-proteosome degradation pathway 2. AD; incomplete penetrance
629
3. Possible polymorphic variant that is protective (possibly just Asian families) B. Clinical features: 1. Levodopa responsive 2. Family history is compatible with AD inheritance with incomplete penetrance Park-6 (PINK1) A. General considerations: 1. Chromosome 1p36; recessive with haploinsufficiency 2. AR early onset PD 3. Mutation seen in 5% of PD patients 4. Homozygous mutation in the PTEN (phosphatase and tensin homologue deleted on chromosome 10) induced kinase-1 (PINK1) gene: a. Localizes to mitochondria b. May phosphorylate a mitochondrial protein as part of stress response B. Clinical features: 1. Onset third or fourth decade 2. Slow progression and benign course 3. Levodopa responsive 4. Early onset dystonia; not as frequently seen as with Parkin or DJ-1 mutations Park-7 (DJ-1) A. General considerations: 1. Chromosome 1p38; multiple mutations: a. Recessive segregation patterns B. Clinical features: 1. Young age of onset 3. Focal dystonia (common) 2. Slow progression 4. Psychiatric manifestations Park-8 (Dardarin or LRRK2) A. General considerations: 1. Chromosome 12q; AD: a. GLY20 19 Ser + 6 other mutations 2. Mutated gene includes a MAPKK class (mitogenactivated protein kinase) domain: a. Putative importance is apoptotic pathway b. Increased representation sporadic (1.6%) and familial PD (4.6%) B. Clinical features: 1. Onset in sixth decade; (35–78) 2. Levodopa responsive 3. Asymmetric C. Pathology: 1. Brainstem Lewy bodies (LB) 2. Diffuse LB 3. Parkin like A9 SNpc nigral degeneration Park-9 A. General considerations: 1. AR B. Clinical features:
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SECTION XIV. Basal Ganglia and Movement Disorders
1. Patients present as parkinsonism C. Neuropathology: 1. SNpc A9 involvement (substantia nigra) 2. Globus pallidus and pyramidal tract degeneration Familial Parkinsonism
A. General considerations: 1. Prominent parkinsonism is a feature of many disorders: a. Tau-associated disease b. Trinucleotide repeat disorders c. Hallervorden–Spatz disease d. Wilson’s disease Tau-Associated Parkinsonism A. General considerations: 1. Neurofibrillary tangles consist of insoluble fibrillar aggregates of hyper phosphorylated Tau protein 2. Tau H1 haplotype of the Tau gene is associated with progressive supranuclear palsy (PSP) and corticobasal degeneration; may be a risk factor for PD Frontotemporal Dementia Parkinsonism (FTD-P14) A. General considerations: 1. AD; chromosome on 17 2. Coding or splice site mutations in the Tau gene are causative: a. Coding mutations cause decreased binding of Tau protein to microtubules b. Splice site mutations destabilize a stem-loop structure that regulates alternate splicing of exon 10 that increases four repeat isoform c. Parkinsonism is associated with exon-10 missense mutations or mutations that affect exon-10 splicing d. PSP and CBD patients also have excess four-repeat Tau isoforms Clinical Variants of FTD-17 PD Disinhibition–Dementia–Parkinsonism–Amyotrophy Complex (DDPAC) 1. Presents with personality and behavioral changes 2. Rigidity, bradykinesia, loss of postural reflexes 3. Amyotrophy of extremities 4. Rapidly progressive (mean survival of 13 years) 5. Pathology: a. Atrophy and spongiform degeneration in the frontotemporal cortex b. Neuronal loss and gliosis in the amygdala, substantia nigra pars compacta (A9) and anterior horn cells c. No Lewy bodies Pallido-Ponto-Nigral Degeneration (PPND)
A. Clinical features: 1. Dementia 3. Increased reflexes 2. Dystonia 4. No amyotrophy
Familial Progressive Subcortical Gliosis
A. General considerations: 1. AD; chromosome 17q 21–22 B. Clinical features: 1. Dementia 2. Personality change 3. Extrapyramidal signs and symptoms C. Pathology: 1. Prion protein accumulation in the frontal and temporal lobes
Atypical Parkinsonism Described In
1. Kii peninsula of Japan 2. Guadeloupe Islands of Western Pacific 3. Guam A. General considerations: 1. Tau pathology and neurofibrillary tangles is seen in all 2. Tau pathology of Kii peninsula and Guam: a. Alzheimer type b. Guadeloupe has Tau pathology similar to that of PSP 3. Midbrain Tau pathology occurs in Niemann-Pick disease type C: a. Failure of upgaze b. Juvenile parkinsonism
Trinucleotide-Repeat Disorders
A. General considerations: 1. Huntington’s disease (HD), spinocerebellar atrophies, DRPLA, Kennedy’s syndrome 2. Associated with cerebellar ataxia, cognitive dysfunction, chorea, anterior horn cell disease depending on the specific disorder 3. In general, they code for a polyglutamine repeat sequence that leads to intracellular inclusions
Fragile X-Mental Retardation Tremor Ataxia Disorder
A. General considerations: 1. Permutations of the FMR1 gene (55–200 repeats; full expansion of the trinucleotide repeat is greater than 200 CGG repeats in the 5-untranslated part of the gene 2. Rare in women with one normal X-chromosome B. Clinical features: 1. Postural tremor 4. Cognitive dysfunction 2. Ataxia 5. Parkinsonism 3. Autonomic dysfunction C. MRI evaluation: 1. Increased signal in the middle cerebellar peduncles
Chapter 1. Bradykinetic Disorders Parkinsonism in Autosomal Dominant Spinocerebellar Ataxias
SCA 3/Machado Joseph Disease and SCA2
A. General considerations: 1. 18F-dopa PET scans have demonstrated basal ganglia hypometabolism 2. SCA2 parkinsonism symptoms are more common in Chinese than Caucasian patients 3. SCA 3 parkinsonism is more common in AfroCaribbean patients B. Clinical features: 1. Responsive to L-dopa Parkinsonism In Juvenile Variant of Huntington’s Disease (Westphal)
A. General considerations: 1. Chromosome 4p16.3 2. Large CAG repeats 3. 90% are of paternal lineage B. Clinical features: 1. Presents in teens 3. Seizures 2. Akinetic rigid syndrome X-Linked Dystonia Parkinsonism (PYT3)
A. General considerations: 1. Primarily found in Filipinos from the Panay Islands; also found in some non-Filipinos 2. Known as Lubag 3. Possible missense mutation in exon 4 of the Xchromosome in Lubag patients 4. Rare in female carriers B. Clinical features: 1. Presents with a mixed movement disorder 2. Blepharospasm or limb dystonia 3. Symptoms generalize within the first decade 4. Forty percent of patients have Parkinsonism 5. Poorly responsive to L-Dopa 6. Severe masseter dystonia Rapid-Onset Dystonia Parkinsonism (DYT12)
A. General considerations: 1. Encodes the alpha 3 subunit of the sodium-potassium pump B. Clinical features: 1. Rapid onset of symptoms; progresses over hours 2. Initiated by physical and emotional stress 3. Present with cranial and limb dystonia 4. Dysarthria and dysphagia 5. Parkinsonism 6. Not L-dopa responsive
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Parkinsonism in Dentantanto-Rubro-Pallido-Luysian Atrophy (DRPLA)
A. General considerations: 1. AD; chromosome 12 p 13.3 B. Clinical features: 1. Cerebellar ataxia 4. Dystonia 2. Parkinsonism 5. Seizures 3. Myoclonus
Parkinsonism Features of Wilson’s Disease
A. General considerations: 1. AD; chromosome 13q 14–21 B. Clinical features: 1. Onset 6–40 years of age; neurologic symptomatology in the early twenties 2. Presentation is psychiatric, neurologic or as liver disease 3. Severe dysarthria 4. Wing-beating tremor 5. Postural abnormalities 6. Dystonia 7. Parkinsonism 8. Kayser–Fleisher ring in the cornea (accumulation in Descemet’s membrane) a. Present in all patients with neurologic disease 9. Rare chorea 10. No sensory symptoms 11. Depression, personality changes, emotional lability with cognitive decline C. Laboratory evaluation: 1. Increased urinary copper excretion (>100 μg/24 hr) 2. Low plasma ceruloplasmin ( than horizontal plane); convergence paresis; inability to initiate saccades 9. Orolingual apraxia 10. Parkinsonism (bradykinesia) 11. Increased reflexes and clonus 12. Juvenile Westphal variant: a. Akinetic rigid syndrome with seizures
Syndromes with Prominent Parkinsonism Features and Known Genetic Loci
1. SCA 2 – Chromosome 12 2. Machado–Joseph, disease – SCA3 chromosome 14q 24, 3–32 3. Hallervorden Spatz disease – 20p 12.3 4. Huntington’s disease – 4 p 16.3 (Westphal variant) 5. Dentato-Rubro-Pallido-Luysian atrophy chromosome 12p13.3 6. Wilson’s disease – chromosome 13 q 7. Fronto temporal dementia – chromosome 17 8. Rapid – onset dystonia Parkinsonism Dy 12 9. X-linked dystonia Parkinsonism (DYT 3) 10. Fragile X-mental retardation tremor ataxia disorder – (FMR1 gene) 11. Familial progressive subcortical gliosis (prion disease) – chromosome 17q21–22 Differential Diagnostic Points in Genetic Parkinsonism
1. Recessive PD may occur in small families and be misdiagnosed as sporadic. Parental consanguinity is a hint. 2. Incomplete penetrance occurs in dopa responsive dystonia 3. Male to male transmission excludes X-linked recessive inheritance Idiopathic Parkinson’s Disease
MRI Evaluation of Familial Parkinsonism
1. Usually normal 2. Hallervorden Spatz disease (PANK 2 gene): a. Low signal in the internal segment of the globus pallidus b. Axonal vacuolization (Spheroids) 3. Fahr’s disease: a. Bilateral calcification of the basal ganglia b. Calcification of subcortical white matter and the dentate nucleus 4. Niemann Pick type C (NPC 1 gene): a. Diffuse cerebellar atrophy b. Mild cerebral atrophy 5. Huntington’s disease: a. Atrophy of the caudate nucleus (“box car” atrophy) b. Frontal lobe atrophy 6. Wilson’s disease: a. Putamen > caudate T2-weighted lesions b. Midbrain and occasional thalamic lesions 7. Neuroferrotinopathy: a. T2-weighted lesions in the globus pallidus 8. Fronto temporal dementia parkinsonism chromosome 17: a. Mesial temporal lobe atrophy
A. General characteristics: 1. There must be degeneration of components of the substantia pars compacta (SNpc on A9) 2. Usually it is the ventral tier dopaminergic neurons of SNpc that project to the posterior lateral putamen 3. Lewy body formation B. Clinical features: 1. Cardinal signs: a. Akinesia – bradykinesia b. Tremor at rest (4–6 Hz) c. Rigidity (negri’s signs; cogwheel in type) d. Autonomic dysfunction e. Cognitive decline in approximately 30% of patients Brady and Akinesia
1. Most distressing symptoms to patients. When severe the patient is frozen. 2. Suffer “freezing” episodes; they are unable to change motor programs rapidly and freeze when turning or going through a doorway 3. An akinetic patient may initiate movement rapidly if frightened 4. Patients at the end of effective therapy with L-Dopa and other agonists experience “off” episodes during which bradykinesia, akinesia and fatigue makes any form of movement difficult
Chapter 1. Bradykinetic Disorders Tremor
1. Occurs at rest (4–6Hz), almost pathognomonic for IPD 2. Occurs in the hand with metacarpophalangeal flexion; progresses to involve the entire arm and becomes bilateral. The hand may be involved (“up and down”); the leg may be involved, in extreme case. The tremor may persist during movement as well as at rest. 3. Tremor is embarrassing, but does not interfere with activities of daily living 4. Responds well early to L-Dopa and trihexyphenidyl Rigidity
1. More in extremities than axial musculature 2. “Catching” or cogwheel character (Negr’s sign) 3. May have stiffness throughout the range of motion of the affected extremity 4. Contributes to the flexed-stooped posture of the patient 5. Generalized stiffness of the body
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4. Once the patient is in motion he cannot position his body over its center of gravity so that he festinates and is unable to control progression. The gait is shuffling and has no or decreased associated arm movements 5. Failure of upgaze and poor smooth pursuit. The patient utilizes saccadic substitution. 6. Hypomimia and hypohemia 7. Swallowing dysfunction due to the failure of posterior pharyngeal striated muscles to deliver the bolus of food to the esophagus. There may be concomitant dysfunction of the cricopharyngeal muscles (external esophageal sphincter); cranial nerve IX 8. Micrographia (failure to maintain movement) during writing 9. Sialorrhea (less spontaneous swallowing)
Differential diagnosis of Parkinson’s Disease
1. Parkinsonism as a component of Multiple System Atrophies (MSA)
Loss of postural reflexes
1. Frequent falls with characteristic humeral and hip fractures; unable to extend arms to brace themselves. 2. Falling backwards is characteristic of the last portion of a posturally induced movement Autonomic Dysfunction
1. 2. 3. 4. 5. 6.
Becomes evident in moderately advanced disease Difficulty initiating micturition Obstipation Sexual dysfunction Seborrheic dermatitis Postural hypotension (worsens as the illness progresses)
Cognitive Decline
1. Depression 2. Poor executive function 3. Bradyphrenia (inability to process or formulate ideas quickly) 4. Decreased short term memory 5. Inability to change motor sets 6. Some patients suffer concomitant Alzheimer’s Disease or diffuse Lewy Body Disease 7. Hallucinations from dopamine therapy Associated Neurological Deficits
1. Decreased spontaneous blink and all subconscious movement 2. Sleep disruption due to sleep apnea and REM sleep disorder 3. Gait ignition failure
General Features of MSA
1. A group of neurodegenerative diseases with varying degrees of dysfunction of the following systems: a. Cortical (cognitive dysfunction) b. Basal ganglionic function c. Cerebellar dysfunction d. Autonomic dysfunction e. Pyramidal signs f. Stimulus sensitive myoclonus of hands and face g. Extreme neck flexion h. Inspiratory stridor (laryngeal muscle dysfunction) i. Parkinsonian features have poor response to levodopa 2. Differentiated by: a. Clinical examination b. MRI , SPECT, and PET scanning 3. Rest tremor is slight or absent
Distribution of Signs and Symptoms
A. Olivopontocerebellar Atrophy (OPCA): 1. AD, AR, and sporadic forms 2. Sporadic OPCA presents with: a. Ataxia b. Dysarthria c. Cerebellar dysfunction d. Parkinsonism is mild e. Approximately 20% respond to levodopa f. MRI demonstrates: 1) Pontine atrophy – “mattese cross” (prominence of crossing fibers that make up the middle cerebellar peduncle (MCP)
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2) Atrophy of the olivary nuclei 3) Atrophy of the mid vermis 4) Some varieties have peripheral neuropathy, retinal degeneration, dorsal column deficits, and cranial nerve dysfunction 5) Primary deficits of cerebellar function in all varieties Striatonigral Degeneration (SND)
1. Severe akinetic rigid syndrome; minimal tremor 2. Do not respond to L-Dopa 3. Dystonia (particularly in the upper extremity); arm is held upward 4. More cognitive defects than idiopathic Parkinson’s Disease 5. MRI demonstrates atrophy and signal change in the putamen 6. Reduced uptake of raclopride with PET and 23 iodobenzamide SPECT is noted in the striatum 7. Loss of dopamine receptors in projection zones of A9 Distribution of Signs in MSA
1. Approximately 28% have all four major manifestations 2. 18% have parkinsonism, corticospinal and autonomic dysfunction 3. 11% have parkinsonism and autonomic dysfunction 4. 10% have solely parkinsonism 5. Parkinsonism was not found in 11% of patients 6. Autonomic dysregulation develops in greater than 90% of patients: a. A poorly levodopa responsive parkinsonian patient with “cold hands” and hypotension suggests MSA 7. Autonomic dysregulation is manifest as: a. Impotence in males b. Urinary incontinence in women c. Orthostatic hypotension is the most disabling symptom: 1) Upright hypotension 2) Supine hypertension 3) Heat, exercise, large meals precipitate syncope 4) “coat hanger headaches” just prior to syncope (across the trapezius muscles) 8. Wheelchair bound after 4 years; median survival is 9.5 years
Shy–Drager Syndrome
A. General characteristics: 1. Autonomic dysfunction is the seminal feature B. Clinical features: 1. Onset is between 40–69 years of age 2. Most prominent symptom is postural hypotension (precedes parkinsonism)
3. Forward-flexed rigid stance 4. Lose consciousness and fall due to severe hypotension 5. Iris atrophy (holes in the iris) 6. Dementia 7. Ataxia 8. Bowel, bladder, and sexual dysfunction early in the process of the illness 9. Cold mottled hands (livedo reticularis) at clinical presentation 10. Progression is more rapid than idiopathic Parkinson’s Disease
PSP (Progressive Supranuclear Palsy)
A. Clinical features of PSP: 1. Parkinsonian patients who respond poorly to levodopa; 1–8% may have PSP pathologically 2. Median age of onset is 64 years of age (50–77) 3. Supra nuclear ophthalmoplegia is seminal: a. Poor vertical saccades early b. Downward saccades affected first c. Hypometria of saccades vertical > horizontal d. Abnormal smooth pursuit e. Blepharospasms f. Apraxia of eye lid opening g. Ptosis, marked lid retraction h. Decreased blinking i. Pseudointernuclear ophthalmoplegia j. Nystagmus k. “Square wave jerks” (nystagmus recording) l. Pathologic lid retraction m. Poor convergence n. Poor reading and eye contact o. Vertical saccades accomplished by moving their eyes in a lateral arc p. Complete ophthalmoplegia (late) 4. Personality change with frontal lobe dyscontrol 5. Falling, imbalance, gait disorder much earlier than IPD 6. Axial rigidity > appendicular 7. Dysphagia and dysarthria 8. Falling backwards: 9. Rigid hyperextension of the neck; IPD has flexed neck posture 10. Gait abnormalities: a. Stiff and broad based b. Knees and trunk extended (IPD stooped with knees flexed; narrow base) c. Arms slightly adducted; IPD increased flexed carrying angles of the arm d. Pivot rather than turning en bloc as occurs with (IPD)
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11. Absent tremor 12. Characteristic facies: a. Deep nasolabial folds c. Staring expression b. Wide eyed 13. Early they may present with prominent akinesia; gait ignition failure and freezing 14. Rare findings: a. Limb rigidity > axial b. Mild tremor at rest c. Upper limb apraxia, myoclonus, chorea d. Respiratory dysfunction 15. Arm levitation (more common than the posterior alien hand seen with CBGD) 16. Higher blood pressure than other neurodegenerative disorders 17. Differential Diagnosis of Supra nuclear ophthalmoplegia: a. Niemann Pick type C c. Fahr’s disease b. Lewy body dementia B. MRI/CT evaluation: 1. Early midbrain atrophy C. Pathologic changes consistent with PSP may be associated with: 1. Creutzfeldt–Jacob disease 3. MSA 2. Progressive subcortical gliosis D. Differential diagnosis of falling backwards 1. IPD 3. Acquired hepatolenticular degeneration 2. NPH
c. Affected limb may assume an abnormal posture or levitate 7. Parietal S1 type sensory loss 8. Progression to: a. Dysarthric c. Supranuclear gaze palsy b. Dysphagia d. Rare cerebellar signs 9. Frontotemporal neurobehavioral disorder may develop 10. Rare aphasia C. Neuroimaging: MRI and SPECT: 1. Asymmetric cortical atrophy: a. Frontal and parietal lobe 2. Some patients: a. Focal asymmetrical frontotemporal distribution of atrophy b. May have generalized atrophy D. Pathology: 1. SNpc; GP, and STN are involved 2. Swollen cortical neurons 3. Tau containing neuropil threads 4. Tau containing astrocytes 5. Filamentous inclusions (tau protein) 6. Affected areas: a. Rolandic regions b. Posterior frontal and parietal cortex c. Late disease: 1) Insular cortex 2) Tip of the temporal lobe
Corticobasal Degeneration
Lewy Body Dementia
A. General characteristics: 1. Degeneration of: a. Cortical areas b. Substantia nigra c. Basal ganglia d. Swollen neurons in affected areas (neuronal achromasia) 2. Glial and neuronal accumulation of tau protein B. Clinical features: 1. Equal sex incidence 2. Average age of onset is 60 years of age 3. Six to ten years disease duration 4. Asymmetrical: a. Rigidity d. Jerking of an arm or leg b. Clumsiness e. Limb ideomotor apraxia c. Stiffness f. Postural instability 5. After 2–3 years: a. Dystonia rigidity and akinesia of the limb b. Hemimyoclonus 6. Posterior parietal alien limb: a. Limb moves without voluntary control b. Patient feels as if the affected limb may not belong to him
A. General characteristics: 1. Hallmark is the accumulation of Lewy bodies throughout the cortex to a greater degree than is noted with IPD and aging 2. An alpha synucleinopathy B. Clinical features: 1. Onset is sixth to seventh decade; average age is 68 years 2. Visuo spatial, attentional and problems solving abilities are seen early 3. Fluctuations in cognitive abilities are striking 4. Visual hallucinations are a seminal feature 5. Fluctuations of alertness and Parkinsonian features 6. Associated clinical features: 7. Repeated falls: a. Syncope b. Sensitivity to neuroleptics c. Transient loss of consciousness d. Auditory and tactile delusions e. Transient ischemic like episodes 7. Rest tremor, parkinsonian rigidity and bradykinesia occur but not to the same degree as in IPD
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Post-Encephalitic Parkinsonism (1915–1927)
Drug-Induced Parkinsonism
1. Sequela of Von Economo’s or epidemic encephalitis; also known as encephalitis lethargic 2. Rare (almost all patients have died) 3. Parkinsonism occurred weeks to years after the encephalitis 4. Tremor as prominent as that in IPD 5. Oculogyric crises (usually spasm of the superior rectus and inferior oblique muscles; any muscles may be affected) 6. Personality and behavioral changes 7. Autonomic crises; hypertension, severe hyperhydrosis 8. Bulbar palsies 9. Ophthalmoplegia 10. NFT tangles and neuronal loss in SNpc of A9 11. Sleep-wake cycle disruption
A. General characteristics: 1. MPTP (methyl-4phenyl-2,3,6-tetrahydropyridine) 2. Designer drug produced from overheated Demerol specifically destroys dopaminergic cells of SNpc A9 B. Clinical features: 1. Irreversible and progressive illness 2. Dramatically rapid onset of parkinsonism 3. Tremor faster than 4–6Hz of IPD 4. Respond to L-Dopa early; side affects develop quickly dependent on the severity of SNpc loss rather than length of treatment 5. Reflexes generally increases 6. May be very similar to IPD
Differential Diagnostic Features Between MSA and Parkinson’s Disease
1. 2. 3. 4. 5.
Shy-Drager SND (Striatonigral degeneration) CBGD (Cortico basal ganglionic degeneration) Olivoponto cerebellar degeneration Lewy body disease
The immediate clues that one is dealing with a system degeneration is the lack of response to levodopa in its parkinsonian feature, a low blood pressure and cold hands. Shy-Drager syndrome is dominated by autonomic failure. Small clues are iris atrophy (deep anterior chamber of the eye and atrophic iris) as well as cognitive dysfunction. Striatonigral degeneration is predominantly an akinetic rigid Parkinsonian patient that has no tremor at rest more rigidity than an IPD patient and does not respond to levodopa. Occasionally, these patients have levitation of an arm. The difficult diagnostic problems occur between IPD and PSP. The supranuclear gaze palsy, often is associated with eye lid apraxia, falls, and the head is held in extension. It is associated with frequent falls after the onset of illness. The deep nasolabial folds and stare are minor diagnostic features. The hallmark of diffuse Lewy body disease is dementia, visual hallucinations and clear fluctuation of cognitive and parkinsonian features. These patients may develop levitation of an upper extremity. Corticobasal ganglionic degeneration is suspected when a patient presents with clear asymmetric akinetic rigid state, an alien hand and primary sensory (S1) sensory loss. Pick’s disease is demonstrated by an expressive aphasia that is slowly progressive. Olivopontocerebellar degeneration may have dorsal column dysfunction, retinal disease and cranial nerve abnormalities in addition to clear cerebellar ataxia.
Reversible Drug-Induced Parkinsonism
1. Antipsychotic medications: a. Phenothiazines and butyrophenones b. Bradykinesia and rigidity c. No tremor d. Shuffling gait; increased carrying angles of the arms during walking 2. Haloperidol and fluphenazine: a. High potency c. Acute extrapyramidal effects b. Low dose 3. Prochlorperazine (Compazine): a. Antiemetic b. Acute extrapyramidal effects most often cervical dystonia 4. Metoclopramide (Reglan): a. May cause chronic parkinsonism b. No tremor 5. Reserpine: a. Parkinsonism d. G.I. hemorrhage b. Nasal stuffiness e. Rarely used now c. Depression 6. Calcium channel blockers: a. Diltiazem c. Flunarizine b. Cinnarizine 7. Alpha-methyl dopa (Aldomet): a. False neurotransmitters
Toxic Causes of Parkinsonism
1. Manganese: a. Manganese miners b. Welders c. Clinical manifestations: 1) Severe depression as an early symptom 2) Bradykinesia and akinesia are dominant presentation 3) Loss of postural reflexes
Chapter 2. Hyperkinetic Disorders
2.
3.
4.
5.
4) Frequent falls 5) Rare tremor Post hypoxic: a. Parkinsonism: delayed onset from the sentinel event b. Associated with: myoclonus, choreoathetosis and cortical deficits c. Bilateral GP, destruction with carbon monoxide Carbon tetrachloride: a. Dry cleaning toxic exposure b. Akinetic-rigid presentation Methanol: a. Suicide attempts (antifreeze; “moonshine”) b. Akinetic-rigid presentation c. Severe optic neuropathy with hemorrhagic optic neuritis d. Increased T2 signal on MRI of the striatum Mercury: a. Industrial exposure b. Akinetic-rigid presentation c. Choreoathetosis d. Peripheral neuropathy e. Minamata Bay Japan large toxic exposure that demonstrated the above features
Movement Disorders Associated with Long-Term Treatment of Parkinson’s Disease
1. End of dose failure: a. Return to baseline bradykinesia or akinesia b. Tremor returns 2. Peak dose dyskinesia: a. Choreoathetosis at period of maximum absorbed concentration of L Dopa 3. Early morning dystonia: a. Awakening with dystonia of the lower extremity (plantar flexion – inversion of the foot) 4. “Off periods”: a. Severe bradykinesia-akinesia b. Occurs suddenly c. May last 30 minutes to hours d. Associated with “freezing” (inability to change motor sets); go through a doorway; change directions 5. “On periods”: a. Duration of maximum benefit of medications 6. “On-off” phenomenon: a. Periods of benefit from medication associated with sudden episodes of bradykinesia 7. “On-off” dystonia 8. Dyskinesia-improvement-dyskinesia
Differential Diagnosis of Secondary Parkinsonism
Hemiatrophy hemiparkinsonism Normal pressure hydrocephalus
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Pseudobulbar Palsy Lacunar infarctions of the basal ganglia (hypertension; diabetes) Binswanger’s Disease (atherosclerotic ischemic demyelination) Alzheimer’s Disease Neoplasm Vascular malformation Infection: HIV; cryptococcus, Creutzfeldt–Jakob Disease Severe depression Head trauma (major) Pugilistic (multiple minor) Post-hypoxia
Rare Causes of Parkinsonism
1. NPH (normal pressure hydrocephalus) 2. Third stage syphilis (trombone tongue) 3. Vascular parkinsonism: a. Lacunar infarctions of basal ganglia b. Gait and balance most affected c. Lower half Parkinsonism: 1) Vascular disease of the periventricular descending corticospinal fibers that project to leg neurons 4. Severe depression (pseudo Parkinsonism) 5. Wilson’s Disease 6. Huntington’s Disease: a. Juvenile akinetic-rigid form b. Seizures c. An end-stage phenomenon in the choreic form 7. Hallervorden-Spatz Disease (PANK-2) 8. Pseudo-bulbar palsy (emotional incontinence) 9. Alzheimer’s disease (cognitive decline; memory loss, visual spatial domain dysfunction) 10. Hemiatrophy/hemiparkinsonism (congential MCA occlusion) 11. Neoplasm 12. Creutzfeldt–Jakob variant 13. Binswanger (atherosclerotic demyelination) 14. Repeated head trauma (Pugilistic parkinsonism) 15. Hypoparathyroidism (rare; calcified basal ganglia)
Chapter 2 Hyperkinetic Disorders General categories: 1. Tremor 2. Myoclonus 3. Tardive dyskinesia 4. Ballism 5. Chorea
6. 7. 8. 9. 10.
Athetosis Dystonia Paroxysmal dyskinesias Akathisic movements Tics
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Tremor
Parkinson’s Disease
A. General considerations: 1. Definition: a. Involuntary movement b. Rhythmic c. Oscillatory about a fixed point d. Due to alternating or synchronous contractions of agonist and antagonist muscles e. May occur at rest or with movement or on holding a static posture B. Differential Diagnosis: 1. Physiologic 2. Pathologic: a. Parkinson’s Disease b. Parkinsonian syndrome c. Physiologic tremor (exaggerated) d. Tremor of peripheral nerve origin e. Benign essential tremor f. Dystonic tremor g. Drugs h. Cerebellar disease i. Midbrain (“rubral”) tremor j. Psychogenic tremor k. Wilson’s disease l. Toxins m. Metabolic
A. General considerations: 1. VIM nucleus of the motor thalamus is the thalamic oscillator (burst neurons that fire at the same frequency as the tremor) 2. Proprioceptive feedback from displaced joints sustains the tremor B. Clinical features: 1. Head tremor is rare: a. Up and down when present b. Lips and jaw are more prominent in PD than in other conditions 2. Pronation-supination of the forearm; rhythmic, thumb and finger movements of a metacarpophalangeal flexed hand (“pill rolling” character) 3. Frequently asymmetrical at onset 4. Postural kinetic component; has a latent period when the hands are out stretched; essential tremor does not 5. Chin, jaw and tongue may be affected 6. Severe late stage patients may demonstrate postural kinetic and intention tremor 7. Walking may increase the hand tremor
Physiologic Tremor
A. General considerations: 1. Mechanical reflex component 2. 8–12 Hz entrainment of motor units 3. May not be seen with unaided eye 4. Enhanced by: a. Fatigue g. Alcohol withdrawal b. Anxiety h. Catecholamine excess c. Thyrotoxicosis i. Steroids d. Narcotic withdrawal j. Caffeine e. Hyperglycemia k. Theophylline f. Pheochromocytoma 5. Absent at rest 6. Present with maintained posture 7. Activated by severe muscle fatigue
Pathologic Tremors
Resting Tremor
A. General considerations: 1. 3.5–7 Hz 2. Disappears or is markedly attenuated with intention 3. Characteristic of basal ganglia diseases
Postural Kinetic Tremor
A. General considerations: 1. 6–11 Hz frequency 2. Occurs in the antigravity muscles of the extremities and trunk 3. Associated head titubation, jaw tremor and involvement of the voice
Benign Essential Tremor
A. General considerations: 1. Family history is obtained in 17–70% 2. Increased incidence of Parkinson’s disease 3. Affects men and women equally 4. AD form; two loci: a. Chromosome 3q13 (Icelandic; Tajiks) b. HS1-BP3 gene B. Clinical features: 1. Seen with maintenance of a specific posture 2. Rare at rest 3. Kinetic 4. A few patients may only demonstrate it with a fixed posture 5. Usually abduction-adduction or flexion–extension of the hand; rarely pronation-supination 6. Most often monosymptomatic 7. May be associated with: a. Poor fine hand movements
Chapter 2. Hyperkinetic Disorders
8. 9. 10. 11. 12. 13. 14.
15. 16. 17. 18.
19. 20.
b. Balance and gait disturbance Rarely affects the jaw (distinguishing point from PD) Rarely associated dystonia Malignant hyperthermia (rare) Migraine Fragile X-pre-mutations (have essential tremor) HS1-BP3 gene: a. Head tremor more common in women than men Head tremor: a. Vertical yes-yes (rare) b. Horizontal no-no is usual (PD is vertical head tremor when present) c. Usually associated with hand tremor Frequency is 4–10 Hz Slowly progressive Late stages: a. Tremor of the voice, palate and tongue Handwriting: a. Rounded letters are produced with sharp angularity b. Large letters Age: frequency declines; amplitude increases Responds to alcohol, gabapentin; benzodiazepine, primidone; beta adrenergic blockade
Clinical Variants
A. General considerations: 1. Orthostatic tremor B. Clinical features: 1. Rapid irregular and asynchronous tremor of the legs and trunk induced by standing 2. Onset: middle aged or elderly patients 3. Unsteadiness in the legs with fear of falling 4. Loss of extensor tone in the legs 5. Difficulty in initiating gait 6. Pain in the legs when standing 7. Wide based stance but walk normally 8. Signs and symptoms abolished with sitting 9. 13–18 Hz burst firing in antigravity muscles 10. Tremor may occur in the trunk and cranial musculature 11. Isometric contracture of muscles may induce tremor (16 Hz) during the supine posture 12. Asymptomatic hypertrophy of thigh and calves (rare) 13. Described with pontine lesions 14. It is a task specific tremor C. Primary writing tremor: 1. Affects writing in isolation 2. No associated (or minimal) postural or kinetic component 3. Possibly initiated by hand position 4. 1/3 of patients have family history of the disorder D. Isolated voice tremor:
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1. May be associated with spasmodic dysphonia E. Kinetic predominant head tremor F. Combined resting and postural tremor
Wilson’s Disease
A. General considerations: 1. AR; chromosome 13q 14–21 2. 75% present with liver signs and symptoms, psychiatric manifestations or tremor may be early features 3. Hepatitis and cirrhosis present prior to CNS manifestations 4. Nephropathy: amino acidosis, phosphaturia, uricosuria (low serum uric acid), increased urine copper B. Clinical features: 1. Kayser–Fleischer ring (copper deposition on Descemet’s membrane; seen upper limbus of blue-eyed patients; seen in 100% of patients with CNS manifestations 2. Associated neurologic signs: a. Dystonia e. Dysarthria b. Chorea f. Seizures c. Myoclonus g. Parkinsonism d. Gait disturbance h. Cerebellar signs C. Pathology: 1. Atrophy of putamen primarily; some in globus pallidus 2. Glial modification 3. Diffuse atrophy of cerebellum and cerebral cortex 4. Opalski cells
Dystonic Tremor
1. In context of sustained abnormal contracture 2. “Jerking” tremor-like movement: a. With intention b. Passive movement of the dystonic muscles c. Pain in distribution of the affected segment d. Frequently of peripheral origin (chronic regional pain syndrome); most often mistaken for dystonia of central origin. Allodynia of the affected part is often present.
Intention (Kinetic or Action Tremor)
A. General considerations: 1. Most commonly seen with cerebellar disease 2. Oscillation during the terminal 1/3 of a specific movement which decreases as the target is approached. B. Clinical features: 1. Specific cerebellar lesions cause specific patterns of tremor: a. Lateral cerebellar hemispheric lesion (dentatesuperior cerebellar peduncle) extremity tremor
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b. Tremor of the head and trunk vermian or fastigial lesions c. Postural tremors (6–10 Hz) cerebellar outflow tremor: 1) Involvement of the superior cerebellar peduncle near the red nucleus has been termed a “rubral” tremor. Clinical observation in some patients is that the tremor is more severe with lesions near the red nucleus (“rubral tremor”); 2–5 Hz 2) A tremor may be seen with involvement of the cerebellum at any level 3) Usual pathologies: Midbrain Rubral Tremor: a) Sequelae of severe head trauma b) Coma c) Lesions close to the red nucleus interrupt the dentato-thalamo-rubral pathway d) Delayed onset after the coma (weeks to months) Stroke Involving: a) Interpeduncular artery (top of the basilar) b) Thalamoperforate artery (P1) branch of the posterior cerebral artery (PCA) c) Medial posterior choroidal (PCA) Tremor of Peripheral Nerve Origin
1. 2. 3. 4. 5.
Often following trauma (CRPS I/II) Exaggerated physiological tremor Increased by sympathetic stimulation 2–8 Hz frequency Possible spindle mechanism (sympathetics innervate muscle spindles) 6. Kinetic and postural 7. Weeks to months after injury Drugs that Cause Tremor
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
Amphetamines Alcohol withdrawal Antihistamines Anticholinergics Lithium Valproate Epinephrine Caffeine Adrenocorticoids Theophylline Thyroid beta adrenergic agonists Neuroleptics Calcium channel blockers (nimodipine, flunarizine) Lidocaine Amiodarone Nicotine
Neuroleptic Tremors
1. 2. 3. 4. 5. 6. 7.
8.
9.
Postural Bilateral Associated with parkinsonism Beta 2 adrenergic agonists Lithium tremors: a. Rest c. Kinetic b. Postural d. 3–15 Hz Valproic Acid: a. Resting, kinetic, postural tremors Tricyclic antidepressants: a. Postural and kinetic tremors b. Associated with chorea and myoclonus c. 10% respond to Inderal Ethanol withdrawal: a. Generalized tremor b. 7–14 Hz c. Increased by activity and emotional stress Nicotine: a. Increases amplitude of physiological tremor
Metabolic Causes of Tremor
1. Uremia 2. Thyrotoxicosis 3. Hypocalcemia
4. Hypomagnesemia 5. Hypophosphatemia
Toxic Causes of Tremor
1. 2. 3. 4.
Mercury poisoning Ethylene oxide Carbon monoxide Heat stroke (kills Purkinje cells)
Psychogenic Tremor
1. 2. 3. 4. 5.
Abrupt onset Sporadic course Spontaneous remission Clinical inconsistencies Unresponsive to drugs
6. 7. 8. 9.
Changing characteristics Lessens with distractibility Increases with attention Responds to placebo
Chorea
A. General characteristics: 1. Definition: Sudden, irregular unpredictable brief involuntary irregular movements of the extremities, facial or truncal musculature. 2. Specific muscles involved depend on the illness; Huntington’s more truncal > than appendicular while Sydenham’s is more appendicular than truncal
Chapter 2. Hyperkinetic Disorders
3. May occur at rest or with intention, in this instance they may be masked as semi purposeful (parakinesia) 4. The movements may be unilateral or bilateral, cease in sleep and are exacerbated by stress 5. Associated with increased or decreased tone 6. Hyperpronation of the upper extremity with extension 7. Intermittent contracture of grip (milk-maids hand) 8. Difficulty sustaining movement (inability to maintain the extruded tongue) 9. Facial grimacing and interruption of smooth breathing patterns are characteristic
Hereditary Causes Huntington’s Disease
A. General characteristics: 1. AD 2. Varies in different populations 3. Between 4–7/100,000 people 4. Low frequency less than 1/100,000: a. Finland c. Black population of the USA b. Japan 5. Chromosome 4: a. CAG repeat (37–86) range for disease 6. Inverse correlation with CAG repeat length: a. Age of onset c. Rate of progression b. Age of death d. Other clinical features: 1) Correlation strongest with early > late onset disease 7. Sporadic HD: a. Expansion from a large repeat in an unaffected male patient b. Intermediate alleles c. Unstable expansion 8. No variance of repeat length in different tissues: a. Repeat size altered in gametogenesis: 1) Highest in spermatogenesis: 2) Juvenile onset with paternal transmission b. Polyglutamine tract in Huntington gene is translated: 1) Binds to glyceraldehydes 3-phosphate dehydrogenase (GAPD) B. Clinical presentation: 1. Variable onset: a. Juvenile (4–19 years of age) b. Early (20–34 years of age) c. Midlife (35–49 years of age) d. Late onset is greater than 50 years of age e. 10% present as juvenile f. 25% present as late onset 2. Anticipation: a. Progressive increase in the length of the tandem repeat
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b. Longest tandem repeats associated with the earliest onset c. Late onset disease/maternal transmission C. Clinical patterns: 1. Hyperkinetic: a. Most common form b. Chorea first clinical manifestation c. Usual form: 1) Middle or late onset disease 2) Variable rate of progression d. Hyperreflexic e. Hypotonic f. Lurching gait g. Choreatic eye movements h. Dementia: 1) Frontal lobe features 2) Choreatic movements may precede or follow the dementia 2. Juvenile or early onset disease (Westphal variant): a. Inheritance of the gene from an affected father b. Rapid clinical progression c. Some patients: 1) Neuropsychological disturbance > movement disorders d. Bradykinesia e. Rigidity f. Seizures g. Movements persist through sleep h. Differential diagnosis of akinetic rigid HD 1) Wilson’s disease 2) Juvenile Parkinsonism 3) Neuroaxonal dystrophy 4) Metabolic storage disorders 3. Late state Disease: a. Uncommunicative: 1) Orolingual chorea 2) Cognitive dysfunction 3) Rigidity 4) Dystonia 5) Dysphagia (aspiration pneumonia) 6) Duration of disease: a) Shorter in patients with: (1) Juvenile (2) Early onset disease D. Laboratory evaluation: 1. CT: a. Enlarged lateral ventricles (box car ventricles) b. Flattening or absence of the caudate nucleus c. PET studies: 1) Hypometabolism of the caudate and putamen nuclei
Differential Diagnosis of Huntington Chorea
1. Sydenham’s chorea:
SECTION XIV. Basal Ganglia and Movement Disorders
642
2.
3.
4.
5.
6.
a. Earlier age of onset b. Self limited c. Euphoria but no dementia d. May be familial e. Rheumatic heart disease f. Unilateral (hemichorea) in 50% g. Apparent flaccid paralysis (chorea mollis) Chorea with SLE: a. More acute onset b. Chorea: 1) More localized 2) Periodic Neuroleptic chorea (tardive dyskinesia): a. Stereotypic movements (repetitive) b. Oral Lingual buccal dyskinesia (most characteristic) c. Gait is normal; lurching in HD Alzheimer’s/Pick complex: a. Mental disorder may be similar b. Language involvement c. No aphasia in early HD d. Myoclonus > chorea Neuroacanthocytosis: a. Mild chorea d. Peripheral neuropathy b. Tics e. Increased serum CPK c. Tongue biting f. Red cell acanthocytes Hereditary non-progressive chorea: a. Begins in childhood b. Does not progress c. No dementia or personality disorder
Causes of Chorea
Hereditary
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Huntington’s Disease Hereditary non-progressive chorea Neuroacanthocytosis Wilson’s disease Ataxia telangiectasia Lesch–Nyhan Syndrome Hallervorden–Spatz Disease (PANK-2) Pelezuis Merzbacher disease Paroxysmal kinesogenic choreoathetosis DRPLA Familial abetalipoproteinemia Aceruloplasmalemia Abetalipoproteinemia DHL 1 (Huntington like acanthocytosis) Alzheimer’s (late) Ferritonapthy
Infectious/Immunologic/Hematologic
1. Sydenham chorea 2. Encephalitis 3. SLE
4. 5. 6. 7. 8.
Behçet’s disease Subacute sclerosing pan encephalitis Lyme’s disease Neurosyphilis Polycythemia vera
Drug Induced
1. 2. 3. 4.
Levodopa D2 agonists Anti-convulsants (phenytoin) Neuroleptics
5. Metoclopramide 6. Steroids 7. Amphetamines
Metabolics/Endocrine/Toxins
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
Chorea gravidarum Hyperthyroidism/hypothyroidism Birth control pills (BCP) Hyperglycemia nonketotic encephalopathy Hypoparathyroidism Hypo or hypercalcemia Hypernatremia Renal failure Mercury poisoning Carbon monoxide poisoning Cocaine “crack dancing”
Vascular
1. 2. 3. 4. 5.
Hemichorea/hemiballism (STN lesion) Periarteritis nodosa Polycythemia vera Primary cardiolipin syndrome Congophilic angiopathy
Other
1. Senile chorea 2. Essential chorea
3. Paraneoplastic striatal encephalitis
Neuroacanthocytosis
A. General characteristics: 1. Molecular basis of chorea-acanthocytosis: a. Chromosome 9q21: VPS1 13 A gene b. Two splice variants are formed the longer variant of which is associated with chorea c. AD chorea acanthocytosis: 1) JPH3; an expansion of CTG/CAG repeats within the junctophilin 3 gene in chromosome 16 q 24.3 d. Rare acanthocytosis noted in Hallervorden–Spatz disease; PANK 2 gene B. Clinical features: 1. Mean age of onset (32 and range 8–62 years of age) 2. Major movement disorder is chorea 3. Progressive disorder
Chapter 2. Hyperkinetic Disorders
4. Other movement abnormalities include: a. Chorea most prominent sign b. Dystonia (lingual action dystonia) c. Tics (motor and phonic) d. Parkinsonism (akinetic rigid) e. Initial lip and tongue biting 5. Associated features: a. Cognitive decline b. Psychiatric disturbances c. Dysphagia (secondary to oral facial lingual dystonic movements) d. Dysarthria e. Seizures (grand mal usually) occur in 50% of patients f. Vertical ophthalmoparesis g. Amyotrophy of extremities h. Axonal neuropathy i. Absent reflexes 6. Genetically heterogeneous: some patients have associated: a. Abetalipoproteinemia b. McLeod Syndrome
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1. CTG/CAG repeat expansion within the junctophilin gene (JPH3) on chromosome 16 q 24.3 repeats that are pathologic are 41–58 2. Junctophilin-3 the encoded protein may regulate calcium and appears to be important in membrane structure B. Clinical features: 1. Onset occurs in the third to fourth decades 2. May present with chorea or Parkinsonism 3. Frequent dystonia 4. Feeding dystonia or oral facial dyskinesia with mutilation are not prominent 5. No multisystem organ involvement 6. Frontal subcortical dementia is prominent C. MRI evaluation: 1. Generalized atrophy of the basal ganglia 2. Advanced cortical atrophy (some patients) 3. White matter changes in several case reports D. Pathology 1. Striatal atrophy 2. Putamen and globus pallidus are involved
McLeod Syndrome
Familial Hypobetalipoproteinemia Type 1
A. General characteristics: 1. Male carriers of the McLeod blood group B. Clinical features: 1. Onset between 18–61 years (mean of 35 years) 2. One third present with choreatic movements 3. 20% present with seizures and 40% develop them during the course of the illness 4. Differential point between chorea acanthocytosis and the McLeod syndrome: a. Less or no lip or tongue biting or branchial symptoms and involuntary in salivation in the McLeod syndrome 5. Absent deep tendon reflexes 6. 50% develop muscle weakness 7. Frequent dilated cardiomyopathy 8. 1/3 of patients have non-symptomatic hepatosplenomegaly 9. Frontal subcortical dementia is seen C. Laboratory evaluation: 1. Elevated CK level up to 4000 units 2. No specific immunohistochemistry staining for XK and Kell antigens of the sarcoplasmic membranes 3. Erythrocyte acanthocytosis with compensated hemolysis
A. General characteristics: 1. AD: a. FHBL2 gene on chromosome 3p 22–p 22.1 2. Obligate heterozygotes for FHB1 have hypocholesterolemia but no neurological deficits 3. Majority of familial hypobetalipoproteinemia patients have no known gene defect 4. Fat malabsorption occurs due to absent apolipoprotein B and inability to form chylomicrons 5. Neurologic disease is secondary to vitamin E deficiency B. Clinical features: 1. Acanthocytosis 2. Retinitis pigmentosa 3. Dorsal column degeneration 4. Proximal myopathy 5. Fat malabsorption 6. Decreased cholesterol levels
Huntington’s Disease (HD Like 2 Acanthocytosis)
A. General characteristics:
Abetalipoproteinemia (Bassen Kornzweig Disease)
A. General characteristics: 1. AR: a. Enzyme encoded is microsomal triglyceride transfer protein B. Clinical features: 1. Progressive neuropathy (large fiber) 2. Proximal myopathy
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SECTION XIV. Basal Ganglia and Movement Disorders
3. Dorsal column dysfunction; loss of vibration and deep tendon reflexes 4. Ataxia 5. Decreased cognition in approximately 1/3 of patients 6. Decreased [18F fluro] fluorodopa uptake in the putamen cell membrane and caudate nuclei 7. RBC acanthocytes: a. Decreased fluidity of the red blood cell membrane b. Altered lipid composition
Genetic Differential Diagnosis of Neuroacanthocytosis that Demonstrate Chorea
1. 2. 3. 4. 5. 6. 7.
HD (adult); AD; IT 15 gene HDL 1 – AD; PRNP gene HDL2 – AD; JPH3 – gene HDL 4 – AD; ? – gene one patient SCA 3 – AD; 14; FTL 1 gene SCA 17 – AD – TBP gene DRPLA – AD – DRPL gene
1. AR or X-link recessive a. Gene possibly involved in iron sequestrations B. Clinical features: 1. May present with ataxia 2. Evolves to basal ganglia features suggestive of Hallervorden Spatz disease
HARP (Hypoprebetalipoprotemia)
A. General characteristics: 1. Part of the pantothenate kinase spectrum of disease 2. Homozygous nonsense mutation in the PANK 2 gene B. Clinical features: 1. Hyperprebetalipoproteinemia 2. Retinitis pigmentosa 3. Pallidal degeneration with a clinical spectrum similar to patients with PANK 2
Hereditary Aceuroplasminemia
Neuro ferritinopathy – AD – FTL (ferritin light chain gene) Benign hereditary chorea – AD – TITF Wilson’s disease – AR; ATP71 Hallervorden – Spatz – AR; PANK2 gene Karak syndrome – AR; X-gene McLeod Syndrome – X – XK, X gene Lubag (Filipino dystonia Parkinsonism – X; DYT3 Lesch-Nyhan Syndrome – X; HPRT gene Chorea acanthocytosis – AR; VPS 13 gene HARP – Part of the PANK-2 spectrum of disease Unusual Disease with Chorea as a Manifestation
Neuroferritinopathy (Adult Onset Basal Ganglial Disease)
A. General characteristics: 1. AD 2. Mutation of the ferritin light chain gene; affects protein folding and stability 3. Mutations B. Clinical features: 1. Onset in the third to sixth decade 2. Spectrum of presentation: a. Chorea c. Akinetic rigid syndrome b. Dystonia C. Pathology: 1. Ferritin and iron precipitates in the basal ganglia
Karak Syndrome
A. General characteristics:
A. General characteristics: 1. AR; loss of function mutation in the ceruloplasmin gene 2. Ceruloplasmin function: a. Rate of iron flux from CNS and systemic cells 3. Hepatic iron accumulation 4. Increased iron stores in hepatocytes, reticuloendothelial cells 5. Beta cells of the pancreas are affected with consequent diabetes mellitus B. Clinical features: 1. Present in adult hood 4. Dementia 2. Peripheral retinal degeneration 5. Dysarthria 3. Dystonia C. Laboratory evaluation: 1. Microcytic anemia 2. Elevated serum ferritin 3. Absence of serum ceruloplasmin ferroxidase D. MRI evaluation: 1. Increased Fe++ noted in the basal ganglia (decreased signal on T2 weighted images) 2. Involvement of the cerebral cortex
Lesch Nyhan Syndrome (HPRT)
A. General characteristics: 1. X-linked; deficiency of hypoxanthine-phosphoribosyl transferase 2. Kelly Seqniller variant a. Hyperuricemia with no CNS signs
Chapter 2. Hyperkinetic Disorders
B. Clinical features: 1. Choreoathetosis 2. Biting of the lower lip 3. Spasticity C. Laboratory evaluation: 1. Hyperuricemia
4. Mental retardation 5. Nephrolithiasis
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1. Chorea may involve contralateral part of the body and spare the face 2. Usually seen in middle aged patients 3. Abrupt onset C. Pathology: 1. Hemorrhage 3. Complication of thalamotomy 2. Tumor (rare)
Benign Hereditary Chorea Chorea Of Cardiac Surgery (Post Pump Chorea)
A. General characteristics: 1. Chromosome 14q B. Clinical features: 1. Early childhood onset 2. Most severe symptoms occur in the second decade 3. Does not progress after adolescence 4. Normal life expectancy 5. Some improvement with age 6. Distal extremities are affected
Dentato-Rubral-Pallidal Atrophy (DRPLA)
A. General characteristics: 1. Autosomal dominant; most prevalent in Japan 2. Haw River Disease in southern USA 3. CAG repeat; overlap with SCA 15 and 17 SCA locus: a. Expanded trinucleotide repeat of the coding region of the gene which translate polyglutamine stitches that cause: 1) Nuclear aggregates B. Clinical features: 1. Age of onset is the fourth decade (may range from second to seventh): a. Early onset form: 1) Myoclonus, epilepsy, mental retardation b. Late onset: 1) Ataxia, choreoathetosis, dementia, parkinsonism 2) Dystonia 3) Postural kinetic and intention tremor C. Pathology: 1. Atrophy of globus pallidus, subthalamic nuclei, substantia nigra, inferior olive and thalamus 2. Cerebral white matter involvement (one patient) 3. Corneal endothelial cell loss
Hemichorea
A. General characteristics: 1. Structural lesions of the contralateral subthalamic nucleus, thalamus, or caudate nucleus 2. May be on the spectrum of hemiballism B. Clinical features:
A. General characteristics: 1. Usually seen in children 2. Risk factors: a. Prolonged pump time b. Circulatory arrest
c. Deep hypothermia
Choreoathetoid Encephalopathy After Cardiac Surgery
A. General characteristics: 1. Seen after congenital heart surgery 2. Possibly due to vasoconstriction of the cerebral circulation (due to alkalosis during re-warming) B. Clinical features: 1. Choreoathetosis 3. Hypotonia 2. Oro-facial dyskinesias 4. Pseudobulbar palsy
Sydenham’s Chorea
A. General characteristics: 1. Following streptococcal infection with consequent rheumatic fever and heart valve involvement. Mitral > aortic 2. Familial tendency 3. Rarely occurs without heart disease 4. Adult recrudescence: a. Associated with increased anti-streptolysin titer (ASO titer) b. Jaccoud’s arthritis (adults) c. Generalized chorea 5. May resolve spontaneously in 3–6 months B. Clinical features: 1. Behavioral abnormalities (hyperactivity) 2. “Milk maids” hands; inability to sustain a movement 3. Incoordination 4. May have a grad mal onset: a. Usually begins abruptly (worsening over 2–4 weeks) 5. Quick semi purposeful movements: a. Jerking movements of the arms and legs b. Decreased ability to walk c. Involuntary movements of facial musculature with dysarthria
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SECTION XIV. Basal Ganglia and Movement Disorders
6. “Warner” hand a. Flexed wrist; extended fingers 7. Chorea may recur: a. First time during pregnancy (chorea gravidarum) b. While taking oral contraceptives 8. Primarily distal extremities involved 9. Choreiform tongue movements
3. 4. 5. 6. 7.
b. Diazepam drug of choice Hypoparathyroidism Perinatal encephalopathy Basal ganglia calcification Infantile hemiplegia Head trauma
8. 9. 10. 11.
Thyrotoxicosis HIV infection Anoxia Brain tumor
Variants of Kinesigenic Dyskinesia Paroxysmal Kinesigenic Dyskinesia (Paroxysmal Kinesigenic Choreoathetosis)
A. General characteristics: 1. AD; several loci; chromosome 1 p and 2 q 2. Some family members may have infantile convulsions B. Clinical features: 1. Attacks initiated by sudden movement or startle; last seconds to minutes 2. Hyperventilation may induce attacks 3. Movements may be preceded by paresthesias, crawling sensations or anxiety 4. Movements consist of dystonic posture, ballism, chorea, athetosis or various combinations 5. May affect speech and cause falls 6. Movements habituate 7. Acquired etiologies: a. Head trauma b. Demyelinating disease c. PSP d. Putaminal and thalamic infarction e. Hypoparathyroidism with basal ganglia calcifications f. Hyperglycemia g. Vascular malformation 8. Respond (90%) to anticonvulsants
A. General characteristics: 1. Paroxysmal exertion induced dyskinesia B. Clinical features: 1. Induced by prolonged exercise 2. Legs affected greater than arms
Paroxysmal Hypnogenic Dyskinesia
A. Clinical features: 1. Involuntary movements only occur during sleep
SCA 7
A. General characteristics: 1. AD B. Clinical features: 1. Myokymia 2. Nystagmus 3. Extraocular muscle dysfunction 4. Vertigo 5. Ataxia and tremor
Chorea in SLE Paroxysmal Non-Kinesigenic Dyskinesia (Paroxysmal Dystonic Choreoathetosis)
A. General characteristics: 1. AD; chromosome 2 q 26–31; calcium channelopathy B. Clinical features: 1. Attacks last minutes to hours 2. Occur spontaneously at rest 3. Dystonia, chorea, athetosis, ballism and speech arrest; combinations of these movements may occur 4. Preceded by paresthesias, stiffness and occasionally formications 5. Triggered by stress, fatigue, caffeine, alcohol 6. Frequency is less than PKC C. Pathology: 1. Familial 2. Some patients linked to chromosome 2 q: a. Migraine prevalent in these patients
A. General characteristics: 1. Occurs in 20% of SLE patients 2. Often associated with the SLE anticoagulant B. Clinical features: 1. Appears in younger patients 2. Lasts days to years 3. May be sole manifestation of the disease 4. Episodic
Chorea Gravidarum
A. General characteristics: 1. Usually starts after six weeks of pregnancy 2. May recur with each pregnancy 3. May be triggered by birth control pills in those that have chorea in pregnancy
Chapter 2. Hyperkinetic Disorders Senile Chorea
A. General characteristics: 1. Choreic movements begin insidiously 2. Mild signs; involve the limbs 3. Rare, lingual facial movements 4. Slow progression
Tardive Dyskinesia
A. General characteristics: 1. Usual cause is dopamine receptor antagonists or neuroleptic medication 2. Most common drugs: a. Metoclopramide d. Amitriptyline b. Amoxapine e. Stelazine c. Perphenazine f. Promethazine 3. Dopamine receptor dysfunction in the motor loop that synapses in the face area of the putamen may be causative 4. Abnormal movements occur: a. During drug treatment c. May be permanent b. After drug withdrawal 5. Usually 3 months of exposure is required 6. Exacerbation of movements may occur with drug withdrawal; increasing the dose may dampen movements B. Clinical features: 1. Orofacial dyskinesia; the buccolingual masticatory syndrome (BLM): a. Rhythmical involuntary movements of the tongue, face, mouth or jaw b. Choreiform movements of the extremities c. Distal athetosis d. Abnormalities of gait, trunk and posture e. Axial dystonias: 1) Patients > 50 years of age 2) May coexist with buccal lingual masticatory (BLM) and choreoathetosis 3) Neck flexion and lordosis 4) Pelvic rocking and thrusting f. Respiratory dyskinesia with involuntary chest and diaphragmatic movements g. Often accompanied by tardive akathisia: 1) Inner compulsion to move 2) Restlessness 3) Uncomfortable sensations of the body as a whole or specific body parts h. Tardive dyskinesia variants: 1) Tardive dystonia: a) Accompanied by tardive akathesia or tardive dyskinesia b) Sustained and torsional movements c) Facial dystonia (blepharospasm) with or without facial grimacing
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d) Jaw deviations protrusion or sustained opening or jaw closure (striking in DYT3 or Lubag) e) Dystonic neck posturing (retrocollis) 2) Tardive dyskinesia variants: a) Generalized chorea d) Tardive dystonia b) Tardive akathisia e) Tardive myoclonus c) Tardive tics 3) Tardive dyskinesia accompaniments: a) Respiratory dyskinesia c) Pelvic thrusting b) Body rocking Differential Diagnosis of Tardive Dyskinesia
1. Tardive dyskinesia (TD) follows the long term use of all neuroleptic medication: a. Two years of use b. Some patients acquire the syndrome in six months c. Phenothiazines d. Butyrophenones e. Anti-emetic drugs 2. Schizophrenic patients (drug naïve): a. Stereotyped and repetitive movements b. Complex involuntary hyperkinetic dyskinesia c. Isolated tics 3. Orofacial dyskinesia in normal patients: a. Elderly b. Early senile dementia 4. Huntington’s disease: a. Protrusion of tongue is abnormal; it usually is normal in BLM 5. Wilson’s Disease 6. Withdrawal emergent dyskinesia: a. Usually seen in children b. Dyskinesias that occur transiently after withdrawal of neuroleptics 7. Unilateral striatal lesions may cause bilateral oral buccal dyskinesia
Abdominal Dyskinesia
A. General characteristics: 1. Continuous sinuous rhythmic movements of the abdominal wall Differential Diagnosis
1. Abdominal trauma 2. Propriospinal myoclonus 3. During emergent withdrawal from neuroleptics
Ballismus
A. General characteristics:
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SECTION XIV. Basal Ganglia and Movement Disorders
1. Rapid large amplitude flinging movements of an extremity 2. Proximal girdle muscles are primarily involved 3. At least 2/3 of the corpus Luysii or its efferents must be destroyed 4. Usual artery that is infarcted is the thalamoperforate artery from the P1 segment of the PCA. Infarction of the anterior choroidal artery (carotid) and the interpeduncular artery from the top of the basilar or posterior communicating artery may be causative. 5. Rarely ballismus may occur from striatal, cortical or thalamic lesions B. Clinical features: 1. Proximal limb girdle involvement 2. Face is usually spared 3. Sudden onset 4. Patients may restrain their arm under a belt or tie it down 5. Often associated with hemichorea particularly if there is a metabolic cause (hyperosmotic state) 6. Exhausting for patients; ceases during sleep 7. May be seen bilaterally 8. Ceases during sleep Differential Diagnosis
1. Ischemic infarct of the contralateral STN 2. hemorrhage of the basal ganglia; hypertensive or due to a vascular malformation 3. Rare causes: a. Abscess b. HIV c. Basal ganglia calcification d. Levodopa therapy e. Parkinson’s disease surgery f. head trauma g. Tuberculosis h. Demyelinating disease (ADEM > MS)
Akathisia
A. General characteristics: 1. Definition: the subjective sensation of restlessness associated with an inability to stay still. Movement relieves the sensation. B. Clinical features: 1. Complex stereotyped movements of the extremities and trunk 2. Shifting weight, crossing and uncrossing legs, rocking back and forth 3. Vocalizations; moaning, humming, or groaning 4. Acute akathisia occurs with initiation of medicine 5. Chronic treatment (tardive akathisia); increased by drug withdrawal 6. Movements are present throughout the day
Differential Diagnosis of Akathisia
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Dopamine antagonists Neuroleptic treatment Parkinsonism/Parkinson’s disease Post encephalitic Parkinsonism Tourette syndrome Huntington’s Disease Obsessive compulsive disease (OCD) Myriadit (jumping Frenchman of Quebec) TIC disorders Oromandibular dystonia
Differential Diagnosis of Orofacial Dyskinesia
Associated clinical signs: 1. Drug induced (primarily D2 antagonists): a. Levodopa (associated chorea) b. Triphenyl hexedine (dry mouth) c. Antihistamines (neck muscle dystonia) d. Stelazine (most potent by milligram) e. Tricyclic antidepressants (those with basic phenothiazine structure) 2. Huntington’s disease: a. Associated dementia and choreatic eye movements 3. Hepatocellular degeneration: a. Setting of chronic liver failure b. Dysarthria c. Falling backwards 4. Cerebellar infarction: a. PICA b. Salt and pepper facial pain 5. Edentulous patients: a. Multiple “rodent like” mouthing movements 6. Dystonia: a. Meige’s syndrome: 1) Dramatic associated blepharospasm b. Tardive dystonia: 1) Associated choreiform movements 7. Tics: a. Associated complex stereotyped extremity movements 8. Tremor: a. Up-down head tremor; slight side to side jaw tremor; a prominent chin tremor 9. ET (essential tumor) (side to side head tremor) 10. Cerebellar tremor of neck and jaw: a. Associated postural kinetic tremor of body > extremity intention tremor 11. Myoclonus (facial) 12. Hemifacial spasm: a. Large facial fasciculations b. Risus sardonicus branch of VIIth nerve may be first affected muscle 13. Myokymia: a. Seen around the soft tissues of the eye (often not evident)
Chapter 3. Dystonia
14. Facial nerve synkinesia: a. Jaw winking b. Mentalis muscle often most severely affected c. Deep ipsilateral nasolabial fold 15. Bruxism: a. Associated TMJ joint disease with atrophic masseter muscles 16. Epilepsia partialis continua: a. Thumb involvement at the same rhythm of eye blinking b. Cortical nystagmus to the contralateral side
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Differential Diagnosis of Athetosis
1. Congenital anoxia with bilateral damage ot the globus pallidus, red nucleus, mid brain tegmentum and descending periventricular corticospinal pathways 2. Kernicterus 3. Wilson’s Disease 4. Stroke or tumor that involves the striatum and spares the cortex 5. Severe recovered head trauma 6. Post anoxia from hanging
Pseudoathetosis Hemifacial Spasm
A. General characteristic: 1. Definition: brief irregular, clonic twitches that may build up to a sustained contracture of facial muscles that usually lasts for seconds, but may continue for minutes. B. Clinical features: 1. Movements may begin around the eye and later spread to the lower facial muscles 2. Persists in sleep 3. Approximately 15% of patients have bilateral involvement 4. Contractions are dyssynchronous 5. Rarely bilateral Differential Diagnosis of Hemifacial Spasm
1. Aberrant branch of AICA (or the artery itself) that intermittently compresses the VIIth nerve: a. Especially likely if the patient is aware of a postural trigger 2. Bell’s palsy 3. Neoplasm of the CPA angle 4. Cranial dystonia 5. Tic
Athetosis
A. General characteristics: 1. Definition: slow writhing involuntary large amplitude that primarily involve the distal extremity muscles. Facial and axial muscles may also be involved in severe cases. B. Clinical features: 1. Associated episodic hypertonic muscle contractions of affected muscle groups 2. Abnormal movements may be unilateral or bilateral 3. Often associated with facial grimacing and dysarthria 4. Mixed with chorea and dystonia
A. General characteristic: 1. “Finger playing” sinuous movements of the outstretched upper extremity fingers 2. Updrift 3. Proprioceptive deficits Differential Diagnosis of Pseudoathetosis
1. Large fiber 20–22 μm fiber (proprioceptive and vibratory sensation loss) 2. Large neuron dorsal root ganglion cell loss: a. Sjögren’s syndrome b. Cis-platinum c. Syphilis (dorsal root entry zone) d. Paraneoplastic e. Autoimmune (Richter’s variant of GBS) 3. Dorsal column and nuclear lesions: a. If from posterior medullary artery infarction there may be large flinging movements of the arms b. Loss of vibratory sense; the only other lesion that produces this is in the sensory thalamus (VPL)
Chapter 3 Dystonia A. General characteristic: 1. Definition: Slow, sustained involuntary movements and postures that involve both axial and proximal muscles 2. Predominant characteristics: a. Slow and axial-athetotic dystonia b. Superimposed involuntary jerks-myoclonic dystonia c. Dystonic postures: 1) Torticollis; tortipelvis 2) Scoliosis and lordosis 3) Dropped, inverted and plantar flexed foot d. Dystonic tremor:
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SECTION XIV. Basal Ganglia and Movement Disorders
1) Fast distal tremulous movements 3. Excessive cocontraction of antagonist muscles during a voluntary movement 4. Spreading contraction of muscles not needed for a specific movement 5. Spontaneous cocontraction of agonists and antagonist muscles
3) Intermediate forms 2. Secondary dystonias: a. Metabolic defects b. Presumed metabolic defects c. Neuronal degenerations d. Non-degenerative conditions e. Psychogenic dystonia
Distribution
Idiopathic Torsion Dystonia
1. 2. 3. 4.
A. General characteristics: 1. Genetics: a. AD; chromosome 9; ITD1 gene b. Reduced penetrance in non-Jews c. Single mutation d. Sporadic cases e. Incidence > 1/15000 persons B. Clinical features: 1. Begins as focal action dystonia 2. 15–70% chance to generalize 3. Usually plantar flexion and inversion of the foot while walking 4. 5–10 years to reach maximum disability 5. May stabilize and a few may improve; partial remissions occur 6. Different manifestations within the same family; some family members generalize while others remain focal
Generalized Segmental (two contiguous areas) Focal (one extremity or motor group) Multifocal (two or more body parts)
Clinical Features
1. Generalized dystonia is most often seen in young patients 2. Focal and segmental dystonia occurs in middle age to older patients 3. Muscle groups most frequently involved are: a. Orbicularis oculi d. Inverters of the foot b. Forearm flexors e. Sternocleidomastoid c. Wrist flexors 4. Specific movements are repetitive 5. Sensory tricks are common (early): a. Finger to one eye to block blepharospasm b. Finger to forehead to black torticollis 6. Action dystonia: a. Early in the course of the disease only the muscles that are used are affected b. Later dystonia spreads to other non-used groups c. Aggravated by specific activities
Dystonia by Etiology
1. Primary dystonia: a. Idiopathic torsion dystonia: 1) Hereditary 2) Sporadic b. Focal segmental, multifocal (including adult onset). 1) Cranial dystonia (oculo-oro-mandibular) 2) Spasmodic torticollis 3) Writer’s cramp 4) Spasmodic dysphonic 5) Musicians 6) Overuse syndromes c. Autosomal dominant alcohol responsive myoclonic dystonia d. Benign idiopathic dystonia of children e. Idiopathic paroxysmal dystonia: 1) Paroxysmal kinesogenic dystonia 2) Paroxysmal non-kinesogenic dystonia
Focal, Segmental or Multifocal Dystonia Spasmodic Torticollis
A. General characteristics: 1. Usually sternocleidomastoid mastoid and trapezius muscles are most affected; scalene muscles are affected early 2. More frequent in women than men 3. Tonic or clonic contracture of neck musculature: a. Fixed and spastic deviation of the head to an awkward position (retro, latero or enterocolic) 4. Named by the sternocleidomastoid muscle that contracts 5. Movements are jerky early in the course of the disease 6. Sensory tricks; touching the forehead, resting the back of the head on an object is effective in blocking the specific dystonia; effect lost with time 7. Pain and tension are noted in the absence of head turning 8. High incidence of postural tremor and essential tremor 9. Progresses for 5 years and then stabilizes; a minority regress
Chapter 3. Dystonia
10. Remissions (partial or full) occur myoclonus) HIV related (rare) Post infectious autoimmune disease (ADEM) Dialysis dysequilibrium syndrome Hypoglycemia (seizures more common) Hepatic failure (asterixis more frequent) Renal failure (common) Hyponatremia (lethargy myoclonus) Von-Ketotic hyperglycemia (segmental myoclonus is almost diagnostic) Multiple carboxylase deficiency Mitochondrial diseases (MERRF most common) Biotin deficiency (seizures predominate) Lance–Adams syndrome (postural kinetic tremor; tremor with intention predominate) Post traumatic (seizures; cognitive decline) Posthypoxic (Lance–Adams Syndrome; rubral tremor predominates) Heat stroke (DIC, cardiac and renal failure) Electric shock (cardiac arrest) CRPS supervenes if patient survives Tumor (nucleus gigantocellularis; rare) Herpes zoster (brainstem inflammation) Post thalamotomy (Voa, Vop, Vim, thalamic nuclei are involved) Mollaret’s triangle (dentato-olivary-rubral connections; interrupted by stroke) Celiac disease (peripheral neuropathy and myopathy predominate) Whipple disease (myoarrthymia of the jaw, with large joint arthritis and malabsorption syndrome are diagnostic) Paraneoplastic syndrome (neuropathy and cerebellar degeneration predominate)
Miscellaneous Toxins That Cause Myoclonus
1. Bismuth: a. Encephalopathy b. Myoclonus c. Anterior horn cell death with weakness and fasciculation d. Severe spongiosis of layer 5 of the motor cortex 2. Methylbromide (rash) 3. Mercury (concomitant cognitive cerebellar and basal ganglia disease)
Chapter 4. Myoclonus Categories of Processes Associated with Myoclonus in Adulthood
Marden Classification: 1. Physiologic 2. Essential myoclonus 3. Epileptic myoclonus 4. Components of seizures 5. Progressive myoclonic epilepsies 6. Secondary myoclonus 7. Ataxic syndromes 8. Basal ganglia diseases 9. Ataxias 10. Myoclonus with Dementia 11. Viral encephalitis 12. Metabolic abnormalities 13. Associated with toxins and drugs 14. Damage to the CNS
Asterixis (Negative Myoclonus)
A. General considerations: 1. Definition: sudden brief loss of postural tone usually in extension of the wrist and hand; may be elicited with flexion and abduction of the thighs 2. Related to dysfunction of the nucleus gigantocellularis of the brainstem 3. Bilateral asterixis: a. Usually metabolic in origin b. Bilateral structural lesions of the mid pons or mesencephalon 4. Unilateral asterixis: a. Metabolic or toxic process coexists with an underlying structural lesion of motor pathways. b. Described with lesions in: 1) Ventrolateral thalamus 2) Motor cortex and parietal lobe 3) Ipsilateral pons or medulla 4) Midbrain asterixis: a) Segmental drop attack Differential Diagnosis of Asterixis (negative myoclonus)
1. 2. 3. 4.
Hepatic failure Renal failure Respiratory failure Acidotic states: a. Diabetic ketoacidosis b. Poisoning (large anion gap) 5. Hyperosmolar states: a. Usually high blood sugar (1500–2000 mg%); nonketotic diabetic ketoacidosis b. Hyperlipidemia c. Renal failure
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Spinal Myoclonus
A. General considerations: 1. Definition: a. Repetitive myoclonic jerking of an extremity with flexor muscle predominance. Two basic types: 1) Simple segmental myoclonus 2) Propriospinal myoclonus B. Clinical features: 1. Simple segmental myoclonus are repetitive myoclonic movements of one extremity that may be rhythmical and differ slightly in amplitude and frequency. The myoclonus involves one or more adjacent segments Differential Diagnosis
1. 2. 3. 4. 5. 6. 7.
Hyperosmolar state (non-ketotic diabetic ketoacidosis) HZ infection Trauma Paraneoplastic syndromes HIV Spinal arteriovenous malformation Arteriography of thoracic intercostal arteries
Propriospinal Myoclonus
A. General considerations: 1. Definition: rhythmic or arrhythmic spontaneous or rarely stimulus sensitive flexion or extension of the axial muscles. There may be spread to the extremities, but not to cranially innervated muscles. 2. Neurophysiologic studies reveal: a. A characteristic pattern of order of recruitment. The myoclonic generators are mid thoracic segments which are followed by propagation up and down the spinal cord. b. Involved propriospinal fibers conduct at 3–11 meters/second Differential Diagnosis of Propriospinal Myoclonus
a. b. c. d. e. f.
Tumor Demyelinating disease Infection Spinal anesthesia Alpha interferon therapy (renal cell carcinoma) Cervical hemangioblastoma
Palatal Myoclonus
A. General considerations: 1. Rhythmic contractions usually 60–180/minute of the palate and pharyngeal innervated musculature. The palatal muscle contractions may occur with synchronous rhythmic movements of the ocular muscles, diaphragm, head and neck.
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SECTION XIV. Basal Ganglia and Movement Disorders
2. Persists in sleep 3. Usually caused by lesions of Mollaret’s triangle. These are projections between the red nucleus, inferior olive, and the dentate nucleus. 4. Inferior olivary nucleus appears to be the generator Differential Diagnosis of Palatal Myoclonus
a. Rarely from cortical lesions b. Epilepsia partialis continua (similar) c. Vascular (vertebral artery)
d. Traumatic e. Neoplastic f. Demyelinating
Rhythmic Palatal Myoclonus
A. General considerations: 1. Marked division into symptomatic and essential forms Symptomatic Palatal Myoclonus B. Clinical features: 1. Onset fourth to sixth decade 2. Males > females 3. Frequency of 107–164 cycles/minute 4. May present with ear click 5. Does not cease with sleep 6. Persists for life 7. Extra palatal involvement 8. Due to levator palatini contraction C. Pathology: 1. Hypertrophied inferior olivary nucleus 2. Cerebellar or brainstem disease (vascular most often)
Essential Rhythmic Palatal Myoclonus
A. Clinical features: 1. 26–420 cycle/minute 2. Not associated with structural brainstem or cerebellar pathology 3. Equal in males and females 4. Onset second to fourth decades 5. Presents with ear click (eustachian tube movement either when opposed or when breaking the surface tension when opening) 6. Not associated with nystagmus or extremity tremor 7. Remissions may occur 8. May or may not remit during sleep 9. Due to tensor veli palatini contractions
Oculopalatal Myoclonus
A. General considerations: 1. Oculopalatal myoclonus is often seen in conjunction with a vertical one and one half syndrome that involves the VIIth nerve:
a. Lateral Variant: 1) Jerky oblique, torsional and rotary nystagmoid components associated with lateral palatal myoclonus b. Midline variant: 1) Vertical pendular eye movements (equal superior and inferior displacement without pause) 2) Associated symmetrical bilateral palatal myoclonus Lingual Myoclonus: a. Occurs with Arnold Chiari malformations
Chapter 5 Tic Disorders A. General considerations: 1. Definition: repetitive intermittent stereotypic movements that include the following features: a. Sudden and rapid b. Predominantly clonic c. Temporarily suppressible for variable lengths of time d. Preceded by a strong urge to make the specific movement e. Spectrum of tics: 1) Simple blinks or jerks 2) Complex coordinated movements and vocalizations 3) Clonic 4) Choreic 5) Dystonic B. Clinical features: 1. Simple tic: one group of muscles is involved 2. Often start around the eyes or mouth and then spread to the neck; shoulders or generalize. 3. Consist of: a. Eye blinking c. Jerking extension of the head b. Nose twitch d. Shoulder shrug 4. Complex tics: a. A stereotypic series of movements that involve different groups of muscles; a coordinated sequence of movements. b. Neck turning, snorting and hand movements c. Linguistically meaningful utterances 5. Chronic tic 6. Tonic or dystonic tic: a. Slower in onset b. Prolonged 7. Vocal tics: a. Motor tics that involve respiratory, laryngeal, pharyngeal, oral and nasal musculature b. Complex vocalizations: 1) Coprolalia 2) Echolalia
Chapter 6. Miscellaneous Movement Disorders Differential Diagnosis of Tic Disorders
1. Drugs: a. Levodopa d. Phenytoin b. Neuroleptics e. Lamotrigine c. Carbamazepine f. Phenobarbital 2. Basal ganglia diseases: a. Neuroacanthocytosis b. Encephalitis lethargica c. Vascular disease d. Carbon monoxide poisoning e. Carbon disulfide poisoning f. Trauma g. Gilles de la Tourette syndrome h. Obsessive compulsive disorders
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2. Some patients suffer a clear peripheral neuropathy or radiculopathy 3. May occur in the fingers B. Clinical features: 1. Continual flexion-extension of the toes; usually unilateral, but may be bilateral 2. Sinusoidal pattern that persists in and may alter sleep 3. Deep pain of a boring nature (deep muscle pain afferents) in the affected extremity; not dermatomal or restricted to a nerve distribution. 4. Similar clinical constellation occurs in the fingers and arm 5. Normal neurological examination in both those with chronic moving toe and fingers
Gilles de la Tourette Syndrome (GTS)
Restless Leg Syndrome (Ekbom’s Syndrome)
A. General considerations: 1. Genetics: AD; bilinear or polygenic 2. Prevalence between 1–10 per ten thousand children B. Clinical features: 1. Childhood onset; prior to age 22 2. Simple or complex motor tics 3. Vocalizations: a. Sniffing, throat clearing, spitting 4. Complicated motor activity: a. Jumping, kicking, bizarre gait 5. Coprolalia (obscene language) 6. Copropraxia (obscene gesturing) 7. Severe Gilles de la Tourette (GTS): a. Elaborate sequential multiple complex movements b. Echolalia and coprolalia 8. Mild GTS: a. Tics are primarily in the face b. Minor vocalization C. Associated disorders: 1. Attention deficit hyperactivity disorder 2. Obsessive compulsive disorders 3. Behavior disorders D. Pathology: 1. Atrophy of caudate and putamen (versus congenital smallness)
A. General considerations: 1. Family history in some patients 2. Dopaminergic mechanism is possible B. Clinical features: 1. Criteria for diagnosis: a. Irresistible urge to move the legs associated with paraesthesias and dysesthesias b. Motor restlessness c. Increased by rest and relieved by motor activity d. Increased symptoms in the late evening and night 2. Approximately 50% of patients have arm restlessness 3. Associated pain is non-dermatomal or in a peripheral nerve distribution 4. Associated myoclonic jerks or sustained dystonic postures may be associated 5. A large percentage of patients suffer periodic leg movements of sleep: a. Flexor contractions of one or both legs b. Dorsiflexion of the foot and flexion of the knee c. Occur at 20 second intervals in stage I or II of nonREM sleep 6. Associated medical conditions with RLS: a. Degenerative spine disease b. Dopaminergic deficiency c. Deficits of iron metabolism d. Chronic obstructive lung disease e. Vitamin deficiency f. Diabetes mellitus g. Pregnancy h. Uremia i. Malabsorption syndromes j. Cancer k. Amyloid 7. Rare Associations: a. Multiple sclerosis b. Atlantoaxial dislocation
Chapter 6 Miscellaneous Movement Disorders
Moving Toe Syndrome
A. General considerations: 1. Possibly a basal ganglia disorder
SECTION XIV. Basal Ganglia and Movement Disorders
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8. Associated medical conditions movement of sleep: a. Isaac’s syndrome d. b. Motor neuron disease e. c. Demyelinating disease f.
with periodic limb Spinal cord injury Spinal anesthesia Syringomyelia
Multiple Patterns of Movement Disorder in One Patient
Parkinson’s disease: Parkinsonism, choreoathetosis, dystonia, myoclonus Huntington’s Disease: Choreoathetosis, parkinsonism, myoclonus, dystonia Hallervorden–Spatz (PANK-2): Parkinsonism, myoclonus choreoathetosis, dystonia Wilson’s Disease: Ataxia choreoathetosis, parkinsonism, myoclonus, dystonia Neuroacanthocytosis: Tics, parkinsonism, dystonia, ataxia, myoclonus choreoathetosis
Hyperekplexia
A. General characteristics: 1. AD in most instances; mutations in the GLRA1 gene; chromosome 5q33–35: a. Encodes the alpha 1 subunit of the glycine receptor B. Clinical features: 1. Onset in the neonatal period 2. Abnormal startle reaction elicited by: a. Auditory and somatosensory stimuli b. Transitory stiffness during the neonatal period c. Affected neonates have died with generalized muscular stiffness 3. Adult patients: a. Falling, attacks accompanied by momentary generalized muscle stiffness 4. Reduced startle response occurs in PSP and Parkinson’s disease 5. Coffin-Lowry syndrome: a. Sound startle induced drop attacks b. May have several types of movement disorders that include cataplexy, drop attacks, prolonged tonic reaction
Chapter 7 Differential Diagnosis of Hyperkinetic Movement Disorders
The hyperkinetic movement disorders are the choreas, myoclonic diseases, ballisms, dystonias, tics and those seen with
sleep. The difficulty is not distinguishing the categories, but correctly diagnosing the entitles within a specific category. Huntington’s disease is probably the most common of the choreas that will be encountered. The severity of the dementia, choreatic eye movements and lurching gait are dramatic. Family history is sometimes hard to get, but when obtained, it is clear that this is AD. Sydenham’s chorea is not hard to diagnose in childhood. As an adult, it may be associated with old rheumatic heart diseases, is often familial, and may not have an antibody response to streptococcus. Rarely, it is associated in an adult with Jaccoud’s arthritis. Benign familial chorea is not associated with cognitive decline and has a normal life span. Medications, particularly D2 agonists, anticonvulsants, steroids and neuroleptics, cause chorea. “Crack dancing” is becoming a craze. Patients that have chorea on birth control pills often get it during pregnancy. As noted earlier, many systemic diseases, particularly SLE, hyperthyroidism as well as metabolic derangements such as renal failure are associated with chorea. Recent post pump chorea and CHAP syndrome (choreoathetosis; orofacial dyskinesis, hypotonia and pseudobulbar palsy) declare themselves by the circumstances. Hereditary diseases in which chorea may be a component of the symptom complex all have striking seminal features are: Niemann Pick type 2C (failure of vertical gaze), Pelizaeus, Merzbacher (nystagmus), Wilson’s disease (Kayser–Fleischer ring) Lesch–Nyhan syndrome (mutilated lower lip), ataxia telangiectasia (ataxia and scleral telangiectasia) the mitochondrial encephalopathies (hearing loss, short stature, cardiomyopathy) and paroxysmal kinesogenic choreoathetosis (chorea and dystonia). Neuroacanthocytosis (Huntington disease like-2), familial abetalipoproteinemia, ferritinopathy and Bassen Kornzweig) all have a complex of akinetic rigid features, tic, seizures, and rarely vertical gaze deficits. DRPLA also has a gamut of other movement dysfunctions (seizures, dementia, and myoclonus) as well as acanthocytes on blood smear. Hemichorea most often is seen with congenital disease of the striatum (severe hemiplegia) with atrophy of the affected side. Infarction of the thalamus (thalamoperforate artery), trauma, post ViM thalamotomy for tremor, hemorrhages and tumor are causative. Hemiballismus is an instant diagnosis. The proximal flailing movements require the arm to be tied down. Usually, it is secondary to infarction of the interpeduncular artery from the top of the basilar artery or the thalamoperforate artery. Tardive dyskinesias almost always have an oral lingual buccal component. The extremities, axial musculature and diaphragm may develop rhythmic movements over time. Akathisia, dystonic sustained movements (tardive dystonia) as well as facial dystonia, blepharospasm, mandibular dystonia and neck dystonia occur. Neuroleptic induced oculogyric crisis, myoclonus and tremors occur.
Chapter 7. Differential Diagnosis of Hyperkinetic Movement Disorders
Abdominal dyskinesias usually occur after trauma and may be difficult to distinguish from propriospinal myoclonus. The clue is surgery in the former and progressive waves of spreading myoclonus in the latter. Athetosis is immediately recognized by its slow, sinuous writhing quality that primarily affects distal musculature. Pseudoathetosis is an updrift of the extremities with sinuous finger piano playing movements. It is usually seen in the context of congential stroke, birth trauma, anoxia, kernicterus or Wilson’s disease. The dystonias are easily diagnosed because of the obvious abnormally held posture. The features that are peculiar to the diagnosis are sensory “tricks” dystonic spasms, and peculiar stereotyped maintained postures (dropped plantar flexed and inverted foot, retrocollis or torticollis). Dystonic spasms and tremors may be confusing. The dystonia of chronic regional pain syndrome (CRPS) is very common, often associated with severe allodynia. It may occur without pain. It is invariably misdiagnosed. Movement specific, athletic and musicians’ dystonia are easily diagnosed by the specific initiating movement. Possibly a re-wiring of the motor cortex or incorrect programing by the SMA or PMC of the intended movement. Continued input to the brain changes functional glucose metabolism of the active area of the homunculus. Rarely, peripheral surgery such as discectomy in the neck causes axon rewiring or ephaptic conduction such that intended extension of the wrist results in hand flexion. Spasmodic dysphonia is differentiated from lesions of components of the Xth nerve by its intermittent nature. These patients also demonstrate other neurologic abnormalities such as tremor. The paroxysmal dyskinesias cannot be missed as a group due to their spectacular onset. Paroxysmal kinesigenic dyskinesias is composed of chorea athetosis, ballism and dystonic postures. Interruption of speech as well as frequent falls may be confusing. The attacks usually last for seconds to minutes. Spontaneous paroxysmal non-kinesigenic dyskinesia are not initiated by movement and last from minutes to hours. They are similar to kinesigenic dyskinesia, but are triggered by stress, alcohol and caffeine. Specific paroxysmal dyskinesias are easily defined by initiating triggers such as sleep, or exercise, and whether they are short lasting (less than five minutes) or long lasting (greater than five minutes). Paroxysmal ataxia and tremor has been designated as a spinocerebellar degeneration (SCA 7). It is likely that these paroxysmal disorders will be defined as channelopathies. The differential diagnosis of myoclonus is wide and the setting in which it occurs most often determines the diagnosis. Hospital settings suggest metabolic or toxic etiologies. Renal failure and post dialysis-states often are accompanied by
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intention myoclonus. Hyperosmolar states from non-ketotic hyperglycemia often is segmental. Myoclonus with hepatic insufficiency is accompanied by asterixis, lethargy and hyperreflexia. Mitochondrial diseases and myoclonus should always be expected in a short patient with deafness, fatigue with exercise and cardiomyopathy. The Lance–Adams syndrome of post hypoxic myoclonus should be expected following resuscitation from cardiac arrest or any anoxic state. The intention and postural kinetic components of the syndrome are seminal. Most poisonings are accompanied by nausea, vomiting, and a large anion gap with a large and long fiber neuropathy. The hereditary progressive myoclonic epilepsies are rare, dementia predominates. Neuronal ceroid lipofuscinosis and Lafora body disease are most often seen in adults. Visual hallucinations and occipital lobe symptomatology is seen in 50% of patients with Lafora body disease. Dementia and severe ataxia are the seminal features of Ramsay–Hunt syndrome. Myoclonus is a feature of all of the basal ganglia degenerations. Most present with akinetic rigid features. Low blood pressure and cold hands suggest MSA. Severe dysarthria, wing-beating tremor and a Kayser–Fleisher ring are pathognomonic of Wilson’s disease. The “eye of the tiger” sign cannot be missed in the globus pallidus by MRI in HallervordenSpatz disease (PANK-2). Rapid dementia with myoclonus in an adult is CreutzfeldtJacob disease until proven otherwise. The 14-3-3 protein and neuron specific enolase as well as a characteristic EEG support the diagnosis. Late severe Alzheimer’s disease may demonstrate myoclonus, but the loss of memory and cognitive impairment have made the diagnosis long before myoclonus is prominent. Both may have anterior cell involvement with fasciculations. Diffuse Lewy body disease may be associated with myoclonus, but visual hallucinations, transient loss of consciousness, falls and fluctuations in cognitive abilities are its most prominent characteristics. Palatal myoclonus cannot be missed if the palate is examined. Rhythmic contractions of the platysma muscle, clicking in the ears and ocular and diaphragmatic movements secure the diagnosis. Rhythmic palatal myoclonus has torsional and rotary nystagmus while in the midline form pendular nystagmus is noted. The spinocerebellar ataxias, particularly SCA3/Machado– Joseph disease have myoclonus as a component of the movement disorder. Bulging eyes and amyotrophy often are present. Propriospinal myoclonus is striking with axial and extremity arrhythmic jerks. The myoclonus of the abdomen is striking. Myoclonus diagnosed in the office is primarily a hereditary form, part of an ataxic syndrome or rarely a fragment of seizure activity.
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Section XV THE CEREBRAL CORTEX / BEHAVIORAL NEUROLOGY
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Chapter 1. The Left Frontal Lobe Introduction
1. Clinical anatomical correlation as well as functional studies with PET, SPECT, functional MRI and magnetoencephalography reveal that distributed networks form the anatomical basis of behavioral neurology. In essence, a lesion in varied areas of the brain may destroy a functional network which may cause a specific deficit. However, it is still clinically useful to assign major functions to specific anatomical areas of the brain with the understanding that this one area may be only one link in a distributed network. Diaschisis of Von Monakow is another concept that must be borne in mind when performing pathological, anatomical and clinical correlation. This concept suggests that the anatomical connections of a distributed network have metabolic and neurotransmitter concomitants, which may cause a neurological deficit at a distance from the injury. Discharge from one area of the brain if severe and persistent may damage either its homologous area or another part of the distributed network by: 1. Glutamate-NMDA excitotoxicity mechanism 2. Induction of apoptosis from intracellular calcium dysregulation 3. Neural plasticity induced by immediate early response genes Many anatomical pathological clinical correlates have withstood the test of time, but basic mechanisms have changed. Most external sensory information reaches the cortex through the thalamus. Autonomic and properties of the homeostatic condition of the body are projected from the brain stem and hypothalamus through the medial thalamic nuclei to the limbic cortex. These areas consist of medial temporal and insular cortices, orbital cortex and the cingulate gyrus. Specific areas of the reticular formation activate specific areas of the cortex.
Chapter 1 The Left Frontal Lobe Executive function, planning and proper behavioral choices given specific options are major functions of the left frontal lobe. Broca’s aphasia and transcortical motor conduction aphasia occur with area 44 and superior Broca’s lesions. Immediately anterior to area 44 is the frontal operculum and the area triangularis. Lesions in this area cause a particular lack of facility with writing (out of proportion to hand weakness) and cortical negative variant grammatical mistakes. Various apraxias occur with frontal lobe lesions. An apraxia is the inability to perform an individual or sequential task with normal motor, sensory and coordinative abilities.
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A specific motor function is first conceived and is denoted as an engram. The electrophysiological correlate is the cortical negative. Variant these Bereitschaft (readiness) potentials are recorded over the prefrontal and supplementary motor cortices. This is then translated into the required movement. Disorganization of simple or sequential engrams are the core of apraxia. Various apraxias are seen with left frontal lobe lesions. These include ideomotor apraxia (engram encoded in area 6) in which there is inability to perform a single command such as saluting or using a comb. A patient with a colossal apraxia (right handed, left brain dominant) is unable to perform a simple task with the left hand. The command is decoded in Wernicke’s area and projects to the left premotor area, crosses the corpus callosum (anteriorly) to synapse in the right prefrontal area and then projects to the right precentral gyrus (which controls the left hand). If the patient does not perform as well, motorwise as he should for the consequences of his deficit (a lack of facility of the movement) this is a limb-kinetic apraxia. Patients with area 6 premotor lesions may suffer the anterior alien hand syndrome. This syndrome, also known as “inter manual conflict” is evident when one hand undoes the work of the other. A patient may put his glasses on with the right hand only to have them removed with the left. Patients may suffer acute mutism and severe orobuccolingual apraxia with bilateral frontal opercular lesions. These are usually caused by seriatim prefrontal branch strokes of the middle cerebral artery. Forced thinking, fatigue during the completion of a task, visual neglect to objects in the right hemi-field and directional hypokinesis may all occur with right premotor lesions. Constructional apraxia and perseveration, as well as failure of attentional mechanisms are also characteristic of left frontal deficits.
Left Frontal Lobe
Major Behavioral Deficits
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.
Poor planning Poor behavioral choices Poor executive function Broca’s aphasia Acute mutism Bilateral frontal opercular lesions – aphemia Alien hand (inter manual conflict) Callosal apraxia Ideomotor apraxia Limb kinetic apraxia – paracentral lobule Writing apraxia (Exner’s area) Eyelid opening apraxia Constructional apraxia Right directional apraxia (hypokinesis) Visual neglect of right hemispace
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SECTION XV. The Cerebral Cortex / Behavioral Neurology
16. Imitation-utilization behavior (environmental-dependency) 17. Undue fatigue during the completion of a task 18. Paratonia (inability to change position once the extremity is placed) 19. Gait apraxia Minor Behavioral Deficits
1. 2. 3. 4. 5.
Executing sequences Inability to follow consecutive hand movements Inability to copy facial movements Difficulty following multiple commands Inability to pair blink responses with voluntary saccades (the loop involved is from the posterior parietal cortex to the second the frontal convolution) 6. Echopraxia 7. Sitting apraxia
perform complex behavioral motor functions requiring multiple sequences. It is important in memory retrieval that is pivotal for working memory. The frontal eye fields are located in the DLPC which initiate saccadic eye movements and are important in ocular fixation. Prefrontal cortex dysfunction may present as a pseudodepressed syndrome manifesting psychomotor inhibition, apathy, indifference, lack of drive and decreased emotional reactivity.
DLPC (Major Behavioral Deficits)
1. Pseudodepression syndrome a. Psychomotor inhibition b. Apathy c. Indifference d. Lack of drive e. Decreased emotional reactivity
The Right Frontal Lobe Other Behavioral Deficits
The distributed functions of the right frontal lobe are most involved with emotional control and inhibitory control over the limbic system. Deficits in this lobe are associated with disinhibition of personal behavior, hygiene and sexual conduct. Patient’s demonstrate “witzelsucht” (inappropriate jocularity) and impersistence. 1. Disinhibition: a. Personal behavioral c. Sexual activity b. Hygiene 2. Inappropriate jocularity “witzelsucht” 3. Impersistence of a motor task 4. Neglect and directional hypokinesis of left hemispace 5. Stimulus familiarity and novelty abnormalities 6. False recognition syndrome with confabulation
Minor Right Frontal Lobe Deficits
1. Understanding and mediating negative emotions 2. Area 6 and 8 lesions are associated with simultanapraxia (inability to coordinate both sides of the body to accomplish a motor function) 3. Right frontal eye fields direct bilateral search of the visual landscape 4. Retrieving the temporal order of stimuli
Dorsolateral Prefrontal Cortex
The dorsolateral prefrontal cortex (DLPC) is important as a store of knowledge to solve problems of the immediate environment, to perform internally generated motor tasks and to
1. Obsessive-compulsive behavior 2. Ventromedial prefrontal: a. Aggressive violent behavior
General Deficits
1. 2. 3. 4. 5. 6.
Decreased procedural learning Decreased ability to index events in time Failure to develop internal references Parapraxia Working memory Deficits of awareness of near extrapersonal space a. Space that is within the grasp of the examiner 7. Switching motor programs 8. Abulia-telephone (response) 9. Post stroke depression: a. Severity of depression is related to the proximity of the lesion to the frontal pole 10. Release of approach behavior
SMA (Supplementary Motor Cortex)
The supplementary motor cortex is instrumental in coordinating the muscle activation of both sides of the body, speech, and the generation, temporal sequence and preparation of movements. 1. Aphasia (similar to Broca’s) 2. Motor function: a. Coordinating movements of both sides of the body during a task (walking; swing phase and stance phase)
Chapter 2. The Parietal Lobe
b. Generation of movement (important for designing engrams of movement) c. Temporal sequence of a motor task d. Entraining motor sequences e. Mirror movements (may be seen if damaged) f. Response to internal cues g. Priming (encoding of consciously inaccessible knowledge) h. Sequentially memory guided saccades
Orbitofrontal Cortex
1. Pseduo-psychopathic behavior: a. Disinhibition b. Facetiousness c. Sexual/personal behavior d. Lack of concern for the effects of behavior 2. Bilateral lesions cause retrograde amnesia 3. Failure to break previously learned associations 4. Medial orbital frontal lesions are associated with confabulation 5. Mania 6. Autonomic regulation of vagal tone
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General Parietal Lobe Sensory Function (Similar in Each Hemisphere)
1. Two-point discrimination 2. Localization of extremities and objects in near and far space (outside of the examiner’s grasp) 3. Graphesthesia 4. Stereognosis 5. Point localization 6. Perceptual rivalry of double simultaneous stimuli. Nonperception of the damaged side 7. Posterior parietal cortex a. Reaching 7a b. Grasping 7b 8. Anterior superior portion of the posterior parietal cortex a. Manipulation or active touch 9. Posterior superior parietal cortex a. Inability to utilize stereotopic vision for hand movements b. Optic apraxia (area 5) 10. Gesture representations: a. Bilateral ventral medial parietal lobe b. Inability to recognize objects (area 7) 11. Inferior parietal lobe a. Memory or recognition of spatial position 12. Medial parietal lobe-sense of direction (R > L) 13. Intraoral sensation (parietal operculum)
Chapter 2 Right Parietal Lobe
The Parietal Lobe
The parietal lobe is central to somatosensory function, awareness of personal and extrapersonal space, awareness of the body parts in space and their ability to function. Recently, it has been shown that there is a gravitational awareness In which the patient is aware of the relation between his body position to the vertical plane. This is known as the subjective visual vertical. Area of interest visual cells in the posterior parietal regions (7a) prime the frontal eye fields to focus on specific objects of interest. There is a “loathness” to move of the contralateral extremities following parietal lesions. The left parietal lobe is vital for reading, writing and receptive speech. Lesions of area 3b of SI (the primary parietal cortex or postcentral gyrus) cause the sensation of heaviness in the extremity and are the receptive areas for muscle spindles. Areas 3b and 1 information from cutaneous afferents that signal texture of a palpated object. Area 2 is for “shape” information and receives afferents from deep tissues (joints, fascia, tendons). Posterior thalamic areas as well as reticular nuclear afferents project to posterior insular cortex as well as SI and SII.
1. 2. 3. 4.
5. 6. 7. 8. 9. 10. 11.
12. 13.
Visuospatial processing Asomatognosia (denial of a body part) Denial of illness-assosoganosia Asimultagnosia: a. Inability to synthesize specific parts of an object into a whole (eyes, ears and nose, but patient cannot synthesize this into a face) Left visual inattention (neglect) Aprosody; flat speech without the proper intonations appropriate for the circumstances Constructional apraxia Dressing apraxia Pressure of speech Inability to judge the directional orientation of lines (right posterior parietal areas) Benton and Von Allen’s facial recognition test: a. Post rolandic areas b. Ability to discriminate unfamiliar faces A response to a question posed to an adjacent patient Right superior parietal cortex: a. Visual manual coordination b. Optic ataxia c. Landmark test; ability to judge a previously bisected line
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14. Gourmand Syndrome a. Eating disorder 15. Decreased short term memory 16. SII: asymbolia for pain: a. The whole body is represented (head dorsal and feet ventral) b. Sensation of heat that may envelop the entire body 17. Topographic disorientation-right medial parietal lobe 18. Topographic amnesia (inability to remember shape and locations) 19. Alloesthesia: a. Touch on the abnormal side is transferred to a homologous position on the normal side b. Impulse control disorder
are pivotal for registration and consolidation of short term memory. The temporal lobes are one of the anatomical substrates of personality in and of itself due to its anatomical projections to the limbic system and frontal lobe (uncinate fasciculus). Left Temporal Lobe
1. 2. 3. 4. 5.
Left Parietal Lobe Function
6.
1. Von Gerstmann syndrome: a. Right left confusion b. Inability to cross the midline c. Finger agnosia d. Conduction aphasia e. Dyslexia with or without agraphia 2. Bilateral deficits in point localization 3. Alexia without agraphia (area 39, 40, 41) 4. Conduction aphasia: a. Disconnection of Wernicke’s and Broca’s area b. Damage to the arcuate fasciculus 5. Inferior left posterior parietal lobule: a. Deficits in auditory verbal short term memory 6. Superior parietal lobule-appreciation of detail 7. Parieto-occipital junction – Balint’s Syndrome a. Deficit in visual scanning b. Optic ataxia (undershooting an object) c. Deficits of visual fixation (unable to break fixation) 8. Color anomia 9. Anomic aphasia (supramarginal gyrus) 10. Posterior alien hand (posterior parietal areas 5 and 7) 11. Ideational apraxia: a. Supramarginal gyrus b. Left superior lobule
7.
Chapter 3 The Temporal Lobe The temporal lobe’s distributed functions include receptive speech, particularly Wernicke’s area and the basal temporal language area. The inferior temporal gyrus is essential for object recognition while the middle temporal gyrus visual area is vital for recognition and tracking of moving objects. The dorsal parietal areas are most important for delineating interest and position of objects. Medial temporal lobe structures
8. 9. 10. 11.
Wernicke’s aphasia (area 22, 23) Rostral pole (proper name anomia) Sensory conduction aphasia Short term memory loss Basal temporal language area: a. Receptive speech/anomia b. Deficits in confrontational naming Color anomia: a. Medial temporal lobe b. Fusiform gyrus Temporal/occipital junction a. Dorsal 1) Pure Alexia Semantic memory: a. Left inferior temporal gyrus Superior temporal gyrus: a. Consolidation of memory Grammatical comprehension: a. Anterior temporal lobe Temporo-parietal junction: a. Object word naming
Right Temporal Lobe
1. Anterior temporal lobe: a. Anxiety/panic attacks 2. Amusia 3. Aprosody 4. Agitated delirium: a. Superior and middle temporal gyrus 5. Aura of hunger 6. Priming for memory 7. Non-verbal amnesia 8. Pathologic crying 9. Right hippocampus a. Non-verbal task processing: 1) Spatial information 2) Less readily verbalizable visual stimuli 10. Parahippocampal gyrus: a. Encoding of spatial information for long term storage Bitemporal Lobe Diseases
1. Klüver–Bucy Syndrome (KBS) a. Hypermetamorphopsia (all objects receive the same visual attention)
Chapter 4. The Occipital Lobe
b. c. d. e.
Hyperorality Hypersexuality Sham rage Severe memory deficits
Differential Diagnosis of Causes of KBS
1. 2. 3. 4. 5.
Herpes simplex Head trauma Radiation through the temporal lobes (pituitary tumors) Kindling from an opposite temporal focus Temporal lobectomy: a. The opposite side is defective
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Cingulate Gyrus
1. Anterior cingulated gyrus (area 24): a. Deficits in motivation b. Activated by movement (dorsal) c. Lesions may be associated with bradykinesia 2. Specific anterior cingulated gyrus functions: a. Selection of targets from competing inputs b. Divided attention c. Selection of action d. Modulates autonomic activity e. Generates internal emotional responses f. Integrates emotional and cognitive aspects of behavior
Amygdala
Posterior Cingulated Gyrus
1. Seizure (order of signs) a. Freezing response b. Pale (lack of emotional expression) c. Slow contralateral turning (may be ipsilateral turning as well) d. Automatism: 1) Smacking the lips or chewing 2. Medial nuclear group discharge: a. Ictal fear: 1) Abdominal location 2) Free-floating; cannot be linked with an expected or past event 3) Associated with excessive anxiety 4) Feeling of impending doom 3. Urbach–Wiethe disease (calcification of the amydala) a. Defective: 1) Processing of emotional facial expression 2) Emotional prosody 3) Emotional memory 4) Bilateral amydala damage: a. Impaired in processing fear in facial expressions b. Defective prosody b. Normal intelligence c. Calcification of the amydala bilaterally in 50% of patients
1. Learning and memory impairment 2. Activated with pain (right side)
Cingulate Gyrus
The cingulate gyrus is an integral component of the anterior limbic system which is composed of the mamillary bodies, the mamillothalamic tract, anteroventral thalamic nucleus and the hippocampus. It is involved in those conditions that affect the limbic system specifically such as herpes simplex infection, anti-Hu antibody mediated paraneoplastic encephalomyelitis and seizure disorders. It distributed functions are associated with attention, motivation, the effectual components of movements, and the “suffering” component of pain.
General Cingulate Signs
1. Tic disorders have been described with interruption of pathways to the orbitofrontal cortex 2. Obsessive compulsive behavior 3. Hemineglect of contralateral space
Chapter 4 The Occipital Lobe The occipital lobe is central to all aspects of vision. Knowledge of occipital lobe function has been meticulously accrued from elegant physiological and anatomical studies of primates which have been buttressed by clinicopathological correlations in patients and by recent functional imaging studies with PET, SPECT, functional MRI and electrophysiological studies. Stimulation of the calcarine cortex area 17 in awake patients produces noncolored, nonmoving flashes of light with occasional geometric designs. Stimulation more anteriorly in areas 18 and 19 produces moving, colored geometric figures in the contralateral visual field. Stimulation in areas of junction of the temporo/parietal/occipital cortex causes visual distortion, phosphenes, photopsia, complex visual hallucination and palinopsia. Occasionally a fixed visual hallucination may be seen or a positive bright yellow scotomata is noted with lesions in this area. Color naming many be lost with lesions of the fusiform gyrus and visual agnosia supervenes with bilateral lesions of the junction of the temporo/occipital cortex. Word blindness occurs with a left posterior cerebral artery occlusion that destroys the splenium of the corpus callosum.
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That isolates Wernicke’s area from the right occipital lobe (the left is infracted). Visual memory may be disturbed with lesions of the inferior longitudinal fasciculus such that visual images cannot be compared with prior images in hippocampal circuits. Metamorphopsia, unusual interest in all visual objects, occurs with lesions of the occipital-parietal cortex, optic radiations, chiasmatic, retrosplenial areas and with retinal lesions.
Cortical Blindness (Anton’s Syndrome)
These patients have suffered bilateral damage to both visual cortices and to the optic radiations. They have: (1) inability to see; (2) are euphoric; (3) have normal pupillary function; (4) deny blindness and confabulate vision. They may be able to move around a room without hitting large objects, possibly related to islands of preserved retinal rod vision. Pure Alexia
Disorders of Complex Visual Processing
Visual Agnosia
Visual agnosia is a disorder of higher behavior in which an alert, intelligent, non-aphasic patient with normal visual perception does not recognize a visual stimulus. Prosopagnosia
Prosopagnosia is a visual agnosia characterized by an inability to recognize previously known human faces and to learn new ones. Recognition through other sensory channels is intact. These patients are unable to recognize stimuli that belong to a group that have numerous subcomponents. Patients can perform generic recognition. They recognize the class to which a stimulus belongs but are unable to identify a specific member within the generic class. The defect lies in the appropriate evocation of contextual memory. Lesions associated with prosopagnosia beyond the acute stage are bilateral. They compromise either the inferior and or mesial visual association cortices of the lingual and fusiform gyrus or their adjacent white matter. They involve the equivalent portions of the central visual pathways in the left and right hemispheres, Split brain patients recognize faces normally when presented tachistoscopically to each hemisphere as do patients who have undergone right hemispherectomy. Most patients have suffered emboli to the distal branches of the posterior cerebral arteries which may occur at different times. Some patients have suffered bilateral tumor involvement. It has also been observed as an epileptic phenomenon. Visual Object Agnosia
These patients are unable to recognize the generic class to which an object belongs. A defect of visual naming is common as is alexia. Some patients with object agnosia may recognize the object when it is moved or rotated. These patients may complain of “unclear” or “blurred” vision, possibly related to a selective defect of low spatial frequency vision that impairs appreciation of static, low contrast stimuli. Moving, high contrast stimuli may be appreciated. Visual object agnosia patients have bilateral lesions in the ventral and mesial part of the occipital temporal visual areas that extend dorsally and laterally.
Alexia without agraphia or “word blindness” is a disorder of visual pattern recognition. These patients can copy what they cannot read, have normal visual acuity and have normal recognition of nonverbal visual stimuli. They are unable to evoke the appropriate associated material when confronted with words. The necessary lesions to cause the syndrome must disconnect both visual association cortices from the dominant language area. Lesions of the splenium of the corpus callosum cause interhemispheric disconnection and combined with a lesion of the left occipital cortex cause disconnection of visual associative cortex with the language area. A lesion in the tapetum, beneath and underneath the occipital horn, can disrupt both callosal and left visual association fibers and thus cause pure alexia. Patients may have alexia and visual agnosia with an additional right visual associative cortex lesion.
Disorders of Spatial and Topographic Orientation
These patients demonstrate an acquired inability to locate a familiar room in their house, a common public building, and are unable to utilize verbal direction to locate a specific place. This type of deficit may occur secondary to unilateral hemispatial neglect or from a global amnestic syndrome. These specific defects underlie a lack of visuospatial memory whereby the architectural or topographic detail cannot trigger the retrieval of stored memories that could be utilized to plan a route to the desired destination. Bilateral lesions of the inferior and superior visual association cortices especially the right occipital parietal areas cause this deficit. Patients with bilateral lesions of the superior and inferior visual cortices and those with prosopagnosia may have impaired ability to learn new topographic paradigms. Patients with unilateral or bilateral posterior visual association cortex lesions may be unable to identify cities on a map, to draw a state or country and suffer geographical orientation deficits.
Disorder of Color Perception
There are acquired disorders of color perception that involve all or part of the visual field with preservation of formed vision. Patients with central achromatopsia lose color vision in a portion or all of their visual field. They report the deficit as
Chapter 5. Arousal
a dulled or washed out but distinguishable color or as complete loss of color so that the patient only sees objects as black or white. Patients otherwise see accurately in the colorless portion of their visual field. Patients with full field achromatopia have impairment in portions of their visual field, visual agnosia, and blindness for form and vision in the remaining. A lesion of the left inferior occipitotemporal cortex may cause pure right hemiachromatopsia alexia from damage to intra and interhemispheric visual pathways within the left occipital cortex. These lesions often are embolic to the terminal branches of the posterior cerebral artery that supplies the fusiform and lingual gyri.
Disorders of Color Naming
These patients can match colors, but are unable to name them, but have no aphasia or defect of color perception. They have concomitant right homonymous hemianopia, intact color perception in the left field and pure alexia. The lesion responsible for this color naming defect is in the left hemisphere between the occipital and temporal lobe. The right homonymous deficit is a lesion in the geniculate body, optic radiation or visual cortex. Some patients demonstrate more difficulty in naming colors to confrontation than on pointing to them given their name (a “one way” defect). In general, disorders of hue and color perception are associated with prosopagnosia and those of color naming are associated with alexia and “word blindness”.
Disorders of Color Association
Some patients suffer the inability to associate a specific color with a specific object which is done easily by patients with an isolated color naming defect.
Disorders of Spatial Analysis
Balint’s Syndrome
These patients suffer defects of visual disorientation, optic ataxia, and ocular apraxia. Visual disorientation and optic ataxia can occur concomitantly with one of the other two components of the syndrome. Many patients have inferior quadrantic visual field defects. Balint’s syndrome is an acquired inability to perceive the visual field as a whole and to perform visually guided movements and shift gaze to new stimuli in the visual field. The patient most often sees only the macular component of the visual field, but even this fragment of the field moves erratically from quadrant to quadrant. These patients fail to orient to new stimuli that appear in the peripheral field unless the erratic movement of the macular component settles on it.
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They have simultagnosia, the inability to report more than one or two components of a scene which also may suddenly vanish as the center of vision shifts. Patients also complain that moving objects are difficult to see. Concomitantly patients suffer optic ataxia which is the inability to grasp an object using visual guidance. They can point to objects on their own body and to the origin of the sounds. They frequently undershoot the intended object. Patients suffer ocular apraxia and are unable to generate a saccade that will fix gaze on a new stimulus that enters the periphery of the visual field. Balint’s syndrome is most often seen following damage to bilateral occipital parietal watershed regions between the anterior and posterior cerebral arteries and the middle cerebral artery. In the entire syndrome there is frequent involvement of Brodmann’s area 7, 19, and 39. Most lesions causing Balint’s syndrome are seen in the occipital parietal cortex. Patients with visual disorientation in isolation have bilateral lesions of the supra calcarine cortex with sparing of the parietal cortex. Area 7 of the parietal lobe contains cells that respond and direct gaze to interesting new stimuli that appear in the peripheral field and are important in visually guided hand movements. The superior occipital striate and peristriate cortex are important to perception of the visual field as a whole. Disturbance of Stereopsis
The ability to discriminate depth from binocular visual cues is stereopsis. Two-dimensional projections of threedimensional objects are projected to slightly different portions of the left and right retinas. This horizontal disparity provides the anatomic basis of stereopsis. There seems to be stereoptic function in each hemisphere. The striate and peristriate cortex have cells that respond to binocular stimuli. The ability to perceive the directional orientation of lines is a right parieto-occipital function. The ability to discriminate unfamiliar faces (matching of unfamiliar faces) is associated primarily with right occipital lesions although it has been noted in some patients with fluent posterior aphasias. This task can be performed in patients with a prosognosia as this deficit is one of recognition of familiar faces. In general terms, lesions of the inferior visual cortices are associated with color perception and pattern recognition whereas damage to the superior occipitoparietal cortices are associated with visuospatial deficits.
Chapter 5 Arousal The interplay between the ascending reticular activating system and posterior thalamic nuclei interact to determine the state of wakefulness. The ascending reticular activating system starts in the lateral medulla. It receives projections from
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the spinothalamic system and all major special senses. The dorsal pons, periaqueductal grey and intralaminar nuclei of the thalamus are its major subcortical components. The intralaminar nuclei project bilaterally to the cerebral cortex. Each cortical area is activated by a reticular activating system projection. Disruption of this anatomic system is primarily related to disorders of arousal.
Major Anatomical Areas that Compromise Arousal
1. 2. 3. 4. 5.
Lateral > medial reticular formation Dorsal pons Periaqueductal gray of the midbrain Intralaminar thalamic nuclei Bilateral cerebral cortex a. There is full alertness with one functioning hemisphere
Disorders of Arousal
1. Central uncal herniation a. Vascular disease: 1) MCA stem or carotid occlusion 2) Basal ganglionic hemorrhage 3) Thalamic hemorrhage b. Epidural/subdural hematoma c. Brain tumor d. Rare metabolic causes: 1) Acute hepatic failure 2) Poisoning that decrease the production of ATP e. Abscess 2. Bilateral thalamic infarction a. Top of the basilar syndrome: 1) One thalamic peduncle (of Percheron) that supplies both thalami 2) Dorsomedial and intralaminar nuclei are the most important thalamic structures for arousal. a) Anterior thalamic lesions may cause waxing and waning of alertness
Cerebral Herniation that Causes Lethargy to Stupor
1. Cingulate gyrus herniated under the falx: a. Compromises venous outflow and is a major cause of central herniation b. Usual lesions are structural above the tentorium 2. Transtentorial diencephalic: a. Compresses the midbrain RAS at the periaqueductal grey b. Becomes terminal with rupture of Duret’s pontine and midline mesencephalic arteries with hemorrhage
3. Unilateral uncal herniation: a. Unilateral temporal lobe swelling from tumor, trauma, or vascular event b. IIIrd nerve palsy is an early sign 4. Upward Herniation: a. Posterior fossa lesions b. Most often in children with posterior fossa tumors c. Extraocular movement paralysis occurs prior to pupillary involvement 1) Compression of the collicular plate by the superior vermis
General Causes of Disorders of Arousal
1. Thalamic/subthalamic infarction a. Top of the basilar embolus b. Vertebrobasilar infarction 2. Acute agitated delirium: a. Caudate nucleus infarction b. Bilateral temporal lobe dysfunction c. Right sided temporo-parietal occipital lesions d. Orbitofrontal cortex 3. Hyper alertness or insomnia a. IIIrd ventricular lesions b. Anterior thalamic lesions 4. Sleep disturbances: a. Sleep apnea b. Locus ceruleus lesions c. Pedunculopontine nuclear lesions 5. Basal forebrain lesions a. Abulia 6. Delirium (drugs, toxins, metabolic disorders) 7. Chronic vegetative state 8. Akinetic mutism 9. Locked in syndrome Akinetic mutism is a state of disordered arousal in which the patient neither initiates nor responds to any verbal stimulus. Patients may have visual tracking movements that appear to be purposeful. Lesions may be in the basal forebrain of the frontal lobe and are from trauma, anterior cerebral artery aneurysm, or tumor. Abulic patients resemble those suffering from akinetic mutism but differ in that with intense verbal stimulation they may be induced to respond or to move. Difficulties with initiation of speech or movement predominate. Lesions are similar to those with akinetic mutism. Chronic Vegetative State: patients are not conscious and do not respond to verbal or painful stimuli. They may have reflexive visual tracking movements. Lesions may be in the dorsal forebrain, dorsal pons, periaqueductal gray or lateral reticular activating system and cortex. Trauma, basilar artery stroke and increased intracranial pressure with herniation are causative.
Chapter 6. Memory and Amnesia
Chapter 6 Memory and Amnesia Isolated memory disorders or amnesia frequently occur following bilateral involvement of limbic structures. In a core amnesic syndrome, patients suffer a global anterograde and retrograde memory deficit with occasional confabulation. Other cognitive functions including attention, and motivation are intact. Anterograde amnesia is the inability to learn new material. Retrograde amnesia is the inability to remember events prior to injury. Rabat’s law is frequently seen which states that the older memories are most resistant to amnesia. Retrograde amnesia with a temporal gradient, loss of most recent memory is different from amnesia for remote events. Confabulation is the use of fabricated verbal responses concerning questions about recent events. This appears to be a compensatory mechanism to conceal a severe short term memory deficit. Patients with the amnestic syndrome may retain learning tasks that depend on the acquisition of motor skills.
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Thalamic Lesions
Bilateral dorsomedial thalamotomies cause transient loss of temporal organization and chronology of the patient’s experience. Thalamic infarcts affecting the paramedian and dorsomedial nuclei are associated with severe antegrade and retrograde memory loss. Unilateral left thalamic lesions in the dorsomedial or anterior thalamic nuclei have been associated with anterograde amnesia particularly for language.
Basal Forebrain Lesions
Lesions affecting the septum, hypothalamic and caudal orbitofrontal regions from tumor or anterior communicating aneurismal rupture cause severe amnesia. These pathologies may damage the septal nuclei and the nucleus basalis of Meynert which would destroy the cholinergic innervation of the limbic and frontal cortex.
Bilateral Fornix Lesions Amnesias with Bilateral Limbic Involvement (The Amnestic Syndrome)
Patients with tumors or bilateral section of the fornix may develop an amnestic syndrome.
Korsakoff’s Syndrome
The syndrome is most often from thiamine deficiency (alcohol, pernicious vomiting, renal dialysis) and may be progressive or follow a global confusional state. It may be accompanied by ataxia, ophthalmoplegia, nystagmus and peripheral neuropathy. After the acute confusional state clears, the patient may be left with variable difficulty in acquiring new information, confabulation, and a temporal gradient of retrograde amnesia. Korsakoff’s Syndrome (three major features) 1. Euphoria, anosognosia, confabulation 2. Disorientation, difficulty in maintaining goal directed activity 3. Pure memory impairment The temporal evaluation of Korsakoff’s syndrome may feature each of the three components. Anatomically, there are bilateral lesions of the mamillary bodies, the anterior column of the fornix, hypothalamic nuclei, the dorsal medial nuclei of the thalamus, medial pulvinar and lateral dorsal thalamic nuclei. Dorsal medial nuclei of the thalamus may be important for confabulation as well as memory.
Cingulate Lesions
Bilateral cingulotomies are associated with transitory memory disorders with confabulation similar to Korsakoff’s Syndrome. These patients may also suffer difficulty in ordering memories in a proper temporal sequence. Amnestic syndromes after callosal commissurotomy or posterior corpus callosum tumors may be due to posterior cingulate gyrus damage.
Selective Amnesias from Unilateral Temporal Lesions
The recognition of recurring nonsense figures, faces and maze learning may be deficient after right temporal lobe lesions. The recall of verbal material is disturbed after left temporal lobectomy. These impairments are independent of the modality in which they are presented. The right temporal lobe can recognize nonverbalizable tactile patterns better than the left after commissurotomy.
Hypothalamic Tumors
Amnesias of Unknown Anatomical Cause
Amnestic syndromes have been reported in cases of hypothalamic tumors particularly in those surrounding the floor and walls of the third ventricle.
Head trauma: a. Long fiber bundles including the fornix are damaged by shearing forces
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b. The temporal poles and the orbitofrontal cortex are often severely damaged. c. There is a correlation between the amount of damage in these areas with the severity of ante grade and retrograde amnesia Electroconvulsive therapy: a. Comparable to head injury b. Unilateral ECT-material specific amnestic syndromes.
Psychogenic Amnesias
Epilepsy
Anatomical Basis of Memory
Fugues and amnesias occur in patients with complex seizures. Hippocampal involvement occurs in the amnesia of chronic epilepsy.
Memory can be divided into three major phases: 1. Inscription: a. This takes place during the first 30 seconds, is an electrical process that occurs primarily in the medial hippocarpal structures. It appears to be related to reverberating circuits and acetylcholine is the primary neurotransmitter. 2. Consolidation: a. The structures that are most important for this phase of memory are: 1) The medial hippocampus 2) The mammillary bodies and the mamillothalamic tract 3) The dorsomedial nucleus of the thalamus b. Messenger RNA is synthesized during this phase of memory c. It is vulnerable to intrusion 3. Protein synthesis: a. Memory appears to be related to protein synthesis that occurs in specific parts of the brain b. Long term potential of individual cells utilizing NMDA receptors appears to be important 4. Retrieval: a. The dorsolateral frontal cortex is important for activating and retrieving memory that has been consolidated b. Cueing appears to occur here 5. Forgetting may be related to unfolding of the tertiary structures of synthesized proteins.
Drugs
1. Benzodiazepines cause a state similar to transient global amnesia. 2. Amytal induces “blackouts”. 3. Scopolamine memory loss similar to amnestic syndromes.
Huntington’s Disease
Memory loss can occur early in HD.
Depression
Depression is associated with a partial and relatively mild memory disorder probably in the encoding stage of short term memory.
Transient Global Amnesia
Men are more frequently affected than women; it is primarily anterograde amnesia that lasts for 3 to 24 hours. Anterograde amnesia is acute; the patients are aware and anxious as well as perplexed. Temporal disorientation is severe; spatial disorientation is variable. Retrograde amnesia affects the 1st few hours preceding the onset of the disorder. Some biographical data is forgotten. General knowledge is intact and there are no accompanying intellectual or neurologic deficits. Recovery is rapid. Differential diagnosis includes posterior cerebral artery ischemia, migraine headache, seizures. Transient global amnesia may appear during periods of high stress.
Benign Senescent Forgetfulness
The greatest difficulty is for names and details although minor events are easily recalled. Cueing improves performance. The deficit may be at the retrieval stage.
These are also known as functional retrograde amnesia (“forgetting the disagreeable”). It occurs after strong emotion or psychologic trauma. Loss of personal identity, patients forget their names and their past, but memory for recent events is normal. Anxiety is not great although it is often accompanied by a fugue, which ceases after a few days or weeks.
Confusional States
An acute confusional state is a change in mental status, the most important feature of which is failure of attention. Most often there are no neurological signs other than a coarse tremor, myoclonus, or asterixis. Vigilance is defective in intensity and selectively. Attention either wanders aimlessly or is suddenly focused with inappropriate intensity or an irrelevant stimulus becomes the source of distractibility. Thought and skilled movement are diminished by interference, impersistence and perseveration. The stream of thought is interrupted by frequent intrusions of competing thoughts and sensations.
Chapter 6. Memory and Amnesia
The three cardinal features of confusional state are: (1) disturbance of vigilance and heightened distractibility; (2) inability to maintain a coherent stream of thought, and (3) inability to carry out a sequence of goal-directed movements. Perceptual distortions lead to illusions and hallucinations. Patients frequently are disoriented, have memory deficits; mild anomia, dysgraphia, dyscalculia and constructional deficits are common. Judgment is poor, insight lacking, affect is labile with a curious tendency for facetious witticism. Some confusional states are apathetic others cause extreme agitation (barbiturate, opioid, alcohol withdrawal). Confusional states fluctuate from hour to hour and are exacerbated at night.
Causes and Mechanisms
1. 2. 3. 4. 5. 6.
Toxic-metabolic encephalopathy Multifocal brain lesions Head trauma Epileptic seizures Space-occupying lesions Focal brain lesion
Toxins and drugs that interfere with cholinergic transmission are particularly apt to produce confusional states. Drugs with anticholinergic effects (antihistamines, neuroleptics, antidepressants) also cause confusional states.
Multifocal Brain Disease
1. 2. 3. 4. 5.
ALZ (abiotrophies) Meningitis Encephalitis Anoxia DIC
6. 7. 8. 9.
Fat emboli Head trauma Ictal/postictal state SDH
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Unilateral Neglect As a Disorder of Directed Attention
Unilateral neglect is a fundamental disturbance in directed sensory attention. Some patients are abnormally distracted by sensory events within the intact hemispace. One mechanism that may underlie extinction is the abnormal magnetism of the stimulus toward the intact side. There may be task related shifts in the inner representation of space.
Motor Aspects of Unilateral Neglect
The motor aspects of attention, orienting, scanning and searching within extrapersonal space are deficient in patients with unilateral neglect. Patients with left unilateral neglect have difficulties with the manual exploration of the environment. This implies that at certain stages of motor integration, the motor programs are organized not according to muscle groups that are being activated, but according to the hemispace within which the movement is to occur.
Motivational Aspects of Unilateral Neglect
Neglect can occur with lesions of the posterior parietal cortex, lateral prefrontal cortex, cingulate gyrus, striatum and thalamus. It may be seen with lesions of the right inferior parietal lobule. Lesions of the superior parietal may be more closely associated with neglect behavior. Patients with parietal damage have multimodal extinction to double simultaneous stimulation; they neglect the internal sensory representation of left extrapersonal space and they have difficulty with leftward shifts of attention.
The Limbic Connection in Neglect
Medial frontal infarcts involving the cingulate region of the right hemisphere cause unilateral neglect of left hemispace. Focal Brain Lesions
Unilateral lesions in the parahippocampal fusiform and lingual gyrus on either side of the brain. Infarcts of the posterior parietal and inferior prefrontal regions of the right hemisphere. The left caudate nucleus and the intraparietal gyrus on the right side have been associated with acute confusional states.
Detection, Vulnerability, and Clinical Course
An acute confusional state maybe the presenting clinical sign of an underlying systemic disease. The elderly and those with pre-existing brain disease (dementia) are more vulnerable to mild metabolic stress. Patients that demonstrate extreme vulnerability and indolent recovery may have an underlying dementing illness such as diffuse Lewy Body Disease.
The Reticular Component
Brain stem raphe, NLC, pontomesencephalic cholinergic nuclei of the PF project to PG (and almost all parts of the cortex). This input may regulate the overall attentional tone in area PG. A vector function such as directed attention operates on a background of underlying matrix of attentional tone. The frontal eye fields mediate the internal planning and spatial organization of eye movements. The inferior parietal lobule projects to the superior colliculus and the frontal eye fields. In humans bifrontal lesions, that include the frontal eye fields disturb the ability to systemically scan complex visual scenes in the absence of a gaze paresis. Unilateral lesions that include the frontal eye fields can cause contralateral neglect. Head and eye deviation may be a manifestation of neglect rather than weakness.
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674 Subcortical Neglect
Unilateral neglect has been seen after lesion of the thalamus. Possibly the DM and medial putamen are most important. The medial pulvinar projects to the posterior parietal lobe and the DM projects to the frontal eye fields. Unilateral striatal damage is a cause of neglect in humans.
Neglect of the Body Surface and Motor Neglect
Right hemisphere lesions also demonstrate motor neglect or negligence (motrice) reluctance to use the contralateral limbs in the absence of weakness. Specific commands to use the limb may overcome this hypokinesis. This type of deficit has also been noted with lesions of the striatum, thalamus, and frontoparietal cortex. This type of motor neglect is confined to the contralateral extremity and may be seen from lesions in either hemisphere (a “loathness to move”). These patients may have no neglect for extrapersonal space. Right hemispheric specialization for attention is demonstrated by: (1) simple reaction times to ipsilateral visual stimuli are faster with the left hand; (2) patients with right hemisphere lesions have bilateral deficits in reaction time more frequently than those with left hemisphere lesions; (3) in split brain patients, vigilance performance is better when the task is being performed by the right hemisphere; (4) right hemisphere damaged patients show smaller galvanic skin responses in reaction to stimulation than left hemisphere damaged patients; (5) event-related patients and EEG desynchronization occur in the left hemisphere after stimulation of only the right hand whereas this occurs in the right hemisphere after stimulation of either hand; (6) F18 -2DG activation is increased in the right hemisphere to a greater degree than the left when a relevant visual stimulus is placed centrally. Unilateral neglect for the right side of space may develop rarely after left hemisphere lesions but suggests bilateral damage. Attentional deficits are the major component of the hyperkinetic state of childhood, infantile autism and schizophrenia. This deficit may represent the breakdown of a possible filtering mechanism that normally differentiates relevant from irrelevant stimuli.
Chapter 7 Aphasia and Apraxia
Broca’s Aphasia
The major components of Broca’s aphasia are difficulty initiating and articulating speech, nonfluency, and an output of less than 20 words per minute. The phrases are short and
have abnormal rhythm, inflection and timbre. The patient utilizes meaningful substantive words with a lack of syntactic language. This agrammatism is noted by a decreased use of prepositions, articles, grammatic modifiers and the use of endings which delineate plurals, possessives and tenses. Patients with anterior aphasia have a specific disturbance in use of syntactic aspects of language. Repetition is abnormal particularly for simple syntactic words and endings. Comprehension is abnormal particularly for syntactic function words such as the difference between in and on. Confrontation naming is abnormal, but performance is improved with a phonetic or contextual cues. Reading comprehension is impaired due to failure to understand grammatically significant words. Writing is abnormal, out of proportion to weakness, and demonstrates omission of grammatical words and misspelling of substantive words. Persistent Broca’s aphasia is frequently associated with an ideomotor apraxia of the left hand. A significant number of patients demonstrate apraxia in handling objects and for imitation of movement with the left arm and face.
Wernicke’s Aphasia
These patients demonstrate fluent verbal output and a normal to increased rate of word production with normal prosody and phrase length. Grammatical structure is nearly normal although there is a lack of substantive words. There are characteristic verbal or semantic paraphasic errors (word substitutions), literal or phonemic paraphasias (consonant errors), and neologisms (nonexistent) word errors. Wernicke’s aphasia patients cannot comprehend or repeat spoken language. In some patients comprehension of midline commands may be spared. Naming ability is severely impaired. Reading and writing comprehension may be involved to varying degrees. Some patients are more “word deaf” than “word blind” while others demonstrate the reverse. Some patients with Wernicke’s aphasia lack insight to their deficit. A hemiparesis is unusual; a superior quadrantic defect may be present as well as an apraxia on imitation and object handling.
Conduction Aphasia
Patients with conduction aphasia have a fluent verbal output with more literal than verbal and nonlinguistic paraphasic mistakes. The patient’s comprehension is preserved to a much greater degree than is the ability to repeat. Naming is impaired due to literal paraphasic substitutions. Reading aloud is performed poorly but comprehension is relatively well preserved. Writing demonstrates omissions, spelling errors and altered sequences of words and letters. Patients may have concomitant paresis, cortical sensory loss, visual field deficits and apraxia on verbal command, imitation and object handling. Most lesions producing conduction aphasia affect the supramarginal gyrus and the arcuate fasciculus.
Chapter 7. Aphasia and Apraxia Transcortical Motor Aphasia
Transcortical motor aphasia is characterized by difficulty in initiating speech. Patients stammer, may be dysarthric but repeat sentences almost flawlessly. Patients have difficulty in naming but have relatively well preserved comprehension. They can read aloud and for comprehension. Writing is performed poorly. Patients frequently suffer a hemiparesis and may demonstrate ideomotor apraxia of the left hand to verbal command. Lesions that cause TCM aphasia have been described in the supplementary motor area or in the frontal lobe high in the lateral convexity above Broca’s area or low, anterior to Broca’s opercular area.
Transcortical Sensory Aphasia
A transcortical sensory aphasia is similar to Wernicke’s aphasia with fluent paraphasic speech and poor comprehension but in contradistinction to Wernicke’s aphasia has preserved repetition. These patients have a nominal aphasia and cannot read or write. They may have a concomitant significant hemisensory deficit and visual field deficit with a minimal hemiparesis. These patients frequently have damage of the angular gyrus, second and third temporal gyrus or a border zone ischemic lesion of the parieto-temporal junction.
Mixed Transcortical Aphasia or Isolation of the Speech Area
These patients suffer damage to the anterior and posterior vascular border zone areas. They cannot initiate speech, name objects, follow commands, read or write. Most patients have suffered anoxic injury but a few have been reported with acute carotid occlusion, head trauma and severe cerebral edema.
Global Aphasia
Most patients with global aphasia have suffered damage to the frontal and parietotemporal language areas from carotid occlusion or stem middle cerebral artery embolism. Occasionally an anterior branch MCA occlusion can cause the syndrome but this picture then evolves into a Broca’s aphasia. These patients cannot initiate speech, follow commands, read, write, repeat or name. Most patients suffer a concomitant right hemiplegia but some have documented with minimal motor or sensory loss.
Anomic Aphasia
This is the most common aphasia. Patients are unable to find the correct word in spontaneous speech, writing and on confrontation. These patients are fluent, can repeat and com-
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prehend spoken and written language. The ability to find words while writing may be more secure than during speech. In general, patients have concomitant deficits in comprehension and read and write with difficulty. A lesion of the left temporoparietal junction is most characteristic although anomic aphasia has been seen with dominant hemisphere frontal, temporal and parietal lesions. It has rarely been reported following right hemisphere and subcortical pathologies. Brain tumors may cause a slowly progressive anomic aphasia. Anomic aphasia may be seen in neurodegenerative diseases, post head injury, and with metabolic and toxic disorders. In the later situation, patients have evidence of an acute confusional state and writing is more impaired than speaking. Pure anomic aphasia may occur with supramarginal gyrus lesions.
Subcortical Aphasia
Infarction, hemorrhage or tumor in the caudate putamen and thalamus have produced subcortical aphasias. These aphasias have an acute onset often with initial mutism or cerebral hypophonia. The verbal output is slow and poorly articulated. Some patients demonstrate high pitched slow and poorly articulated speech, spastic dysarthria, while others, produce hyperkinetic slurred speech. Naming and reading are relatively well preserved. These aphasias are very similar clinically to those seen after damage to the supplementary motor area or infarction of the anterior cerebral artery territory.
Differential Diagnosis of Aphasia
One of the most common entities misdiagnosed as aphasia is mutism which is the total cessation of verbal output. The most common brain areas associated with mutism are frontal, supplementary motor, left thalamic, mesencephalic, and left posterior inferior frontal area of Broca. If a patient can write normal sentences when speech returns, speech will be normal with only a few aphasic errors.
Dysarthria
Motor speech disturbances such as ataxia, hypo or hyperkinetics, spastic or aphemic speech be misinterpreted as aphasia. Aphasia can only be diagnosed when a disturbance of language function is manifested by incorrect grammar or choice of words is demonstrated. Abnormal phonology, the learned rules for producing the sounds of a specific language occurs only with aphasia.
SECTION XV. The Cerebral Cortex / Behavioral Neurology
676 Aphemia
Aphemic patients have great difficulty with articulation. They can express themselves in written language and fully comprehend written and spoken language. Word choice and syntax are normal. Aphemia is a severe disorder of verbal output. Many patients are mute in the acute stage and demonstrate a transient right hemiparesis. The usual lesions causing aphemia occur either directly in Broca’s area or destroy the white matter under the left frontal operculum that destroys the outflow pathways of Broca’s area. As the patient recovers, the patient’s speech is hypophonic and poorly articulated. Speech is grammatically intact but the prosodic quality is often altered. Lesions of the medial frontal cortex, the supplementary motor area or the cingulate gyrus may simulate aphemia.
Pure Word Deafness
Patients’ with pure word deafness cannot comprehend spoken language, but can identify nonverbal sounds. These patients are fluent, able to read and write, but can neither comprehend spoken language or repeat it. Patients have been reported in which word deafness and Wernicke’s syndrome occur concomitantly. These patients demonstrate a fluent aphasia in which there is a greater deficit in comprehension than in writing. The anatomic lesions that cause severe word deafness are damage to Heschl’s gyrus and destruction of the radiations from the medial geniculate body as well as the callosal fibers from the contralateral superior temporal gyrus. This combination of lesions isolates the left hemisphere auditory association cortex from any auditory input. The second localization for the syndrome is bilateral damage to the midportion of the superior temporal gyrus. Nonverbal auditory agnosia, the inability to recognize nonverbal sounds, occurs with lesions of the right hemisphere. Cortical deafness occurs with bilateral damage to Heschl’s gyrus and their connections. In this state, patients are aware of words and sounds but cannot interpret them.
Differential Diagnosis of Aphasia
1. 2. 3. 4.
Aphemia Mutism Pure word deafness Auditory agnosia
5. Cortical deafness 6. Dysarthria 7. Nonverbal auditory agnosia
Written Language Impairments
Alexia without Agraphia
These patients suffer an inability to comprehend written material. The patient can recognize words spelled aloud, graphesthetically produced words on the palm, or words constructed with blocks that are palpated. Most patients can
recognize a few letters. Patients frequently suffer a partial or complete right homonymous hemianopsia and impaired naming and understanding of color names in the face of normal color vision. A few patients have impairment or loss of color vision, central achromatopsia. There may be an associated anomia. The usual lesion is occlusion of the left posterior cerebral artery with infarction of the left occipital lobe and the splenium of the corpus callosum which prevents transfer of visual information from the right occipital lobe to the left angular gyrus. Occlusion of the dominant middle cerebral artery or its distal branches may also lead to an acquired loss of the ability to read or write from infarction of the parietal lobe. These patients often have concomitant mild hemiparesis, hemisensory loss, partial visual field deficit and anomic aphasia. Lesions of the posterior inferior frontal cortex of the dominant hemisphere may impair the ability to comprehend syntactic structures and lack the ability to comprehend syntactic structures such as function words and endings. These patients may understand substantive words but cannot recognize relational words. This defect is seen in both spoken and written language. These patients also have difficulty in understanding sequences of semantically significant words. These patients frequently have a concomitant Broca’s aphasia, hemiparesis and mild hemisensory loss.
Paralexia
Paralexia refers to substitutions of words or syllables when reading aloud. Synonym substitutions, somatic paralexia (truck for Lorrie) is associated with substitution of nouns for objects and an inability to read nonsense and function words. This type of dyslexia follows severe damage to the dominant hemisphere language areas and may be seen during recovery from complete alexia.
Agraphia
If patients suffer aphasia in spoken language, writing is also abnormal. Agraphia can be delineated into anterior frontal or posterior parietotemporal syndromes. The graphia associated with anterior Broca’s aphasia is associated with large, poorly constructed words and is dominated by misspelling, and omission of function words and endings. The agraphia of dominant posterior hemisphere lesions consists of well formed words that generate abnormal sentences characterized by misspelling, abnormal word order and omissions that are devoid of meaning. Occasionally, posterior parieto-temporal lesion agraphia resembles that noted from anterior lesions. Nondominant hemisphere lesions cause visual-spatial agraphia in which the patient is able to formulate correct letters and words but has great difficulty arranging them
Chapter 7. Aphasia and Apraxia
correctly on the page and having them progress from one line to the next. Isolated agraphia may occur from lesions of the angular gyrus of the dominant hemisphere or at times is associated with other aspects of Von Gerstmann syndrome. Aphasic agraphia has been recently described. The first group of patients were able to write real words to dictation but not nonsense words. This phenomenon has been thought to be a disturbance of phoneme-grapheme transformation (surface agraphia) from a lesion of the posterior superior temporal lobe. The inverse of this deficit, an inability to write nonphonemic real words (e.g. through) with the ability to write phonetically nonsense words (geebe) has been ascribed to posterior inferior parietal damage and is thought to be a disorder of lexical grapheme transformation.
Anatomic Areas Associated with Agraphia
1. 2. 3. 4. 5. 6. 7. 8.
Anterior-frontal (inferior frontal lobe and Broca’s area) Posterior parietal temporal areas Acute confusional state Visual spatial agraphia (right parietal lobe) Gerstmann syndrome area 39, 40 Exner’s area (area 6 frontal lobe) Surface agraphia (posterior superior temporal gyrus) Dysgraphia (posterior inferior parietal lobe)
Word Finding Impairment
Inability to find specific words in spontaneous speech or in naming on confrontation is noted in all aphasias. Word finding impairment results from lesions in many different regions of the brain. It has been noted in many forms of dementia most prominently the FTD complex as well as with other pathologies such as increased intracranial pressure, acute confusional states, subcortical lesions and psychoses.
Word Selection Anomia
The patient is unable to name an object on confrontation by any sensory modality but can describe its use and can select it when it is named by the examiner. This pure word finding deficit is secondary to damage in Brodmann’s area 37 (the temporooccipital junction of the dominant hemisphere).
Semantic Anomia
The patient is both unable to name the presented object nor can he select it when it is named. It appears as if the word has lost its symbolic meaning as both the comprehension and use of the name are deficient. Some patients may be able to repeat the required name even though they are unable to recognize the object or to name it themselves. This latter phenomenon is seen in both Wernicke’s and transcortical sensory aphasia.
Disconnection Anomia
There are three different forms of disconnection anomia. Modality specific anomia naming is performed adequately in all sensory modalities except one. A patient with associative agnosia cannot name on confrontation but can easily do so by palpation. In auditory agnosia, the patient cannot identify the source of a sound but can name it when the object is seen. Category specific anomia refers to the inability of the patient to name a specific stimulus category although naming ability is preserved in all other spheres. A common example of this anomia occurs with color naming in posterior cerebral artery stroke. The patient may be unable to name presented colors or to select a color in response to its spoken name. The patient can match and correctly uses color names in purely auditory verbal tasks. Some patients may have greater difficulty in body part than object naming and some cannot name inanimate objects.
Word Production Anomia
The patient appears to know the desired name but has difficulty in producing it. There are three categories of this type of aphasia: (1) articular initiation difficulty; (2) paraphasic dysnomia; (3) word elocution dysfunction. Articulatory initiation anomia is characterized by the aide that a phonetic or contextual clue gives to initiation of the correct word. Paraphasic word production anomia is characterized by ease of initiation of a word that is contaminated with literal paraphasic substitutions. The incorrect word is often a neologism or an incorrect name. Articulatory initiation aphasia is seen in Broca’s and transcortical motor aphasia while paraphasic anomia is concomitant with Wernicke’s or conduction aphasia. Word evocation anomia occurs in both anterior and posterior type of aphasia.
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Aphasic Anomia
1. Word production anomia: a. Articulatory initiation anomia (Broca’s aphasia) b. Paraphasic anomia – Wernicke’s arcuate fasciculus c. Word evocation anomia: 1) Systemic disease 2) Anterior, posterior speech areas 3) Subcortical 2. Word selection anomia (Brodmann’s are 37) 3. Semantic anomia (angular gyrus) 4. Disconnection anomia: a. Either or both hemispheres b. Corpus callosum
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SECTION XV. The Cerebral Cortex / Behavioral Neurology
Syndromes of Calculating Impairment
Aphasic Acalculia
The patient is not able to utilize numbers as a language entity. The patient cannot comprehend or write numbers correctly or substitute one number for another. Aphasic acalculia is seen in most aphasics and follows damage to the dominant hemisphere. Visual Spatial Acalculia
The patient can compute, understands numbers and computational signs but is unable to place numbers in the correct position in space. Thus, he cannot align numbers in columns or place decimal points which interferes with complex calculations although he can manipulate individual mathematical functions. The lesion affects the non-dominant hemisphere at the parietoccipital junction. Anarithmia
These patients are not able to manipulate numbers or compute. They can recognize and reproduce individual numbers, understand their value but cannot compute. This defect is noted from dominant posterior parietal lesions. Apraxias
Apraxias are the inability to perform an individual or sequential function with intact motor, sensory and coordinative abilities. Different areas of the brain are specific for specific forms of apraxia. Specific Apraxia by Anatomical Site
1. Oral-buccal-lingual apraxia (insular cortex; if bilateral Foix–Chavany–Marie Syndrome) 2. Ideomotor: inferior parietal; lobes, SMA, premotor cortex (L>R) 3. Limb kinetic (same as ideomotor apraxia) 4. Dressing apraxia (right parietal lobe) 5. Constructional (right frontal, right parietal lobes) 6. Eyelid opening (frontal lobe; 2nd frontal gyrus) 7. Ideational (left posterior parietal area 5 and 7) 8. Sympathetic apraxia (corpus callosum, left and right prefrontal cortex) 9. Gait apraxia (leg fibers around the lateral ventricles, paracentral lobule) 10. Conceptual apraxia: a. Associative knowledge (tool action)-frontal lobe b. Mechanical knowledge advantage tools offer (frontal lobe)
Oral Motor Apraxia
1. 2. 3. 4.
Landau–Kleffner seizure disorder Benign rolandic epilepsy Anterior perisylvian Foix–Chavany–Marie syndrome: a. Bilateral insular cortical lesions
The cardinal features of oral-buccal-lingual apraxias is the loss of the patient’s voluntary ability to utilize muscles of mastication, swallowing and speech. Those muscles innervated by the first four branchial arches. The patients have difficulty with speech, swallowing, chewing and pursing of the lips. Patients are not able to touch their upper lip with the tongue on command. Coughing, sneezing and involuntary movements are preserved. Limb kinetic and ideomotor apraxia refers to the inability of a patient to carry out a single purposeful movement such as a salute or the demonstration of how to turn a key in a lock or how to comb ones’ hair on command. The patient may perform the task slightly more competently with the appropriate object. Lesions that cause ideomotor apraxia are primarily seen in area 6 of the premotor area and area 6 of the supplementary motor cortex. [An anterior alien hand syndrome may be seen with this lesion (area 6). Ideomotor apraxia may occur with conductive aphasia.] Ideational Apraxia
The patient is unable to correctly carry out the correct sequence of a common task although each separate part can be successfully performed. The patient would be unable to demonstrate how he would smoke a cigarette even when given the cigarette. He would be expected to show how the cigarette is removed from the package, inserted into the mouth and lit. Lesions causing ideational apraxia are noted primarily in the left posterior parietal area 5 and 7. Patients may be unable to start the sequence or abandon it in the middle. A posterior alien hand syndrome may be seen with lesions in this area. Patients may have an inability to handle real objects even though they can mimic the use of the object. Constructional apraxia is impairment in the ability to construct the copy of a visually presented object with blocks or by drawing. Patients must be able to perceive the elements of the object, their spatial relationships and possess the motor ability to perform the task. Both left and right parietal lesions can cause a defect in constructional praxis. Right parietal lesions are more commonly associated with constructional apraxia than left sided lesions. The deficit is more severe and is often associated with a neglect of the left side of the object being copied. Patients with left parietal lesions and constructional apraxia frequently suffer a concomitant fluent aphasia. A deficit in constructional ability is hard evidence of a parietal deficit.
Chapter 7. Aphasia and Apraxia Dressing Apraxia
Patients with dressing apraxia are not able to dress themselves properly even when they are given the specific garment. This apraxia is most often noted in patients with right occipitoparietal or bilateral occipitoparietal lesions. Dressing apraxia is rarely if ever noted in isolation. It may be seen in demented or confused patients as well as those with left sided neglect or Balint’s Syndrome.
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It is organized similarly to that of propositional language of the left hemisphere (i.e. expression is anterior and decoding of gestures and affect is posterior). The linguistic components of prosody may be altered by either right or left hemisphere lesions but affective or attitudinal components are disrupted primarily by damage to the right hemisphere. Lesions bordering the right sylvian fissure cause defects of affective language known as aprosodies which may be encoding or decoding in type.
Callosal Apraxia
Callosal apraxia and sympathetic apraxia are the inability to form a simple command with the left hand although the right hand performs it easily. Gait Apraxia
Patients that suffer gait apraxia have normal pressure hydrocephalus or various lesions that may interfere with the pedunculopontine nucleus or other locomotor centers. Patients have difficulty in initiating the swing component of gait, walk as if they are on eggs or have a foot grasp of the floor. Basal ganglia disease and severe lacunar strokes that affect the descending corticospinal system should be considered in this differential diagnosis. Movement and Task Specific Praxis
Conceptual praxis refers to the associative knowledge of tool action while mechanical knowledge refers to the advantage tools offer. Frontal lobe degeneration is associated with this conceptual praxis. Eyelid opening praxis is seen with superior frontal gyrus deterioration. Patients are unable to open their eyelids to command. This apraxia may be seen in isolation or in conjunction with other neurological features of neurodegenerative diseases. Prosody refers to the rhythm of speech and the modulation of emotional tone to the content of speech. Timbre is the modulation of tone in accordance with the rhythm and content of speech. Prosody
Prosodic features of language are a graded phenomenon which adds complexity and richness to language. Kinesics is the study of limb body and facial movements associated with nonverbal communication. Movements used for semantic or referential purposes are pantomime whereas movements used to modify, emphasize or embellish are gestures. Movements frequently are a blend of referential, emotional and attitudinal content. Disorders of pantomime (referential deficit) are caused by left hemisphere damage associated with aphasia. Gestured kinesics is often spared in aphasic patients. The right hemisphere is dominant for the affective prosodic components of language and gestural behavior.
Motor Aprosopia
These patients have a right hemisphere and variable left hemisensory deficit. The responsible lesion is in the right frontal and anterior parietal opercula. Many of these patients have transient anosognosia and dysarthria. It may be observed with subcortical and internal capsular lesions. They have a flat monotone speech, no spontaneous gesturing, poor repetition of emotional state but intact comprehension of affective prosody and emotional gesturing. Under extreme emotional stress, these patients demonstrate emotion. Sensory Aprosodies
These patients have excellent affective prosody in speech with spontaneous gesturing. They lack auditory comprehension of affective (crying or coughing) prosody, visual comprehension of emotional gesturing and repetition of affective prosody. A left cortical sensory loss and left homonymous hemianopsia may be present. The causative lesion is in the right posterior temporal and posterior parietal opercula. Patients may appear inappropriately euphoric. Global Aprosody
These patients have suffered a large right frontal, parietal, temporal lesion or a deep right intracerebral hemorrhage. They demonstrate a dense left hemiparesis, hemisensory deficit and homonymous hemianopsia. They have a severe deficit of comprehension and repetition of affective prosody and visual comprehension of emotional gesturing. Transcortical motor, sensory, and mixed aprosodies are similar to their left hemisphere phonological aphasic counterparts. Transcortical motor aprosopic patients have aprosopic gestalt monotone speech with preserved repetition and comprehension of affective prosody and emotional gesturing. Transcortical sensory aprosody patients have spontaneous affective prosody, emotional gesturing with normal repetition but are unable to comprehend affective prosody. Patients with mixed transcortical aprosody have lesions that involve the right supra sylvian region and posterior temporal operculum. The right hemisphere plays a dominant role in decoding and encoding affective expression as well as the interpretation of nonverbal and paralinguistic aspects of communication.
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Section XVI DEMENTIA
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Chapter 1. Introduction
Chapter 1 Introduction A. General considerations: Most dementing illnesses have specific clinical patterns of deterioration, destroy particular areas of the brain in a sequential manner and are associated with seminal features. They are now being categorized on a molecular biological, genetic and neuropathologic basis. As noted in the beginning of the chapter on behavioral neurology, the brain appears to function normally as an incredibly complicated assembly of integrated loops. There clearly is long term potentiation and long term depression in many aspects of learning and memory. In the former, specific integrated loops and neurons have greater synaptic efficiency whereas in the latter these neurons are suppressed and their synapses cannot fire. Neurotransmitter systems such as acetylcholine have been associated with memory and many other aspects of cortical function. The interplay of GABAergic and acetyl cholinergic systems at the thalamic level appears to be important in the state of consciousness and directed attention. Dopamine has a major role in basal ganglia function at all levels and most probably with subcortical dementia. Serotonin has been shown to be pivotal in many aspects of emotional expression and pain. Thus, dementing processes that destroy neurotransmitter systems in the brainstem may have far reaching neurological manifestations. A fundamental aspect of all dementing processes appears to be the loss of synapses as well as neurons. Synaptic loss is the best correlate of the severity of dementia. Synaptogenesis and maintenance of formed synapses may depend on functional use, neurotrophic factors and connectivity. Synaptic “pruning” certainly occurs in many of the childhood and early adult storage diseases. The intense interest in the formation of nuclear and cytoplasmic inclusions points to the role of protein metabolism in cell function. The exact mechanism of cellular death when inclusions are found is not known, but is suspected to be failure of normal axonal transport, apoptosis or inability to control free radicals. Synucleopathies, in which alpha synuclien is a major component of nuclear inclusions are often clinically associated with hallucinations. The tauopathies are characterized by hyperphosphorylation of tau protein in neurons and glia. The electrical correlates of normal brain function and that which occurs with dementing illness is now being unraveled. The EEG is often slow in dementing illness. The ability to make cortical negative variants or readiness potentials prior to a movement or specific task allows some insight into the brain’s functional activity. The recent discovery of thalamically generated gamma waves points to their importance in perception. Magnetoencephalography, allows for a precise localization of an electrical event that is time locked. Its major
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use at the moment is to help localize epileptic foci. It appears to take 0.5 msec to process a stimulus to a perception. This figure has come from an analysis of cortical negative variant potentials and thalamically generated gamma waves. Functional MRI, PET and SPECT all localize an area of activity during a specific event, but do not detail the sign of the event (inhibitory or excitatory) or localize its precise origin, the synapse or neuron. Most (estimated to be 85%) of electrical activity occurs at synapses. Further complicating this particular aspect of neural function is the precise anatomy of the synaptic connection. Whether it is on the pedicle of the spine or the neuron itself may determine the functional activity of this neuron (excitatory or inhibitory). The clinical entities detailed below probably will not be subject to change. Their underlying mechanisms will be discovered and then they will show the dynamic plasticity of the nervous system and will move into different categories. B. Clinical features: 1. Fundamental characteristics of a dementing illness: a. The cognitive impairments is acquired b. The impairment involves multiple domains of cognitive function c. There is no impairment of arousal d. Deterioration of previously acquired intellectual abilities of sufficient severity to interfere with social or occupational function e. Memory impairment with at least one other aspect of cognitive behavior 2. Disturbances of higher cognitive function: a. Aphasia c. Agnosia b. Apraxia 3. Personality change 4. No intoxication or delirium
Basic Clinical Features of Cortical Dementias
1. Neuropsychological deficits: a. Memory impairment: 1) Recall not aided by cues 2) Decreased retention b. Dysphasia e. Poor visuospatial abilities c. Dyspraxia f. Decreased problem solving d. Agnosia 2. Speed of cognitive function: a. Normal 3. Psychiatric manifestations: a. Depression d. Delusions b. Hallucinations e. Apathy c. Day to day variability (LBD) 4. Motor abnormalities: a. Depends on specific dementing illness; often specific (loss of vertical gaze PSP; asymmetry, corticobasal ganglionic degeneration) 5. Severity and progression: a. Dependent on specific dementing illness
SECTION XVI. Dementia
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b. Significant inter and intrafamilial variance in genetic illnesses c. Variability is the rule in sporadic disease Basic Clinical Features of Subcortical Dementia
1. Neuropsychological deficits: a. Frontal memory impairment: 1) Recall aided by cues 2) Decreased verbal fluency and recall 2. Speed of cognitive function: a. Slow 3. Psychiatric manifestations: a. Apathy b. Depression 4. Motor abnormalities: a. Dysarthria b. Extrapyramidal signs 5. Severity and progression: a. Mild to moderate b. May be intermittent due to specific structural lesions Primary Dementing Illness
Definition: 1. Primary characteristics of dementia will be a feature of the clinical presentation of the illness. 2. Differential diagnosis of primary degenerative dementing disease: a. Alzheimer’s disease b. Dementia with Lewy bodies (DLB) c. Frontotemporal dementia and variants d. Multiple system atrophy: 1) Striatonigral degeneration (SND) 2) Olivopontocerebellar atrophy (OPCA) 3) Shy–Drager syndrome (SDS) e. Corticobasal ganglionic degeneration (CBGD) f. Progressive supranuclear palsy g. Hallervorden–Spatz disease h. Creutzfeldt–Jacob disease i. Gerstmann–Straüssler–Schenker j. Wilson’s disease k. ALS with dementia l. Huntington’s disease m. Pick’s disease n. Primary progressive aphasia (late stages) o. Heidenhain variant of JC disease p. Posterior dementia with medial temporal sclerosis
Chapter 2 Alzheimer’s Disease and Dementia with Lewy Bodies A. General characteristics:
1. Epidemiology: a. Approximately 4 million Americans affected b. Prevalence doubles every five years after the age of 60 c. 20% of patients 75–85 years of age are affected d. 40% of people over the age of 85 are affected e. Number of people 85 or older will double prior to the year 2020 2. Genetic factors associated with Alzheimer’s disease: a. Familial form 5–10% of patients b. Mutations causing early onset AD: 1) Chromosome 21: a) Encodes 695–770 aa precursor protein b) Gene has 19 exons c) Exon 16/17 codes AB (amyloid beta) d) Amyloid beta (39–43 aa); pathologic amyloid fibril) 2) Specific mutations: a) Exon 17 (3 mutations); codon 717 b) Most common is APP 717 (Val 717 I Leu) c) Val/phe 717; Val 717 Gly d) Double mutation of exon 16 at codon 670 to 671 3) Early onset ALZ: a) Mutations flank amyloid beta sequence b) Mutations within the sequence cause hemorrhage 4) Mutation causes increased production of amyloid 5) Altered APP processing 6) Clinical features of the 717 codon mutations: a) 717 Val/Glycine: (1) Myoclonus (2) HCVD (3) Heart disease b) 717 Val/ILe: (1) Klüver–Bucy like syndrome (without hyper metamorphopsia or hypersexuality) (2) NPH (3) Auditory hallucinations (4) Pyromania
Presenilin
Presenilin I
1. Chromosome 14 2. S182 gene: a. Missense mutation b. Encodes a 467 aa protein c. 100 mutations all but one identified are missense d. Missense mutations – Codon 141 (N 141 I); M239 V e. Mutation in the sixth hydrophilic loop f. Amyloid B 42 (43) long AB formed
Chapter 2. Alzheimer’s Disease and Dementia with Lewy Bodies
g. Presenilin protein is located within: 1) Nerve cells 3) Endoplasmic reticularum 2) Golgi apparatus 3. Clinical features: a. Age at onset (35–55 years) b. Progressive aphasia c. Myoclonus d. Generalized seizures e. Penetrance complete by age 60 f. Extrapyramidal signs g. Range of onset varies within families h. Duration of the disease is short (5.8–6.8 years) i. Pathology: 1) Neurofibrillary tangles 2) AB plaques 3) Amyloid angiopathy-consist of: a) AB fibril b) Highly dense osmophilic particles Presenilin II
1. Chromosome I 2. Gene PS 2 gene: a. Seven transmembrane domain b. Encodes 448 aa protein c. 67% homology to PS I d. 12 exons; 2 non-coding e. Missense mutation
Volga Germans
A. General considerations: 1. Chromosome 1 B. Clinical features of PSN II mutations: a. Age of onset 54.9 ± 8 years b. Variation at age of onset: 40–75 years c. Two patients > 80 years of age with no clinical signs d. Penetrance usually > 95% e. Duration of illness 7.6 years C. Pathology: a. Aβ plaques b. Congophilic angiopathy D. Increased production of amyloid-beta throughout the brain
Genetic Risk Factors for Late Onset AD
A. General characteristics: 1. ApoE4 gene: a. Proximal long arm of chromosome 19 b. Risk factor for late onset AD c. Apo E important for: 1) Lipid transport 2) Metabolism
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3) Targeting and clearance of amyloid β-peptide 4) “Wear and tear” repair d. Apo E allele frequency: 1) E2 /E2 – 1% 4) E2 /E3 – 12% 2) E3 /E3 – 60% 5) E2 /E4 – 2% 3) E4 /E4 – 3% 6) E3 /E4 – 20% e. E4 allele: 1) Noted in 40% of patients with late onset ALZ 2) If a patient is homozygous for the E4 allele he has a 90% chance of ALZ by age 80 3) The E4 allele bestows an earlier onset of sporadic ALZ 4) The E4 allele is found in the normal frequency in early onset familial AD 5) 50% of ALZ disease does not have the E4 allele f. Pathology of ApoE: 1) ApoE associated with: a) Senile plaques (found within plaques) b) Amyloid angiopathy c) Neurofibrillary tangles 2) Binds to amyloid-beta fibrils: a) Greater Aβ aggregation
LDL-Receptor Related Protein
1. Chromosome 12 2. Mediates the molecular affects of ApoE4 3. HLA-A2 gene: a. Chromosome 6 b. Alleles may regulate the inflammatory response to AD pathology 4. Bleomycin hydrolase: a. Chromosome 17 b. Involved in APP processing Clinical Features of Classic Alzheimer’s Disease Stages of Illness
1. Amnesic stage (approximately two years): a. Disorders of memory: 1) Episodic 2) Semantic b. Language dysfunction – mild 2. Dementia (approximately two years): a. Loss of cognitive function b. Difficulties with activities of daily living c. Plateaus of function alternating with precipitous decline 3. Vegetative state (many years): a. Inability to perform activities of daily living b. Difficulties with communication
The Cognitive Defects in Alzheimer’s Disease
1. Attention:
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SECTION XVI. Dementia
a. Definition: 1) The ability to select specific information to process 2) Limitation of selective attention: a) Divided attention: (1) Inability to process multiple sources of information as efficiently as one source b. Focused attention: 1) Difficulty in blocking irrelevant information c. AD patients: 1) Difficulty in dividing attention 2) Better at focusing their attention 3) Difficulty in disengaging from an attended stimulus d. Alertness in AD patients: 1) Phasic changes: a) The time to process an expected input 2) Tonic changes: a) Slow decline in performance during a long and repetitive task e. Language deficits: 1) Failure of semantic speech (the production and comprehension of meaning of words): a) Inability to find the appropriate word b) Comprehension of complex sentences c) Inability to search semantic categories d) Poor production of a semantic association to a given stimulus e) Minimal difficulty with syntax; speech is grammatically correct f. Memory: 1) Severe disruption of memory 2) Deficiencies in encoding new information 3) Memory for distant events (remote memory): a) Less disrupted b) Demonstrate a temporal gradient (recall distant information better than more recent information) 4) Implicit memory relatively preserved in some studies but deficient in others
Neuropsychiatric Aspects of Alzheimer’s Disease
1. Behavioral changes in Alzheimer’s disease: a. Psychosis d. Anxiety b. Agitation e. Personality change c. Depression f. Neurovegetative changes 2. Distribution of behavioral changes in ALZ disease a. Apathy – 72% d. Hallucinations – 10% b. Agitation – 60% e. Anxiety – 48% c. Delusion – 22% 3. Neuropsychological detection of preclinical Alzheimer’s disease: a. Deficits on confrontation naming abilities b. Decreased abstract reasoning c. Decreased memory (encoding)
d. Delayed recall (list learning task a good psychometric measure for differentiating early AD from normal aging)
Alzheimer’s Disease Variants
1. Alzheimer’s disease with extrapyramidal features: a. Faster rate of decline b. Earlier neuropsychiatric manifestations 2. Subgroup of AD patients with visual complaints: a. Present with Balint’s syndrome b. Complex visual complaints c. Decreased occipital cortex and visual association area metabolism by PET 3. Variant of AD with spastic paraparesis: a. Deletion of exon 9 of presenilin I b. Clinical features: 1) Finnish kindred 2) Spastic paraparesis 3) Onset (40–60 years of age; mean 50.9 years) 4) Memory impairment 5) Decreased hand coordination 6) Dysarthria c. Pathology: 1) “Cotton wool” plaques 2) Immunoreactive for beta amyloid 3) No congophilic cores d. MRI: 1) Temporal and hippocampal formation atrophy e. PET: 1) Bilateral temporoparietal hypometabolism
British Dementia
A. General characteristics: 1. Chromosome 13 2. Familial presenile dementia with spastic paraparesis or cerebral familial amyloid angiopathy B. Clinical features: 1. Progressive tetraparesis 3. Onset in 5th decade 2. Cerebellar dysfunction C. Pathology: 1. Severe cerebral amyloid angiopathy 2. Neurofibrillary tangles 3. Non-neuritic amyloid plaques
Presenilin 1 – 1 Gene Mutations
A. General characteristics: 1. Chromosome 14 B. Clinical features: 1. E280 A mutation:
Chapter 2. Alzheimer’s Disease and Dementia with Lewy Bodies
a. Headache 2. Mutation in 46V: a. Prominent myoclonus 3. Ser169Pro codon mutation: a. Myoclonic seizures
Risk Factors for AD
1. Genetic: a. Mutations causing early onset AD: 1) Amyloid precursor protein gene: a. Chromosome 1 b. APP gene mutations 2) Presenilin: a. Presenilin 1 (PS 1) gene mutations on chromosome 14 b. Presenilin 2 (PS2) gene mutation; chromosome 1 b. Genetic risks for late onset Alzheimer’s disease: 1) Apo E4 gene (chromosome 19) 2) LDL receptor related protein (chromosome 12) 3) HLA A2 gene (chromosome 6) 4) Bleomycin hydrolase (chromosome 17) 2. Age is the major risk factor 3. Geographic distribution: a. Similar incidence world wide 4. Women more affected than men 5. Prevalence putatively related to education background 6. Weak associations: a. Head injury (repeated) c. Never married individuals b. Parental age at birth 7. E4 allele: a. No change in progression rate (some studies show increased progression) b. Decreased frequency with age c. Increased ischemic heart disease d. Earlier death e. E2 allele protective 8. Age associated cognitive decline: a. Brain atrophy: 1) Normal control 0.4% per year 2) ALZ disease 2.4% per year b. Deficits associated in only one of six cognitive areas (memory) c. Greater than six month duration d. One standard deviation below values for age matched controls e. ApoE4: no relation with cognitive decline of aging 9. MCI (minimal cognitive impairment)
Pathology AD
1. Extensive neuronal loss: a. Strategic loss of the cholinergic neurons of the nucleus basalis of Meynert of the substantia innominata is important for the early memory deficit
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2. Intraneuronal neurofibrillary tangles (FT’s) associated with: a. Neuritic plaques and dystrophic neurites: 1) Filamentous insoluble inclusions 2) Located in the cell body 3) Extend into the dendrites but not the distal axons b. NFT tangles: 1) Major component is the hyper phosphorylated microtubule associated protein tau: a) Tau normally binds to tubulin to stabilize microtubules b) Hyper phosphorylated to an aggregate cell function c) Ghost tangles represent insoluble residues in dead neurons c. Evolution of NFT spread: 1) Earliest area is entorhinal cortex; progression to limbic cortex; last area involved is cortex 2) Tau differential diagnosis: a) Post encephalitic PD e) Repeat head trauma b) PSP f) Pick’s complex c) FTD g) Age d) GBGD d. The amyloid plaque: 1) Amyloid plaques are extracellular and diffuse initially 2) Later stages they are cored 3) 50–200 mm in diameter (cores) 4) Cored plaques: a) Surrounded by dystrophic neuritis b) Reactive glial inflammatory response c) Plaque core: (1) 70% of proteinaceous material is amyloid beta (derived from enzymatic cleavage of APP) (2) Abnormal organelles (3) Tau protein (4) Apo lipoprotein E (ApoE) e. Synaptic alternations: 1) Decreased presynaptic terminal density 2) Disconnected neurons 3) Synaptic pruning f. Cerebral amyloid angiopathy (CAA): 1) A feature of AD 2) Can occur separately 3) Associated with hemorrhagic stroke a) AD Dutch disease 4) ApoE allele predisposes for angiopathy in contra distinction for ApoE4 that predisposes for AD g. Granulovacuolar degeneration: 1) Mainly confined to the hippocampus 2) Vacuoles are found in pyramidal cells that contain a single granule: a) Reactive with anti neurofilament antibodies
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SECTION XVI. Dementia
h. Plaques and tangles noted in normal aging: 1) Less widely distributed 2) Few numbers; amyloid can be abundant with pathologic aging i. Distribution of pathology (amyloid plaques): 1) Amygdala 2) Hippocampus: a) Dentate gyrus (molecular layer) b) CA 1 and CA 3 c) Subiculum 3) Layers III, V of the entorhinal cortex 4) Layer II is NFT 5) Temporal parietal neocortex > frontal lobe 6) Laminar degeneration posterior cingulated cortex j. Histological diagnosis of AD requires both neuritic amyloid plaques and NFT’s in the neocortex
Dementia with Lewy Bodies (DLB)
A. General characteristics: 1. Alpha synuclein plaques in greater numbers throughout the cortex than expected B. Clinical features: 1. Initial deficiencies: a. Deficits of frontal subcortical abilities b. Decreased visuospatial skills 2. Later: a. Memory deficits C. Core components of the syndrome: 1. Fluctuating cognitive function with pronounced variation in attention 2. Recurrent visual hallucinations a. Formed; detached 3. Parkinsonism: a. Bradykinesia and rigidity b. Rare tremor c. Poor response to L-dopa 4. Associated features: a. Repeated falls b. Syncope and transient loss of consciousness c. Neuroleptic hypersensitivity d. Delusion (other than visual) often paranoid e. Urinary incontinence later than cognitive decline f. REM sleep disorder g. Depression D. Pathology: 1. The number of cortical LBs is variably correlated with the severity of the dementia: a. Temporal lobe Lewy Bodies correlate with visual hallucinations 2. Cortical Lewy Bodies: a. Lack a clearly definable central core and distinct peripheral corona b. Inclusions formed from aggregated masses of intermediate neurofilaments
c. Major antigenic components of LBs: 1) Presynaptic protein alpha synuclien 2) NF proteins 3) Ubiquitin (involved in the nonlesional intracellular degradation of cellular products) d. Cortical Lewy bodies occur: 1) Cingulate gyrus 4) Frontal cortex 2) Entorhinal cortex 5) Amygdala 3) Insular cortex
Chapter 3 Fronto Temporal Dementias (FTDs) A. General characteristics: 1. Less common and earlier onset compared to AD dementias 2. Approximately 5% of all primary dementias 3. Onset earlier than 65 years of age B. Clinically heterogenous and encompass: 1. Pick’s disease 2. Primary progressive aphasia in Pick’s disease 3. Familial progressive subcortical gliosis 4. Frontal lobe disorders lacking distinctive histology 5. Progressive aphasia with dementia 6. Frontal lobe degeneration with motor neuron disease 7. DDPAC (disinhibition-dementia-parkinsonism-amyotrophy complex) 8. Hereditary dysphasic disinhibition dementia 9. FTD with parkinsonism linked to chromosome 17 10. PPND (palliopontine nigral degeneration) C. Clinical features: 1. Deficits in behavior and social interaction: a. Occur early b. Out of proportion to the memory deficit c. Loss of personal hygiene and deficient grooming d. Loss of social graces e. Social withdrawal f. Disinhibition g. Impulsivity h. Distractibility i. Hyperorality; hyperphagia j. Stereotyped and perservative behaviors k. Depression l. Apathy m. Psychosis n. Obsessive stereotyped behavior o. Diminished speech output to mutism p. Decreased executive function q. Loss of judgment and insight 2. Expressive speech dysfunction: a. Loss of fluency b. Stereotypic speech
Chapter 3. Fronto Temporal Dementias (FTDs)
c. Echolalia 3. Associated neurologic signs: a. Early and prominent frontal release signs b. Incontinence after cognitive changes is present c. Parkinsonism later in the course of the disease d. Visuospatial memory, orientation functions are preserved e. Praxis is preserved 4. MRI: a. Frontal and anterior temporal lobe atrophy 5. AchE inhibitors are ineffective 6. Genetics of FTD: a. Familial in 40–50% of cases b. Variant with Parkinsonism: 1) Linked to chromosome 17q 21–22 (FTDP-17) 2) Families with FTD P-17 have: a) Abnormalities of tau protein c. Gene for tau: 1) On chromosome 17 close to or within the FTDP17 region 2) Expressed in neurons > glia 3) Has 6 isoforms 4) Important for microtubule stabilization binding and assembly 5) Splicing mutations occur in the FTDges
FTD Variants
1. Syndromes linked to FTD P-17: a. Palliopontine nigral degeneration (PPND) b. Familial multiple system tauopathy with presenile dementia (FMST) c. Familial progressive subcortical gliosis
FTD P-17 (Fronto Temporal Dementia and Parkinsonism)
A. General characteristics: 2. AD; chromosome q 21 B. Clinical features: 1. Age of onset 51 years 2. Parkinsonism 3. No resting tremor 4. Corticospinal tract degeneration without wasting or fasciculation 5. Supranuclear ophthalmoplegia: a. Apraxia of eyelid opening 6. Autonomic function spared early: a. Incontinence of bowel and bladder late 7. Seizures rare but may occur late in the course of the illness 8. Mean duration from onset to death is three years 9. Variability of phenotype within families
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10. Family linked to chromosome 3 with same clinical features C. EEG: 1. Normal until later in life D. Pathology: 1. Neuronal loss, gliosis and spongiosis: a. Frontal and temporal lobes b. Cingulate gyrus c. Substantia nigra pars compacta 2. Increased CSF tau protein 3. Ballooned neurons in the frontal lobe
FTDP-17 (P302 L) Mutation
A. General characteristics: 1. C to T change in exon 10 2. Codes for mRNA with four microtubule binding repeats (4R) 3. 4 R tau repeats aggregated in both gray and white matter
Disinhibition–Dementia–Parkinsonian–Amyotrophy Complex (DDPAC)
A. General characteristics: 1. FTD variant a. Chromosome 17 B. Clinical features: 1. Mean age at onset is 45 years of age 2. Disinhibition 3. Klüver-Bucy features 4. Schizophrenic behavior 5. Social withdrawal 6. Initial preservation of orientation, speed of processing and calculation 7. Hyperphagia 8. Later symptoms: a. Perseveration c. Decreased speech b. Constructional apraxia d. Poor calculation ability 9. Parkinsonism: a. Rigidity c. Postural instability b. Bradykinesia 10. Spinal cord: a. Fasciculation b. Muscle wasting C. Pathology: 1. Anatomic areas of involvement: a. Anterior temporal lobes d. Pyriform cortex b. Entorhinal cortex e. Amygdala c. Cingulate gyrus 2. Circumscribed laminar spongiosis: a. Limbic areas b. Association cortices 3. Neural intracytoplasmic inclusions:
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SECTION XVI. Dementia
a. Phosphorylated neurofilament lattice like formation with ubiquitin b. Located in brainstem nuclei, hypothalamus, and basal ganglia c. Negative for amyloid 4. Oligodendroglial cytoplasmic inclusions similar to those seen in multiple system atrophy
Pallido-Ponto-Nigral Degeneration (PPND)
A. General characteristics: 1. Missense mutations in exon 10 of the tau gene 2. Mutations in the intron adjacent to the exon 103 splice site: a. Encodes tau isoform with 4 MT (microtubule) binding repeats B. Clinical features: 1. Stage I: a. Mild dementia and parkinsonism 2. Stage II: a. Moderate Parkinsonism b. Dementia c. Dysarthria d. Pyramidal tract dysfunction e. Extraocular muscle dysfunction f. Sensory abnormalities 3. Stage III: a. Severe parkinsonism c. Dysphagia b. Dementia 4. Stage IV: a. Terminal 5. Dementia 6. Rapidly progressive parkinsonism 7. Begins > 30 years of age 8. Dystonia 9. Perservative vocalization 10. Pyramidal tract dysfunction C. Pathology: 1. Neuronal and glial rich tau (inclusions): a. Formed from aggregated neurofilaments b. Hyperphosphorylated tau proteins c. Morphological and biochemical patterns simulate: 1) Sporadic CBD 2) PSP
Familial Progressive Subcortical Gliosis (FPSG)
A. General characteristics: 1. AD B. Clinical features: 1. Onset in presenium 2. Slowly progressive course 3. Early clinical features: a. Personality change
b. Depression c. Disinhibition d. Degeneration of social graces e. Memory impairment f. Psychotic symptoms 4. Late clinical features: a. Progressive dementia b. Verbal stereotypies c. Decreased speech output d. Echolalia e. Features of Klüver Bury syndrome 5. Terminal clinical manifestations: a. Profound dementia c. Dysphagia b. Mutism d. Extrapyramidal signs C. Pathology: 1. Generalized cerebral atrophy: a. Frontal and temporal lobes most severely affected b. Fibrillary astrocytosis in subcortical white matter c. Subpial and deep layers of frontal and temporal lobe are affected 2. Tau mutation: a. over expression of soluble four repeat tau isoform b. causes neuronal and glial tau pathology
Hereditary Dysphasic Disinhibition Dementia (HDDD)
A. General characteristics: 1. AD; 17q 21–22 a. Not tangere specific B. Clinical features: 1. Global dementia 2. Disproportionate dysphasia 3. Frontotemporal symptoms C. Pathology: 1. Asymmetric frontotemporal atrophy (left side) 2. Status spongiosis 3. Neuronal loss in layer II of the cortex 4. Astrocytic reaction of the cortex
Progressive Language Disorder Due to Lobar Atrophy of FTD
1. Clinical features: a. Patients are heterogeneous b. Anomia is a prominent presenting complaint c. Language dysfunction includes: 1) Nonfluent and agrammatic 2) Fluent aphasia with profound loss of word meaning d. Associated features in some patients: 1) Associative agnosia 3) Behavior disorder 2) Personality change 2. SPECT and CT evaluation: a. Left hemisphere abnormalities
Chapter 3. Fronto Temporal Dementias (FTDs)
b. Bilateral fronto temporal cortices are atrophied 3. Pathology: a. Atrophy gliosis and spongiform change b. No senile plaques or neurofibrillary tangle
Clinical Similarities of PSG, DDPAC, FTD, PPND
1. 2. 3. 4.
Presenile age at onset Behavioral manifestations Variable degrees of frontal lobe atrophy Parkinsonism: a. Most sever in: 1) DDPAC 3) FSG 2) PPND 4) Less severe in FTD 5. Degeneration to varying degrees of: a. Caudate c. Substantia nigra b. Hippocampus 6. All four disorders may have: a. Different mutations in the same gene b. Variant expression of a single mutation c. Different genes in close proximity
Primary Progressive Apraxia in Pick’s Disease
A. General considerations: 1. Multimodal apraxia 2. No degradation of intelligence or deterioration of personality until late B. Clinical features: 1. Apraxia: a. Limb clumsiness b. Inappropriate positioning and alignment of fingers for specific movements c. Decreased speed of movement of the hands and fingers d. Gestural apraxia is evident 2. Pick’s disease component: a. Apraxia of speech: 1) Articulatory difficulty without language breakdown 2) Lesion of the left pars operculum rather than the pars triangularis 3) Buccofacial apraxia and dysarthria
4. 5. 6. 7. 8.
9.
a. Early nonfluent aphasia b. Echolalia c. Isolated word finding difficulty d. Relative preservation of auditory comprehension Aberrant motor behavior Disinhibition Euphoria Apathy Rare patients: a. Early memory loss b. Painful symptomatology Predictors of Pick’s disease a. Frontal dementia b. Early cortical dementia: 1) Aphasia 4) Memory (usually preserved) 2) Apraxia 5) Severe frontal lobe features 3) Agnosia c. Marked personality change at onset d. Klüver–Bucy symptomatology e. Absence of ideomotor apraxia f. Absence of gait abnormalities at onset
Frontal Lobe Dementia with Motor Neuron Disease
A. General considerations: 1. Occurs in approximately 30% of patients with ALS B. Clinical features: 1. Typical upper and lower motor neuron clinical findings C. Pathology: 1. Cortical degeneration; large cell loss, gliosis and spongiform change 2. Substantia nigra and cranial nerve involvement 3. Anterior horn loss 4. Ubiquitinated inclusions 5. Amygdala, thalamus striatus, substantia nigra are variably involved
Lacking Distinctive Pathology
A. General considerations: 1. Atrophy of the frontal lobes 2. Vacuolated second cortical layer 3. Astrocytosis of deeper layers 4. Hippocampus (CAI; subiculum involved)
Pick’s Disease
A. General considerations: 1. AD 2. Chromosome 17 B. Clinical features: 1. Early personality changes 2. Deterioration of social skills 3. Prominent language abnormalities:
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Pathologic Changes Common to all Frontal Lobe Dementias
1. Frontal and temporal lobe atrophy 2. Variable striatal and nigral involvement 3. Pick’s disease variable:
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SECTION XVI. Dementia
a. Loss of neurons in all layers of the frontotemporal cortex b. Microvacuolation c. Astrocytosis d. Intraneuronal inclusions (Pick’s bodies): 1) Hyperphosphorylated tau 2) Ubiquitin positive 3) Argyrophilic 4) Associated with ballooned neurons which are not int the same neuron as the Pick body
Differential Diagnosis of FTD Vs Alzheimer’s Disease
1. FTD: a. Early non-cognitive behavioral change b. Better calculation abilities than AD c. Decreased verbal output d. Reiterative speech e. Verbal stereotype and echolalia f. Visuospatial skills g. Less severe memory impairment less severe
Criteria for the Diagnosis of FTD
A. General considerations: 1. Character change and disordered social conduct are the dominant features 2. They maintain: a. Spatial skills c. Praxis b. Perception d. Memory B. Core diagnostic features: 1. Insidious onset with gradual progression 2. Decline in social conduct 3. Impairment of personal conduct 4. Emotional blunting 5. Loss of insight C. Associated clinical features of FTD: 1. Behavioral: a. Decline in hygiene and grooming b. Mental rigidity or inflexibility c. Distractibility d. Impersistence e. Hyperorality f. Dietary changes g. Perseveration h. Stereotypy i. Utilization behavior D. Speech and Language: 1. Altered speech output: a. A spontaneity c. Pressure of speech b. Economy of speech 2. Echolalilia 3. Perseveration
4. Mutism E. Neurological Examination: 1. Primitive reflexes 3. Akinesia and rigidity 2. Incontinence 4. Tremor F. Laboratory evaluation: 1. Neuropsychological tests: a. Impairment of frontal lobe function b. Absence of: 1) Amnesia 3) Perceptual spatial disorder 2) Aphasia c. EEG is normal d. Frontal and anterior temporal abnormalities by MRI, SPECT and PET scanning
Diagnostic Exclusion Features for FTD
1. Clinical: a. Abrupt onset; ictal events b. Early severe amnesia c. Spatial disorientation d. Myoclonus e. Corticospinal tract weakness f. Cerebellar ataxia g. Choreoathetosis 2. Diagnostic: 1. Brain imaging: a. Predominant post central structural or functional deficits b. Multifocal lesions on CT or MRI 2. Laboratory evaluation: a. Inflammatory markers b. Metabolic abnormalities Progressive nonfluent aphasia vs FTD: 1. Clinical features: a. Language: 1) Disorder of expressive language is the dominant feature rather than behavioral change (PPA) 2) Insidious onset and gradual progression 3) Nonfluent spontaneous speech with one of: a) Agrammatism b) Phonemic paraphasia c) Anomia d) Pressure of speech e) Idiosyncratic word usage f) Absence of phonemic paraphasias g) Surface dyslexia and dysgraphia h) Preserved calculation b. Behavior: 1) Loss of sympathy and empathy (FTD) 2) Narrowed preoccupation (FTD) 3) Parsimony (FTD) 4) Normal (PPA) c. Neurological examination: 1) Absent or late primitive reflexes (PPA)
Chapter 3. Fronto Temporal Dementias (FTDs)
2) Akinesia and rigidity (FTD) 3) Tremor (FTD) 4) Normal (PPA) d. Diagnostic evaluation: 1) Neuropsychological testing in temporal component of FTD: a) Profound semantic loss b) Failure of word comprehension c) Poor naming d) Decreased face and object recognition 2) Preserved: a) Phonology and syntax b) Elementary perceptual processing c) Spatial skills e. EEG is normal f. Pathology: 1) Structural and functional anterior temporal lobe defects
Differential Diagnosis of Progressive Nonfluent Aphasia vs. FTD
a. May feel that PPA may be a subgroup of FTD
PPA
1. Behavioral: a. Early preservation of social skills to a much greater degree than loss of language 2. Language: a. Agrammatism: 1) Omission or incorrect use of grammatical terms: a) Articles, prepositions, verbs, inflexion and derivatives 2) Phonemic paraphasia: a) Sound based errors b) Use of incorrect phoneme b. Motor deficit of speech: 1) Stuttering or oral apraxia 2) Repetition of parts of a word; particularly the first consonant c. Impaired repetition d. Some alexia and agraphia: 1) Phonemic paraphasias
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Semantic Aphasia tasks vs FTD
A. General characteristics: 1. Specific posterior speech disorder whereas FTD is primarily an anterior speech dysfunction B. Clinical features: 1. Fluent empty spontaneous speech 2. Reduced use of nominal terms 3. Increased use of broad generic terms 4. Loss of word meaning 5. Disorder of single word comprehension C. Semantic paraphasias: 1. Semantically related words replace correct nominal terms 2. Super ordinate category substitution (e.g. animal for camel) 3. Coordinate category errors (dog for elephant) D. Prosopagnosia: 1. Inability to recognize familiar faces 2. Auditory or somatic modalities confer immediate recognition E. Logo clonic and festinant speech: 1. Logo clonic: a. Effortless representation of the final syllable 2. Festinant speech: a. Rapid effortless reiteration of individual phonemes 3. Rapid loss of train of thought 4. Associative agnosia: a. Impairment of object identity: 1) Tactile and visual sphere is preserved 5. Preserved: a. Matching and drawing reproduction b. Single word repetition c. Relative preservation of repetition of sentences d. Ability to read aloud and to write to dictation (orthographically regular words) Associated Clinical Diagnostic Features
1. 2. 3. 4. 5.
Pressure of speech Idiosyncratic word usage Absence of phonemic paraphasias in spontaneous speech Preserved calculation Parsimony (abnormal preoccupation with money and financial economy) 6. Loss of sympathy and empathy
Diagnostic Evaluation of PPA
Diagnostic Evaluation
Neuropsychology: 1. Presence of normal scores on one or more tests of frontal lobe function 2. No loss of information from immediate to delayed recall 3. Normal face and object recognition 4. Normal scores on spatial cognitive tasks
1. Neuropsychological testing: a. Profound semantic loss b. Failure of word comprehension and naming c. Poor face object recognition 2. Preserved a. Phonology and syntax
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SECTION XVI. Dementia
Olivo Ponto Cerebellar Atrophy (OPCA)
A. General characteristics: 1. Autosomal dominant or recessive forms B. Clinical features: 1. Appendicular ataxia 2. Dysarthria 3. Cranial nerve degeneration and retinal degeneration in variant forms 4. Parkinsonism 5. Mild peripheral neuropathy C. Pathology: 1. Neuronal loss and gliosis 2. Found in oligodendrocytes 3. Ubiquitin positive 4. Inferior olives a. Atrophy, gliosis, neuronal loss
Cortico Basal Ganglionic Degeneration (CBGD)
A. General characteristics: 1. Chromosome 17; H haplotype B. Clinical features: 1. Asymmetric 2. Akinetic rigid syndrome 3. Apraxia (ideomotor, ideational) 4. Parietal cortical sensory loss associated with: a. Limb akinesias (loathness to move) b. Cataleptic posture: 1) Usually levitation of an extremity 5. Alien hand syndrome: a. Posterior type b. Failure to recognize the hand as one’s own c. Groping movements (usually anterior alien hand) d. Complex involuntary movement 6. Atypical clinical features: a. Marked speech disturbance b. Dementia c. Complex tremor d. Rarely the hand is aggressive (attempts to strangle the patient) C. Pathology: 1. Ballooned achromatic neurons: a. Neurofilament protein positive 2. Astrocytic plaques: a. Annular clusters of thick short tau positive deposits b. Within distal processes of cortical astrocytes 3. Pick’s type b: a. Cortical degeneration with swollen chromatolytic neurons
1. Chromosome 17q21–q22 3. Hi haplotype 2. AO/AO allele B. Clinical features: 1. Akinesia and axial rigidity 2. Head held in extended position (to utilize vestibular ocular reflexes for downgaze) 3. Dysarthria 4. Pyramidal tract dysfunction 5. Failure of downgaze (primarily) 6. Frequent falls (severe loss of postural reflexes) 7. Deep nasolabial folds 8. Sexual disinhibition 9. Frontal lobe dementia 10. Arm levitation 11. Eye lid apraxia (inability to open eyes on command) 12. Fall backwards 13. Stimulus sensitive myoclonus 14. Bilateral grasp reflex 15. Increased reflexes 16. Extensor posturing C. Pathology: 1. Neurofibrillary tangles: a. Flame straight filaments, distinct from those of AD b. Astrocytic gliosis which are paired filaments 2. Lesions noted in the: a. Superior colliculi d. Reticular formation b. Pretectal areas e. Subthalamic nucleus c. Periaqueductal gray Differential Diagnosis of Spontaneous Arm Levitation
1. 2. 3. 4.
Parietal lobe lesion (posterior alien hand) CBGD (cortico basal ganglionic degeneration) PSP Dorsal column lesions (associated with flailing movements) 5. Hemiatrophy hemiparkinsonism Differential Clinical Features between CBGD and PSP
1. PSP: a. Vertical gaze (down gaze) abnormality early b. Unilateral dystonia early 2. CBGD: a. Striking asymmetry at presentation b. Cortical parietal sensory loss c. Stimulus sensitive and action induced myoclonus d. Severe limb apraxia e. Vertical gaze paresis is late The Tauopathies
Progressive Supranuclear Palsy (PSP)
A. General characteristics:
FTD-17 Parkinsonism
1. FTD-17 chromosome dementia variants:
Chapter 4. Prion Disease
2. 3. 4. 5. 6.
a. PPND (pedunculo pallidal pontine nigral degeneration) b. DDDAC (depression-disinhibition amyotrophy complex) c. FSCG (familial subcortical gliosis) d. HDDD e. FTDP-17 (missense mutations): 1) Exons 9, 10, 12 2) 3 intronic mutations (regulate alternative splicing of exon 10) f. PPA (primary progressive aphasia) CGBD (corticobasal ganglionic degeneration) PSP: a. Classic atypical form missense mutism (R406W) Parkinson’s disease ALS dementia complex of Guam Head trauma Postencephalitic parkinsonism
Lesion Common Diseases with Dementia as a Major Clinical Feature
Hallervorden Spatz Disease
A. General characteristics: 1. AR; chromosome 20p12.3-p13 2. Pantothenic acid kinase 2 deficiency (PANK2 gene) B. Clinical features: 1. Onset in childhood, teens, adult 2. Basal ganglionic type rigidity 3. Dysarthria 4. Athetosis 5. Pyramidal tract dysfunction C. Pathology: 1. Neuronal loss in SNPC and the GPi/GPe 2. Pigment deposition in the same neurons (SN/GP) a. Iron pigment deposition b. Axonal swelling and dystrophic changes c. Spheroids d. Fe++ deposition in the same areas seen in infantile neuroaxonal dystrophy
Post Encephalic Parkinsonism
A. General characteristics: 1. Pandemic of 1918 (apparently of specific virus) 2. Rare sporadic cases B. Clinical features: 1. Autonomic storms (fluctuating blood pressure, sweating, pupillary dilatation) 2. Oculogyric, crisis, ophthalmoplegia 3. Volatile personality changes 4. Akinetic rigid state 5. Prominent tremor 6. Sleep inversion
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7. Central respiratory irregularities 8. Obsessive compulsive behavior 9. Somnolence C. Pathology: 1. Midbrain atrophy 3. Gliosis 2. Neurofibrillary tangles
Wilson’s Disease
A. General considerations: 1. AR; chromosome 13 B. Clinical features: 1. Onset in teenage years 2. Kayser–Fleisher ring (copper-deposition on Descemet’s membrane) 3. Slow mental deterioration 4. Wing beating tremor (proximal flinging of the arms) 5. Hypotonia 6. Hyperreflexia C. Deficiency of ceruloplasmin: 1. Copper deposition in the brain 2. Destruction of the liver by copper induced cirrhosis D. Pathology: 1. Hepatolenticular degeneration 2. Spongiform degeneration: a. Necrosis b. Cavitation c. Putamen > globus pallidus > thalamus > cortex d. Alzheimer’s type I glia (large, pale, multilobulated astrocytic nuclei) e. Opalski cells: 1) Found in the BG 2) Large astrocytes 3) Eccentric small nuclei 4) Abundant foamy cytoplasm 5) Copper deposits
Chapter 4 Prion Disease
A. General considerations: 1. Prion protein exists in normal healthy brain: a. Coded by the host genome b. Located on chromosome 20; PRNP gene 2. Exists in two isoform: a. PPC cellular isoform (host protein): 1) Exists in normal brain 2) Proteinase sensitive PrP (sen) b. PrP sc (scrapie) isoform (altered protein): 1) Proteinase resistant form
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3.
4.
5.
6.
SECTION XVI. Dementia
c. The function of cellular (normal) isoform of PrP is unknown: 1) PrP is a normal constituent of the neuronal cell membrane 2) Transported along axons and accumulates at the neuromuscular junction 3) Polymorphism at the codon 12 q of the PrP gene (val–val): a) Increased cognitive impairment in the elderly b) 129 homozygosity at codon 12 q for sporadic form c) Val/val at codon 129 for the iatrogenic and acquired form d) Met/met at codon 129 for the new variant Hereditary form of prion disease: a. Transmission of a mutant PrP gene: 1) Produces an altered protein 2) 10–15% of prion diseases are hereditary b. Infection with the altered protein: 1) Introduction into normal host brain causes: a) Conversion of the normal host PrP into the abnormal PrP isoform b) Alpha helix of the normal protein is converted to the beta sheet c) The process facilitated by another protein d) Evidence of efficient prion convulsion is a short incubation time e) Prion strain properties are enciphered in the tertiary structure of PrP sc f) This influences the molecular interactions between the normal and disease specific isoform Mutations in the PrP gene: a. Chromosome 20 b. Cause conformational changes of the PrPc protein: 1) Shift from the normal alpha helix to a beta sheet 2) Affects the degree of glycosylation of the PrPc protein Secondary tertiary structure of PrP sc determines: a. Size of protein b. Differences c. Different mutations cause different pathologic changes: 1) Spongiosis 2) Amyloidosis 3) Neurofibrillary degeneration 4) Congophilic angiopathy 5) Gliosis 6) Neuronal loss d. The tertiary structure of the PrP sc fragment causes the different pathologies Prion protein (PrP sc) fragments are: a. Neurotoxic b. Fibrillogenic c. In a beta sheet secondary structure d. Proteinase resistant
Creutzfeldt–Jacob Disease
A. General considerations: 1. Average of 1 case/million people 2. 10% have family history of presenile dementia that is not CJD 3. Prolonged incubation > 20 years have been noted in infectious etiologies 4. Human transmission described from: a. Corneal transplant c. Dural graft b. EEG electrodes e. Growth hormone 5. Invariably fatal B. Clinical features: 1. Rapidly developing dementia with myoclonus 2. Early stages: a. Gait ataxia c. Personality change b. Visual disturbances d. Dizziness 3. Later stages: a. Aphasia b. Apraxia c. Confusion d. Stupor e. Myoclonic jerks usually occur 2–3 months from onset of the disease 4. In 5–10% of patients the illness may last > 2 years
Classification of Classic Form by the Underlying PrP Polymorphism at Codon 129
A. General considerations: 1. PrPsc type 1: a. Met codon 129: 1) Usual CJD presentation of dementia and myoclonus (CJD-M/M1) 2) Size of the protease resistant core 21 kD 2. PrP sc type II: a. Size of the protease resistant core 19 kD b. Met1/met (CJD M/M2): 1) Longer disease duration and lack of myoclonus c. Met/Val: 1) Related to variant with Kuru plaques (CJD-M/V) d. Val/Val: 1) Ataxia and late dementia (CJD-V/V) e. CJD with M/V and V/V polymorphism at 129: 1) Less pathology in the neocortex 2) Involve primarily the deep nuclei and cerebellum B. EEG findings: 1. Distinction repetitive sharp waves 2. Intervals of 1–2 Hz (periodic complexes) 3. Progressive slow background C. MRI: 1. Increased diffusion in the cortex 2. T2 weighted lesions in the pulvinar D. Pathology:
Chapter 4. Prion Disease
1. Cerebral atrophy 2. Spongiosis: a. Vacuoles within the neuropil that contain membrane fragments b. Gliosis c. Neuronal loss d. Abnormal fibrils e. Pathological changes are to a different degree and combination of: 1) Fragment size 2) Tertiary structure of the protein 3. Type I/II coexist 33% of the time
Pathologic Distribution of Involvement by Polymorphism of Codon 129
1. Met/Met at codon 129: a. Mild b. Occipital lobe c. Low PrP sc load d. Few focal PrP sc amyloid deposits e. No amyloid plaques 2. Met/Val at codon 129: a. Multiple lesions throughout the brain b. Parahippocampal gyrus particularly involved c. Numerous plaques 3. Val/Val at codon 129: a. Younger age at onset ( 80 year of age have approximately a 15% incidence 4) Japan has a high prevalence of vascular dementia; >50% of all demented patients 5) Prevalence of dementia is approximately 15% of stroke patients >60 of age 6) Vascular disease mixed with ALZ possibly 30– 35% of dementia B. General characteristics: 1. Single brain lesions (unless strategic locations) in general do not lead to dementia 2. Strategic brain lesions: a. May affect attention b. Have a global effect on behavior 3. Protracted time course of months to years is associated with dementia: a. Characteristics of the lacunar state b. Global encephalopathy over hours to days: 1) Characteristic of the vasculitis of autoimmune disease 4. Vascular dementia progressive with the exception of: a. Intracranial hemorrhage b. Cardiac arrest
Dementia from Strategic Vascular Lesion
A. General characteristics: 1. Some patients’ mental changes are the presenting or only manifestation of stroke: a. Approximately 15% of strokes (may have minimal transient motor or sensory symptoms or signs) b. Small cortical or subcortical infarcts or hemorrhages that are asymptomatic c. Cognitive deficit determined by location
Middle Cerebral Artery
1. Angular gyrus syndrome (posterior division of MCA) 2. Acute confusional states: a. R > L MCA b. Infarctions of: 1) Middle frontal gyrus 2) Middle temporal gyrus 3) Inferior parietal lobule 4) Head of the left caudate nucleus 5) Right temporo-parietal-occipital cortex c. Possible global deficit of selective attention causes confusion: 1) Clinical deficits: a) Inattentive to relevant stimuli b) Distractible c) Arousal is intact d) Lack of concern for the illness e) Disorientation f) Anomia g) Inability to maintain coherent thought h) Restless agitated and at times aggressive d. Most acute confusional states last: 1. Days to weeks 2. Occasionally they are permanent
Anterior Cerebral Artery
1. ACA branch occlusions with dementia: a. Fronto polar artery b. Callosomarginal artery c. Neuroanatomical structures destroyed: 1) Orbital cortex 2) Mediofrontal cortex d. Clinical signs: 1) Mental inertia (abulia) 2) Indifference and apathy 3) Emotional blunting 4) Infarct causes subtle deficits of: a) Divergent thinking b) Temporal organization c) Executive and planning strategies 5) Behavior may be triggered by environmental stimuli: a) Imitation behavior b) Utilization behavior
Posterior Cerebral Artery
1. Infarction of varying degree in: a. Occipital lobe c. Midline mesencephalon b. Mediotemporal areas d. Thalamic nuclei 2. Occipital lobe lesions and behavior: a. Color vision (lingual fusiform gyrus)
Chapter 6. Secondary Dementias
b. Color naming c. Alexia without agraphia (visual field deficit in the left occipital lobe; concomitant damage of the corpus callosum) d. Visual distortions and hallucinations (perceived in the hemianopic or entire VF) e. Bilateral lesions: 1) Visual agnosia 2) Cortical blindness 3. Medial temporal lobe infarction: a. Severe amnestic deficit: 1) Often bilateral involvement 2) Severe hippocampal formation damage 3) Never occurs in isolation; it occurs with anoxia, ischemia of cardiac arrest or severe hypotension (heart or abdominal surgery)
Subcortical Infarction
1. Thalamic vascular disease and dementia: a. Intralaminar artery infarction from P1 (first division of the posterior cerebral artery) b. Single artery supplying both territories of the intralaminar artery (the thalamic peduncle of Percheron) c. Small arteries of the posterior communicating artery: 1) Supply the anterior thalamus 2. Clinical features: a. Bilateral involvement: 1) Disturbance of consciousness 2) Ocular and eye movement deficits (vertical gaze) from midbrain lesions 3) Unilateral infarction of the thalamus: a) Inattention b) Motor neglect c) Anterograde amnesia d) Left sided lesions (aphasia): (1) Fluent paraphasic speech (2) Perseverative speech (3) Anomia (4) Spared repetition e) Right sided lesion: (1) Hemineglect
Multi-Infarct Dementia
1. Most common form of vascular dementia 2. Accrued defects in: a. Supratentorial nuclei and white matter b. Basal ganglia c. Subcortical white matter d. Internal capsule e. Lesions are bilateral 3. Clinical features: a. Patients older than 50: men > women b. Episodic focal deficit that include: 1) Hemiparesis 5) Confusion 2) Hemisensory deficit 6) Ataxia 3) Aphasia 7) Diplopia 4) Dysarthria 8) Dizziness c. Partial recovery; usually minimal residual from each episode d. Cognitive deficits occur early or late: 1) Dependent in location of the lesions e. Prior to cognitive decline: 1) Gait disturbance 2) Urinary incontinence f. Concomitant medical problems in most patients: 1) HCVD 2) CHF 3) Diabetes mellitus 4) Intermittent claudication 5) Angina 6) Myocardial infarction 7) Generalized vascular disease 8) Valvular disease
Primary Accumulation of Deep Subcortical Lesion Cause
1. 2. 3. 4. 5.
Slowed psychomotor processing Decreased attention Decreased concentration Poor memory Inertia
Associated Neurological Signs Caudate Lesions
1. Disruption of caudate frontal lobe circuits 2. Left caudate head: a. Acute agitation b. Thalamic aphasia: 1) Disruption of fibers to AV and DM thalamic nuclei 3. Frontal lobe syndrome
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1. Pyramidal tract dysfunction 4. Pseudobulbar palsy 2. Spasticity 5. Hypomimia 3. Parkinsonism 6. Instability of gait
Accumulation of Cortical Lesions Causes:
1. Aphasia 3. Apraxia 2. Visuospatial deficits 4. Amnesia
SECTION XVI. Dementia
704 Mixed Cortical and Subcortical Forms
Vascular Dementia Compared to AD
1. Insight infrequently preserved
1. Less severe memory deficit 2. More severe frontal lobe deficits: a. Apathy c. Executive dysfunction b. Lack of initiative 3. Incontinence 4. Gait disturbance 5. Clinical progression and duration of dementia is more variable
Both Cortical and Subcortical Minimal Ischemic Deficits
1. May have abrupt onset 4. Depression 2. Step wise deterioration 5. Fluctuating course 3. Nocturnal confusion
Binswanger’s Disease MRI Evaluation
1. Infarctions in multiple cortical areas 2. Lacunar infarction of the basal ganglia, thalamus, internal capsule, centrum semiovale 3. T2 weighted lesions around the ventricles (“ventricular capping”) 4. Large strategic infarcts 5. Periventricular white matter lesions prominent on T2 weighted images 6. Ventricular enlargement 7. Loss of between 50 ml to 100 ml of brain tissue is necessary for multi infarct dementia: a. If dementia is present with less than this amount of tissue loss there is concomitant AD
Dementia of Lacunar Infarction
1. “État e lacuniere” 2. The degree of dementia accompanies the degree of white matter destruction 3. Associated closely with HCVD 4. Numerous microscopic infarcts in the cortex cause cortical granular atrophy
Inherited Vascular Diseases Associated with Dementia
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
CADASIL HCHWA (Icelandic) HCHWA (Danish) HCHWA (British) HERNS Moya-Moya disease Hereditary hemorrhagic telangiectasia Fibromuscular dysplasia PXE (pseudoxanthoma elasticum) Homocystinuria
A. General characteristics: 1. Diffuse white matter damage of vascular etiology 2. Deficient blood supply leading to blood vessel wall damage B. Clinical features: 1. Progressive longstanding dementia 2. Subacute neurologic symptoms and signs 3. Patients are 50–70 years old 4. Males and females are equally affected 5. Usually hypertensive patients 6. Occipital preponderance C. Pathology: 1. Brain weight is normal 2. Often associated with atherosclerosis of large vessels 3. Enlargement of lateral and third ventricle 4. Periventricular white matter myelin pallor 5. Lacunes in deep gray matter of the pons 6. Minor degrees of cortical infraction 7. Myelin changes are most severe in: a. Frontal lobe b. Parietal and occipital lobe c. Bilateral distribution usually symmetrical d. Increased size of Virchow–Robin spaces e. Deficient blood supply due to vessel wall changes HCVD D. Imaging evaluation: 1. Lateral ventricular enlargement more prominent posteriorly
Normal Pressure Hydrocephalus
Epidemiology
A. General characteristics: 1. Probably 2–3% of dementias 2. Occurs in sixth and seventh decade 3. Two specific groups of NPH patients: a. Secondary to a disease or injury: 1) Predisposes to obstruction of CSF flow or reabsorption
Chapter 6. Secondary Dementias
2) Predisposing causes: a) Subarachnoid hemorrhage b) Head injury c) Meningitis d) Aqueductal stenosis (that obstructs) e) Syringomyelia f) Basilar 4. Ventricular enlargement causes: a. Stretch of the long descending corticospinal leg fibers that are periventricular (increased reflexes and gait apraxia) b. Bladder fibers: 1) Paracentral lobule fibers to the frontal lobe become dysfunctional c. Cognitively important fibers that are affected: 1) Cortico-cortical 2) Transcallosal B. Clinical features in sequence of development: 1. Gait disturbance 2. Dementia (subcortical in type): a. Slowing of information processing b. Decreased attentiveness c. Poor concentration d. Apathy e. Poor abstract thought f. Memory relatively well preserved 3. Falling backwards 4. Urinary incontinence C. Pathology: 1. Normal brain weight 2. Well preserved cortical ribbon 3. Minimally thinned corpus callosum 4. Mild pallor of periventricular white matter 5. Often constant: a. Vascular pathology b. Alzheimer’s pathology D. Imaging evaluation: 1. Severely dilated lateral and IIIrd ventricles 2. Absence of significant cortical atrophy 3. Dilated temporal horn out of proportion to the others ventricles 4. Transventricular edema 5. Altered CSF flow through the cerebral aqueduct
Metabolic Disease Associated with Dementia
1. Mitochondrial cytopathies: a. MELAS e. LHON b. KSS f. COX dehydrogenase c. MNGIE g. PDHC d. Leigh’s disease h. Cytochrome oxidase deficiency Renal Failure
A. General characteristics:
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1. Patients on hemodialysis 2. Lessened in frequency with aluminum free dialysates B. Clinical features: 1. Slowly progressive course 4. Myoclonus 2. Occasionally remittent 5. Seizures 3. Dysarthria 6. Dysphasia C. EEG: 1. Paroxysmal sharp waves and polyspike wave forms
Uremic Encephalopathy
A. General characteristics: 1. HCVD 2. Anemia 3. Blood uremia nitrogen > 60 mg/dl 4. Parathyroid hormone may be involved in the cognitive changes of uremia B. Clinical features: 1. Cognitive defects in all spheres 2. Memory deficits 3. Process fluctuates C. Pathologic features: 1. Subdural hemorrhage in 1–3% of patient 2. Generalized and variable neuronal loss 3. Perivascular necrosis and demyelination 4. Neuroanatomical areas of involvement: a. Cerebral cortex b. Subcortical nuclei of the brainstem c. Cerebellum 5. Alzheimer type 2 astrocytes are prominent
Liver Failure with Dementia
A. General characteristics: 1. Probably directly related to serum ammonia level 2. Liver has direct effect on Alzheimer type II glia B. Clinical features: 1. Acquired hepatolenticular degeneration: a. Occurs in patients with several episodes of hepatic encephalopathy; usually cirrhotic patients b. Subcortical dementia c. Falling backwards d. Parkinsonism e. Severe dysarthria f. Choreoathetosis C. Pathology: 1. Patchy cortical laminar or pseudo laminar necrosis 2. Polymicrocavitation at the corticomedullary junction and the striatum 3. Diffuse Alzheimer’s type 2 astrocytosis 4. Neuronal loss in the cortex, cerebellum and basal ganglia
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SECTION XVI. Dementia
Thyroid Failure with Dementia
Vitamin B12/Folic Acid Deficiency
A. General characteristics: 1. Myxedema madness 2. Hashimoto’s encephalopathy 3. Apathetic hyperthyroidism B. Clinical features of myxedema: 1. Lethargic; bradyphemic 2. Subcortical dementia 3. Associated neurologic findings: a. Proximal myopathy b. Ataxia (Purkinje cell loss) c. Hearing loss d. Occasional facial pain (mucopolysaccharide invasion of the Vth nerves) e. Bilateral carpal and tarsal tunnel syndromes f. Sensorimotor neuropathy g. Delayed relaxation phase of reflexes C. General medical features: 1. Interstitial deposition of hydrophilic muccopolysiarides with retention of: a. Fluid c. No increased ADH b. Sodium 2. Scleromyxedema: a. Generalized papular eruption b. Dermal fibroblast proliferation c. Monoclonal paraproteinemia d. Clinical features: 1) High fever 3) Coma 2) Seizures 4) Dermatoneuro syndrome e. Laboratory evaluation: 1) Increased CSF protein and IgG 2) Increased interleukin-6 (IL6) driving the encephalopathy
A. General characteristics: 1. Neurological signs and symptoms: a. Precipitated by nitrous oxide anesthesia b. Folate administration if both B12 and folate are deficient c. May occur with low normal levels in some patients B. Clinical features: 1. Apathy 2. Gradual intellectual deterioration 3. Associated neurological features: a. Loss of cranial nerve I b. Optic neuropathy c. Subacute combined degeneration of the spinal cord d. Ataxia 4. Folic acid deficiency: a. Usually mild cognitive impairment b. Associated with mania (megaloblastic mania)
Addison’s Disease
A. General characteristics: 1. Most due to autoimmune disease 2. Rarely the Tbc or adrenoleukodystrophy in the USA 3. Associated autoimmune diseases: a. B12 deficiency b. Thyroid deficiency c. Autoimmune neuropathy d. MG e. Peripheral neuropathy f. Diabetes mellitus B. Clinical features: 1. Personality change 2. Apathy 3. Cognitive impairment 4. Flexed posture 5. Thin muscles (type II atrophy) 6. Severe fatigue; asthenia 7. Increased K+ in association with hyponatremia 8. Depressed reflexes
Chronic Hypoglycemia
A. General characteristics: 1. Multiple episodes of seizures and coma lead to the neurological sequela B. Clinical features: 1. Gradual deterioration of intellectual function 2. Associated with: a. Motor neuropathy c. Involuntary movements b. Ataxia C. Pathology: 1. Neuroanatomical areas of neuronal loss: a. Neocortex layers III–VI b. Purkinje cell loss c. Globus pallidus internus (Gpi) d. Anterior horn cell
Calcium Metabolism (Hyper)
A. General characteristics: 1. Usually cognitive deficits at 13 mg/dl 2. Metastatic disease, hyperthyroidism, hyperparathyroidism are the major etiologies; immobilization in young patients with rapid bone turnover B. Clinical features: 1. Lethargy progressing to stupor 2. Early stages poor cognitive function 3. Associated neurological findings: a. Absent reflexes c. Absent bowel sounds b. Profound lethargy 4. In association with hyperparathyroidism: a. Muscle aches and cramps b. Rare pseudo ALS syndrome:
Chapter 7. Adult Lysosomal Disorders with Dementia
1) Fasciculating tongue 2) Hyperactive reflexes 3) Muscle weakness (proximal)
Hypocalcemia
A. General characteristics: 1. Often seen in uremic states 2. Hereditary and acquired hypoparathyroidism 3. Vitamin D deficiency 4. Acute pancreatitis B. Clinical features: 1. Cognitive impairment 2. Neuromuscular irritability: a. Chvostek’s & Trousseau’s sign b. Hyperactive reflexes 3. Seizures 4. Asterixis 5. Basal ganglia dysfunction and calcification
a. Heads to galacto sialidosis 4. Defect in saposin β: a. Causes a disorder similar to metachromatic leukodystrophy Adult form: 1. Onset may be in the first decade 2. Slowly progressive 3. Dystonia 4. Spasticity 5. Ataxia 6. Myoclonus 7. No visceral involvement Pathology (adult type 3): 1. Minimal storage of gangliosides in cerebral cortex 2. Atrophy of the caudate, putamen and globus pallidus (neural loss and gliosis) 3. Meganeurite formation noted in the basal ganglia and pyramidal neurons of the cortex 4. Stored ganglioside is PAS positive 5. No vacuolated lymphocytes
Cushing’s Syndrome (Iatrogenic or Organic)
A. General characteristics: 1. Primarily: iatrogenic; either steroid administration; adrenalectomy 2. Sterol hydroxylase 22 deficiency 3. Adrenal tumors B. Clinical features: 1. Behavioral change: a. Steroid psychosis c. Depression b. Mania 2. Subcortical dementia (with withdrawal) 3. Proximal myopathy 4. Pseudo tumor cerebri (with withdrawal)
Chapter 7 Adult Lysosomal Disorders with Dementia GM1 Gangliosidosis (Type 3)
A. General characteristics: 1. Chromosome 3 2. β-galactosidase: a. Requires a protective protein that is encoded on chromosome 20 (stabilizes β-galactosidase) b. Activates neuraminidase c. Activates saposin β: 1) An activator protein 2) A physiological detergent within the lysosome 3. A defect in protective protein:
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GM2 Gangliosidosis
A. General characteristics: 1. Tay Sachs disease: a. Deficiency of hexosaminidase A 2. Sandhoff’s disease: a. Deficiency of hexosaminidase A and B 3. AB variant: a. Deficiency of ganglioside activator protein
GM2 Gangliosidoses
A. General characteristics: 1. AR inheritance 2. Hexosaminidase A locus: a. Alpha subunit b. Chromosome 15 3. Hexosaminidase B locus: a. Beta subunit b. Chromosome 5 B. Clinical features: 1. Infantile form (all types same signs): a. Onset 3–6 months with developmental delay b. Mental retardation c. Macrocephaly d. Exaggerated startle response e. Blindness f. Cherry red spot in the retina g. Seizures 2. Juvenile onset: a. Spinocerebellar symptoms
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SECTION XVI. Dementia
Hexosaminidase A Deficiency in Adults (Type B)
A. General characteristics: 1. Mutations in the ∞-subunit; does not associate with β subunit 2. Type B: a. Low hexosaminidase A activity B. Clinical features: 1. Slowly progressive deterioration from early childhood 2. Most common presentation is motor neuron disease 3. Ataxia 4. Dysarthria 5. Recurrent psychosis 6. No seizures 7. No ocular abnormalities 8. Tremor 9. Peripheral neuropathy C. Pathology: 1. Large increase of GM2 ganglioside: a. Less storage in cortex of ganglioside than in infantile or juvenile form b. Storage in brainstem, cerebellum, basal ganglia and spinal cord c. Co-existent lipofuscin stage D. Laboratory evaluation: 1. Enzyme assay of white blood cells or fibroblasts 2. Assay for β-galactosidase activity
Adult Batten’s Disease (Kufs’ Disease)
A. General characteristics: 1. AR inheritance 2. Chromosome; gene CLN4 B. Clinical features: 1. Type A: a. Onset at approximately age 30 b. Progressive myoclonic epilepsy c. Dementia d. Ataxia 2. Type B: a. Behavioral changes c. Facial dyskinesia b. Dementia C. Pathology: 1. Excessive lipofuscin like substance in brain neurons and GI tract 2. Deposition in mega neurites of the basolateral amygdaloid complex 3. Storage may be layers III–VI of the cerebral cortex 4. Involvement of basal ganglia and brainstem nuclei 5. No vacuolated lymphocytes
Niemann–Pick Disease
A. General characteristics: 1. Group 1: a. Deficient sphingomyelinase: 1) Type A. Neurovisceral: a) Occurs in infants, juveniles and adults 2) Type B: a) Visceral only b) Occurs in infants, juveniles and adults 2. Group 2: a. No sphingomyelinase deficiency: 1) Type C: a) Pure visceral form B. Clinical features: 1. Type A: (infantile, juvenile and adult form): a. Clinical features (adult form): 1) Variable hepatosplenomegaly 2) Dementia 3) Spasticity 4) Seizures
Group II (Type C)
A. General characteristics: 1. Not sphingomyelinase deficient B. Clinical features: 1. May be very late onset (age 59) 2. Adults with dementia 3. Ataxia 4. May have unexplained splenomegaly 5. Dystonia in 25% of patients 6. Loss of vertical eye movements 7. Interfamilial variation of phenotype C. Pathology: 1. Group I (sphingomyelinase deficient): a. Enlargement of the liver and spleen b. Slight brain atrophy c. neuronal and glial ballooning d. Foamy histocytes: 1) Contain cholesterol esterase (sudanophilic) 2) Globus pallidus; substantia nigra and the dentate nucleus e. Niemann–Pick cell: 1) 20–90 μm; foamy histocyte 2) Filled with uniform vacuoles 2. Type II (sphingomyelinase is present): a. Cerebral atrophy b. Neuronal ballooning: 1) Basal ganglia; brainstem and spinal cord are affected c. Axonal swelling (contains finely granular storage material) d. Defect of intracellular utilization of cholesterol
Chapter 7. Adult Lysosomal Disorders with Dementia Gaucher’s Disease
A. General characteristics: 1. Genetics: a. AR b. Chromosome 1 q 21 (mutation L444P) c. Deficient glucocerebrosidase B. Clinical features: 1. Bone pain (vascular changes in the metaphysis of long bones) 2. Collapse of vertebral bodies with spinal cord compression 3. Other patients: a. Easy bruisability b. Myoclonic epilepsy (adult) c. Horizontal gaze palsy (juvenile) d. Spasticity C. Pathology: 1. Gaucher cells are seen perivascularly 2. Neuronal loss in cortex layer III and V of the cortex; the cerebellum and basal ganglia 3. Gaucher cell: a. 20–100 μm b. Cytoplasmic fibrillar material; PAS positive
Metachromatic Leukodystrophy
A. General characteristics: 1. Chromosome 22; AR 2. Deletion splice mutations and substitutions 3. Deficit of aryl sulfatase A B. Clinical features: 1. Age of onset is 20–50 2. Present with subtle organic brain syndrome: a. Impaired concentration b. Memory dysfunction c. Schizophrenic behavior d. Emotional lability 3. Seizures are rare: a. Duration of illness is approximately 14 years b. Unusual movements c. Increased reflexes d. Spasticity e. Rare presentation occurs without psychiatric symptoms 4. Variant of arylsulfatase A gene mutation: a. D281 Y b. Adult patient c. Slowly progressive psychiatric and cognitive decline 5. Pseudo deficiency of arylsulfatase A: a. Mutations in the gene b. No disease produced c. No disease produced
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d. Two patients reported with abnormal neurological findings with pseudo arylsulfatase A deficiency C. Pathology: 1. Loss of myelin throughout the brain 2. Neuronal depositions of sulfatide in: a. Basal ganglia d. Spinal cord neurons b. Dentate nucleus e. μ fibers are spared c. Brainstem nuclei 3. Peripheral nerves: a. Loss of myelinated fibers b. Sulfatides in macrophages and Schwann cells
Mucosulfatidosis
A. General characteristics: 1. Pathological changes of MLD and gross neuronal storage of ganglioside coexist 2. Adult onset forms described 3. Multiple sulfatase deficiency (or Austin variant of MLD) B. Clinical features: 1. Ichthyosis 2. Retinitis pigmentosa 3. Corneal clouding 4. X-ray changes are subtle (spade ribs) 5. Ataxia 6. Increased reflexes 7. Meningeal thickening with hydrocephalus 8. Spasticity C. Pathology: 1. Chemical deposits in the brain consist of: a. Increased sulfatides c. Ceramide galactoside b. Gangliosides d. Mucopolysaccharides D. Electron Microscopy: 1. Lamellated inclusions within neurons 2. Sulfatide inclusions within macrophage 3. Membrane vacuoles within endothelial cells E. Diagnostic evaluation: 1. urinary sulfatides and mucopolysaccharides a. Absence of arylsulfatase A and B in cultured fibroblasts 2. Neutrophiles contain alder granules
Krabbe’s Leukodystrophy
A. General characteristics: 1. Genetics: a. AR; chromosome 14 q 31 b. Deficiency of galacto-cerobroside-β-galactosidase B. Clinical features: 1. Adult disease: a. May have very late onset (up to 72 years) b. Gait abnormality
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SECTION XVI. Dementia
c. Progressive spasticity d. Demyelinating peripheral neuropathy e. Visual dysfunction f. No seizures C. Pathology: 1. Gross loss of myelin 2. Astrocytic gliosis 3. Globoid macrophages; generally around blood vessels 4. Late onset patients the appearance of globoid cells may be delayed 5. Globoid cells are PAS positive 6. Cortex may be relatively normal: a. Loss of neurons in the dentate b. Inferior olives 7. Straight or curved tubule crystalloid inclusion in Krabbe’s globoid cells D. Diagnosis: 1. Enzyme assay of leukocytes or fibroblasts 2. Increased CSF protein E. MRI: 1. Minimal changes
Mucopolysaccharidosis (Adult Form)
A. General characteristics: 1. Storage of mucopolysaccharides within liposomes of most tissues 2. Early death or survival in all forms B. Clinical features: 1. Severe and mild disease for all various forms 2. Hepatosplenomegaly 3. Coarse features 4. Mild to severe mental retardation 5. Skeletal changes that may cause spinal cord compression 6. Corneal clouding (I, IV, VI and VII) 7. Carpal tunnel syndrome 8. Cardiomyopathy 9. Aortic and mitral valve incompetence 10. Normal intelligence in Schie’s disease; Morquio’s; Maroteaux–Lamy 11. Sanfilippo: a. Severe behavioral disturbance b. No skeletal abnormality
Mucopolysaccharidoses (Adult Forms)
A. General characteristics: 1. Mucopolysaccharidosis are AR: a. Exception is MPS II (Hunter) which is X-linked recessive Adult forms with dementia: 1. I-Hurler: a. Chromosome 4 p 16.3
b. Deletions; substitutions c. Enzyme defect: 1) ∞-L-Iduronic dose d. Urinary excretion of glucosaminoglycans (GAG): 1) Dermatan sulfate 2) Hunter’s II: a) X-linked recessive Xq27–28 b) Enzyme defect; alpha-L0 iduronate sulfatase 3) Deletions/insertions/point mutations 4) Excretion of dermatan sulfate e. Sanfilippo (type III): 1) Chromosome 12 q 15 (type D) 2) Enzymes involved: a) Heparin N sulfatase (type A) b) Alpha-N-acetyl glucosaminidase (type B) c) Acetyl CoA d) N-acetyl glucosamine-6-sulfatase (type D) e) Galactase-6-sulfatase (type D) 3) Urinary excretion of heparin sulfate 3. Morquio (type IV): a. Type IV: 1) Chromosome 16 q 24 b. Point mutations/deletions C. Pathology: 1. Neuronal storage throughout the brain, spinal cord, ganglia of the GI tract 2. Older patients: a. Storage of lipopigments D. Diagnosis: 1. Urinary excretion of glycosamine glycans 2. Enzyme assay of leukocytes or cultured fibroblasts
Neuraminidase Deficiency Sialidosis Type I
A. General characteristics: 1. Deficient X-neuraminidase 2. Chromosome 10 at 10 per q 23 B. Clinical features: 1. Cherry red spot myoclonus 2. Presentation in first decade 3. Slight intellectual decline or normal intelligence 4. Alternating periodic nystagmus 5. Myoclonus 6. Bilateral macular cherry red spots 7. Cystic long bone changes 8. No hepatosplenomegaly 9. Corneal clouding in some patients C. Pathology: 1. Minimal neuronal storage in cortex
Chapter 7. Adult Lysosomal Disorders with Dementia
2. Marked in GI tract 3. Some vacuolation of neurons in: a. Cortex c. Thalamus b. Basal ganglia 4. PAS positive foam cells in the marrow D. Diagnostic evaluation: 1. Urinary excretion sialyl oligosaccharide most often
Sialidosis Type II
A. General characteristics: 1. Genetics: a. AR b. Chromosome 10 at 10 p ter–q 23 B. Clinical features: 1. Coarse facial features 2. Skeletal dysplasia 3. Progressive loss of vision 4. Corneal cloudiness 5. Bilateral macular cherry red spots 6. Deafness 7. Mild to moderate mental retardation C. Pathology: 1. Neuronal storage of ganglioside like substance in brain and GI tract 2. Neuronal storage (adult case): a. Brainstem b. Anterior horn cell c. Nucleus of Meynert (substantia innominata)
Galactosialidosis
A. General characteristics: 1. Deficiency of neuraminidase/B-galactosidase: a. Chromosome 20 at 20 q 13.1 b. Codes for a protective protein: 1) Required for aggregation of B-galactosidase monomers 2) Activates neuroaminidase 3) Carboxypeptidase activity B. Clinical features: 1. Wide clinical heterogenicity 2. Infantile, late infantile, juvenile, adult forms 3. Adult: a. Variable retardation b. Angiokeratomata c. Ataxia d. Myoclonus e. Cherry red macular lesions f. Juvenile adult forms common in Japanese patients C. Pathology: 1. Atrophic brain 2. Loss of cortical neurons
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3. Lipofuscin accumulation in layers III, V, and VI of the cortex 4. Demyelination 5. Stored material (resembles membrane cytoplasmic bodies) 6. Vacuolated lymphocytes 7. Foamy cells in the bone marrow D. Diagnostic evaluation: 1. Sialyloligosaccharides in the urine 2. Vacuolated lymphocytes and foamy cells in bone marrow 3. Enzyme analysis of cultured fibroblasts
Mucolipidosis I and III
A. General characteristics: 1. Located on chromosome 4 q 21–q 23 2. Enzyme defect: a. N-acetlglucosamine-1-phosphotransferase 3. Clinical features: a. Present in early childhood b. Restriction of joint mobility c. Mild skeletal dysphasia d. Rare corneal clouding e. Mild mental retardation 4. Laboratory evaluation: a. Both ML II and III: 1) Elevated levels of serum lysosomal enzymes (Bglucosidase and amylosulfate A) 2) Decrease of B-galactosidase and alpha-fucosidase in cultured fibroblasts 3) Vacuolated lymphocytes and foam cells noted in bone marrow 5. Pathology: a. Disorder primarily affects mesenchymal tissue b. Myelination is normal in PNS and CNS c. Brains is normal; no neuronal storage
Mucolipidosis II (I-Cell Disease)
A. General characteristics: 1. Chromosome 4 q 21–q 23 2. N-acetylglucosamine 1-phophotransferase B. Clinical features: 1. Similar Hurler’s disease 2. Skull and skeletal deformities 3. Short stature 4. Psychomotor retardation 5. Corneal clouding 6. Infantile form: a. Cardiac b. Skeletal deformities C. Diagnostic evaluation: 1. No mucopolysaccharidases
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SECTION XVI. Dementia
Mucolipidosis III
A. General characteristics: 1. Pseudo Hurler polydystrophy 2. Chromosome 4 q 21–q 23 B. Clinical features: 1. Presents in early childhood 2. Increasing restrictions of joint mobility 3. Carpal tunnel syndrome 4. Mild cognitive deficits 5. Rare corneal clouding C. Pathology: 1. To any endothelial cells 2. Myelination is normal in both PNS and CNS 3. Primarily a disease of mesenchymal tissue D. Laboratory evaluation: 1. In both MLP II and III there are high levels of serum lysosomal enzymes: a. Arylsulfatase A b. β-glucuronidase 2. Decreased levels of alpha-fucosidase and β-galactosidase in fibroblasts
B. Clinical features: 1. Resembles Hurler’s syndrome 2. Coarse fascias 3. Psychomotor retardation 4. Dysostosis multiplex 5. Gingival hyperplasia 6. Recurrent bacterial infection 7. Deafness 8. Corneal and lenticular opacities C. Pathology: 1. Vacuolization of nerve cells in: a. Cerebral cortex b. Brain stem c. Spinal cord d. Loss of cerebellar granular layer e. Vacuoles in astrocytes and endothelial cells f. Diffuse gliosis and loss of myelin D. Diagnostic evaluation: 1. Vacuolated lymphocytes 2. Alpha mannosidosis in leukocytes
β -Mannosidosis Mucolipidosis IV
A. General characteristics: 1. No skeletal abnormalities B. Clinical features: 1. No skeletal abnormalities 2. Infantile patients: a. Psychomotor retardation b. Hepatosplenomegaly C. Milder patients (juvenile adult): 1. Corneal clouding 2. Ataxia D. Diagnostic evaluation: 1. Urinary excretion: a. Sialyloligosaccharides E. Pathology: 1. Neuronal storage in CNS and PNS with PAS positive granules 2. Phospholipids and gangliosides 3. Increased autofluorescent lipofuscin 4. Neuronal loss with astrocytosis 5. Membranous cytoplasmic bodies in endothelial cells of blood vessels
Mannosidosis (Juvenile Adult Type II)
A. General characteristics: 1. Two forms: a. Alpha mannosidosis b. β-mannosidosis c. Severe infantile form type I d. Milder juvenile–adult type II form e. AR inheritance
A. General considerations: 1. Decreased activity of lysosomal β-mannosidase B. Clinical features: 1. Mental retardation 2. Deafness 3. Mild dysmorphic features 4. Peripheral neuropathy (one patient) 5. Angiokeratoma (2 brothers) C. Diagnostic evaluation: 1. Vacuolated lymphocytes are not seen 2. Fibroblasts vacuolated 3. Direct enzyme assay of leukocytes
Fucosidosis
A. General characteristics: 1. Type I-infantile severe form with death by age one 2. Type II-juvenile–adult form 3. Deficient alpha-fucosidase B. Clinical features: 1. Facial dysmorphisms are similar to the mucopolysaccharidoses 2. Angiokeratomas are present 3. Vascular tortuousities in conjunctiva and retina C. Pathology: 1. Enlarged or small brain 2. Neural ballooning in all areas; olivary nuclei and thalamus in particular 3. Granulovacuolar storage in all organs 4. Foam cells in the bone marrow
Chapter 7. Adult Lysosomal Disorders with Dementia
5. Vacuolated lymphocytes in the blood D. Diagnostic evaluation: 1. Foam cells in the bone marrow 2. Fucose compounds in the urine
Aspartylglycosaminuria
A. General considerations: 1. Chromosome 4; several mutations 2. Aspartylglycosaminidase enzyme activity decreased B. Clinical features: 1. Common in Finland; described widely 2. Coarse facies 3. Sagging coarse skin (cheeks) 4. Mental retardation 5. Joint laxity 6. Macroglossia 7. Short stature 8. Systolic murmur 9. Dysostosis multiplex 10. Rare hepatosplenomegaly 11. Excitable, psychotic behavior in adults 12. Spondylosis/spondylolisthesis (3 adolescents) 13. Angiokeratomata noted in some patients C. Pathology: 1. No consistent brain macroscopic changes 2. Cranial hyperostosis 3. Some patients thickened and crenated mitral valves 4. Neuronal cytoplasm is filled with vacuoles: a. Cerebral cortex c. Less evident in the brainstem b. Basal ganglia 5. Neurons and glial cells contain increased lipofusion D. Diagnostic evaluation: 1. Leukocytes demonstrate no activity of aspartoglucosaminidase 2. Large excretion of aspartylglycosamine
Sialuria
A. General considerations: 1. Genetics: a. AR b. Long arm of chromosome 6 c. Salla disease: 1) Occurs primarily in Finland d. Defect of transport of sialic acid with secondary defect of glucuronic acid B. Clinical features: 1. Usually psychomotor retardation in first two years of life 2. Survive to adulthood 3. Adults IQ less that 30 4. Spasticity
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5. Ataxia 6. Athetosis 7. Mild coarse facies C. Pathology: 1. Vacuolated lymphocytes in peripheral blood 2. Gyral atrophy (adult autopsy); atrophy of the cerebellar folia 3. Loss of nerve cells in the cortex, astrocytosis, increased lipofusion 4. Occasional NFT (neurofibrillary tangles) 5. Thalamus, basal ganglia, spinal cord involved D. Diagnostic evaluation: 1. Large increase of free urinary sialic acid E. MRI: 1. Reduction of white matter; normal cortical ribbon; thin corpus callosum
Fabry’s Disease (Alpha Galactosidase Deficiency)
A. General considerations: 1. Genetics: a. X-linked recessive b. Chromosome X q 22.1 c. Alpha galactosidase A deficiency B. Clinical features: 1. Angiokeratoma corporis diffusum: a. Punctate red black telangiectasias bathing suit distribution b. Mucous membranes c. Rarely absent 2. Proteinuria to renal insufficiency 3. Retinal, conjunctival, corneal abnormalities 4. Burning pain and paresthesia of the extremities (small fiber neuropathy) 5. Fever with paresthesia 6. Autonomic dysfunction: a. Decreased sweating b. Decreased saliva and tear formation c. Decreased intestinal motility 7. Hypertrophic cardiomyopathy, mitral insufficiency 8. Minor to major manifestations may occur in female heterozygotes 9. Mental deterioration from renal failure, cardiomyopathy and stroke 10. Differential diagnosis of angiokeratoma: a. Fucosidosis b. Sialidosis (ML1) c. Galactosialidosis d. Aspartylglycosaminuria e. Adult alpha-N-acetylgalactosaminidase deficiency f. Dermatological conditions C. Pathology: 1. Accumulation of ceramide trihexoside and dihexoside in blood vessels and endothelial cells
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SECTION XVI. Dementia
2. Foam cells in bone marrow aspirates 3. Accumulation of ceramide trihexoside: a. Amygdala b. Hypothalamus c. Brain stem d. Anterior horn cells e. Brain pathology related to vascular changes; small infarcts f. Involvement of leptomeninges g. Peripheral nerves are involved; particularly small fibers D. Diagnostic evaluation: 1. Biopsy demonstrates PAS positive deposits in the walls of blood vessels which also stain with Luxol fast blue 2. Absent alpha-galactosidase in fibroblasts Alpha-N-Acetylgalactosaminidase Deficiency (Schindler’s Disease)
A. General considerations: 1. Deficiency of alpha-N-acetylgalactosaminidase activity 2. Chromosome 22 q 3.1–q13.2 B. Clinical features: 1. Children 2. Pyramidal tract signs 3. Hypotonia 4. Myoclonus 5. Early visual impairment C. MRI evaluation: 1. Atrophy of cerebellum, brainstem and cervical spinal cord Type II Glycogenosis (Acid Maltase Deficiency)
A. General considerations: 1. Genetics: a. AR; chromosome 17 q 23 b. Deficient acid alpha-1,4-glucosidase B. Clinical features: 1. Marked respiratory muscle weakness 2. Presents in second and third decade 3. Weakness of skeletal muscle: a. Vacuoles filled with soluble B-particle glycogen b. Some adults do not have myopathy 4. No excess glycogen noted in adult heart C. Pathology: 1. No neuronal glycogen storage in adults 2. Cerebral vasculature demonstrates glycogen in the adult form D. Diagnostic evaluation: 1. Muscle biopsy with characteristic vacuoles (subsarcolemmal) 2. Peripheral blood; lymphocytes show small discrete cytoplasmic granules
Farber’s Disease (Farber’s Lipogranulomatosis)
A. General characteristic: 1. Genetics: a. Defect in lysosomal ceramidase activity b. Increased free ceramide; also increased glycolipids, mucopolysaccharides, GM3 c. AR inheritance B. Clinical features: 1. Infantile form: a. Onset early months of life b. Painful swelling of joints c. Subcutaneous nodules over affected joints d. Hoarse cry e. Feeding difficulties f. Psychomotor or retardation g. Prolonged survival reported C. Pathology: 1. Neuronal storage: a. Brainstem b. Basal ganglia c. Anterior horn cells of spinal cord d. Cortical neurons and those of GI tract involved to a lesser extent 2. Subcutaneous nodules: a. Formed by collection of foam cells 3. Stored material and neurons (PAS positive) 4. Zebra bodies in neurons
Wolman’s Disease and Cholesteryl Ester Storage Disease
A. General characteristics: 1. Genetics a. AR b. Enzyme defect is acid lipase 2. Infantile form: a. Diarrhea, vomiting, failure to thrive b. Hepatosplenomegaly c. Adrenal calcification d. Anemia and fever e. Death by six months 3. Milder form in infants: a. Abdominal distention b. Diarrhea and vomiting c. Survive with mild hepatomegaly
Cholesteryl Ester Storage Disease
A. General characteristics: 1. Genetics: a. AR: chromosome 10q 23–q23.3 b. Defect of acid lipase B. Clinical features:
Chapter 7. Adult Lysosomal Disorders with Dementia
1. Hepatitis like illness 2. Adrenal calcification 3. Pulmonary vascular obstruction 4. Atherosclerosis in longstanding survivors C. Pathology: 1. Deposition of glycerol esters (triglycerides) and cholesteryl esters 2. Brain demonstrates no gross changes 3. Calcification of the deeper layer of the adrenal gland 4. Lipid laden foamy cells of the mononuclear phagocyte system 5. Fibrillary gliosis of the white matter D. Diagnosis of Wolman’s or cholesteryl storage disease: 1. Increased triglyceride and cholesteryl esters are present in liver and adrenal gland
Cystinosis
A. General considerations: 1. Genetics: a. Chromosome 17 q b. Defect of carrier mediated transport of cysteine B. Clinical features: 1. Infant nephropathic form: a. Failure to thrive b. Fanconi syndrome c. Death first decade d. Photophobia due to crystals within the conjunctiva and cornea e. Depigmentation of the retina: 1) Slight decrease of visual acuity f. Fair complexion and hair g. Hypothyroidism by age 10 2. Intermediate form: a. Later onset of renal disease b. Survival to age 30 possible 3. Benign cystinosis: a. No renal involvement b. Corneal and retinal changes 4. Long survivors (on dialysis) a. Swallowing problems b. Neurological deterioration C. Pathology: 1. Necrosis of internal capsule and brachium pontis 2. Multifocal cystic necrosis and spongy change in cerebrum (28 yo adult) 3. Vascular disease with cystine deposition 4. Deposition of crystals widespread and is mainly within the mononuclear phagocyte system D. Diagnostic evaluation: 1. Bone marrow aspiration 2. Electron microscopy: a. Crystals are within lysosomes
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Differential Diagnosis of Lysosomal Storage Diseases
Most of the lysosomal storage diseases have an adult form that will display seminal neurological features. They are rare and will be mixed with other dementing illnesses which makes their diagnosis difficult. Outstanding neurological features that suggest these disorders are: 1. Dysmorphisms of the face 2. Clouded cornea 3. Cherry red spot in the retina 4. Spasticity 5. Myoclonic epilepsy 6. Adrenal dysfunction or calcification 7. Angiokeratoma GM1 gangliosidosis has the combination of dystonia, ataxia and spasticity. The adult form of GM2 (hexosaminidase A) deficiency presents as anterior horn cell disease. Behavioral and psychiatric episodes strengthen the diagnosis. Niemann Pick (sphingomyelinase) type C is striking due to the vertical gaze ophthalmoparesis that is seen. Gaucher’s disease in adults often is suspected due to long bone changes, myoclonic epilepsy and bleeding. Metachromatic leukodystrophy should be suspected in an adolescent or young adult with psychiatric problems and spasticity. Facial coarseness, corneal clouding, skeletal dysostosis with normal intelligence suggest Morquio’s, Schie’s or Maroteaux–Lamy forms. Deficiency of neuraminidase formally sialidosis I and II are suggested by cherry red spot myoclonic epilepsy, cystic long bone changes, skeletal dysplasia and deafness. Galactosidases have myoclonic seizures and cherry red spots in the retina, but angiokeratoma of the skin as well. Abnormalities of joint mobility, corneal clouding suggests mucolipidosis II and III. Angiokeratoma are distinctive and suggest fucosidosis, sialidosis, galactosialidosis and alpha-Nacetylgalactosaminidase. Fabry’s disease will be encountered and has angiokeratoma in the bathing suit distribution. The overwhelming complaints of these patients are burning hands and feet from their small fiber neuropathy. They also are very heat sensitive due to failure to sweat and have suffered coma during hot weather. The mucosulfatidoses have ichthyosis, retinitis pigmentosa and corneal clouding. Wolman’s disease and cholesteryl ester storage disease are associated with calcification in the adrenal glands. The latter is also associated with accelerated atherosclerosis. Adult Krabbe’s disease has the unusual combination of spasticity and features of a demyelinating neuropathy with normal MRI and no protein elevation in the CSF. Kuf’s disease (neural ceroid lipofuscinosis) is suspected in a middle aged patient with myoclonic epilepsy, dementia and ataxia.
SECTION XVI. Dementia
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Chapter 8 Peroxisome Single Enzyme Defects of Adolescence and Adulthood
Adrenal Insufficiency without Neurological Symptoms
A. Clinical features: 1. High risk of late neurologic disease 2. Oldest patient described with Addison’s disease is 78
X-Linked Adrenal Leukodystrophy
A. General considerations: 1. Genetics: a. X-linked recessive disorder of beta oxidation of very long chain fatty acids (VLCFA) b. Defect of lignoceric-CoA synthetase c. A member of the ATP binding transporter family d. Involved in the transport of fatty acyl CoA substrates across the peroxisomal membrane e. Accumulation of VLCFA is associated with neurologic damage 2. Sub types occur within families 3. Different sub types occur within kindreds 4. Manifesting female carriers occur 5. Common link among the disorder is: a. An excess of VLCFA esters (carbon chain length greater than 22) b. Detected in plasma, cultured fibroblasts and affected tissues B. Clinical features: 1. Adolescent form: a. Onset is 11–21 years of age b. Dementia c. Hearing loss d. Visual deficit e. Pyramidal deficits f. Extrapyramidal dysfunction g. Cerebellar signs h. Increased pigmentation i. Adrenal failure manifested by: 1) Episodic vomiting and diarrhea 2) Hypotension 3) Severe weakness and fatigue 4) Low serum sodium and high serum potassium
Adult Cerebral Type
A. Clinical features: 1. Schizophrenia like symptoms 2. Dementia 3. Spasticity 4. Aphasia 5. Auditory and visual deficits 6. Aphasia 7. May or may not have adrenal insufficiency
Asymptomatic Carriers of the Genetic Defect with Elevated VLCFA
A. Clinical features: 1. High risk of later neurologic symptoms 2. Oldest patients are males between 60–70 years of age
Adrenoleukodystrophy Female Heterozygotes
A. General considerations: 1. Female carriers of the gene defect may develop neurologic symptoms 2. Non-random X-chromosome inactivation that favors expression of the mutant allele is the mechanism 3. Usually is the phenotype adrenomyeloneuropathy (AMN) B. Clinical features: 1. Onset in the fourth decade 2. Mild signs 3. Slowly progressive course
Adrenomyeloneuropathy
A. General considerations: 1. The slowly progressive phenotype B. Clinical features: 1. Onset age 20–30 years 2. Slowly progressive 3. 50% have cerebral involvement 4. Often presents with clumsiness and legs stiffness 5. Spastic paraplegia 6. Impotence and incontinence 7. Sparing of the upper arms 8. Adrenal insufficiency in 60–70% of patients 9. Adrenal symptoms may precede neurological signs and symptoms
Differential Diagnosis of AMN
1. 2. 3. C.
Demyelinating disease Familial spastic paraparesis Spinocerebellar atrophy Pathology: 1. Caudal rostral progression of the leukodystrophy
Chapter 8. Peroxisome Single Enzyme Defects of Adolescence and Adulthood
2. Occipital, parietal, temporal lobes most severely affected 3. Bilateral symmetrical lesions 4. Severe demyelination of: a. Optic nerves b. Fornix c. Hippocampal commissure d. Posterior cingulum e. Partial sparing of the subcortical arcuate fibers f. Corpus callosum g. Internal capsule 5. Brainstem and spinal cord less affected: a. Involvement of descending tracts only 6. AMN involvement of: a. Brainstem (minimal) b. Cerebellum (moderate) c. Lumbar corticospinal tracts d. Cervical fasciculus gracilis e. Dorsal spinocerebellar tracts 7. Advancing demyelination: a. Sparing of axons b. PAS + macrophages 8. Neurons generally preserved 9. Peripheral nerves: a. Loss of large and small diameter fibers 10. Adrenal glands are atrophic 11. EM examination: a. Needle like trilaminar bodies b. May also be found in nerves, conjunctiva and skin D. Diagnostic evaluation: 1. Excess of VLCFA (greater than 22 carbons) in: a. Plasma c. Affected tissue b. Cultured fibroblasts E. MRI evaluation of the cerebral forms of ALD: 1. Involve the corpus callosum 2. Primarily posteriorly 3. Symmetrical T2 weighted signal posterior > anterior 4. Minimal if any, involvement of arcuate fibers
Unusual Leukodystrophies That May Be Seen in Adulthood with Dementia Pelizaeus Merzbacher
A. General considerations: 1. Genetics: a. X-linked inheritance b. Well documented female patients have been described c. X q 21.33–22 location of myelin proteolipid gene (PLP): 1) Mutations 2) Duplications of the gene 3) Little correlation between genotype and phenotype
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4) Mutation of PLP gene: a) Noted in X-linked spastic paraplegia (SPG2) b) Pelizaeus Merzbacher B. Clinical features: 1. Onset of nystagmus in infancy (horizontal with torsional rotary components) 2. Stridor 3. Spasticity 4. Developmental delay 5. Ataxia 6. Seizures occur in some patients 7. Optic atrophy by age 5 8. Death may occur at any age up to fifth decade C. Laboratory evaluation: 1. Abnormal brainstem auditory potentials D. MRI: 1. Lack of periventricular myelin E. Pathology: 1. Brain is atrophic 2. Cerebellar atrophy 3. Loss of myelin with tigroid pattern of residual myelin 4. Lack of oligodendroglia 5. Increased astrocytes
Alexander’s Disease
A. General considerations: 1. Genetics: a. GFAP mutations B. Clinical features: 1. Onset in infancy or later childhood 2. Adult form described 3. Dementia 4. Seizures 5. Spasticity C. Adult form: 1. Dysphagia 2. Ataxia 3. Brainstem cranial nerve dysfunction 4. Psychological deterioration 5. Focal disease (brainstem) has been reported 6. Macrophalli 7. Regression of developmental milestones D. MRI: 1. Increased T2 signal primarily in the brainstem E. Pathology: 1. Large brain 2. Indurated white cortical ribbon 3. Diffuse demyelination; rarefaction of white matter 4. Innumerable Rosenthal fibers: a. Around blood vessels b. Subpial c. Subependymal zones d. Contain GFAP and α-B-crystallin
SECTION XVI. Dementia
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e. Gliosis F. MRI evaluation: 1. Increased T2 weighted signal primarily in the brainstem
Chapter 9
2) Korsakoff’s psychosis: a) Medical dorsal nucleus affected most frequently > submedius > lateral dorsal > medial pulvinar b) Neuropathological changes in: (1) Cortex (4) Cerebellum (2) White matter (5) Brainstem (3) Diencephalon
Toxic Disorders with Dementia Marchiafava Bignami Disease Aluminum
A. General considerations: 1. Role in Alzheimer’s disease and dialysis dementia is unlikely to be significant 2. Mechanisms of action in vitro: a. Increases phosphorylation of heavy and medium weight neurofilament subunits b. Induces cross linking between neurofilaments c. Disrupts transcortical processing Alcohol and Dementia A. General considerations: 1. Wernicke–Korsakoff: a. Often seen with alcohol abuse b. Differential diagnosis: 1) Starvation diets 2) Prolonged IV treatment without vitamin supplementation 3) AIDS 4) Gastric stapling B. Clinical features: 1. Classic clinical syndrome of Wernicke–Korsakoff: a. Ophthalmoplegia c. Ataxia b. Nystagmus d. Encephalopathy 2. Core clinical feature of Korsakoff’s psychosis: a. Amnestic state b. Deficits in memory: 1) Anterograde episodic memory deficit 2) Normal semantic memory 3) Relatively intact non-declarative memory c. Normal intelligence and learned behavior d. Differential diagnosis: 1) Diencephalic tumor or trauma e. Pathology of Wernicke–Korsakoff (W-K): 1) Lesions are most characteristic in the: a) Mammillary bodies b) Periventricular III and IV ventricles c) Sylvian aqueduct (perisylvian) d) Hemorrhage noted in 5% of patients e) Chronic Wernicke–Korsakoff: (1) Shrinkage and discoloration of the mammillary bodies (Fe++ deposition from hemorrhage)
A. General considerations: 1. Male alcoholics 2. Originally described male red wine drinkers 3. Rarely seen in non-alcoholics B. Clinical features: 1. Acute form: a. Seizures c. Death b. Disorder of consciousness 2. Chronic form: a. Progressive dementia b. Interhemispheric disconnection syndrome C. Pathology: 1. Necrotizing, cystic lesions of the: a. Corpus callosum b. Optic chiasm c. Anterior commissure d. Centrum semiovale e. Middle cerebellar peduncles f. Demyelination with sparing of axons D. MRI evaluation: 1. Diffuse swelling of the corpus callosum
Central Pontine Myelinolysis
A. General considerations: 1. Most commonly seen with Wernicke Korsakoff syndrome 2. 4–12% incidence with Wernicke Korsakoff syndrome 3. Also noted in patients with: a. Post orthotropic liver transplantation b. Severe burns c. Hyponatremia d. Anorexia e. Immune suppressed states B. Clinical features: 1. Young or middle aged adults 2. Flaccid tetraplegia 3. Facial, glottal and pharyngeal paralysis 4. Often occurs during an acute illness 5. Frequently patients are locked in 6. May have a striking recovery C. Pathology:
Chapter 9. Toxic Disorders with Dementia
1. Lesions often in the center of the basis pontis at the level of the Vth nerve: a. Extends from below the midbrain through the upper 2/3 of the pons b. Tegmentum of pons is spared c. Extrapontine lesions occur in 10% of patients: 1) Striatum 4) Centrum semiovale 2) Thalamus 5) Cerebral white matter 3) Cerebellum Manganese
A. General considerations: 1. Exposure due to manufacture: a. Steel d. Fungicide b. Dry cell batteries e. Welding c. Gasoline additive f. Water purification 2. Mn binds to transferrin; transported across the BBB by transferrin receptor mediated endocytosis 3. Preferential accumulation of Mn in the: a. Globus pallidus b. Substantia nigra pars reticularis B. Clinical features: 1. Extrapyramidal syndrome: a. Depression (early) c. Rigidity akinesia b. Loss of postural reflexes d. Minimal or no tremor 2. Initial stage: a. Depression c. Insomnia b. Fatigue d. Poor memory 3. Intermediate stage: a. Psychomotor excitement d. Flexed posture b. Dysphonia e. Gait abnormalities c. Agraphia 4. Late stage: a. Akinetic rigid state b. Dystonic posture C. Pathology: 1. Degeneration of medial GP; and SNPr 2. Some involvement of caudate and putamen D. MRI evaluation 1. Increased signal on T2 weighted images of: a. Striatum c. Substantia nigra b. Globus pallidus
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Organic Mercury
A. General considerations: 1. Mercury vapor and alkyl mercury compounds are the most neurotoxic 2. Inorganic mercury is changed to methyl mercury by microorganisms in estuaries which is then concentrated in fish 3. Methyl mercury is used as a fungicide B. Clinical features: 1. Visual field constriction (tunnel vision) 2. Sensory deficits 3. Ataxia 4. Bradykinesia 5. Cognitive deficits C. Pathology: 1. Spongiosis of the cerebral cortex 2. Involvement of the calcarine cortex, precentral frontal lobe and cerebellar cortex 3. In Minamata Bay disease (poisoning in Japan) involvement of: a. Basal ganglia c. Posterior fossa structure b. Cortex d. Peripheral nerves
Trimethyl Tin
A. General considerations: 1. Industrial exposure: a. Biocides b. Surface disinfectants c. Polymer stabilizers d. Antioxidants in rubber products B. Clinical features: 1. Mental confusion 4. Increased aggression 2. Seizures 5. Insomnia 3. Memory dysfunction C. Neuropathology 1. Neuronal degeneration in: a. Temporal cortex c. Amygdala b. Basal ganglia d. Pontine nuclei
Fetal Alcohol Syndrome Mercury
A. General considerations: 1. Exposure: a. Dental amalgam b. Manufacture of scientific instruments c. Metallic mercury poorly absorbed from GI tract d. Mercury vapor is actively absorbed B. Clinical features: 1. Psychological disturbances with bursts of anger 2. Intention tremor
A. General considerations: 1. Consumption of alcohol during pregnancy B. Clinical features: 1. Facial and ocular defects (thin and straight upper lip, short frenulum) 2. Intellectual and cognitive deficits 3. Cerebellum dysfunction 4. Hearing loss C. Neuropathology: 1. Microcephaly
SECTION XVI. Dementia
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2. 3. 4. 5. 6. 7.
Hydrocephalus Cerebellar malformation Agenesis of corpus callosum Optic nerve hypoplasia Retinal ganglion cell loss Neuronal micro dysplasia
Methyl Alcohol
A. General considerations: 1. Exposure: a. Sterno ingestion by alcoholics b. Methanol is metabolized to formic acid c. Formic acid inhibits cytochrome C oxidase B. Clinical features: 1. Methanol is metabolized to formic acid 2. Formic acid inhibits cytochrome C oxidase 3. Acute exposure: a. Edema of the optic disk (bloody) b. Loss of visual acuity c. Acute coma d. Dementia (in survivors) e. Parkinsonism C. Neuropathology: 1. Edema and petechial hemorrhages in the brain 2. Hemorrhagic necrosis and hemorrhagic leukoencephalopathy 3. Bilateral necrosis of the putamen with cystic changes 4. Loss of retinal ganglion cells, gliosis and axon loss of optic nerves
Solvent Abuse Dementia
A. General considerations: 1. Mixed exposure most common 2. Most often a mixture of: a. Toluene c. Trichloroethylene b. Styrene d. Xylene B. Clinical features: 1. The dementia and personality changes in industrial solvent exposure: a. Psycho organic syndrome b. Deteriorating intellect c. Emotional changes 2. Long term toluene abuse symptoms and signs: a. Cognitive impairment b. Short term memory loss c. Emotional lability d. Ataxia e. Nystagmus f. Tremor g. Hearing loss occurs with: 1) Toluene
2) Styrene 3) Trichloroethylene (often there is concomitant Vth nerve involvement) C. Pathology: 1. Cerebral atrophy 2. Ventricular enlargement 3. Cerebellar and brainstem atrophy: a. More cerebellar atrophy with toluene than other solvents 4. Dementia may precede other signs D. MRI evaluation: 1. Diffuse cerebral and cerebellar atrophy 2. Ventricular enlargement E. Neuropathology: 1. Patchy demyelination of cerebral and cerebellar white matter 2. Trilaminar inclusions within PAS positive macrophages 3. Increased VLCF acids in white matter 4. Cerebral and cerebellar atrophy 5. Irregular μ fiber involvement
Drugs and Toxins that Impair Cognitive Function
1. Arsenic is associated with prominent memory deterioration 2. Barbiturates cause psychomotor slowing 3. Lead encephalopathy causes intellectual deterioration in adults as well as children 4. MPTP generalized intellectual decline with parkinsonism 5. Methotrexate: a. Inhibits dihydrofolic acid reductase b. Intrathecal use combined with craniospinal X-RT causes: 1) Necrotizing leukoencephalopathy 2) Confusion 3) Seizures 4) Ataxia 5) Spasticity 6) Cognitive decline c. Pathology: 1) Periventricular and centrum semiovale white matter affected
Chapter 10 Neoplasms Causing Dementia A. General considerations: 1. Occur with both malignant and benign tumors 2. Dementia determined primarily by site of the neoplasm 3. Slow growing tumors most frequently cause diagnostic confusion
Chapter 10. Neoplasms Causing Dementia
B. Clinical features: 1. Location: a. Midline: 1) Colloid cysts a) Severe positional headache b) Obstructive hydrocephalus 2) Pinealoma: a) Eye movement defects (failure of vertical gaze) b) Hearing loss c) Aqueductal stenosis with hydrocephalus 3) Pituitary tumors: a) Panhypopituitarism b) Chiasmatic visual defects c) Hydrocephalus d) Dementia from thyroid failure 4) Midline thalamic glioma: a) Somnolence b) Aphasia c) Fluctuating levels of alertness
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2. Crosses the midline through the corpus callosum 3. More necrotic on MRI than usual lymphoma 4. Frontal lobe syndrome
Dementia with X-RT for Malignant Tumor
A. General considerations: 1. 5000 rads for whole brain irradiation B. Clinical features: 1. Acutely: a. Demyelination with edema 2. All neurological systems involved: a. Cortex b. Basal ganglia (subcortical dementia) c. Cerebellar ataxia d. Parkinsonism 3. Hypothyroidism and endocrine dysfunction if pituitary area has been irradiated 4. Chronic syndrome after one year: a. Small vessel strokes (proliferative endarteritis) b. Seizure activity
Frontal Lobe Meningioma
Large Areas of Necrosis (Occur After X-RT)
1. Subfrontal tumors 2. Pressure and irritation of the limbic orbitofrontal cortex: a. Seizures b. Personality and behavioral change c. Rarely Foster Kennedy syndrome 3. Dorsolateral prefrontal cortex: a. Frontal lobe syndrome: 1) Poor memory retrieval 2) Deficits of planning, execution and attention b. Global decrease of cognitive function
A. General considerations: 1. Magnetic resonance spectroscopy (MRS) or PET determines if it is tumor recurrence or irradiation necrosis a. PET-increased glucose utilization (tumor) b. MRS-increased lactic acid resonance (tumor) B. Clinical features: 1. Large vessel accelerated atherosclerosis with stroke 2. Small vessel strokes
Paraneoplastic Syndromes with Dementia Glioblastoma Multiforme
Bilateral involvement: 1. Crosses to contralateral side through the corpus callosum 2. Frontal lobe syndrome 3. Seizures 4. Abulia (subfrontal syndrome) Gliomatosis Cerebri
1. Malignant astrocytes around cerebral blood vessels 2. Generalized cognitive decline Lymphoma
1. Primarily noted in AIDS patients
A. General considerations: 1. Primarily immune mediated: a. Anti-Hu antibody (antinuclear) b. Small cell carcinoma of the lung most frequent tumor, breast, GI, ovary and prostate are also common tumors B. Clinical features: 1. Limbic encephalitis 2. Bilateral involvement of the hippocampal formation; parahippocampal gyrus; cingulate gyrus 3. Memory impairment 4. Personality and behavioral change 5. Seizures C. Pathology (limbic encephalitis): 1. Neuronal loss: a. Hippocampus b. Cingulate gyrus
SECTION XVI. Dementia
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c. Lymphocytic perivascular cuffing D. Diagnostic evaluation: 1. Anti-Hu or other paraneoplastic antibodies Ma, Ta, Ri, CAR are positive 2. Increased lymphocytes and protein in CSF
Grade II DAI
Chapter 11
Grade III DAI
Head Trauma as a Cause of Dementia A. General considerations: 1. Outcome of blunt head trauma depends on: a. Duration of coma b. Resolution of post traumatic amnesia c. 40–50 thousand patients a year in the USA are reported B. Clinical features: 1. Subcortical dementia 2. Ataxia 3. Pyramidal tract dysfunction 4. Parkinsonism 5. Pseudobulbar palsy: a. Increased gag reflex b. Bilateral corticospinal dysfunction c. Dysarthria d. Emotional incontinence (laughing without mirth and crying without tears) 6. Severe injury: a. Chronic vegetative state C. Neuropathology: 1. Diffuse (multifocal) brain damage 2. Diffuse axonal injury (DAI) 3. Ischaemic brain damage 4. Brain swelling with increased intracranial pressure 5. Diffuse vascular injury (usually restricted to patients who die shortly after injury)
1. Abnormalities noted in Grade I DAI 2. Focal abnormalities of corpus callosum associated with small hemorrhage (tissue tear hemorrhage)
1. All findings of Grade II DAI 2. Axonal abnormalities in the rostral brainstem Dementia of Repeated Head Trauma
A. General considerations: 1. Boxers, soccer and football players B. Clinical features: 1. Subcortical dementia 2. Rare dysphasia or dyspraxia 3. “LaBelle” indifference: a. Inappropriate or no concern for the degree of disability 4. Memory deficits may be out of proportion to physical disability 5. May present with organic brain syndrome 6. Parkinsonian features 7. Ataxia 8. Pyramidal damage 9. Pseudobulbar palsy C. Pathology: 1. Frontal occipital, temporal and parietal bossing area of injury (hemosiderin) 2. Loss of SNPc and Purkinje cells 3. Cortical Neuronal loss D. MRI evaluation: 1. Global atrophy: a. Commensurate with lesion load 2. Lesions of the corpus callosum 3. Atrophy of frontal occipital and temporal tips 4. Ventricular dilatation
Distinctive Features of Diffuse Axonal Injury (DAI)
1. Diffuse damage to axons (shear line in the centrum semiovale) 2. A focal lesion of the corpus callosum (torn in moderate to severe trauma) 3. Focal lesions in the dorsolateral quadrant or quadrants of the rostral brainstem a. Adjacent to the superior cerebellar peduncles Grade I DAI (Diffuse Axonal Injury)
1. Widespread axonal damage: a. Corpus callosum b. Cerebral hemisphere white matter c. Brainstem
Chapter 12 Vasculitic and Microangiopathic Forms of Dementia A. General considerations: 1. Deficits occur in: a. Cranial nerves b. Peripheral nerves c. Spinal cord d. Large or small vessel stroke 2. Rarer presentation: a. Depressed consciousness c. Dementia b. Confusional states
Chapter 12. Vasculitic and Microangiopathic Forms of Dementia SLE
A. General considerations: 1. Dementia occurs often with acute exacerbations and increased disease activity B. Clinical features: 1. Large and small cerebral infarcts lead to multi-infarct dementia: a. Lupus anticoagulant, anticardiolipin antibodies (ACL antibodies are present) b. Spontaneous thrombosis of large and small vessels c. Stroke syndrome of young adults 2. Associated findings: a. Livedo reticularis (ACL antibodies) b. Libman–Sachs endocarditis (verrucous subvalvular fibrin deposits with emboli) c. History of thrombotic events and abortion is common C. Laboratory evaluation: 1. Prolonged PTT, false positive syphilis serology, thrombocytopenia suggest ACL antibody state D. Pathology: 1. Vasculitis (neutrophils invading cerebral) 85% 2. CSF: a. Increased protein, lymphocytes and IgG b. Decreased complement c. Imaging: 1) SPECT may show defects > MRI
Polyarteritis Nodosa
A. General considerations: 1. Peripheral nerve or plexus lesions (40–60%) 2. CNS involvement: a. 20–40% of patients b. Involvement of large intra and extracranial vessels, intracranial arterioles B. Clinical features: 1. Multifocal deficits 4. Seizures 2. Global encephalopathy 5. Large vessel stroke 3. Dementia 6. Stupor and coma C. Pathology: 1. Necrotizing vasculitis of small and medium sized muscular arteries 2. Segmental lesions 3. Endothelial proliferation 4. Polymorphonuclear and mononuclear cell infiltration of blood vessels 5. Kidneys involved with consequent HCVD
Isolated Vasculitis of the Central Nervous System (Primary Granulomatous Angitis)
A. General considerations:
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1. Involvement of arterioles primarily 2. Occasional involvement of large intracranial vessels 3. No systemic signs of vasculitis B. Clinical features: 1. Affects adults in fifth to eight decade 2. Cognitive decline (subacutely) 3. Seizures 4. Focal neurological signs 5. Headache 6. Impaired consciousness 7. Cranial neuropathy (rare) 8. Spinal cord infarction (rare) C. Laboratory evaluation: 1. Normal sed rate 2. Mild pleocytosis and elevated CSF protein 3. Angiographic demonstration of vasculitis: a. Segmental narrowing of tertiary blood vessels
Giant Cell Arteritis
A. General considerations: 1. Extracranial blood vessels 2. Sed rate usually between 80–120 mm3 B. Clinical features: 1. Severe headache (burning scalp) 2. Blindness (infarction of the posterior ciliary arteries that form watershed with the CRA at the optic disc) 3. Rarely involvement of carotid, vertebral arteries, and arch of the aorta 4. Brainstem and cerebellar involvement 5. Vascular dementia C. Laboratory evaluation: 1. Sed rate elevated
Thrombotic Thrombocytopenic Purpura (TTP)
A. General considerations: 1. Antibody attack on platelets 2. Naked thrombocytes in the bone marrow B. Clinical features: 1. Acute confusional state 2. Psychosis 3. Seizures 4. Renal failure 5. Purpuric skin lesions 6. Rare vascular dementia C. Pathology: 1. Granular atrophy of the cerebral cortex 2. Fibrotic cortical vessels 3. Organized thrombi D. Differential Diagnosis of TTP: 1. Cerebral form of thromboangiitis obliterans
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SECTION XVI. Dementia
Central Nervous System Angioendotheliosis
Rare Chronic Viral Encephalitides with Dementia
A. General characteristics: 1. Malignant lymphoma of blood vessels 2. Affects dural blood vessels B. Clinical features: 1. Subacute dementia over months 3. Renal failure 2. Skin ulcerations C. Pathology: 1. Proliferation of endothelial cells in many organs 2. No inflammation 3. Occlusion of small vessels with secondary thrombosis 4. Ischemic necrosis of the cerebral cortex
A. General considerations: 1. Subacute sclerosing panencephalitis (SSPE): a. Most often follows late immunization with measles vaccine b. Overwhelming a childhood disease c. Adult form has been described B. Clinical features: 1. School failure (earliest cognitive signs) 2. Apraxia 3. Visual spatial difficulties 4. Myoclonus C. Pathology: 1. Dawson’s inclusion bodies: a. Cowdry A bodies b. Large intranuclear inclusions with halo c. Viral (DNA) infections D. Laboratory evaluations: 1. Positive IgG index >7%/100 ml 2. Slightly raised protein 3. Few lymphocytes
Infections Causes of Dementia HIV
A. General considerations: 1. Microglial and macrophage cellular CNS reservoir of infection 2. Cytokine and protein effectors of cell death B. Clinical features: 1. May affect majority of untreated patients 2. May be presenting feature of the illness 3. Forgetfulness 4. Poor concentration 5. Subcortical dementia 6. Later features: a. Increasing psychomotor slowing b. Ataxia c. Paraparesis d. Early cognitive changes in asymptomatic HIV patients C. Laboratory evaluation: 1. Increased lymphocytic pleocytosis 2. Protein usually mildly elevated to 50 mg to 80 mg% D. MRI evaluation: 1. Global atrophy of both grey and white matter atrophy 2. Basal ganglionic atrophy 3. Diffuse white mater increased signal on T2 weighted images (primarily periventricularly) E. Pathology: 1. Diffuse white matter change 2. Subcortical gray matter 3. Relative sparing of the cerebral cortex 4. Macrophages, multinucleated cells and reactive gliosis of affected areas 5. Associated pathologic processes: a. Lymphoma b. Progressive multifocal leukoencephalopathy c. Infections: 1) Toxoplasmosis 5) Herpes simplex 2) Tuberculosis 6) Herpes varicella zoster 3) Syphilis 7) Epstein Barr 4) Cryptococcus
Chronic Rubella Panencephalitis
A. General considerations: 1. Usually occurs after congenital infection; may follow acquired infection in adult B. Clinical features: 1. Early cerebellar findings 2. Lack of myoclonus C. Pathology: 1. Neuronal destruction in cortex, cerebellum, brainstem 2. Perivascular lymphocytic infiltration 3. Myelin destruction, axonal sparing D. Diagnostic evaluation: 1. Early cerebellar findings 2. Lack of myoclonus Progressive Multifocal Leukoencephalopathy
A. General considerations: 1. Occurs in all immuno comprised conditions: a. HIV c. Malignancy b. Renal failure d. Liver disease 2. Chronic infection with JC virus B. Clinical features: 1. Cognitive impairment 2. Ataxia 3. Hemiparesis 4. Hemianopsia and central visual loss 5. Parietal sensory loss 6. Rare brainstem signs and symptoms 7. A few patients with remissions and long survival C. Pathology: 1. Serpiginous coalescent white matter lesions:
Chapter 12. Vasculitic and Microangiopathic Forms of Dementia
a. Parietooccipital origin 2. Large bizarre multinucleated oligodendrocyte (intranuclear occlusions) 3. Confluent foci of demyelination
Neurosyphilis
A. General considerations: 1. Approximately 20,000 cases per year in USA B. Clinical features: 1. May occur 15–20 years after the original infection 2. Memory loss and apathy 3. Expansive paranoid state 4. Dysphasia 5. Apraxia 6. Associated neurological findings: a. Seizures b. Dysarthria c. Tremor d. Trombone tongue tremor (tongue moves in and out) e. Hypertonia f. Paretic pupil with optic atrophy g. Argyl Robertson pupil h. Brainstem strokes i. Rare gummas with focal feature j. Associated HIV is becoming prevalent C. Laboratory evaluation: 1. CSF: a. Slight increase of protein b. Elevated IgG index c. IgM elevation is seen in acute infection d. Few cells (less than five lymphocytes)
Neurosyphilis in AIDS Patients
A. General considerations: 1. Telescoped pattern of infection: a. Primary, meningoencephalitic pattern may develop concomitantly b. Neurosyphilis may develop although primary infection was adequately treated c. Usual treponemal antibody tests may be negative B. Clinical features: 1. Ocular involvement is prominent 2. Syphilitic meningitis is common 3. Gummatous arteritis occurs 4. Fulminant necrotizing hyperinfections anergic stage (quaternary syphilis)
1. Gastrointestinal malabsorption syndrome 2. Large joint arthritis B. Clinical features: 1. Disease of middle aged men (4–6 decade) 2. Neurological signs and symptoms may occur without systemic features 3. Neurologic involvement may be silent: a. Only found at autopsy 4. Dementia 5. Myorhythmia (side to side jaw movement) 6. Ophthalmoplegia 7. Ataxia 8. Hypothalamic syndrome 9. Lymphadenopathy 10. Hyperpigmentation 11. Steatorrhea 12. Associated with AIDS C. Pathology: 1. Abnormal macrophages (Whipple’s bacilli) noted on jejunal biopsy 2. Rod shaped bacilli; gram positive actinomycete (Trophermyma Whipple) 3. Disseminated lesions throughout the CNS; subpial regions of the cortex, basal ganglia, hypothalamus, dentate, brainstem nuclei 4. Small infarcts (less than 5 mm) scattered throughout the brain
Lyme’s Disease Encephalopathy and Dementia
A. General considerations: 1. Borrelia burgdorferi (spirochete) 2. Three stages of the illness 3. Transmitted by ixodid ticks 4. Stage 1: a. Erythema marginata b. Arthralgias 5. Stage 2: a. Occurs weeks or months after the infection b. Onset of neurologic and cardiac involvement occurs in this stage c. Neurologic signs: 1) Meningitis 2) Cranial neuritis (bilateral VIIth nerve) 3) Radiculoneuritis 6. Stage 3: a. Several years after infection b. Arthritis c. Cognitive dysfunction (rare)
Cysticercosis Whipple’s Disease
A. General considerations:
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A. General considerations: 1. Most common helminth with CNS involvement
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2. 3. 4. 5.
SECTION XVI. Dementia
Significant problem in immigrants to North America Seen in 1–3% of post mortem studies in Mexico Unusual in non-pork eating countries Infection caused by the larval stage of the pig tapeworm taenia solium B. Clinical features: 1. Seizures 2. Acute or focal neurological signs 3. Raised intracranial pressure 4. Hydrocephalus 5. Meningeal form 6. Involves the diaphragm 7. Muscle enlargement from inflammation 8. Chronic dementia from the severe lesion load C. Pathology: 1. Most cysts are parenchymal; vary from one to several hundreds 2. Cysts are found: a. Cortex d. Cerebellum b. Deep grey nuclei e. Meninges c. White matter f. Ventricles 3. Racemose variety may occlude internal carotid artery or burst in a ventricle that causes meningitis D. MRI evaluation: 1. Calcified and non-calcified cysts
2. Meningeal and ventricular involvement in some patients 3. Racemose (cystic involvement of IVth ventricle)
Chronic Infections Associated with Dementia
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.
Tuberculosis Neurosyphilis Cryptococcus Histoplasmosis Coccidioidomycosis Histoplasmosis Toxoplasmosis Candida HIV Herpes zoster CMV Lyme’s Disease Cysticercosis SSPE (post infection) Rubella panencephalitis (post infection) Herpes simplex with amnesia
