ELSEVIER CHURClflLL LMNGSTONE The Curtis Center Independence Square West Philadelphia, PA 19106
ELECTRODlAGNOSIS IN CL...
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ELSEVIER CHURClflLL LMNGSTONE The Curtis Center Independence Square West Philadelphia, PA 19106
ELECTRODlAGNOSIS IN CLINICAL NEUROLOGY Churchill Livingstone is an imprint of Elsevier, Inc. Copyright 2005, Elrievier (USA). 1999, 1992, 1986, 1980 All rights reserved.
ISBN 0-443-06647-7
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Medicine is an ever-changing field. Standard safety precautions must be followed but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the treating physician, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the Publisher nor the author assumes any liability for any injury and/or damage to persons or property arising from this publication. Every effort has been made to ensure that the drug dosage schedules within this text are accurate and conform to standards accepted at time of publication. However, as treatment recommendations vary in the light of continuing research and clinical experience, the reader is advised to verify drug dosage schedules herein with information found on product information sheets. This is especially true in cases of new or infrequently used drugs. Recognizing the importance of preserving what has been written, Elsevier prints its books on acidfree paper whenever possible. Fifth Edition Library of Congress Cataloging-in-Publication Data Electrodiagnosis in clinical neurology/ [edited by] Michael J. Aminoff-5th ed. p. ;cm. Includes bibliographical references and index. ISBN 0-443-06647-7 1. Electrodiagnosis. 2. Nervous system-Diseases--Diagnosis. [DNLM: 1. Electrodiagnosis-methods. 2. Nervous System Diseases--diagnosis. E372005] I. Aminoff, Michael J. (Michaeljeffrey) RC349.E53E43 2005 616.8'047547-.~"""""'IV''''''''''''-.r"'''''''''.."."".....-.......------_ ............
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FIGURE J-17 III Paroxysmal, generalized, bilaterally synchronous and symmetric 2.5- to 3-Hz spike-wave activity recorded interictally in the EEG of a patient with absence (petit mal) seizures.
phology of the complexes (p, 58). In some instances, the discharges cease with eye-opening or in response to alerting. There may be inconstantly lateralized amplitude asymmetries or inconsistent asynchronous onsets over the two hemispheres when the recordings on different occasions are compared, but such findings are of no clinical consequence. The background between the generalized bursts of activity occasionally contains isolated spike discharges that may be focal (usually, frontal) in distribution'"; this finding is also without special significance. Similarly, high-voltage intermittent rhythmic delta activity may be found occipitally, especially in children during the first decade of life. EEG findings that are repeatedly normal in a child with clinical attacks resembling absence seizures suggest that a diagnosis of primary generalized epilepsy is incorrect. Absence epilepsy of childhood onset usually presents before the age of 12 years and commonly remits in late adolescence. By contrast, juvenile absence epilepsy presents in the second decade and is associated with less frequent absences but a greater likelihood that seizures will continue into adulthood and that generalized tonic-clonic convulsions will occur. Further details of these disorders are provided in Chapter 4. The absences that occur in juvenile myoclonic epilepsy are associated with spike- or polyspike-wave activity that has a frequency of 2.5 to 4 Hz (with a range of 2 to 7 Hz) and that is enhanced by hyperventilation; there is much intra- and interdischarge variation, and discharges may be interrupted for brief periods.P'
When absence attacks continue to occur in adults, they are often difficult to recognize because of their short duration. 95,96 Such patients usually also have generalized tonic-clonic seizures. Michelucci and colleagues found in adults that the interictal EEG background is normal but may be interrupted by generalized bursts of spike-wave or polyspike-wave discharges and, occasionally, by independent focal spikes; runs of polyspikes sometimes occur during non-REM sleep." Ictally, 3-Hz spike-wave discharges are characteristic, sometimes preceded by polyspikes with or without intermixed spikewave or polyspike-wave discharges. Similar findings have been reported by others.P" Myoclonic seizures. Bursts of generalized spike-wave or polyspike-wave activity are found both ictally and interictally, often with a frequency of 3 to 5 Hz and an anterior emphasis; they may be enhanced especially by photic stimulation or sleep. In juvenile myoclonic epilepsy, discussed in detail in Chapter 4, the interictal EEG usually has a normal background; however, this is interrupted by bursts of generalized, frontally predominant polyspikes or of polyspike-wave or spike-wave discharges having a variable frequency that is often between 3 and 5 Hz but may be higher. Photic stimulation provokes or enhances such abnormalities in 25 to 30 percent of cases, and hyperventilation also activates the epileptiform abnormalities. Focal or lateralizing features or shifting asymmetries are sometimes found. Ictally, the myoclonic seizures are associated with anteriorly dominant polyspike or
Electroencephalography: General Principles and Clinical Applications
polyspike-wave bursts followed by rhythmic delta activity. Absence seizures in this syndrome are accompanied by irregular spike-wave or polyspikewave discharges of variable frequency.P" Tonic-clonic (grand mal) seizures. Generalized, bilaterally synchronous spike discharges, or bursts of spikewave or polyspike-wave activity, or both, may be seen interictally (Fig. 3-18), the latter sometimes being identical to that found in absence attacks. The earliest change during a tonic-clonic convulsion is often the appearance of generalized, low-voltage fast activity. This activity then becomes slower, more conspicuous, and more extensive in distribution and, depending on the recording technique, may take the form of multiple spike or repetitive sharp-wave discharges that have a frequency of about 10 Hz and are seen during the tonic phase of the attack. In other instances, seizure activity may be initiated by a flattening (desynchronization) of electrocerebral activity or by paroxysmal activity such as that which occurs in the interictal period. In any event, as the seizure continues into the clonic phase, a buildup of slow waves occurs and the EEG comes to be characterized by slow activity with associated spike or polyspike discharges. Following the attack, the EEG may revert to its preictal state, although there is usually a transient attenuation of electrocerebral activity, followed by the appearance of irregular polymorphic slow activity that may persist for several hours or even longer. In a few cases, the postictal EEG is characterized by periodic complexes.
F~:=:
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SECONDARY (SYMPTOMATIC) GENERALIZED EPILEPSY
In patients with secondary generalized epilepsy (i.e., with generalized seizures relating to known pathology, such as Lennox-Gastaut syndrome), the background activity of the interictal EEG is usually abnormal, containing an excess of diffuse theta or delta activity that is poorly responsive to eye-opening and may show a focal or lateralized emphasis. Single or independent multiple spike discharges may also be found.I" However, interictal paroxysmal activity characteristically consists of slow spike-wave or polyspike-wave discharges that are usually less well organized than in the primary generalized epilepsies, with a frequency that varies between 1.5 and 2.5 Hz (Fig. 3-19). This activity exhibits a characteristic variability in frequency, amplitude, morphology, and distribution on different occasions, even during the same examination." In some instances it is generalized and exhibits bilateral symmetry and synchrony; in others it is markedly asymmetric, showing a clear emphasis over one hemisphere or even over a discrete portion of that hemisphere. Hyperventilation and flicker stimulation are generally less effective as activating agents than in the primary generalized epilepsies, but non-REM sleep can increase the frequency of the paroxysmal discharges.v' Such paroxysmal activity may also occur as an ictal phenomenon accompanying absence and myoclonic attacks. The most common EEG changes associated
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III Paroxysmal, generalized, bilaterallysynchronous spike-wave and polyspike-wave discharges seen interictally in the EEG of a 62-year-old woman with tonic-clonic seizures caused by primary generalized epilepsy.
FIGURE 3-18
61
62
ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
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stimuli, in the EEG of a 68-year-old woman following cardiopulmonary arrest.
Electroencephalography: General Principles and Clinical Applications
changes are often inconspicuous in patients with hemorrhage into the lower brainstem, but widespread, poorly reactive alpha-like activity may be noted. Cerebellar hemorrhage is associated with little, if any, change unless tonsillar herniation complicates the clinical picture, in which case diffuse slowing results. The EEG findings in patients with cerebral venous or venous sinus thrombosis are similar to, but often more extensive than, those in patients with occlusive arterial disease. When the superior sagittal sinus is involved, the changes are usually bilateral, often variable, and commonly asymmetric. I t is unclear whether the EEG has any role in indicating the prognosis following stroke, and no definite conclusions can be reached on the basis of the few published studies on this point. The EEG has been used to monitor patients undergoing carotid endarterectomy, and this is discussed further in Chapter 9. A reversible posterior leukoencephalopathy has been related to hypertensive encephalopathy. It is associated with characteristic abnormalities on neuroimaging that suggest subcortical edema without infarction.!" Occipital lobe seizures may occur.P" and variable EEG abnormalities may be encountered. The diagnosis, however, is based 011 the clinical and neuroimaging abnormalities. SU.ARACHNOID HEMORRHAGE
Although the EEG may be normal following subarachnoid hemorrhage, diffuse slowing is a common finding, especially in patients with clouding of consciousness. Focal abnormalities may also be observed and can be related to the presence of a local hematoma; to the source of hemorrhage, especially when it is an angioma; or to secondary ischemia by arterial spasm. Continuous EEG monitoring in the intensive care unit is heing used increasingly to detect focal changes
caused by vasospasm while they are still subclinical or at least at a time when the vasospasm may still be reversible. 137 SUBDURAL HEMATOMA
The background activity is sometimes reduced in amplitude or virtually abolished over the affected hemisphere in patients with a chronic subdural hematoma (Fig. 3-28). In other instances, however, a focal ipsilateral slow-wave disturbance is the most conspicuous abnormality, and little suppression of background rhythms is found. In either case, generalized changes (e.g., frontal intermittent rhythmic delta activity) may be present as well, and repetitive periodic complexes have been described in rare instances. Because the EEG is sometimes normal in patients with a chronic subdural hematoma, the possibility of such a lesion cannot be excluded just because the electrophysiologic findings are unremarkable. Indeed, even when abnormalities are found, it can sometimes be difficult, ifnot impossible, to localize the lesion with any certainty owing to the interplay of the various changes described earlier. Moreover, the EEG findings do not reliably distinguish a chronic subdural hematoma from other space-occupying lesions. In all instances, therefore, detailed neuroradiologic assessment is necessary if cases are to be managed correctly. INTRACRANIAL ANEURYSMS AND ARTERIOVENOUS MALFORMATIONS
The findings in subarachnoid hemorrhage have already been described. Focal slow activity is an occasional finding in patients with aneurysms that have not bled, but in uncomplicated cases there is often little to find in the EEG. Following subarachnoid hemorrhage, focal or
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FIGURE 3-28 III! Focal slowing in the right posterior quadrant and suppression of normal background rhythms over this side in the EEG of a patient with a suspected right subdural hematoma.
72
ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
lateralized abnormalities are sometimes present and may be a guide to the site of bleeding. Focal slow activity or epileptiform discharges may be found in the EEG of patients with intracranial arteriovenous malformations. SrURGE-WEBER SYNDROME
Together with depression of normal background activity and the responses to hyperventilation and photic stimulation over the affected hemisphere, irregular slow activity and sharp transients are often seen.P" The reduction in background activity is not necessarily related to the presence and degree of intracranial calcification. Abnormalities sometimes have a more generalized distribution that can be confusing, but in such circumstances they are commonly more conspicuous over the involved side.
Headache Electroencephalography has little relevance to the diagnosis of migraine. In uncomplicated cases, the EEG is usually normal, or shows only minor nonspecific changes between and during migrainous attacks. Focal or unilateral slow-wave disturbances are common, however, particularly in patients developing lateralized aura or neurologic deficits in association with their attacks. Such localized abnormalities usually settle rapidly once the clinical disturbance has resolved, unless infarction has occurred or there is an underlying structural abnormality. Paroxysmal activity is sometimes found, but the proportion of cases with such a disturbance varies greatly in different series. In one study of the EEG in 100 children with migraine, 9 (without a history of epilepsy) were found to have benign focal epileptiform discharges at a time when they were free from headaches. I:19 This incidence of 9 percent is higher than in the general population and is of uncertain significance. It is possible that migraine and such discharges are genetically linked or that the vascular abnormality of migraine leads to cerebral ischemic damage and thus to the EEG abnormality.P" The EEG disturbance, in itself, is insufficient evidence to permit the headaches to be regarded as the manifestation of an epileptic disorder. There is always some concern that an underlying structural lesion may have been missed in patients with chronic headache syndromes that fail to respond to medical treatment. In this regard, a possible role has been suggested for the EEG as a screening procedure for patients requiring further investigation. The EEG is g-enerally less expensive than cranial CT scanning or MR!, but it is also less sensitive to intracranial masses than are these imaging procedures. Whether a costbenefit analysis would justify such a role for the EEG is
uncertain, however, and there is insufficient information in the literature to provide guidance on this point. 140 Moreover, given the implications of delay in the diagnosis of an intracranial mass lesion, it is hard to justify use of the EEG in place of imaging studies when these modalities are readily available and intracranial pathology is suspected clinically.U" There is little if any evidence that the EEG has a useful role in the routine evaluation of patients presenting with headache, and it is not helpful for predicting prognosis or in selecting therapy.r'?
Tumors Tumors may affect the EEG by causing compression, displacement, or destruction of nervous tissue; by interfering with local blood supply; or by leading to obstructive hydrocephalus. Considerable variation exists in the presence, nature, and extent of abnormalities in different subjects, however, and this variability seems to depend, at least in part, on the size and rate of growth of the tumor and the age of the individual patient. An abnormal record is more likely to be found in patients with a supratentorial tumor than an infratentorial one, and in patients with a rapidly expanding tumor rather than a slowly growing lesion. Superficial supratentorial lesions generally produce more localized EEG changes than do deep hemispheric lesions; the latter may lead to abnormalities over the entire side involved or to even more diffuse changes. EEG abnormalities are more common with rostral than with caudal infratentorial lesions." In general, abnormalities are more conspicuous with tumors in children than with those in adults. Even if the EEG is abnormal, however, the changes may be generalized rather than focal. Thus, they would not be particularly helpful in the diagnosis or localization of the underlying neoplasm, although they would provide information about the extent of cerebral dysfunction produced by it. Diffuse abnormalities are common in all patients with cerebral tumors when the level of consciousness is depressed; therefore, in this context, these abnormalities are particularly probable in patients with infratentorial lesions. In addition to diffuse slowing, intermittent bilateral rhythmic delta activity may be seen with a frontal emphasis in adults, or more posteriorly in children. In these circumstances, localization of the tumor by EEG is often less feasible than at an earlier period in the natural history, although a gross asymmetry of such activity between the two hemispheres raises the possibility of a lateralized hemispheric lesion. Earlier records sometimes permit more definite localization, but they may show only subtle changes, which are easily missed. Depression of electrical activity over a discrete region of the brain is a reliable local sign of an underlying
Electroencephalography: General Principles andClinical Applications
cerebral lesion, but this sign may be masked by volume conduction of activity from adjacent areas. The presence of a focal polymorphic slow-wave disturbance (Fig. 3-29) is also important, although such an abnormality has less localizing significance when it is found over the temporal lobe. Focal ictal or interictal sharp activity is of some, but lesser, localizing value unless it is associated with an underlying focal slow-wave disturbance. However, epileptiform activity may precede the appearance of more reliable focal EEG abnormalities by several months or even longer. It usually occurs at the margins of the lesion and is more likely with slowly growing tumors than with rapidly expanding ones and more likely with hemispheric tumors than with brainstem lesions. Some correlation exists between the presence of epileptiform activity in patients with brain tumors and the development of seizures, but in general this correlation is not close enough to be of prognostic relevance. Many patients with such EEG discharges do not have seizures; conversely, many patients with seizures from brain tumors do not have spikes and sharp waves in their EEGs. Epileptiform discharges may be found bilaterally, without obvious focality, in patients with parasagiual or mesial hemispheric lesions, but are often then asymmetric in distribution over the two sides or confined to the vertex.P' A number of other abnormalities have been described in patients with discrete cerebral lesions, including an asymmetry of druginduced fast activity, a local increase in beta activity, and the presence of a mu rhythm; but these findings are of much less significance and can lead to difficulty in determining which of the two sides is the abnormal one. In assessing the findings in patients with suspected brain tumors, it must be borne in mind that the main value of the EEG is in indicating which patients require
more detailed investigation, especially when facilities for CT scanning or MRI are not readily available. Its value even in this regard is limited, however, because a normal or equivocal EEG does not exclude the possibility of a tumor. Deep-seated supratentorial tumors may produce no abnormalities whatsoever at an early stage, and the EEG is likely to be normal in patients with pituitary tumors unless the lesion has extended beyond the pituitary fossa or has caused hormonal changes. Furthermore, there are no abnormalities that will allow the differentiation of neoplastic lesions from other localized structural disorders, such as an abscess or infarct. The EEG can provide no information about the nature of the tumor in individual cases; the findings in patients with tumors of different histologic types or in different locations are therefore not discussed in this chapter. Although its place as a noninvasive screening procedure has largely been taken over by CT scanning or MRI in the developed countries, the EEG still has an important complementary role in the evaluation of patients with known or suspected brain tumors. In particular, the EEG is helpful in the evaluation of episodic symptoms that might either be epileptic in nature or have some other basis, and it provides information about the extent of cerebral dysfunction.
Tuberous Sclerosis There are no pathognomonic EEG features of tuberous sclerosis, but epileptiform activity or changes suggestive of space-occupying lesions may be found. The EEG is often normal in mild cases, but in others focal slow- or sharp-wave disturbances are seen. In more advanced cases, a hypsarrhythmic pattern may be seen during infancy, whereas in older patients the record may contain generalized spike-wave activity or independent
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II Polymorphic slow-waveactivity in the left frontal region in the EEG of a 62-year-old man with a glioma.
FIGURE ]·29
73
74
ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
multifocal spike discharges. Thus, focal or generalized changes may be found in this disorder.
Pseudotumor Cerebri In pseudotumor cerebri, or benign intracranial hypertension, the EEG is often normal, but abnormalities, consisting of a diffusely slowed background and bursts of activity in the alpha-, theta-, or delta-frequency ranges, are sometimes found.
Dementia The EEG changes in most patients with dementia are nonspecific and do not discriminate between the different types of dementing processes. In early cases, the findings may be normal. As the dementia advances, however, the amount and frequency of the alpha rhythm declines, and irregular theta and slower activity appear, sometimes with a focal or unilateral emphasis, especially in the temporal region. In patients with Alzheimer's disease, the alpha rhythm is often lost at a relatively early stage compared with patients with other disorders that cause dementia. As a general rule, abnormalities occur earlier and are much more conspicuous in Alzheimer's disease than in Pick's disease or frontotemporal dementia. In the latter disorder, the EEG is often norrnal'V; even if diffuse slow-wave activity is present, the alpha rhythm is commonly preserved. In some cases, the cause of dementia may be suggested by the EEG findings. Both Creutzfeldt-Jakob disease and subacute sclerosing panencephalitis are commonly associated with characteristic EEG changes, as described earlier. When a focal structural lesion (e.g., a tumor or chronic subdural hematoma) is responsible for the intellectual decline, there may be localized depression of electrocerebral activity or a focal polymorphic slow-wave disturbance, sometimes with relative preservation of the alpha rhythm. In multi-infarct dementia, significant asymmetries in background activity often occur over the two hemispheres, and focal slowwave disturbances are common. The findings in patients with parkinsonism, Huntington's disease, hepatolenticular degeneration, and Steele-Richardson-Olszewski syndrome are discussed on page 79 but are of no help in distinguishing the intellectual decline occurring in those disorders from other diseases associated with dementia. In patients with the dementia sometimes associated with HIV infection, the EEG may be normal or diffusely slowed. Focal slow-wave disturbances in these patients raise the possibility of neoplastic involvement or opportunistic infection. A high incidence of EEG ab normalities has been reported in asymptomatic Hlv-sero-
pOSItIVe homosexual men by sorne.l'" but not other, authors,144-146 raising the possibility that electrophysiologic studies may be useful as a means of indicating subclinical neurologic involvement. Among patients with acquired immunodeficiency syndrome (AIDS), 67 percent have been reported to have EEG abnormalities, usually in relation to dementia or opportunistic infection but sometimes without apparent neurologic disease.r'? Considerable overlap exists between the EEG findings in patients with dementia of the Alzheimer type and mentally normal elderly subjects; thus, the EEG cannot be used to indicate reliably whether an elderly patient has dementia. However, the presence of diffuse slow-wave activity supports the diagnosis of dementia rather than pseudodementia (depression). Again, the EEG findings cannot be used to distinguish with any confidence between an acute and a chronic disturbance of cognitive function, although in the former circumstance abnormalities are more likely to reverse with time. However, a markedly abnormal EEG in patients with clinically mild cognitive disturbances should suggest an acute process, such as a toxic or metabolic encephalopathy.
Metabolic Disorders The EEG has been used to detect and monitor cerebral dysfunction in patients with a variety of metabolic disorders, and changes may certainly precede any alteration in clinical status. The EEG findings may also be helpful in suggesting that nonspecific symptoms have an organic basis. Diffuse (rather than focal) changes characteristically occur in metabolic encephalopathies unless there is a pre-existing or concomitant structural lesion. Typically, desynchronization and slowing of the alpha rhythm occur, with subsequent appearance of theta, and then of delta, activity. These slower rhythms initially may be episodic or paroxysmal and are enhanced by hyperventilation. Triphasic waves (p. 48), which consist ofa major positive potential preceded and followed by smaller negative waves, may also be found and usually are generalized, bilaterally synchronous, and frontally predominant. They are sometimes reactive to external (painful) stimulation. Although triphasic waves were originally thought to be specific for hepatic encephalopathy, they are in fact found in a variety of metabolic encephalopathies'Pr" and have been held to suggest a poor prognosis for survival. 20 Diffuse slowing of the EEG has been described in hyperglycemia or hypoglycemia, Addison's disease, hypopituitarism, pulmonary failure, and hyperparathyroidism. In hypoparathyroidism, similar changes are found in advanced cases; but spikes, sharp waves, and slow spike-wave discharges may also be seen. A lowvoltage record in which the alpha activity is classically
Electroencephalography: General Principles and Clinical Applications
preserved but slowed characterizes myxedema, and there may be some intermixed theta or slower elements, These changes may pass unrecognized, however, unless premorbid records are available for comparison. In hyperthyroidism, the alpha rhythm is usually diminished in amount but increased in frequency, beta activity is often conspicuous, and scattercd theta elements may be present. The findings in Cushing's disease and pheochromocytoma are usually unremarkable. Water intoxication or hyponatremia may cause diffuse slowing of the EEG, and bursts of rhythmic delta activity are also commonly present. Hypernatremia and abnormalities of serum potassium concentration usually have little effect on the EEG. HEPATIC ENCEPHALOPATHY
The EEG shows progressive changes in patients with advancing hepatic encephalopathy, and in general a good correlation exists between the clinical and electrical tindings. 148 In early stages the alpha rhythm slows, gradually being replaced by theta and delta activity, but in some instances it may coexist with this slow activity.l48 As the disorder progresses, triphasic complexes usually (but not invariably) occur symmetrically and synchronously over the two hemispheres, with a frontal emphasis (Fig. 3-30). With further clinical deterioration, the EEG in patients with hepatic encephalopathy comes to
Fp2-F4 F4-C4 C4-P4 f'--..-.I'_r"'V'--r--r~";'.... I"""" v.." """, .... , P4-02 .A--V--v-"I.r-- which reviews available technologies and methods and makes recommendations concerning indications for their use. The technology for LTME has advanced considerably since these guidelines were published, however, and technologic updates are now needed. Nevertheless, the suggestions for a standard terminology for the most common subcategories of LTME, shown in Table 5-1, are still appropriate. This chapter is concerned with the indications for LTME, the available monitoring equipment and methods of procedure, the interpretation of data, and recommendations for specific diagnostic purposes. The equipment and procedures discussed here are appropriate for LTME of adults and children; more details on adaptations necessary for application to infants and neonates can be found elsewhere. I 1,12
INDICATIONS LTME can be expensive and labor intensive, but it is cost effective in many circumstances. Its use should be limited to diagnostic problems that cannot easily be resolved in the routine EEG laboratory.
Differential Diagnosis LTME is often used as a last resort in the differential diagnosis between epilepsy and other disorders associated with intermittent or paroxysmal disturbances that may resemble epileptic seizures. 13 A definitive diagnosis is easily made when habitual events are shown to consist of clinical behaviors characteristic of epilepsy and are associated with well-defined ictal EEG discharges; or when other etiologies can be clearly demonstrated (e.g., cardiac arrhythmias or sleep disturbances). Often, however, the events in question occur without obvious EEG or other electrophysiologic changes. In this case, a diagnosis is usually reached with reasonable confidence based on features of the ictal behavior in association with other clinical and laboratory information. Simple partial seizures usually have no EEG correlates that can be recorded with extracranial electrodes.!" Consequently, seizures without impaired consciousness are most often diagnosed by characteristic behavioral features and, at times, elevated serum prolactin levels.P rather than by the occurrence of ictal EEG discharges. Myoclonic jerks may also have no EEG correlates but usually can be diagnosed on the basis of characteristic motor symptorns.l" Many other nonepileptic disorders can be recognized readily by clinical examination during the habitual event, by review of videotapes, or both. In most of these situations, however, the results of LTME merely confirm the clinical impression derived from historical and other information and are not diagnostic in themselves. The most difficult, and most important, differential diagnosis for which LTME is used is the distinction between epileptic seizures and nonepileptic psychogenic seizures. Because, by definition, nonepileptic psychogenic seizures have no EEG correlates, this diagnosis is usually one of exclusion. Certain features of nonepileptic psychogenic seizures may distinguish them from generalized convulsions; these include uncoordinated nonsynchronous thrashing of the limbs, quivering, pelvic thrusting, side-to-side head movements, opisthotonic posturing, screaming and talking throughout the ictal episode, prolongation for many minutes or even hours, abrupt termination without postictal confusion, evidence of some recall during the ictal event, and features that are not stereotyped but differ from one episode to another. 13 ,17,18 Any of these symptoms, however, can be epileptic phenomena, and differential diagnosis between nonepileptic psychogenic seizures and complex partial seizures is particularly dimcult.'? Furthermore, nonepileptic psychogenic seizures may be associated with autonomic changes (e.g., pupillary dilatation, depressed corneal reflexes, Babinski responses, cardiorespiratory changes, and urinary and fecal incontinence) as well as self-injury induced by falling or biting the lips and tongue. 13 ,18 Consequently,
long-Term Monitoring forEpilepsy
a definitive diagnosis cannot be made solely on the basis of ictal clinical features observed during LTME; other positive evidence (e.g., secondary gain) is necessary. A conclusion that an ictal event captured by LTME is nonepileptic and psychogenic does not, in itself, rule out the existence of an epileptic condition, because some patients with epilepsy also have nonepileptic psychogenic seizures. 13 . IS When the two phenomena coexist, it should be possible to obtain a history of more than one seizure type and to use LTME to record examples of each type to determine which are nonepileptic and which are epileptic. Based on this information, the patient and family can be instructed to record these events separately to determine the effects of antiepileptic and psychiatric interventions on each independently. Nonepileptic psychogenic seizures, which are involuntary and as disabling as epileptic events, need to be distinguished from malingering, which is voluntary simulation, and from factitious disorder, which is selfinduction of epileptic attacks for the purpose of gaining patient status." This differential diagnosis can sometimes be accomplished by data obtained during LTME, but usually it depends on historical information.
Charaderization and Classification Patients with known epileptic seizures that do not respond to antiepileptic medication may be undergoing treatment for the wrong type of epilepsy. In this situation, LTME can provide crucial information that characterizes the epileptic events so that the physician can make a seizure diagnosis" and, when possible, a diagnosis ofa specific epileptic syndrome." Seizure type usually determines the most appropriate antiepileptic drugs and whether a patient might be a candidate for surgical intervention. A specific epileptic syndrome is often associated with a known prognosis, which is helpful information for the patient and physician.!' LTME is particularly useful for distinguishing partial seizures from generalized epileptic events on the basis of characteristic ictal EEG features. It is important to distinguish the different epileptic causes of brief loss of consciousness, which can be a typical absence seizure, an atypical absence seizure, or a complex partial seizure characterized by impaired consciousness only. It may be impossible to distinguish between atypical absences resulting from bilateral or diffuse brain damage and atypical complex partial seizures originating primarily from frontal lobe lesions with secondary bilateral synchrony.22 LTME is also useful for distinguishing simple from complex partial seizures, particularly when trained personnel are available to examine the patient during the ictal event. The hallmark of a complex partial seizure is
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amnesia for the ictal period. Although this information usually has no direct therapeutic relevance, because simple and complex partial seizures are treated with the same medications, a definitive diagnosis can at times have medicolegal implications (e.g., a patient with only simple partial seizures might be allowed to drive), and it is important for counseling patients regarding activities of daily living. Documentation of the degree of disability during and after the seizure can be important in the decision about whether surgical treatment is warranted. More detailed tests (e.g., reaction time tasks) during ictal events can be used to identify subtle disturbances of function for the same purposes.
Determination of Frequency and Temporal Pattern of Seizures When patients are known to have epileptic seizures of a specific type, but it is unclear how often these seizures are occurring, LTME can be used to determine the frequency of ictal events. Patients with seizures that involve relatively brieflapses of consciousness may not be aware of each ictal event; therefore they depend on observers to know whether therapeutic interventions have resulted in benefit. In these situations, LTME is a more accurate way of documenting seizure frequency before and after treatment. Unexplained deterioration in mental function can be caused by unrecognized brief daytime seizures or more severe nocturnal events. Knowledge about the occurrence and frequency of such ictal events is important for medicolegal reasons, for counseling patients regarding the activities of daily living, and for deciding whether surgical intervention is warranted. LTME can reveal when seizures are most likely to occur. At times, this information is useful for identifying specific precipitating factors that might be avoided.F Combining LTME with serum drug level assessments can help to determine whether seizures occur because serum levels are subtherapeutic at specific times of the day, and it can aid in suggesting more effective drug dosing schedules.F'
Localization of the Epileptogenic Region The most common use of LTME is for localization of a discrete epileptogenic region in patients with medically refractory epilepsy who are candidates for surgical therapy. Consideration for surgical therapy is essentially the only situation in which detailed information about localization is of clinical value. This localization includes not only identification of an area that can be removed when localized resection is contemplated, but
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also demonstration that no such well-defined epileptogenic region exists in patients who are candidates for nonlocalized therapeutic surgical procedures such as hemispherectomy and corpus callosum section." LTME is capable of revealing clinical signs and symptoms of habitual ictal events that have localizing value (see Appendix 5-1); however, these clinical behaviors may result from propagation to distant cortical areas and can never be considered definitive evidence of an epileptogenic region." Consequently, identification of the area to be surgically resected usually requires clear demonstration of the site of electrographic ictal onset. Reliable localization of an epileptogenic region can often be determined with scalp and sphenoidal EEG recordings, in association with a variety of other confirmatory tests; but at times LTME with intracerebral, epidural, or subdural recordings is necessary.7.25,26 A variety of electrode types are used for this purpose, including depth, strip, grid, and foramen ovale electrodes. The performance of long-term intracranial EEG monitoring requires specialized technical and clinical expertise to place electrodes, to guarantee patient safety in the recording unit, and to interpret the EEG data obtained. In large part as a result of technical advances in LTME, approximately twice as many patients underwent surgical treatment for medically refractory epilepsy in 1991 as did in 1985. 27 For some surgical procedures (e.g., standard anterior temporal lobectomy), 70 to 90 percent of patients with medically refractory complex partial seizures can expect to become seizurefree, whereas almost all of the remainder experience worthwhile irnprovement.P The results of LTME techniques are also increasingly used to guide extratemporal cortical resections with beneficial results,26,28 and patients with secondary generalized epilepsies who would not have been considered surgical candidates only a few years ago are now benefiting from large multilobar resections and, to a much lesser extent, corpus callosum sections. 29,30 Safe and effective treatment of epileptogenic zones in primary cortical areas can now he accomplished with multiple subpial transection. 31,32
Electrodes should have a hole in the top to permit periodic regelling, and should be applied with collodion and gauze. Sphenoidal electrodes are often used to record from the mesial or anterior aspects of the temporal lobe in the region of the foramen ovale. 22 These electrodes are constructed of fine, flexible, braided stainless steel wire, insulated except at the tip, and are inserted through a needle guide, as illustrated in Figure 5-1. Sphenoidal electrodes may be left in place from days to several weeks. Evidence suggests that earlobe or Tl/T2 placements are better than nasopharyngeal electrodes,34.35 and they are preferred when sphenoidals are not used. Nasoethmoidal, supraoptic, and auditory canal electrodes have also been used but are difficult to place; indications for their use are not defined, and their routine use is discouraged.F Some investigators prefer to lise a
TECHNICAL CONSIDERATIONS Equipment, methods of procedure, and typical system configurations used for LTME are considered in this section, which is adapted, with permission, from guidelines published elsewhere. 1,2.33
Equipment for EEG Recording ELECTRODES
Disk electrodes are used for scalp EEG recordings; needles and electrode caps are not recommended.
FIGURE 5-1 • The placement of sphenoidal electrodes. The needle is inserted approximately 1 inch anterior to the tragus immediately under the zygomatic bone (black dot on lateral view). The tip of the electrode should lie close to the foramen ovale (basilar view). Inset shows how multistranded Tefloncoated wire protrudes from the tip of the insertion needle and is bent backward on the Teflon coating to prevent breakage of wire strands. Inner lip of the needle can also be beveled to further ensure against breakage of the sphenoidal wire. (From Engel J Jr: Seizures and Epilepsy. FA Davis, Philadelphia, 1989, with permission.)
long-Term Monitoring for Epilepsy
variety of basal electrodes (e.g., sphenoidal plus Tl/T2, and other placements on the face and ear) to better define the fields of basal epileptiform transients. % A variety of rigid and flexible depth electrodes are used for intracerebral recording.s" Most are multicontact. constructed of either stainless steel or metals compatible with magnetic resonance imaging (MRI) , such as platinum and nickel-chromium alloy. They are inserted stereotactically by several techniques that enter the skull from the side, back, or top of the head. 26 Depth electrodes are best suited for recording from structures deep within the brain (e.g., the hippocampus and amygdala), orbital frontal cortex, and cortex in the interhemispheric fissure (e.g., supplementary motor area and anterior cingulate). Consequently, depth electrode evaluations are usually preferred in patients with complex partial seizures of limbic origin. 26 Recordings from the surface of the brain are made with strip electrodes or grid electrodes, which can be placed epidurally or subdurally. Strip electrodes are inserted through burr holes, whereas grid electrodes require a craniotomy for placement." Electrode strips consist of a row of stainless steel or MRI-compatible platinum disks embedded in Silastic, or a bundle of fine wires with recording contacts at the tips. Electrode grids consist of 4 to 64 small platinum or stainless steel disks arranged in two to eight rows and embedded in soft Silastic. The disks in strip and grid electrodes are typically spaced so that there is 1 cm from disk center to disk center. Strip and grid electrodes are preferred in patients with partial seizures whose epileptogenic region is likely to be in the lateral neocortex. Strips are easier to insert than grids and can be used bilaterally. Grids are usually used only unilaterally because bilateral craniotomy is rarely justified, but their extensive coverage allows not only accurate topographic mapping of interictal and ictal epileptic events but also detailed functional mapping of normal essential cortex.'17 Intermediately invasive electrodes are used at some centers. Foramen ovale electrodes are constructed of flexible stainless steel or MRI-eompatible metals and contain one to four recording contacts.P They are placed in the ambient cistern through a needle inserted into the foramen ovale and record from hippocampal gyrus in a manner similar to the most mesial contacts of subtemporally inserted strip or grid electrodes. Although foramen ovale electrodes cannot record directly from hippocampus and amygdala, as do depth electrodes, and do not record as broad a field as strip and grid electrodes, they do have a definite advantage over sphenoidal and other extracranial basal electrodes. Epidural peg electrodes are inserted through twist: drill holes in the skull; they can record from selected areas of the lateral cortical surface as an alternative to strip or grid electrodes.P
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Foramen ovale electrodes may be used in association with grid electrodes for more comprehensive recordings of mesial temporal structures, including those on the contralateral side. Also, strip electrodes and epidural pegs may be used contralateral to grid electrodes as sentinel electrodes to identify the occurrence of distant ictal discharge, even though the spatial distribution of these epileptic events cannot be mapped. Similarly, strip or epidural peg electrodes can be used in association with depth electrodes to provide additional information about ictal discharges at the cortical surface. AMPLIFIERS
Amplifiers used for LTME are smaller and lower in power than amplifiers used for standard EEG but should have the following performance specifications: low-frequency response of at least 0.16 Hz; highfrequency response of at least 70 Hz; noise level less than 0.5 J.1V RMS; input impedance of at least 1 Mohm; common mode rejection of at least 110 dB; and dynamic range of at least 40 dB.! ,:l3 If a preamplifier is used, preamplification input impedance must be greater than 100 Mohm.P Amplifiers should be able to capture a minimum of 24 channels, and more preferably, 32 or greater, at a minimum of 200 samples per second. The analog-todigital converter should have a minimum of 12-bit resolution with the ability to discriminate the EEG at 0.5 J.1V steps or less.33 To prevent aliasing artifacts, a high frequency antialiasing filter with a minimum rolloff of 12 dB/octave must be used before digitization." The maximum cutoff frequency for the antialiasing filter is determined by the sampling rate. For example, at a sampling rate of 200 Hz, the amplifier must have an antialiasing high-frequency filter no greater than 70 Hz. For higher sampling equipment, proportionately higher-frequency cutoffs can be used. For recording purposes, the low-frequency filter should be set at 0.16 Hz or less. The use of notch filters for acquisition is discouraged. Because LTME systems allow data to be modified when reviewed, frequency filters and gain of the recording system should be set initially to obtain maximum information rather than clean tracings. Amplifiers may be mounted on the head, carried on the body, or remote from the patient. The closer the amplifier is to the signal source, the shorter are the electrode leads and the less artifact that results from movement or interference. The amplifier is most commonly carried on the body because of size and weight. In scenarios where the patient has violent or continuous movement, the amplifier may be mounted on the head to minimize artifact. Small, lightweight amplifiers and preamplifiers are commercially available for this purpose, although they are limited in the number of
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channels that can be recorded. Movement and interference artifact is worst with remote amplifiers, and this arrangement is least satisfactory for recording seizures. TRANSMISSION
Standard cable used for routine EEG is the simplest and most widely available means of transmission, but it greatly impairs patient mobility and is associated with the greatest amount of artifact. Telemetry refers to a system in which the EEG signal is amplified close to the patient, multiplexed, and then transmitted to a remote recording device, where it is decoded.l" With cable telemetry, the multiplexed signal is transmitted over a lightweight cable that consists of a single wire that is long enough to allow the patient to move around the room. Cable telemetry is inexpensive, is associated with low interference, and is the most common form ofEEG telemetry used; however, patient mobility is relatively limited. More mobility is possible with radio or infrared telemetry, in which signals are transmitted without a wire, but the range of these devices is still restricted, and there is increased interference with the EEG signal from outside sources. To overcome this patient restriction, some recently developed systems can store the multiplexed signal directly onto flash memory within the amplifier/headbox and retransmit it to the system at a later time. This allows the patient to be unhooked from the system for moderate periods (up to 4 hours with most systems) and move about freely without loss of data. Although this does not offer the same degree of freedom as radio telemetry, it has the advantage of allowing the patient limited periods in which they are not restricted by cable lengths without subjecting the data to radio frequency interference artifacts. Ambulatory recording for longer periods (discussed in Chapter 6) is a specific form of LTME in which the patient wears the recording device and no remote transmission is necessary. However, because of limitations of storage, the number of channels are limited, and often these devices are event recorders and do not provide continuous long-term records. Amplification close to the body and multiplexing of the resultant strong signal accounts for the major advantage of telemetry. The low-voltage signal travels only a short distance and so is less prone to movement artifact and interference from outside sources. Recordings of epileptic seizures, which are usually associated with considerable movement, are therefore relatively artifact-free compared with ictal recordings obtained in a routine EEG laboratory. These advances have made feasible LTME with scalp and sphenoidal electrodes. Multiplexers typically combine 16 to 64 channels into a single channel of information, which is then demultiplexed at some later point. If the multiplexed signal is recorded and stored, the recording
apparatus must have a higher frequency response than if the signal is demultiplexed before recording and storage. RECORDING, STORAGE, RETRIEVAL, AND REVIEW
Many methods of EEG recording and storage are currently available. 1- 4,38-40 The simplest, a continuous paper printout, is an expensive and labor-intensive approach that requires a dedicated EEG machine and the attention of a qualified technologist. The inability to manipulate the waveforms in addition to the bulky nature of paper printouts have made this technique obsolete for LTME. Current systems use analog-to-digital conversion methods, and the data is stored on a computer hard drive, server, or compact disc/DVD media. Previous systems used videocassette recorders, or audiotape recorders in the case of ambulatory cassette recording; this has given way to digital systems using large-storage hard drives or flash memory, Digital video has replaced analog video and videotape. This approach allows continuous unattended recording from 6 hours to several days, depending on the system. Digital storage allows data to be easily modified on review, and it is amenable to computer reduction and analysis. Compact discs and DVDs are also less bulky and cheaper to store than videotapes. The storage capacity of the system depends on the sampling rate and the number of channels acquired. For 32 channels of EEG sampled at 200 Hz, a compact disc can hold approximately 20 hours of continuous data, whereas DVD media can store approximately 90 hours. Higher sampling rates and greater numbers of channels decrease this amount proportionately. Systems that permit selected EEG storage employ a built-in time delay so that the data stored include EEG activity recorded both before and after the device is triggered. 1-4 ,40 Computer-recognized interictal or ictal events are used to activate the system, so only the events of interest are stored. Because computerized detection programs are not completely accurate, false-positive detections and failure to detect genuine events occur. However, this approach greatly reduces the amount of data that needs to be stored. Storage can also be activated by a pushbutton that the patient or an observer uses to identify ictal events. Such an event-recording approach requires that the patient or an observer be able to recognize when a seizure is occurring, and seizures that occur without warning or subclinically may be missed. A portable system is now available that allows computerized detection of ictal and interictal events for use with an ambulatory recorder.v'r" The advantages of digital video, including the ability to zoom in on the image after recording and the ease of EEG and video time-locking on review, have made it
Long-Term Monitoring forEpilepsy
the current standard. In addition, the ability to store the video on the same medium as the EEG information has eliminated the need to keep separate libraries of videotapes and EEG. However, the digital video image is the most limiting factor for storage. The minimum video resolution for LTME is 640 X 480 pixels. At this low resolution, even with compression techniques, these image files are very large. The higher the image resolution, the larger are the image files. Thus there is a trade-off between the quality of the image and the amount of video that can be stored. To overcome the difficulty with storage, most systems ofIeI' the ability to edit and delete unwanted video on line before permanent storage, keeping only the clinically necessary video segments. The most common method for review is to display both the EEG and video on a high-resolution monitor. This has several advantages including the ability to reformat the EEG montage, filter settings, and gain. In addition, the digital video image can be time-locked to the EEG via a cursor to easily correlate clinical behavior with the EEG. In order to display the EEG waveform accurately, the display must have certain minimal characteristics. The display should have a minimum scaling ability for each channel such that 1 second of EEG occupies approximately 30 mm, with a resolution of 120 data points per second.P Vertical scaling depends on the number of channels displayed, but a minimum of four pixels per vertical millimeter is required for accurate reproduction of the waveforms.V The system should also offer the ability to digitally mark the EEG for technologist comments, pushbutton events, and automatic detections. The major advance in this area of LTME is the capability to record digitally onto disk or flash memory so that the continuous attention of an EEG technologist is not necessary. This has made 24-hour monitoring relatively inexpensive. The added refinements of computer-detected and patient-triggered selective identification and/ or storage have reduced the amount of data that need to be reviewed. Techniques for rapid review of EEGs have also facilitated data analysis, particularly for ambulatory recording, in which the addition of an audio channel has enhanced recognition of meaningful events." The development of digital recording systems makes it possible to reproduce data on a high-resolution computer monitor in any montage, gain, or filter setting desired. 38.4o Movable time markers, spike maps, and other programs for analysis permit facilitated interpretation, and networking between workstations at multiple locations is feasible.
Equipment for Monitoring Clinical Behavior Methods of monitoring behavior include self-reporting, observer-reporting, video and/or audio recording, and
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detailed monitoring of specific physical or cognitive functions. 1-4.38.39 Self-reporting requires the patient to make notes in a daily diary or log, indicating the occurrence of the specific events in question. This self-reporting can be accompanied by the use of a pushbutton that marks the occurrence of an event on the EEG tracing. Self-reporting is the common method of recording clinical behavior during ambulatory cassette monitoring. Observer-reporting uses the same methods but someone else, such as a parent, maintains a log and activates the event marker. For inpatient LTME, specially trained nurses or technologists can be made available to examine the patient during a seizure in order to elucidate the clinical behavior and to better elicit mental and neurologic deficits. A useful approach to the clinical examination during spontaneous epileptic seizures is shown in Table 5-2. Video and/or audio recording is ideally used in association with self- and observer-reporting and is the usual practice for inpatient LTME. This approach requires one or more video cameras (which are continuously focused on the patient) and a mechanism for synchronizing the video-recorded behavior with simultaneously recorded EEG activity. In selected situations it may also be helpful to use polygraphic instrumentation, continuous reaction time monitoring, or other automated techniques to identify specific physiologic or cognitive disturbances during ictal events. These data are usually recorded along with EEG activity.
TABLE 5-2 • Clinical Examination During Epileptic Seizures A. Ictal phase 1. Mental status a. Determine responsivity to commands, orientation, language function. b. Present a nonsense phrase for later recall, to determine amnesia. 2. Motor a. Note site of initiation and pattern of motor symptoms, clonic and/or postural. b. Note focal or lateralizing motor deficits during spontaneous movements and, if possible, provoke movements to confirm deficits. 3. Sensory In special situations it might be useful to demonstrate a general analgesia to pinprick or to document a specific sensory deficit, such as ictal blindness. B. Postictal phase 1. Observe spontaneous abnormal behavior (e.g., automatisms, combativeness, or unresponsiveness); determine time course of resolution. 2. Examine for specific focal or lateralizing neurologic deficits, including cognitive deficits. 3. Test for recall of nonsense phrase given in A-Ib,to determine amnesia for ictal event. 4. Elicit description, if possible, of aura, behavioral seizure, and postictal symptoms.
From Engel JJr: Seizures and Epilepsy. FA Davis, Philadelphia, 1989,with permission.
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A variety of black-and-white and color video cameras are available for use in LTME, including low light-level cameras and infrared cameras that can record at night. A common approach is to use two cameras, providing a split-screen image with one camera focused on the entire body and the other on a close-up of the face. Lens irises are available that automatically adjust to changing light conditions. Remote zoom and pan-and-tilt devices allow monitoring personnel to maintain the patient in the desired place on the video screen. For large units with several monitoring beds, a full-time monitoring technologist can be employed for this purpose. For smaller units, nurses or EEG technologists can watch the monitor and make adjustments when they have a chance; however, information may be lost. An alternative approach is to allow the patient to maintain the appropriate adjustments of the video equipment. Four approaches to auto tracking are currently available for video monitoring of patients who are moving around a large room. One depends on a radio frequency transmitter worn by the patient. Another uses a coded pulse of infrared light emitted from the camera, which is reflected off a strip worn by the patient and picked up by a detector on the camera. For the third, multiple cameras surround the room and the recording device determines which camera is recording from the patient by use of a computer that senses contrast. The fourth technique uses image processing to track specific defined features of the patient. In previous systems, analog video and/or audio recordings were synchronized with EEG recordings by a specialized time code generator that displays the date and time on the video image digitally and on the EEG in binary code or alphanumeric.l ? With modern systems, EEG and behavior are automatically synchronized when the data is stored digitally, and simultaneous display of EEG and behavior on the video image occurs with the reformatting technique. Clinical events are digitally marked on the EEG record at the appropriate point in time, and then re-reviewed by reading the EEG with the clinical notes. It is also possible to review the video time-locked to the EEG, simultaneously displayed on a high-resolution computer monitor. In this way discrete EEG events can be correlated with behavior directly, or vice versa. Unidirectional and omnidirectional audio microphones can be used during LTME. It is important to have a microphone that eliminates unwanted extraneous noise but does record sounds corning from observers who are describing ictal events, as well as sounds corning from the patient. The most bothersome extraneous noise on LTME units is the television in the patient's room. Consequently, it can be useful to wire the pushbutton that the patient uses to signal the occurrence of an event so that it also automatically turns off the television set.
Digital video is preferred over cassette videotape recorders. Cassette videotape recorders can only record 6 hours of video per cassette, requiring four recorders for 24 hours of continuous, unattended recording. Because digital video records to the computer hard drive or server, the continuous duration of recording is limited only by the storage capacity of the system. Editing and mastering of the digital image is much easier than with the systems used for cassette videotape, and image quality does not degrade with copying. With the networking capabilities of most systems, digital video also adds the ability to remotely view the patient from any location. In the future, both higher data storage systems and new data compression techniques will allow higher resolution video for longer continuous lengths of time.
Methods of Procedure ELECTRODES
Disk and sphenoidal electrodes should be checked periodically for breakage. Regelling of disk electrodes should be performed as necessary to maintain low impedance. Scalp irritation can usually be avoided if the patient uses a strong antidandruff shampoo before the electrodes are applied. Impedance is measured at the beginning, periodically during, and with ambulatory EEG at the end of recording. Impedance should be maintained at less than 5,000 ohms. Malfunction of intracranial electrodes cannot be corrected after they are inserted; however, problems with the special connectors can be resolved, and these must be inspected periodically. Impedance measurements of intracranial electrodes can be performed safely with currents in the range of 10 nA. For patients with intracranial electrodes, the guidelines for indwelling devices should be followed (in the United States, UL type A patient). RECORDING SYSTEM
The integrity of the entire recording system from electrode to storage medium should be checked before beginning LTME, and periodically during the monitoring. This is most easily done by observing the ongoing EEG and by having the patient generate physiologic artifacts. In addition, most systems have automatic impedance checks, can identity loose or bad electrodeto-amplifier connections, and have self-diagnostics to ensure proper recording parameters. The technician should also periodically review the record files to ensure that they are being stored properly. All instruments should also be calibrated as suggested by the manufacturer. More specific calibration systems are recommended for ambulatory EEG recorders.
long-Term Monitoring for Epilepsy RECORDING TECHNIQUES
Although a minimum of 24 channels is recommended for LTME, 32 or more are routinely used and are particularly necessary when basal electrodes are employed. 1•2. 33 Thirty-two channels are standard for scalp and sphenoidal LTME to localize epileptogenic regions for surgery; and 64, 96, or more channels are being used increasingly with intracranial electrodes. Sixteen-channel and 24-channel ambulatory recordings are now also possible with selective storage triggert'd by computerized spike and seizure detection and with an event marker operated by the patient or an observer.i'r" With most recording systems it is possible to record extracranially using a common reference montage, and then to review the data in any desired montage.t" The most useful montage for extracranial recordings with basal electrodes (e.g., sphenoidal, earlobe, or Tl/T2) employs standard lateral temporal bipolar chains in association with independent bipolar chains involving the basal electrode sites (Table 5-3), with additional derivations as equipment allows. Normal variants such as small sharp spikes and 14- and 6-Hz positive spikes are more easily distinguished from epileptic transients
TABLE 5-3 • Basal Electrode Montages forLTME Basal Electrode (PG) Montages Independent from Lateral Temporal Derivations 16-channel 12-channel Fp1-F7 Fpl-F7 F7-13 F7-T3 T3-TS T3-T5 T5-01 T5-01 Fp2-FB Fp2-FB FB-T4 FB-T4 T4-T6 T4-T6 T6-02 T6-02 C3-PGl 0-13 T3-PGl or T3-PGl PG1-PG2 PG1-PG2 PG1-Nz PG2-T4 PG2-C4 Nz-PG2 ECG ECG PG2-T4 T4-C4 C4-Cz ECG Basal Electrode (PG) Montage Not Independent from Lateral Temporal Derivations Fp l-F7 Fp2-FB F7-PGl FB-PG2 PG1-T3 PG2-T4 T3-T5 T4-T6 T5-01 T6-02 From Engel JJr, Burchfiel J, Ebersole Jetal: long-term monitoring for epilepsy: report of anIFCN committee. Electroencephalogr Clin Neurophysiol, 87:437, 1993, with permission.
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in this manner. Inclusion of C3/C4 electrodes on the basal electrode chain is useful when cancellation occurs between basal electrodes and T3 or T4. The same montages are appropriate for 16-channe1 ambulatory recording. When fewer channels are availahle, montages are usually designed to display data symmetrically from both hemispheres, preferentially sampling frontal and temporal regions as discussed in Chapter 6.1.2 Montages used with intracranial electrodes vary greatly depending on the electrodes used and the cerebral areas of suspected involvement.
LYME System Configurations Table 5-4 lists the common basic system configurations recommended by the American Electroencephalographic Society- and the International Federation of Clinical Neurophysiology.' Although newer systems all use digitally acquired EEG and video, older systems are still available and in use for LTME, particularly in developing countries. Their configurations are summarized in this section. Monitoring with paper printout only is appropriate for documentation, characterization, and quantification of clinical and subclinical ictal events and interictal EEG features over a period of hours, as is assessment of the relationship of these EEG events to behavior, performance tasks, naturally occurring events or cycles, or therapeutic intervention. It is not appropriate fill' evaluations that require the patient to move freely or when continuous monitoring is necessary fill' days. This form of long-term monitoring is relatively labor-intensive and becomes progressively more cumbersome with duration. At least 16 channels of EEG data and synchronized video monitoring are required for pr-esurgical localizetion of epileptogenic regions with this and all subsequently described configurations. Because of the limitations of this method, it is no longer considered the standard of care. Monitoring with continuous storage is appropriate for the same purposes as monitoring with paper printout only, but for days and weeks rather than for hours. It is not appropriate for the quantitative analysis of subclinical ictal or interictal features or for evaluations benefiting from complete freedom of movement. Radio telemetry provides more mobility than does cable telemetry; however, video monitoring becomes difficult or impossible when this degree of mobility is required. Computer-assisted selective monitoring is most appropriate for the same purposes as the previous two configurations, but it also records subclinical as well as clinical ictal EEG events. It is not appropriate for evaluations benefiting from complete freedom of movement. Computerized recognition programs generate false-negative and false-positive errors, so important data may be missed with this technique.
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TABLE 5-4 • Commonly Used LTME System Conflaurations Monltorlnl with p.per printout only EEC transmission: "hard wire" (standard cable) ortelemetry (cable orradio) EEC recording/storage: continuous paper printout EEC review/analysis: complete manual review Behavior monitoring: self, observer, and video Monltorlnl with continuous stor'le EEC transmission: cable orradio telemetry EEC recording/storage: analog orvideo tape, digital media (hard disk, server, CD/DVD) EEC review/analysis: selective review ofclinical ictal events, random sampling review for subclinical ictal and interictal events Behavior monitoring: self, observer, and video Computer·asslsted selective monltorlnl EEC transmission: cable orradio telemetry EEC recording/storage: digital tape/disk, computer-assisted selective storage EEC review/analysis: selective review ofclinical and computer-recognized ictal and interictal events on high-resolution monitor Behavior monitoring: self, observer, and video Ambulatory casseUe-seledlve event recordlnl!epoch sampllnl EEC transmission: ambulatory flash memory orhard disk (16- or 24-channel) EEC recording/storage: flash memory, hard disk, ordigital media (CD/DVD); event recording/epoch sampling (periodic orafter trigger) EEC review/analysis: epoch review Behavior monitoring: self, observer
Continuous storage recording with computerassisted event detection is preferred; it is used at most epilepsy centers. This technique reduces the amount of data that need to be reviewed while maintaining the continuous data if a more detailed review is desired. Typically, the data are reviewed, and the technologist saves selected segments. Sixteen- and 24-channel ambulatory monitoring is most appropriate for documentation and quantification of ictal (clinical and subclinical) and interictal EEG features and assessment of their relationship to reported behavior, naturally occurring events or cycles, or therapeutic intervention, when the data are most likely to be obtained outside the hospital or laboratory environment. With the addition of computerized spike and seizure detection, it is also appropriate for detailed characterization of EEG features for classification of seizure types and presurgical evaluation.:" This configuration, as well as the other ambulatory configurations, can be used in an inpatient setting and is particularly useful when mobility is of benefit. The absence of EEG changes during a reported ictal event does not rule out an epileptic condition.
INTERPRETATION OF RESULTS
Artifads EEG data obtained using LTME techniques are likely to contain unusual artifacts that are uncommon, or never encountered, in the standard EEG laboratory (Fig. 5-2). These are often peculiar to the systems in use, and the electroencephalographer working on an LTME unit must become familiar with their appearance. Scalp and sphenoidal electrodes show the usual biologic artifacts seen with standard EEG, but, in addition, chewing, talking, and teeth-brushing can produce dectromyographic (EMG), glossokinetic, and reflex extraocular movement potentials that are more difficult to identify. Intracranial electrode recordings are usually free from biologic artifacts except for pulsation and respiration. Altered electrode-scalp contact and intermittent lead-wire disconnection caused by body movement are the most common sources of mechanical artifacts during LTME. Artifacts induced by movement of a directconnection standard cable are avoided when telemetry systems are used. Rhythmic mechanical artifacts produced by rubbing or scratching the scalp, or movements of the head or extremity (particularly when associated with accompanying biologic artifacts) can be mistaken for ictal discharges. Interference from nearby electrical equipment, electrostatic potentials from movements of persons with dry clothing, or telephone ringing can also produce bothersome EEG transients. Mechanical artifacts caused by body movement and electrical interference are usually much less with intracranial than with extracranial recording. Electrodes, wires, amplifiers, receivers, switches, reformatters, tape recorders, oscillographs, or any other part of the LTME system can potentially cause artifact. Electrode pops, faulty switches or connectors, and contact between dissimilar metals are common causes of spurious transients, whereas chipped silver-silver chloride coating, instability of the electrode-scalp interface, and electrode wire movement are the most common causes of rhythmic slow waves. As with routine EEG, diagnosis of an epileptic ictal EEG event is made by recognition of well-formed spikewave or other characteristic patterns with a believable field and typical ictal progression, followed by postictal slowing and appropriate interictal abnormalities in other portions of the record. Confounding artifacts caused by biologic and mechanical disturbances can usually be identified when simultaneous videorecorded behavior is available. For ambulatory EEG monitoring, when video is not available, it is standard to have the patient and technologist produce common biologic and mechanical artifacts at the beginning or at the end of the recording, where they can be used as a
141
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the lowest morbidity rate (less than I percent)." Infection accounts for the majority of complications and typically is readily eradicated with antibiotics. Other reported complications, which are rare with subdural strips, include unintended extraction of the electrodes by patients in the peri-ictal period (a potential complication of any invasive recording procedure), subdural empyema, and cortical contusion. 22•23 No mortality has been reported with the technique.
RECORDING AND STIMULATION STUDIES WITH SUBDURAL GRIDS
Definition and Indications Subdural grids are similar to subdural strips except that they contain multiple parallel rows of electrode contacts, usually spaced 10 mm apart, embedded in an inert material. Typical arrays are rectangular or square and contain 16 to 64 contacts, although their arrange-
ment can be customized for each patient by simply cutting the grid to conform to the particular need. The large number of contacts available on subdural grids allows coverage of a relatively widespread cortical area compared with other invasive techniques. Hence subdural grids enable ascertainment of the spatial distribution of epileptiform activity. In addition, grids provide a means of performing chronic extraoperative stimulation studies to identify the localization of various cortical functions in relationship to the epileptogenic zone. Subdural grids are used to localize more precisely the epileptogenic region when other studies have established lateralization but have failed to define with sufficient certainty the regional localization of the seizure focus. Subdural grids are also employed when previous recordings suggest localization of the epileptogenic zone to a cortical region likely to sub serve important neurologic function. Commonly, grids are used to define the relationship of frontal or parietal epileptogenic foci to motor and sensory areas or to establish the
172
ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
proximity of frontal or lateral temporal epileptogenic foci to language areas. The ability to identify both epileptogenic cortex and "eloquent" functional cortex is essential in the planning and execution of resective surgery in these regions. Although some functional information can be obtained with the use of intraoperative mapping, the usual lack of ictal recordings in the operating room precludes definite identification of the region from which seizures arise. In addition, from a practical standpoint, young children and some adults do not tolerate intraoperative language mapping, which requires that the patient be awake during the initial portion of the operation. Finally, performing extraoperative recording and stimulation studies over a period of days in an epilepsy monitoring unit allows a more comprehensive evaluation of the epileptogenic region and a more thorough assessment of language function in a setting where the patient is awake, relaxed, and more cooperative.
Techniques Subdural electrode grids are placed through a craniotomy, with scalp and bone flaps tailored both to the area of suspected epileptogenicity and to functional areas that the grid is to cover (Fig. 7-6). An osteoplastic bone flap, in which the bone flap is attached to vascularized muscle flaps, reduces the likelihood of osteomyelitis. Typically, the cortical surface is photographed, the grid is inserted to cover the regions of interest, and additional photographs are made. The intraoperative photographs allow correlation of anatomic landmarks to particular grid contacts, and thus allow the creation of a "map" of the cortical sur-
FIGURE 7·6 • Intraoperative photograph showing placement of a 54--contactsubdural grid following craniotomy.
face that details epileptogenic and functional regions. The grid is sutured to the overlying dura to reduce any tendency to shift. Cerebrospinal fluid leakage is minimized with tunneling and a tight dural closure around the electrode cable. During the course of monitoring with subdural grids, prophylactic antibiotics are administered. For the first 1 to 2 postoperative days, fluid restriction and, sometimes, treatment with steroids are used to reduce the cerebral edema associated with the grid. Contemporary recording techniques involve the use of computerized equipment to amplify, digitize, analyze, and store data. These techniques are particularly valuable for grid recordings, where the capacity to review data (and to manipulate the manner in which it is presented) from a large number of channels is vital. The recordings are obtained in a monopolar fashion, with the reference being an electrode fastened to the skull at the time of craniotomy, a scalp electrode, or an "inactive" electrode on the grid. Cortical stimulation studies, in which electrical current is applied to the cortex through the contacts of the grid, provide valuable information concerning cortical function. Such studies are typically performed during the course of monitoring in the epilepsy monitoring unit. Techniques vary from one center to another, but the general approach is to stimulate sequentially, one contact at a time, the cortical surface underlying the grid to identify motor, sensory, language, and other functional areas. This approach has shown a certain amount of variability from subject to subject in the anatomic localization of sensory, motor, and language functions. 24•25 Mapping is accomplished by briefly passing current through each contact and observing the patient for motor responses; by inquiring about sensory and other phenomena induced by the stimulation; and by testing the patient's language function with the use of a variety of exercises, including counting and picture-naming. Typical stimulation parameters include bipolar 60-Hz square-wave pulses, 0.2 to 2.0 msec in duration. The intensity of stimulation is progressively increased until a clinical response is obtained or an afterdischarge (a repetitive discharge evoked by the stimulation) is recorded, usually at 4 to 12 V with constant-voltage stimulation or 2 to 6 rnA with constantcurrent stimulation. The EEG is monitored during stimulation to detect the presence of afterdischarges. Recognition of afterdischarges is important because the propagation of this activity to cortical areas other than those directly beneath the stimulated electrode contact may provide misleading functional information. Additionally, afterdischarges may evolve to become a clinical seizure. Findings from stimulation studies, along with ictal and interictal data, may then be depicted as a map of the cortical surface covered by the grid. This map allows appreciation of the relationship between
Invasive Clinical Neurophysiology in Epilepsy and Movement Disorders
functionally important areas and epileptogenic areas. Correlation of the map with intraoperative photographs facilitates planning of the surgical resection. Once a sufficient number of localizing ictal recordings have been obtained and mapping studies are complete, the patient undergoes reopening of the craniotomy under general anesthesia. After the grid position is confirmed, the grid is removed and the resection is undertaken based on the map of epileptogenic and functional areas.
cate regions of potential epileptogenicity or may be geographically distinct from the seizure focus. Ictal recordings, with morphologic features as previously described, provide the primary basis for defining the epileptogenic zone, although no standardized approach to their interpretation exists (Fig. 7-7). Although some authors have found subdural grids rarely to be adequate for seizure localization, others have found the technique generally to be quite useful. 26 .27
Advantages. Limitations. and Complications
Findings Interpretation of cortical recordings made with grids is similar to that with strips (previously discussed). One difference is the absence of bilateral information in grid recordings, and this lack can make the assessment of background, interictal, and ictal patterns challenging. As with other invasive recordings, localized background disturbances may be present in the epileptogenic zone. Interictal epileptiform discharges may serve to demar-
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
subdural grids have the highest potential for morbidity (about 4 percent) of any of the invasive techniques because of the requirement for craniotomy and the size of the grid. 28 Infection is the most common complication but is minimized with meticulous technique, proper maintenance of the craniotomy site and electrode cables, and the use of prophylactic antibiotics. Brain edema can occur but usually responds to fluid restriction and diuresis. Less commonly, subdural hematomas may occur.
EPIDURAL RECORDING TECHNIQUES Definition, Indications, Techniques, and Findings Strip or grid electrodes may be placed on top of the dura through burr holes or following craniotomy (rather than in the subdural space) to record activity from the underlying cerebral cortex. Additionally, socalled epidural peg electrodes may be inserted through small skull holes to enable recording in a similar manner, although this technique seems to have fallen out of favor with many epileptologists. The indications for, technical aspects of, and findings with epidural techniques and subdural techniques are similar. The epidural approach may be preferable when electrodes must be placed in regions involved in a previous resection, because adhesions may prevent access to the subdural space.
Advantages, Limitations, and Complications Compared with subdurally placed electrodes, those placed epidurally may be less prone to inciting infection because the intact dura serves as a protective barrier. By the nature of their location, epidural electrodes are easier to place in patients with subdural adhesions from previous surgery. Unlike subdural strips and grids, however, epidural electrode arrays cannot be placed in interhemispheric, basiotemporal, or orbitofrontal regions. Thus, epidural electrodes are reserved mainly for recording from the lateral convexities. Epidural peg electrodes do provide the capacity to obtain relatively extensive coverage of cortex, and these electrodes may be closely spaced to obtain reasonably highdensity regional recordings (with the requirement of relatively extensive trephining in such a case). In distinction to subdural electrodes, stimulation studies cannot be undertaken with epidural electrodes unless the exposed dura is denervated before electrode placement to avoid discomfort to the patient during electrical stimulation.
ELECTROCORTICOGRAPHY Definition and Indications Electrocorticography (ECoC) consists of the intraoperative recording of electrical activity directly from the exposed cerebral cortex. Penfield andJasper developed the technique in the 1940s, and their monograph on the subject remains a masterful and instructive treatise even today.29 Electrocorticography is used to help delineate the epileptogenic cortical region in more detail than that established by the preoperative, noninvasive evaluation. It is employed, along with electrical stimulation, to identify functional cortical areas, much in the same manner as with grid stimulation studies. Finally, ECoC is performed following the initial resection to assess the completeness of the resection and to identify areas of residual epileptiform activity that may be considered for removal. The circumstances during which ECoC is employed vary among epileptologists. At some institutions, recordings are made during all cases of epilepsy surgery, and the intraoperative findings are used to tailor the surgical resection to each patient. At other centers, ECoC is used selectively (e.g., only in extraternporal procedures), or it may be universally performed for research purposes but the findings are then not used in determining the volume of brain tissue to be resected. When resection of central regions is contemplated, motor mapping (in a manner similar to that previously described) may be employed. Such mapping is performed with the patient under general anesthesia but without the use of paralytic agents. Operations undertaken on the language-dominant hemisphere may be performed with the patient under local anesthesia so that intraoperative mapping of language function may be performed, with the findings from this mapping then used to guide the resection. Other centers perform extraoperative language mapping (using subdural grids, as described earlier) for all resections involving the language-dominant hemisphere in which the resection might encroach on cortical areas suspected of being involved in language function. Some surgeons utilize intraoperative language and motor mapping to guide the resection of tumors and other lesions in patients who do not necessarily have epilepsy, with ECoC used primarily to monitor for afterdischarges and to protect the patient from clinical seizures triggered by electrical stimulation.P
Techniques A variety of electrode arrangements may be used in ECoC. Many centers use a crown, attached to the skull, containing a number of electrodes (often 16) that may
Invasive Clinical Neurophysiology in Epilepsy and Movement Disorders
be directed in various positions atop the cortex following craniotomy. This crown provides a flexible means of covering the exposed cortex of interest while it maximizes the access to and the visibility of the cortex (Fig. 7-8). Electrode strips, such as those used for extraoperative subdural recordings, may also be used for intraoperative ECoC, but the fixed interelectrode distances reduce versatility. Particularly for temporal lobe resections, crown or strip electrodes are often supplemented with depth electrodes and individual flexible wire electrodes. In such cases the depth electrodes are typically inserted through the middle temporal gyrus to enable the distal contacts to record from medial structures (the amygdala and hippocampus), providing electrophysiologic information from structures often involved in the epileptogenic process but not readily sampled by means of the cortical surface electrodes. Flexible wire electrodes offer the advantage of insertion beneath the dura, allowing recordings from neocortical subternporal regions not otherwise accessed. In extraternporal cases, wire electrodes enable recording from the interhemispheric fissure or from other neocortical areas not directly exposed during the craniotomy. The post of the crown is typically used as the ground, and an electrode clipped to the exposed dura provides the reference. Referential and bipolar montages can be used. Despite the relatively hostile electrical environment of the operating room, high-quality recordings with little artifact can be obtained. Correct selection of filters can limit the interference and amplifier blocking produced during cortical stimulation. The stimulation parameters are similar to those described earlier for grid recordings, although monopolar or bipolar stimulation can be used.
FIGURE 7-8 • Intraoperative photograph demonstrating the placement of the crown electrode used for electrocorticographv (ECoG).
175
A close working relationship between the epileptologist, the anesthesiologist, and the neurosurgeon is mandatory for obtaining high-quality and useful electrophysiologic data. Although practices vary, many epileptologists find that inducing anesthesia with an opiate (e.g., fentanyl) and maintaining general anesthesia with the opiate and an inhalational agent (e.g., nitrous oxide) provides effective anesthesia and permits acquisition of a satisfactory ECoC. For procedures in which it is desirable for the patient to be awake (e.g., language mapping), local analgesia and sedation with opiates and other agents, including droperidol, are used."
Findings The activity recorded during ECoC usually is composed of a mixed-frequency background, often with a considerable amount of fast activity; but the frequency, amplitude, and morphology may vary substantially from case to case. The factors influencing the appearance of this activity include the level of consciousness of the patien t, the particular anesthetic and sedative agents employed during the operation and their concentrations, the region of the cortex from which the activity is recorded, and the nature of the underlying pathologic disturbance. Halogenated inhalational anesthetic agents (e.g., halothane, enflurane, and isoflurane) invariably increase the amount of fast activity present, and this effect often persists for some time after discontinuation of the drug. A profuse amount of background fast activity obscures the recognition of epileptiform discharges, significantly reducing the usefulness of the recording. In general, ECoC from the central, perirolandic cortex demonstrates predominantly fast activity that can be quite rhythmic and sharp in appearance, mimicking epileptiform activity. Recordings from other regions (e.g., the temporal neocortex) contain predominantly intermediate frequency activity with less fast activity. When ECoC is undertaken in cases of brain tumors or other structural lesions, suppression and slowing of the activity recorded in the vicinity of the lesion are commonly seen (Fig. 7-9). In the course of the usual, relatively brief intraoperative ECoC recording, one rarely records a seizure. Thus, in most cases, identification of interictal epileptiform discharges provides the basis for delineating the epileptogenic zone during epilepsy surgery. Epileptiform discharges recorded by ECoG can assume spike, polyspike, and sharp-wave morphologies and can be of varied amplitude (Figs. 7-10 and 7-11). Many authors maintain that the site of interictal epileptiform discharges is related to the site from which seizures themselves arise and, moreover, that removal of the tissue producing interictal epileptiform abnormalities is
176
ElEaROOIAGNOSIS INCLINICAL NEUROLOGY
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important in achieving seizure control.V Although some series have found that the absence of epileptiform discharges on postresection ECoG predicts a successful postoperative outcome, and the presence of residual discharges is usually associated with incomplete seizure control following surgery, other reports have concluded that ECoG is of little value in guiding the surgical resection.P:" Pharmacologic activation procedures using intravenous administration of methohexital, etomidate, or other medications may enhance the frequency with which epileptiform discharges are recorded (Fig. 7-12, A and B), although more significance is placed on the spontaneously appearing discharges than on those that are induced.
Advantages, Limitations, and Complications Intraoperative ECoG with mapping provides the ability to define epileptogenic and functionally important cortical areas relatively quickly and with more spatial precision than when this information is obtained extraoperatively with the use of implanted, fixed-array elec-
trodes. It allows acquisition of the information, at the time of a single craniotomy, for the resective surgery, and these proximate ECoG findings are then available for the planning of the operation. When intraoperative ECoG provides sufficient information to proceed directly with the resection, it spares the patient the risk (albeit small), discomfort, and cost associated with invasive monitoring. As previously mentioned, ECoG typically provides only interictal information about the epileptogenic zone, and the relevance of the distribution of interictal discharges to the zone of ictus onset and the requisite tissue that must be resected to abolish seizures is not always clear. At times, the intraoperative recordings contain no epileptiform abnormalities and are thus not helpful. In such cases, when better definition of the epileptogenic region in relation to functional areas is required, a subdural grid is usually placed and extraoperative monitoring carried out before resection. Performing ECoG prolongs the duration of the operation and the total time during which the patient receives anesthesia. Thus such an operation theoretically carries the risk of increased morbidity compared with an operation of shorter duration, but this concern seems to be of little actual clinical relevance.
Invasive Clinical Neurophysiology in Epilepsy and Movement Disorders
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MICROELEORODE RECORDINGS IN THE SURGICAL TREATMENT OF MOVEMENT DISORDERS Basal ganglia surgery for Parkinson's disease and other movement disorders dates back to the 1940s, after it was fortuitously discovered that lesions of the globus pallidus could improve parkinsonian symptoms. Various techniques, including pallidotomy and thalamotomy, gained popularity until the introduction of more effective pharmacologic therapies, particularly levodopa. As the limitations and adverse effects of these medications became clearer, however, surgical options for the treat-
ment of Parkinson's disease, essential tremor, dystonia, and other movement disorders provoked renewed interest. The development of deep brain stimulation (DBS) therapy heralded a new era in surgical intervention for movement disorders, and this treatment is now in common use. Several technologic advances have contributed to the revitalization of surgical therapy for movement disorders. With improvements in modern functional stereotactic neurosurgical techniques and neuroimaging, identification of the neuroanatomic structures of interest and placement oflesions and brain stimulators in these structures has become more precise. Additionally, advances in
178
ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
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the understanding of the neurophysiologic underpinnings of Parkinson's disease (and, to a lesser extent, other movement disorders) have provided the scientific rationale for a surgical approach to the treatment of these disabling conditions. The advent of deep brain stimulation therapy provided a nondestructive, adjustable, and reversible treatment with advantages over ablative surgical procedures. Of special interest for the present discussion, neurophysiologic recordings from the basal ganglia and the thalamus have enhanced the precision with which lesions are made or stimulator leads are placed. The following sections address the use of microelectrode recordings to guide implantation of deep brain stimulation leads, pallidotomy, and thalamotomy.
Definition and Indications Microelectrode recordings are obtained with the use of a fine recording electrode, typically having a tip diameter of 15 to 25 11m, through a burr hole or twist-drill
hole in the skull with a trajectory toward a stereotactically defined target. The technique enables the recording of extracellular, single-unit neuronal activity. The electrophysiologic properties of the activity so recorded provide an indication of the location of the electrode in relation to the various gray matter nuclei and white matter tracts encountered along the trajectory. Indeed, the characteristic neurophysiologic signatures of cells within the subthalamic nucleus (STN), globus pallidus internus (GPi) , and ventralis intermedius nucleus of the thalamus (Vim) enable identification of the areas targeted in surgical procedures aimed at providing relief from the symptoms of various movement disorders. Furthermore, the motor subterritories within these target nuclei (i.e., the specific regions in which DBS leads are placed or lesions are generated) can be defined, because activity in such areas is modulated by active or passive patient movement. The role of microelectrode recordings in the surgical treatment of movement disorders has not been fully
Invasive Clinical Neurophysiology in Epilepsv and Movement Disorders
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electrocorticogram from the left frontoparietal region in a 9-month-old girl with tuberous sclerosis and intractable seizures. The background consists of mixed-frequency activi ty with a considerable amount of fast activity. No epileptiform discharges are obvious. B, Following the administration of methohexital, background activity is dramatically suppressed and frequent spike and polyspike epileptiform discharges emerge, mainly in electrode 4.
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established, yet many clinicians believe that the current limitations of image-based targeting require the addition of physiologic information to optimize the accuracy of surgical targeting. Current image-guided stereotaxis relies upon historical (preoperative) imaging, coupled with fiducial markers provided by a rigid head frame affixed to the patient's head or by frameless markers embedded in the skull. These techniques have inherent in them several factors that diminish the precision of targeting, including mechanical inaccuracies, image distortion (for MRI-based techniques), brain shifts that occur after preoperative images have been obtained, and variability in the correlation between physiologic function and anatomy. Whether the employment of microelectrode mapping in surgery for movement disorders results in an
~300!J.V 1 sec
improved success rate, greater efficacy, or altered morbidity remains to be settled. One study found that microelectrode recordings significantly altered the ultimate placement of the stimulator lead (by 2 mm or more) relative to the initial site determined by neuroimagingguided stereotactic techniques in 25 percent of patients. 35
Techniques The neurosurgical procedures involved in microelectrode recordings have been well described in the neurosurgical literature and will only be briefly outlined here." The initial target for the microelectrode is determined with the use of CT- or MRI-guided stereotactic
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ELECTRODIAGNOSIS IN CLINICAL NEUROLOGY
techniques. This procedure usually entails attachment of a stereotactic frame to the patient's head, neuroimaging, and calculation of the coordinates for the desired target. Following local analgesia, a small burr hole or twist-drill hole is made in the skull anterior to the coronal suture and lateral to the midsagittal line. The microelectrode, typically constructed of tungsten or platinum-iridium and housed in a protective carrier tube, is inserted under stereotactic guidance and advanced by submillimeter increments with the aid of a microdrive. The neuronal activity is recorded with the use of conventional preamplifiers, AC-De amplifiers, filters, spike triggers, and processors. In addition to an oscilloscope-type visual monitor, an audio monitor provides an effective means of identifying and differentiating the activity recorded from various structures. Microelectrode localization of the target (STN for subthalamic DBS, GPi for pallidal DBS or pallidotomy, or Vim for thalamic DBS or thalamotomy) is based on the characteristic patterns of spontaneous neuronal discharges recorded from the various structures, and on the identification of cells whose activity is modulated by limb movement.
Findings GLOBUS PALLIDUS
Deep brain stimulation of the globus pallidus or pallidotomy for the treatment of Parkinson's disease, dystonia, and various other movement disorders relies on identification of the globus pallidus. Once the microelectrode is advanced to the calculated target for the globus pallidus, recordings enable distinction between globus pallidus externus (GPe) and globus pallidus internus (Gpi); the latter, and particularly its motor-related region, is the desired location in the globus pallidus in which to implant the stimulator lead or place the lesion. In patients with Parkinson's disease, GPe single-cell activity tends to have a lower frequency and a more irregular pattern of firing than does activity recorded from GPi (Fig. 7-13) .36 Two different discharge patterns are characteristic of GPe neurons: (1) a bursting pattern consisting of high-frequency bursts of activity interrupted by pauses; and (2) a low-frequency, irregular pattern.3~ Neuronal activity recorded from GPi, by contrast, is distinctly higher in frequency in the parkinsonian brain; it often assumes a sustained but irregular firing pattern.36-38,40 In patients with dystonia, GPi discharge rates tend to be lower," So-called border cells, located in the laminae surrounding GPe and GPi, are identified by their relatively lower frequency and more regular discharge patterns.36-38 Within both GPe and GPi, cells responsive to active or passive movement, or both, are found. 36•38.40 Although most of these units respond to contralateral limb movement, some respond in a similar manner with
'1 1· H...... rt
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Motor thalamus "tremor cell" (ET) FIGURE 7-13 • Microelectrode recordings of spontaneous neuronal activity from the thalamus and basal ganglia. Each trace represents a l-second recording in a patient with Parkinson's disease (upper 8 traces) or essential tremor (bottom trace). STN: subthalamic nucleus; SNr: substantia nigra pars reticulata; GPe: globus pallidus externus; GPi: globus pallidus internus; ET: essential tremor. (From Starr P: Technical considerations in movement disorders surgery. p. 269. In Schulder M, Gandhi CD [eds]: Handbook of Stereotactic and Functional Neurosurgery. Marcel Dekker, Inc., New York, 2003, with permission.)
ipsilateral movement. In addition, some cells preferentially respond to one phase of movement more than another (e.g., flexion but not extension, or vice versaj.t" Identification of the optic tract, located inferior to the inferior margin of GPi, is important so that one can avoid placing the stimulator lead or lesion in this structure and thereby causing visual deficits. Such identification is accomplished by detecting light-evoked action potential discharges at the base of the pallidum. 36--:IH Microstimulation, in which 2 to 20 ~ of current passed through the microelectrode evokes visual phenomena in the patient's contralateral visual field, is also used for identifying the optic tract.36-38
Invasive Clinical Neurophysiology in Epilepsy and Movement Disorders
To avoid motor deficits, the internal capsule is identified. As for any white matter region, recordings from this structure are characterized by a relative absence of neuronal action potentials and, occasionally, the presence of axonal spikes. Microstimulation of the internal capsule, resulting in contraction of the tongue, face, or hand, confirms localization. 36-38 THAUlMUS
For the surgical treatment of essential tremor or other forms of tremor, the target for stimulator lead implantation or lesion placement is the Vim. The trajectory of the microelectrode for this procedure usually enters the caudate nucleus first, where recordings demonstrate a slow rate (up to 10 Hz) of spontaneous cellular discharges.l" As the electrode enters the dorsal thalamus, the recordings are relatively quiescent except for occasional bursts of actlviry.'" On entry of the microelectrode into the ventral aspect of the thalamus, cells responsive to movement may be detected. So-called "tremor cells," cells discharging at the rate of the patient's tremor, may also be encountered (see Fig. 7_13).:}6.42,4:} Placement of the surgical lesion in the area populated by these tremor cells has been shown to correlate with clinical improvement in the patient's tremor. 44.45 The sensory thalamus can be identified, and thus avoided, by recording cells responsive to light cuta-
neous stimuli. Microstimulation, too, enables identification of the sensory thalamus and the internal capsule." SUBTHALAMIC NUCLEUS
Deep brain stimulation of the STN has emerged as a commonly used procedure to treat the motor symptoms of advanced Parkinson's disease when patients experience disabling symptoms despite optimized pharmacologic therapy." The STN, a major output nucleus of the basal ganglia, exhibits excessive and abnormally patterned neuronal activity in the parkinsonian brain.f Stimulating this structure with high-frequency (greater than 100 Hz) electrical pulses by means of a chronically implanted DBS lead can reversibly suppress the major motor symptoms and signs of Parkinson's disease and provide patients with more consistent and higher-quality motor function." The STN is a small nucleus relative to the other structures targeted in surgery for movement disorders, but its characteristic pattern of neurophysiologic activity enables intraoperative identification with relative ease. With a typical microelectrode trajectory, cells in the caudate nucleus of the striatum and then the dorsal thalamus are recorded en route to the STN. Caudate and thalamic neurons have a relatively low rate of discharge (see Fig. 7-13), and individual units are generally easy to isolate." As the microelectrode is advanced further and the STN is approached, back-
II Microelectrode recording of movement-related STN neuronal activity during passive movement of the contralateral upper extremity. The upper trace shows the microelectrode recording and the lower trace shows output of a wrist-mounted accelerometer. Arrows indicate a burst of neuronal activity evoked by limb movement. The trace represents a 4--second recording in a patient with Parkinson's disease. (Courtesy of Dr. Philip A. Starr.)
FIGURE 7-14
181
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ElECTRODIAGNOSIS IN CLINICAL NEUROLOGY
when single STN units, discharging at rates of 20 to 50 Hz, are isolated. 36 While recording within the STN, particularly within its dorsal aspect, neurons can be identified that respond to active or passive movement of the patient's contralateral arm or leg (Fig. 7_14).48 This movement-induced modulation of activity is most easily perceived as a subtle increase in volume in the audio signal coincident with the movement; this confirms that the electrode is traversing the region of STN subserving motor function-the target for DBS lead implantation. With passage of the microelectrode through the inferior border of STN and into the substantia nigra pars reticulata, the pattern of activity changes abruptly. Higher-frequency activity (50 to 70 Hz), more regular in its pattern and with single units more easy to isolate, appears. In clinical practice, mapping with 1 to 3 microelectrode tracks usually allow confident identification of the relevant borders of STN and its motor subterritory (Fig. 7_15).49.50 From this information, the desired location of DBS lead implantation can be determined.P
Advantages, limitations, and Complications
FIGURE 1·15 • Microelectrode mapping from a case of subthalamic nucleus (STN) DBS surgery, illustrating somatotopy of the motor area. Four microelectrode penetrations were performed in two parasagittal planes. Arm-related cells (filled symbols) are in the anterior, posterior, and lateral aspects of the motor territory, and leg-related cells (open symbols) are in the mediocentral part of the motor territory. Squares represent the most proximal joint (hip, shoulder); circles the middle joint (knee, elbow); and triangles the most distal joint (ankle, wrist) for each extremity. A bold line at the end of a microelectrode trajectory indicates the start of substantia nigra pars reticulata. Microelectrode track reconstructions are superimposed on sagittal plane anatomy drawn from a standard brain atlas, with (A) 11.5 mm lateral to the midline and (B) 13.5 mm lateral to the midline. (From Starr PA, Theodosopoulos PV, Turner R: Surgery of the subthalamic nucleus: use of movement-related neuronal activity for surgical navigation. Neurosurgery, 53:1146, 2003, with permission.)
ground neuronal activity increases. Upon entering the STN, dense, multi-unit recordings are common; the activity is thus seemingly faster than that observed
Stereotactic neurosurgical procedures for the treatment of Parkinson's disease, essential tremor, dystonia, and other movement disorders can diminish the debilitating symptoms of these disorders for many patients. These procedures rely on the precise placement of a stimulator lead or lesion into deep brain structures; thus the exquisite spatial resolution offered by neurophysiologic techniques utilizing microelectrode recording appears to be useful in identifying the target structures of the basal ganglia and thalamus.
REFERENCES 1. NIH Consensus Conference: Surgery for Epilepsy. National Institutes of Health Consensus Conference. JAMA, 264:729,1990 2. Arroyo S, Lesser RP, Awad 1A et al: Subdural and epidural grids and strips. p. 377. In Engel J Jr (ed): Surgical Treatment of the Epilepsies. 2nd Ed. Raven Press, New York, 1993 3. Spencer 58, Williamson PD, Spencer DD et al: Human hippocampal seizure spread studied by depth and subdural recording: the hippocampal commissure. Epilepsia, 28:479, 1987 4. Sirven JI, Malamut BL, Liporace JD et al: Outcome after temporal lobectomy in bilateral temporal lobe epilepsy. Ann Neurol, 42:873, 1997 5. Talairach J, Bancaud J, Bonis A et al: Functional stereotaxic exploration of epilepsy. Cantin Neural, 22:328, 1962
Invasive Clinical Neurophysiology in Epilepsy and Movement Disorders
6. Spencer DO: Depth electrode implantation at Yale University. p. 603. In Engel J Jr (ed): Surgical Treatment of the Epilepsies. Raven Press, New York, 1987 7. EngelJ, Crandall PH: Intensive neurodiagnostic monitoring with intracranial electrodes. p. 85. In Gumnit RJ (ed): Intensive Neurodiagnostic Monitoring (Advances in Neurology, Vol 46). Raven Press, New York, 1987 8. Ajmone-Marsan C: Chronic intracranial recording and electrocorticography, p. 535. In Daly DO, Pedley TA (eds): Current Practice of Clinical Electroencephalography. Raven Press, New York, 1990 9. Hirsch LJ, Spencer SS, Williamson MD et al: Comparison of bitemporal and unitemporal epilepsy defined by depth electroencephalography. Ann Neurol, 30:340,1991 10. Risinger MW, Lee BI, EngelJ Jr et al: Electrographic morphology of ictal recordings from temporal depth electrodes. Neurology, 38:Suppll, 106, 1988 II. Sperling MR, O'Connor MJ: Comparison of depth and subdural electrodes in recording temporal lobe seizures. Neurology, 39:1497, 1989 12. Morris HH, Estes ML, Luders H et al: Electrophysiologic pathologic correlations in patients with complex partial seizures. Arch Neurol, 44:703, 1987 13. Spencer SS, So NK, EngelJJr et al: Depth electrodes. p. 359. In EngelJJr (ed): Surgical Treatment of the Epilepsies. 2nd Ed. Raven Press, New York, 1993 14. Laxer KD, Needleman R, Rosenbaum TJ: Subdural electrodes for seizure focus localization. Epilepsia, 25:651, 1984 15. luders H, Lesser RP, Dinner DS: Chronic intracranial recording and stimulation with subdural electrodes. p. 297. In Engel J Jr (ed): Surgical Treatment of the Epilepsies. Raven Press, New York, 1987 16. Privitera MD, QuinlanJG, Yeh H: Interictal spike detection comparing subdural and depth electrodes during electrocorticography. Electroencephalogr Clin Neurophysiol, 76:379, 1990 17. Sperling MR, O'Connor MJ: Comparison of depth and subdural electrodes in recording temporal lobe seizures. Neurology, 39:1497,1989 18. Spencer SS: Con troversies in epileptology: depth vs. subdural electrode studies for unlocalized epilepsy. J Epilepsy, 2:123,1989 19. Rosenbaum TJ, Laxer KD: Subdural electrode recordings for seizure focus localization. J Epilepsy, 2:129, 1989 20. Barry E. Bergey GK, Wolf AL: Simultaneous subdural gTid and depth electrode recordings of patients with refractory complex partial seizures. Epilepsia, 30:695, 1989 21. Wyler AR, Walker G, Somes G: The morbidity of longte-rm seizure monitoring using subdural strip electrodes. J Neurosurg, 74:734, 1991 22. Rosenbaum TJ, Laxer KD, Vessely M et al: Subdural electrodes for seizure focus localization. Neurosurgery, 19:73, 1986 23. Wyler AR, Ojemann GA, Lettich E et al: Subdural strip electrodes for localizing epileptogenic foci. J Neurosurg, f:iO: 1195, 1984 24. Uematsu S, Lesser R, Fisher R: Individual variations and broad representation of motor and sensory cortex in humans. Epilepsia, 30:643, 1989
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25. Ojemann GA, Ojemannj, Lettich E et al: Cortical language localization in left dominant hemisphere. J Neurosurg, 71:316,1989 26. Masuoka LK, Spencer SS: Seizure localization using subdural grid electrodes. Epilepsia, 34:Suppl 6, 8, 1993 27. Gates JR, Maxwell RE, Fiol ME et al: Usefulness of subdural grid electrodes in resecting epileptic lesions adjacent to eloquent cortex. Epilepsia, 29:660, 1988 28. Spencer SS, Lamoureux 0: Invasive electroencephalography evaluation for epilepsy surgery. p. 562. In Shorvon SO, Dreifuss F, Fish 0 et al (eds): The Treatment of Epilepsy. Blackwell Science, Oxford, 1996 29. Penfield W, Jasper H: Functional Localization in the Cerebral Cortex. Little, Brown, Boston, 1954 30. Berger MS: Minimalism through intraoperative functional mapping. Clin Neurosurg, 43:324, 1996 31. Smith M: Anaesthesia in epilepsy surgery. p. 794. In Shorvon SD, Dreifuss F, Fish 0 et al (eds): The Treatment of Epilepsy. Blackwell Science, Oxford, 1996 32. Ojemann GA: Intraoperative electrocorticography and functional mapping. p. 189. In Wyler AR, Hermann BP (eds): The Surgical Management of Epilepsy. ButterworthHeinemann, Boston, 1994 33. Bengzon A, Rasmussen T, Gloor P et al: Prognostic factors in the surgical treatment of temporal lobe epileptics. Neurology, 18:717, 1968 34. McBride MC, Binnie CD,Janota I et al: Predictive value of intraoperative electrocorticograms in resective epilepsy surgery. Ann Neurol, 30:526, 1991 35. Starr PA, Christine CW, Theodosopoulos PV et al: Implantation of deep brain stimulators into the subthalamic nucleus: technical approach and magnetic resonance imaging-verified lead locations. J Neurosurg, 97:370, 2002 36. Starr P: Technical considerations in movement disorders surgery. p. 269. In Schulder M, Gandhi CD (eds): Handbook of Stereotactic and Functional Neurosurgery. Marcel Dekker, New York, 2003 37. Vitek JL, Baron M, Bakay RAE et al: Microelectrodeguided pallidotomy: technical approach and application for medically intractable Parkinson's disease.J Neurosurg, 88:1027, 1998 38. Lozano A, Hutchison W, Kiss Z et al: Methods for microelectrode-guided posteroventral pallidotomy.J Neurosurg, 84:194,1996 39. Lenz FA, Dostrovsky JO, Kwan HC et al: Methods for microstimulation and recording of single neurons and evoked potentials in the human central nervous system. J Neurosurg, 68:630, 1988 40. Sterio D, Beric A, Dogali M et al: Neurophysiological properties of pallidal neurons in Parkinson's disease. Ann Neurol, 35:586, 1994 41. VitekJL, Chockkan V, ZhangJYet al: Neuronal activity in the basal ganglia in patients with generalized dystonia and hemiballismus. Ann Neurol, 46:22, 1999 42. Lenz FA, Tasker RR, Kwan HC et al: Single unit analysis of the human ventral thalamic nuclear group: correlation of thalamic "tremor cells" with the 3-6 Hz component of parkinsonian tremor. J Neurosci, 8:754, 1988 43. Benabid AL, Pollak P, Gao D et al: Chronic electrical stimulation of the ventralis intermedius nucleus of the thala-
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mus as a treatment of movement disorders. .I Neurosurg, 84:203, 1996 44. Hirai T, Miyazaki M, Nakajima H et al: The correlation between tremor characteristics and the predicted volume of effective lesions in stereotaxic nucleus ventralis intermedius thalamotomy. Brain, 106:1001, 1983 45. Lenz FA, Normand SL, Kwan HC et al: Statistical prediction of the optimal site for thalamotomy in parkinsonian tremor. Mov Disord, 10:318, 1995 46. Limousin P, Krack P,Pollak P et al: Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease. N Engl] Med, 339:1105, 1998
47. DeLong MR: Primate models of movement disorders of basal ganglia origin. Trends Neurosci, 13:281, 1990 48. Theodosopoulos PV, Marks V\J Jr., Christine C et al: Locations of movement-related cells in the human subthalamic nucleus in Parkinson's disease. Mov Disord, 18:791, 2003 49. Starr PA: Placement of deep brain stimulators into the subthalamic nucleus or globus pallidus internus: technical approach. Stereotact Funct Neurosurg, 79:133, 2002 50. Starr PA, Theodosopoulos PV, Turner R: Surgery of the subthalamic nucleus: use of movement-related neuronal activityfor surgical navigation. Neurosurgery, 53:1146, 2003
CHAPTER
Intraoperative Eledroencephalographic Monitoring During Carotid Endarteredomy and Cardiac Surgery
9
GREGORY D. CASCINO and FRANK W. SHARBRQUGH, III
CAROTID ENDARTERECTOMY
EEG CHANGES RELATED TO CAROTID ARTERY CLAMPING
INTRAOPERATIVE EEG MONITORING: METHODOLOGY
CEREBRAL BLOOD FLOW
EEG AND ANESTHESIA Symmetric EEG Patterns at Subanesthetic or Minimal Anesthetic Concentrations Symmetric EEG Changes with Induction Symmetric EEG Patterns at Sub-MAC Anesthetic Concentrations
EEG AND CAROTID ENDARTERECTOMY EVOKED POTENTIALS AND CAROTID ARTERY SURGERY EEG MONITORING AND CARDIAC SURGERY
EEG CHANGES UNRELATED TO CAROTID ARTERY CLAMPING
The intraoperative recording of electroencephalographic (EEG) activity began soon after the development and introduction of the EEG as a neurodiagnostic technique.l" One of the initial clinical applications of the intraoperative recording of cerebral electrical activity was electrocorticography (ECoG) at the time of focal corticectomy for intractable epilepsy.l" This technique was used before the development of extraoperative EEG monitoring to localize the epileptogenic zone in patien ts with partial seizures.l" ECoG is still used at selected epilepsy centers before and after excision of the epileptic brain tissue. The use of ECoG during epilepsy surgery is addressed Chapter 7 in Other potential indications for intraoperative EEG recordings include the monitoring of cerebral function during carotid endarterectomy and cardiopulmonary bypass surgical procedures.r" The rationale for intraoperative EEG monitoring is the detection of electrophysiologic alterations that are intimately associated with cerebral ischemia or cerebral hypoperfusion before the development of cerebral infarction.e" Extracranial or scalp-recorded EEG monitoring during carotid endarterectomy has been shown to be a reliable indicator of cerebral ischemia.F''" The findings obtained with extracranial EEG monitoring at the time of an endarterectomy may lead to an alteration in operative strategy (i.e., may indicate the need for placement of a
carotid artery shunt) .12 Intraoperative EEG recordings have also been performed during cardiac bypass surgery.r"? The effect of hypothermia, however, significantly limits the potential utility of EEG monitoring during the latter procedure." Profound hypothermia produces a suppression ofEEG activity that reduces the diagnostic yield of intraoperative recordings in identifying alterations resulting from cerebral ischemia.v'" Reversible causes of ischemia during cardiac bypass surgery occur much less commonly than during a carotid endarterectomy for carotid artery stenosis." Intraoperative EEG recordings were the first monitoring technique used during carotid and cardiac surgical procedures to minimize the likelihood of a postoperative neurologic deficit that might significantly affect the individual's quality of life. s.12 The potential adverse effects of cardiovascular and cerebrovascular surgery include stroke, cognitive impairment, and a postoperative encephalopathy. 12 Importantly, additional neurodiagnostic studies may be used in the operating room to monitor cerebral perfusion and the effect of anesthesia. fi - 11,13-15 Transcranial Doppler, carotid ultrasound, and xenon blood flow studies are performed in some centers during carotid endarterectomy and cardiac surgery.6-II,l3-15 The use of transcranial Doppler in selected patients may be predictive of cerebral ischemia in the absence of appropriate EEG
207
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
changes." Intraoperative carotid ultrasound is increasingly being used to validate the patency of the internal carotid artery after endarterectomy. II Monitoring the level of anesthesia by the bispectral index may reduce the hemodynamic changes that occur in some patients undergoing cardiopulmonary bypass." This chapter provides an overview of some of the aspects of intraoperative EEG monitoring for the identification of changes related to cerebral ischemia during carotid endarterectomy and cardiac surgery. In particular, the clinical applications and potential limitations of such cerebral function monitoring are considered.
CAROTID ENDARTERECTOMY Carotid endarterectomy is the cerebrovascular surgical procedure most commonly performed to reduce the risk of stroke in patients with symptomatic carotid artery stenosis related to atherosclerosis.6.12-25 Even before the publication of rigorous scientific studies confirming the efficacy of carotid endarterectomy, the use of this operative technique to protect against ipsilateral stroke had become popular.F The increase in the number of operative procedures performed annually in the United States over several years reflects the interest in identifying a protective surgical approach to stroke.P Fewer than 15,000 carotid endarterectomies were performed in 1970, but by 1985 an estimated 100,000 carotid endarterectomies had been performed in the United States. 22 The rationale for this operative procedure is the removal of atherosclerotic thrombotic material that may come to restrict flow and lead to either an occlusion of the carotid artery or an artery-toartery embolus. 21-25 Carotid artery surgery is the direct result of observations in the 1950s that established a relationship between extracranial internal carotid artery disease and stroke. Studies have indicated that carotid endarterectomy is effective in reducing the risk of ipsilateral stroke in patients with high-grade stenosis (70 to 99 percent) of the internal carotid artery.21-25 Selected patients with completed strokes may also be candidates for a carotid endarterectomy, depending on their neurologic deficits and the presence of coexistent medical problems. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) demonstrated a significant reduction in the risk of stroke in patients with carotid artery stenosis greater than 70 percent. 24 Ipsilateral stroke occurred at 24 months' follow-up in 26 percent of 328 nonsurgical patients and in 9 percent of 331 patients undergoing a carotid endarectomy.24 A direct correlation existed between surgical benefit and the degree of carotid artery stenosis. The benefit of carotid artery surgery in the NASCET for patients with 30 to 69 percent stenosis is still undeter-
mined." The Veterans Affairs Symptomatic Stenosis Trial (VASST) also showed a significant reduction in the risk of stroke in patients with carotid artery stenosis of greater than 50 percent who underwent a carotid endarterectomy.P The Asymptomatic Carotid Atherosclerosis Study (ACAS) reported in 1995 that there is an aggregate risk reduction of 53 percent with surgical treatment for asymptomatic carotid artery stenosis.P A total of 1,659 patients were entered into this study.23 All patients had greater than 60 percent carotid artery stenosis and were randomized to surgical or medical therapy." A significant difference was evident between the two treatment groups at 3 years. 23 The risks of carotid endarterectomy must be considered in any discussion of the putative beneficial effects of this operative procedure. The morbidity of this treatment depends on a number of factors including surgical expertise; degree of carotid artery stenosis; the presence of cerebral infarction; and coexistent medical problems, especially ischemic heart disease. The published morbidity of carotid endarterectomy has ranged from 0 to 20 percent.P In one multicenter study, the perioperative morbidity was 2.2 percent and the mortality was 3.3 percent (combined operative complication was 5.5 percent) in "relatively high-risk patients. "25 Importantly, angiography has a reported risk of approximately I percent.F The operative procedure is performed with the patient receiving general anesthesia for both comfort and safety. A combination of nitrous oxide and isoflurane is used at the Mayo Clinic. Induction is routinely performed with thiopental.P The common carotid artery, internal carotid artery, and carotid bifurcation are exposed at the time of surgery. Atherosclerotic changes are most prominent in the proximal internal carotid artery and the carotid bifurcation. Clamping of the internal carotid artery, common carotid artery, and external carotid artery is necessary for an arteriotomy and endarterectomy to be performed.v'< A shunt between the common carotid artery and the internal carotid artery may be placed if the surgical team is concerned that the period of clamping may be associated with cerebral ischemia and perioperative stroke. 5.12 The attitude of neurosurgical teams concerning the use of shunt placement is variable. At the Mayo Clinic, a shunt is placed only ifEEG monitoring of cerebral function or cerebral blood flow studies, or both, suggest a hemodynamic insult that may produce a significant reduction in cerebral blood floW. 5•12 The routine use ofshunts may be associated with an increased risk of cerebral infarction related to artery-to-artery embolus, and it prolongs the duration of the operarion." Importantly, a minority of patients exhibit a significant change in cerebral function monitoring indicative of a hemodynamic insult with a diminished cerebral blood flOW. 5•12 The risk of
Intraoperative Electroencephalographic Monitoring
shunt placement in one study was low, with embolism occurring in 2 of 511 patients (0.4 percent) .14 The introduction of carotid angioplasty and carotid artery sten ting for carotid artery stenosis may be an alternative to carotid endarterectomy.'v-f The methodology for these therapeutic interventions is similar to the techniques introduced for the treatment of cardiovascular disease. Carotid revascularization has also been used in selected patients with restenosis following a carotid endarrerectomy.-" EEG monitoring is not routinely performed during these procedures because the carotid artery is not occluded and there is no consideration of shunt placement. The role for these alternative techniques in the management of asymptomatic or symptomatic carotid artery disease remains under study. 26-28
INTRAOPERATIVE EEG MONITORING: METHODOLOGY Intraoperative EEG monitoring is commonly performed during carotid endarterectomy. There is a diversity of opinion regarding the clinical application of this neurodiagnostic technique in cerebrovascular and cardiac surgery.5.6.12,16 The "hostile" environment of the operating room often makes intraoperative EEG monitoring technically difficult. Potential problems include electrical interference, which produces significant artifacts; difficulty in ensuring the stable application of the electrodes; and the use of anesthesia and pharmacotherapy that may alter the EEG recording. The EEG technologist and electroencephalographer may also have difficulty in examining the patient and in negotiating their way through the operating room because of the surgical team and the necessary equipment. The technical factors that must be considered during intraoperative extracranial EEG monitoring include proper placement of the scalp electrodes (collodion is used at the Mayo Clinic) before anesthesia induction. Usually, 21 to 23 scalp electrodes are used for intraoperative EEG monitoring. 5,12-15 For appropriate intraoperative recordings, at least 8 channels of EEG should be available. In most instances, 16 or 21 channels for EEG monitoring is strongly preferred.4.5.12.13 Proper grounding is essential for patient safety. The use of a 60-Hz filter is required. The linear frequency is set between 1 and 15 or 30 Hz. 5 Sensitivities of 3 to 5 IlV/mm are often necessary for recording the extracranial EEG with the patient under general anesthesia. 5,12-15 A longitudinal bipolar anteroposterior montage is routinely used for intraoperative EEG monitoring.P-V The Laplacian montage may also be useful in identifying a focal alteration. The paper speed during the cerebral function monitoring can be "compressed" from the 30 mm/sec used in routine
209
EEG recordings to 5 mm/sec because of the large amount of data acquired.5.12-15 Subtle changes in amplitude and frequency related to cerebral ischemia can be visualized easily at the slower paper speeds. The diagnostic yield of the reduced paper speed for identifying reversible alterations associated with cerebral ischemia has been demonstrared.S'v" The paper speed can be restored to 30 mm/sec if a continuous or paroxysmal EEG pattern occurs that cannot be iden tified. The use of digital EEG recordings in the operating room has removed concerns regarding paper storage during intraoperative EEG monitoring. The introduction of digital EEG has improved off-line analysis and allowed individuals remote from the operating room to review the EEG as it is being acquired (i.e., "real-time" review). The current practice at the Mayo Clinic is to continue to use a paper speed of 5 mm/sec for digital EEG intraoperative recordings because of the amount of data generated. The technologists at our institution are also more familiar with the effects of cerebral ischemia displayed at a slower paper speed. Computer processing with a compressed spectral array can be used for data interpretation but may have no advantage over visual inspection alone. 5,12.18
EEG AND ANESTHESIA It is necessary to review the relationship between anesthesia and the EEG before considering the effects of cerebral ischemia on the intraoperatively recorded EEG. Anesthetic agents may significantly alter the normal background EEG (Fig. 9-1). To some extent, individual anesthetic drugs may have different effects, depending on their concentrations.5.12.29-31 The EEG patterns produced by different anesthetic agents, when used at concentrations below their MAC level (i.e., the minimal alveolar concentration necessary for preventing movement to a painful stimulus in about 50 percent of subjects), are quite similar. 5. 12,29 Selected anesthetic agents (e.g., thiopental, halothane, enflurane, isoflurane, and nitrous oxide) produce a similar subanesthetic or anesthetic effect associated with a symmetric EEG pattern. 5.12.29-31
Symmetric EEG Patterns at Subanesthetic or Minimal Anesthetic Concentrations Thiopental produces the characteristic drug-induced beta effect at subanesthetic concentrations, which tends to be maximal in the anterior midline distribution. 29 Halothane, enflurane, isoflurane, and 50 percent nitrous oxide, administered at subanesthetic concentrations, also produce a similar pattern. (Fig. 9-2)
210
ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
Fp1-F3M\'!'''*''''''I'''wo''-.'''IN''''''''''Ifr;fo.........,t''''If'-r'M~''v'''k''''''''''~~~~1'4I''-
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~~~'N~,.MJ.---~ ..... .fM.tWV'....l~-_,;..,J\I'A.r-..lVV'-../\/'~~~""""JN,Jl/IItI'lIiW"""""I'W;ol"""" F8-T4 """"" ,.."",.""""'.........."Y"'\f'~~~Nll'Illo/lillljl\l~~ T4-T6 """'"' "........""V-. Date ES, Mar EY, Bugola MR et al: The prevalence of lumbar paraspinal spontaneous activity in asymptomatic subjects. Muscle Nerve, 19:350, 1996 lOti. Sun SF, Streib EW: Diabetic thoracoabdominal neuropathy: clinical and electrodiagnostic features. Ann Neurol, 9:75, 1981 107. Kikta GO, Breuer AC, Wilbourn AJ: Thoracic root pain in diabetes: the spectrum of clinical and electromyographic findings. Ann Neurol, 11:80, 1982 10K. Koffman B,Junck L, Elias SB et al: Polyradiculopathy in sarcoidosis. Muscle Nerve, 22:608, 1999 1m!. Wilbourn AJ, AminoffM]: The electrophysiologic examination in patients with radiculopathies. Muscle Nerve, 21:1612,1998 110. AminotfMJ, Goodin OS, Parry GJ et al: Electrophysiologic evaluation of lumbosacral radiculopathies: electromyography, late potentials, and somatosensory evoked potentials. Neurology, 35:1514,1985 III. Aminoff MJ, Olney RK, Parry GJ et al: Relative utility of different electrophysiologic techniques in the evaluation of brachial plexopathies. Neurology, 38:546, 1988 112. Wulff CH, Gilliatt RW: F waves in patients with hand wasting caused by a cervical rib and band. Muscle Nerve, 2:452, 1979 II:t Cruz-Martinez A, Barrio M, Arpa.J: Neuralgic amyotrophy: variable expression in 40 patients. J Periph Nerv Syst, 7:198, 2002
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114. Lahrmann H, Grisold W, Authier FJ et al: Neuralgic amyotrophy with phrenic nerve involvement. Muscle Nerve, 22:437, 1999 115. Van DijkJG, Pondaag W, Malessy MJA: Obstetric lesions of the brachial plexus. Muscle Nerve, 24:1451, 2001 116. Gnatz SM: The role of needle electromyography in the evaluation of patients with carpal tunnel syndrome: needle EMG is important. Muscle Nerve, 22:282,1999 117. Lahrmann H, Albrecht G, Drlicek M et al: Acquired neuromyotonia and peripheral neuropathy in a patient with Hodgkin's disease. Muscle Nerve, 24:834, 2001 118. Isaacs H: Continuous muscle fibre activity in an Indian male with additional evidence of terminal motor fibre abnormality.J Neurol Neurosurg Psychiatry, 30:126, 1967 119. Auger RG, Litchy \\J, Cascino TL et al: Hemimasticatory spasm: clinical and electrophysiologic observations. Neurology, 42:2263, 1992 120. Mitsumoto H, Levin KH, Wilbourn AJ et al: Hypertrophic mononeuritis clinically presenting with painful legs and moving toes. Muscle Nerve, 13:215, 1990 121. Schoenen J, Gonce M, Delwaide P.J: Painful legs and moving toes: a syndrome with different pathophysiologic mechanisms. Neurology, 34:1108, 1984 122. WulffCH: Painful legs and moving toes: a report of3 cases with neurophysiological studies. Acta Neurol Scand, 66:283, 1982 123. Meinck HM, Thompson PO: Stiff man syndrome and related conditions. Mov Disord, 17:853, 2002 124. Lohmann T, Londei M, Hawa M et al: Humoral and cellular autoimmune responses in stiff person syndrome. Ann NYAcad Sci, 998: 215, 2003 125. Saadeh PB, Cristafulli CF, Sosner J: Electrodiagnostic studies of the neuromuscular respiratory system. Phys Med Rehabil Clin North Am, 5:541, 1994 126. Saadeh PB, Cristafulli CF, Sosner J et al: Needle electromyography of the diaphragm: a new technique. Muscle Nerve, 16:15, 1993 127. Bolton CF, Grand'Maison F, Parkes A et al: Needle electromyography of the diaphragm. Muscle Nerve, 15:678, 1992 128. Lagueny A, Ellie E, Sain tarailles J et al: Unilateral diaphragmatic paralysis: an electrophysiological study. J Neurol Neurosurg Psychiatry, 55:316, 1992 129. Bolton CF: Clinical neurophysiology of the respiratory system. Muscle Nerve, 16:809, 1993 130. AAEM Laryngeal Task Force: Laryngeal electromyography: an evidence-based review. Muscle Nerve, 28:767, 2003 131. Lateva ZC, McGill KC, Johanson ME: Increased jitter and blocking in normal muscles due to doubly innervated muscle fibers. Muscle Nerve, 28:423, 2003
CHAPTER
16 H-Reflex and F-Response Studies MORRIS A. FISHER
H REFLEX Physiology Technique of Recording H Reflexes Uses of H-Reflex Studies Disorders of the Peripheral Nervous System Disorders of the Central Nervous System
H reflexes and F waves are commonly recorded electrophysiologic responses (Fig. 16-1, Fig. 16-2, and Fig. 16-3). H reflexes are reflexes that are produced by afferent conduction in large afferent fibers and by efferent conduction in alpha motor neurons. By contrast, F waves are produced by antidromic activation of the alpha motor neurons. Despite their differences (Table 16-1), they are commonly discussed together. H reflexes and F waves are commonly used for similar clinical problems, are found at comparable latencies, reflect conduction to and from the spinal cord, and involve motor neuron activation.
H REFLEX
Physiology In 1918, Hoffman described a reflex response in calf muscles that followed stimulation of the posterior tibial nerve and was comparable in latency to the Achilles' reflex.t-" In recognition of Hoffman's original contribution, the response was named the H reflex by Magladery and McDougal. 3 Because H reflexes involve conduction from the periphery to and from the spinal cord, they occur at latencies considerably longer than the latency of a direct motor response. A necessary condition for establishing an H reflex is that this "late" response must be larger than the preceding direct motor response. This condition can occur only with central amplification of the motor response caused by reflex activation of motor neurons. Careful observation of H reflexes as they increase in amplitude often reveals a decrease in latency.
F RESPONSE Physiology Technique of Recording F Waves Clinical Application of F-Wave Studies Disorders of the Peripheral Nervous System Disorders of the Central Nervous System
This decrease is consistent with the orderly activation of smaller and then larger motor neurons, with an associated increase in axonal conduction velocities, as would be expected in a reflex response. The arc of the H reflex includes conduction in large, fast-conducting Ia fibers. In that sense, the H reflex is similar to the phasic myotatic ("deep tendon") reflex produced by muscle stretch. Although experimental data support the possible monosynaptic nature of the H reflex, intraneural studies have questioned the exclusively monosynaptic nature of both H and phasic myotatic reflexes." Calf H and Achilles' reflexes are generally correlated.i-" and calf H-reflex amplitudes have been positively correlated with prominence of the Achilles' reflex." Unlike the phasic myotatic reflex, however, the H reflex does not involve muscle spindle activation. This difference may at times explain the presence of calf H reflexes in the absence of Achilles' reflexes, and vice versa. H reflexes are inhibited as the stimulus intensity is increased from submaximal to that required for eliciting a maximal direct (M) response. This relationship has been explained by "collision" of orthodromic impulses with impulses conducted antidromically in motor axons. In fact, this mechanism has little or no role in the inhibition of H reflexes that occurs with increasing stimulus intensity. To be complete, such collision must occur distal to the motor neurons. Allowing for rise-times for motor neuron excitatory postsynaptic potentials (EPSPs) of at least 3 msec, as well as for at least one synapse, the differences in afferent and efferent conduction in H reflexes necessary for collision inhibition have not been established. Large H reflexes are obtained from calf muscles even with supramaximal
357
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
stimulation if the stimuli are timed appropriately with phasic contractions of the muscles.f This indicates that H-reflex inhibition does not depend on peripheral collision of afferent and efferent impulses. Experimental studies in normal and spastic subjects are consistent with central inhibition of H reflexes occurring as stimulus intensities are increased," Inhibitory mechanisms present in the spinal cord can explain H-reflex inhibition. Inhibitory interneurons (Renshaw cells) are activated by antidromic stimulation.l? are distributed widely throughout the motor neuron pool, II and discharge more strongly and with shorter latency as stimulus intensity increases.V H reflexes may be monosynaptic, whereas H-reflex inhibition by Renshaw cells would involve two synapses. Any resulting difference in the onset of inhibitory and excitatory effects may be as brief as 0.3 msec!' and therefore well within a reasonable physiologic range given motor neuron EPSP rise times. Direct connections between motor neurons are also present'V" and could contribute to H-reflex inhibition. Single-fiber dectromyographic (EMG) studies of H reflexes support a process of active inhibition involving inhibitory synapses with stimuli of increasing intensity" H-reflex studies in turn have been used to demonstrate prominent central inhibition, probably from Renshaw cells, following supramaximal nerve stimulation. 16
FIGURE 16-1 • Drawings of H reflexes (upper) and F responses (lower) recorded (R) from calf muscles. Stimulation (S) of the tibial nerve in the popliteal fossa activates Ia fibers with a resultant reflex discharge of motor (m) axons. H reflexes are present at low levels of stimulation, when the M wave may be absent or lower in amplitude than the H reflex, and are inhibited with increasing stimulus intensity. With supramaximal stimulation, low-amplitude, variable F responses are produced by antidromic activation of motor neurons. G, ground. (From Fisher MA: H reflexes and F waves: physiology and clinical indications. Muscle Nerve, 15:1223, 1992,with permission.)
2rnV
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FIGURE 16-2 • H reflexes with increasing stimulus intensity shown in a raster mode (left) and superimposed (right). The inserts show in graphic form that as the M-wave amplitude increases, the H-reflex amplitude initially increases and then decreases. At the highest level of stimulation (last response in the raster mode), the H reflex has disappeared and is replaced with an F-wave (calibration per division, 2 mVand 10 msec).
H-Reflex and F-Response Studies
5 msec
500 fLY
A
5 msec
5mV
B III A, F waves (right) with associated M waves (left) recorded from the abductor pollicis brevis muscle following supramaximal stimulation at the wrist. The inherent variability of F waves is emphasized in the superimposed recordings (B). The chronodispersion is the difference between the shortest and longest F-wave latencies. The persistence in this series of 10 recordings is 90 percent, because in one an F wave is absent. The two largest responses are repeater waves (calibration per division, 5 mV for M waves, 500 IlV; 5 msec). (From Fisher MA: Normative F-wave values and the number of recorded F waves. Muscle Nerve, 17:1185, 1994.with perrnission.)
FIGURE 16-3
TABLE 1&-1 • H Reflexes Ind FWIVes Feature
H Reflexes
F Waves
Response
Reflex
Afferent fibers Efferent fibers Distribution Stimulus intensity Increasing stimulus intensity Amplitude Morphology Motor units
la afferents Alpha motor fibers Restricted low Inhibits response
Antidromic firing of motor neurons Alpha motor fibers Alpha motor fibers Ubiquitous High Facilitates response
large Stable Different from M wave
Small Variable Same as in M wave
359
In infants younger than 2 years, H reflexes are widely distributed.!? Beyond infancy, H reflexes are regularly found in calf muscles (primarily the soleus) and homologous forearm flexors. They are also commonly present in the quadriceps and occasionally in plantar foot muscles. This restricted distribution of H reflexes with age is caused by changes associated with physiologic maturation of the central nervous system (CNS). The fraction of the soleus motor neuron pool activated in an H reflex is usually about 50 percent but can be as high as 100 percent. The ratio of the peak-to-peak maximum H-reflex to maximum M-wave amplitude (HIM ratio) provides a measure of motor neuron pool activation and therefore excitability. The HIM ratio for calfH reflexes is normally less than 0.7. 18 H reflexes involve the activation of a portion of the segmental motor neuron pool and are therefore enhanced by maneuvers that increase excitability of the motor neuron pool. H reflexes can be produced by facilitation maneuvers (e.g., contraction or post-tetanic potentiation) in muscles where they are not otherwise present, such as the small hand muscles. H reflexes have been used to explore the physiology of the CNS. A recent review has emphasized the problems with equating H-reflex responsiveness with motor neuron excitabiliry.l? Such equating of these two phenomena is limited, for example, by the effects of presynaptic inhibition and postactivation depression on H reflexes. With these limitations, H reflexes remain an important tool for investigating the central control of movement. H reflexes have been used to study patterns of central reflex organization. Studies have shown changes in H reflexes consistent with an influence on the reflex of both group Ia and group II afferents. 20 •2 1 H reflexes have been used to analyze patterns of reciprocal inhibition. The methodology for this in the forearm has been well described. 22 •23 Myotatic arcs between proximal and distal muscles also affect H reflexes. Activation of the quadriceps, for example, inhibits the soleus H reflex.v' and this reflex interaction has been employed in techniques for evaluating presynaptic inhibition." Presynaptic inhibition of Ia afferent fibers is decreased on fibers projecting on motor neurons of contracting muscles, but it is increased on afferents to motor neurons supplying muscles that are not involved in the contraction." Passive cyclic movements of the legs produce inhibition ofH reflexes; this is probably because of presynaptic inhibition that can be integrated at the spinal cord leve1. 27 •28 Characteristic changes in H-reflex amplitude can be defined if test stimuli are given at varying intervals after a conditioning stimulus. These excitability or recovery curves vary with the level of stimulation'? (Fig. 16-4) and are not clearly established until 1 year of age.
360
ElECTRODIAGNOSIS IN ClINICAL NEUROLOGY
50 49 48 47 46 45 44 43 42 41 40 39 38 37 36 35 34 33 32 31 30 29 28 27 26 25
40.14
80
39
75
38 37 36 35 34 33
70 65 60 55
32 31 30 29
50 45 40
28 27 26 25 24 22.64
35 30 25 20
Leg length Latency Age (ern) (msec) (yrs) FIGURE 16·4 • Nomogram of the regression of H-reflex
latency on leg length and age. (From Braddom RI,Johnson EW: Standardization of the H reflex and diagnostic use in 81 radiculopathy. Arch Phys Med Rehabil, 55:161,1974, with permission.)
H reflexes are inhibited by vibration as a result of vibration-induced activation of large afferent fibers with consequent peripheral "busy line" interference, presynaptic inhibition of afferent input.t" and activation of spindles in antagonist muscles.V
Technique of Recording H Reflexes H reflexes are readily obtained with percutaneous stimulation and surface recording techniques. Responses are stable, but only at similar conditions of stimulation and recording. The stimulating cathode should be proximal to avoid anodal block. Stimulus pulses of long duration (1 msec) are used to preferentially activate the large sensory fibers." Stimulus frequency should be 0.2 Hz or less to allow full recovery of the H reflex from a prior stimulus. A series of responses should be obtained. Starting with submaximal stimuli and increasing to supramaximal stimulation, one should verify whether the "late"
response can be larger than the preceding direct motor response, determine which H reflex has the largest amplitude, and demonstrate that inhibition of the H reflex occurs with increasing stimulus intensity. Latencies should be measured to the onset of the responses (either negative or positive), and amplitudes should be measured in a peak-to-peak fashion. For calf H reflexes, the posterior tibial nerve is stimulated in the popliteal fossa. Bipolar stimulation is usually adequate. Use of an anode with a large surface area at the patella can decrease stimulus artifact and may provide more discrete cathodal excitation of the nerve in the popliteal fossa. Recordings are made from the soleus muscle. Although techniques vary, a standard and convenient location for the active electrode is medial to the tibia at a point that is half the distance between the stimulation site and the medial malleolus, with the indifferent electrode placed on the Achilles' tendon. H reflexes in the forearm are recorded from the flexor carpi radialis muscle.F The recording electrode is placed at the junction of the upper one-third and lower two-thirds of the distance between the medial epicondyle and the radial styloid. The median nerve is stimulated percutaneously in the cubital fossa. H reflexes are routinely recorded with the muscle at rest. Contraction of the recording muscle will enhance H reflexes by facilitating the motor neuron pool. Such contraction can help to identify H reflexes in muscles in which H reflexes are normally present, as well as elicit H reflexes in muscles where they are not normally found." This facilitation of H reflexes by contraction is sometimes clinically useful and demonstrates that the normal distribution of H reflexes is based on physiologic, not structural, factors.
Uses of H-Reflex Studies The upper limit of normal latency for the H reflex of the soleus is 35 msec, and that of the flexor carpi radialis is 21 msec. H-reflex latencies are directly related to leg or arm length, height, and, to a lesser degree, age 34-36 (see Fig. 16-4). Normal values for infants and children are available. 37.3BWith careful technique, the upper limits of normal for side-to-side latency differences have been reported to be as low as 1.5 msec for calf muscles'" (mean, 0.09 ± 0.70 standard deviation [SD]36) and 1.0 msec for forearm flexor muscles 22 ,g9 (mean, 0.002 ± 0.42 SD). For routine clinical work and consistent with a criterion of 3 SD from the mean, 2 msec should be allowed for side-to-side differences when one records from the calf and 1.5 msec allowed when one records from the forearm. Side-to-side latency differences may be larger in the elderly" The upper limit of normal for the interside ratio of H-reflex
H-Reflex and F-Response Studies
amplitudes for calf muscles has been reported as 2,41 but a preferable figure for general clinical work is probably 3. This is similar to the interside ratio for H-reflex amplitudes in the forearm." Calf and forearm H reflexes are usually present in normal subjects. As with phasic myotatic reflexes, however, this statement is not always true, and symmetrically absent H reflexes are not necessarily abnormal. The percentage of absent responses increases in the elderly.f DISORDERS OF THE PERIPHERAL NERVOUS SYSTEM
H reflexes are a sensitive test for polyneuropathies and may be abnormal even in mild neuropathies. H reflexes involve conduction in proximal fibers. These studies can therefore define proximal nerve injury and may be abnormal even when distal studies are unremarkable. Absent H reflexes are characteristic of acute idiopathic polyneuropathy (Guillain-Barre syndrome). This loss of H reflexes occurs early after onset of the disorder, and absent H reflexes often may be an isolated finding in these patients if studied within several days after the onset of their illness. H reflexes can also be abnormal in plexopathies'" and in radiculopathies. H reflexes in the forearm flexor muscles may be abnormal with C6 or C7 root injury,39 and calf H reflexes may be abnormal with S1 radiculopathies.r'V H reflexes are affected by injury to both the dorsal and the ventral roots. H reflexes can therefore be important in the electrodiagnostic evaluation of radiculopathies by documenting nerve injury even when needle EMG is unrevealing owing to sparing of the ventral roots.
361
weeks to months following a cerebrovascular lesion associated with the appearance of features of the upper motor neuron syndrome (e.g., increased tone, brisk reflexes, and extensor plantar responses). In patients with chronic upper motor neuron lesions, vibratory inhibition of H reflexes is less than expected, possibly because of decreased presynaptic inhibition.P In contrast, vibratory inhibition of H reflexes may be enhanced in patients with acute cerebral lesions. H reflexes are relatively well preserved acutely after spinal shock at a time when both Achilles' reflexes and H-reflex recovery curves are depressed.'? Alterations in soleus H reflexes have been related to specific features of the upper motor neuron syndrome, in particular, decreased vibratory inhibition of H reflexes with hypertonia, increased HIM ratios with increased reflexes, and late facilitation of the recruitment curve with clonus." Within several months after a central injury, H-reflex excitability curves can show an abnormally rapid pattern of recovery (Fig. 16-5) associated with increased HIM ratios. 5,28 These patterns differ from those in patients with parkinsonian rigidity or cerebellar hypotonia."
-
Controls ... -. Patients with spasticity
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FIGURE 19·2 II Sympathetic efferent pathways from the spinal cord.
Paravertebral ganglion
Gray ramus communicans
Target Prevertebral ganglion
hypogastric, splanchnic, and mesenteric plexuses (Table 19-1). The head and neck are innervated by preganglionic neurons in the TI and T2 segments through the superior cervical ganglion and the upper four cervical TABLE 19·1 • The Sympathetic Outflow from the Thoracolumbar Cord
Target Structure
Outflow
spinal nerves. The upper limb is supplied by preganglionic neurons in the T2 to T8 segments and the stellate ganglion, with varying contributions from the middle cervical and upper thoracic ganglia. The legs are supplied from the TI0 to 1.2 segments through the paravertebral ganglia. Postganglionic sympathetic fibers differ in their properties depending on their target organ. Thus, cutaneous sympathetic fibers have differing conduction velocities depending on whether they are vasomotor or sudomotor in function."
SKOIId-order neuron Inparaverte"'al ga.,11a Eyes Salivary glands Face Head Upper limbs Heart Tracheobrochialtree Lungs Pulmonary vessels Trunk Lower limbs
Parasympathetic Efferent Pathways The parasympathetic cranial and sacral outflow is summarized in Table 19-2. The peripheral ganglia are located close to the target organs so that the postganglionic pathways are short.
CLINICAL ASPEOS OF DYSAUTONOMIA
SKOIId-onter neuron In pnvertebral gallliia Nerve Greater splanchnic
Ganglian Celiac
Plexus Hypogastric
Lesser splanchnic
Superior mesenteric
Splanchnic
Small intestine Colon
Lumbar splanchnic
Ihferior mesenteric
Mesenteric
Distal colon Bladder Genitalia
Liver. bile ducts. gallbladder Pancreas Spleen Stomach Small intestine Proximal colon
The clinical features of dysautonomia are described in standard textbooks, but a brief summary is provided here as they point to the need for investigation and are reflected by the manner in which patients are investigated. The most disabling feature is probably an impaired regulation of blood pressure, especially postural hypotension or paroxysmal hypertension. Other cardiovascular abnormalities include syncope, disturbances of cardiac rhythm, and facial flushing. Disturbances of sweating are also common and are manifest by impaired thermoregulatory sweating (anhidrosis or hypohidrosis) or hyperhidrosis. Symptoms of gastrointestinal dysfunction include dysphagia from esophageal peristalsis or impaired relaxation of the esophageal
410
ElEaRODIAGNOSIS INCLINICAL NEUROLOGY
TABLE 19-1 • Parasympathetic Efferent System
Broinstem outflow
Sacral outflow(S2-S4)
Nerve
Peripheral Ganglia
Target Structure
Oculomotor Facial
Ciliary Pterygopalatine Submandibular
Glossopharyngeal Vagus
Otic Ganglia orplexuses related to target organs
Pelvic
Pelvic
Eye Palatine glands Submaxillary glands Sublingual glands Parotid glands Heart Airways and lungs Abdominal viscera Distal colon and rectum Bladder Genitalia
From Aminoff MJ: Electromyography in Clinical Practice. 3rd Ed. Churchill Livingstone, New York, 1998, with permission.
sphincter; early satiety, postprandial discomfort, gastric fullness or distension, and vomiting from gastroparesis; and intestinal pseudo-obstruction, constipation, or diarrhea from altered intestinal motility. Urinary frequency, urgency, and incontinence are features of bladder involvement in some patients, whereas hesitancy, retention, or overflow incontinence occurs in other patients depending on the site of the lesion. Fecal incontinence may occur. Sexual disturbances are common. Impotence may have many causes including an underlying dysautonomia. Lesions of the sacral roots or pelvic nerves may be responsible and, in women, may lead to a failure of arousal. The effect of cord lesions depends on their completeness and segmental level. Neuro-ophthalmologic disturbances are other manifestations of a dysautonomia that are well described and beyond the scope of this chapter. In patients being evaluated for symptoms suggestive of dysautonomia, nonneurologic causes of their complaints require exclusion because they are often reversible. Clinical evaluation is directed with this in mind. The neurologic examination may suggest the cause of a dysautonomia. In particular, it may reveal evidence of a polyneuropathy or of a focal CNS lesion, or a combination of signs (parkinsonism with or without upper or lower motor neuron or cerebellar signs) indicative of a degenerative disorder (e.g., multisystem atrophy).
TESTS OF AUTONOMIC FUNCTION
Cardiovascular Tests Tests of cardiovascular function are important and provide information about both the parasympathetic and sympathetic divisions of the autonomic nervous system.
HEART RATE VARIATION
In normal resting subjects the heart rate is determined mainly by background vagal activity. The laboratory tests of heart rate variation are therefore mainly tests of parasympathetic function. Heart Rate Variation with Breathing An increase in heart rate occurs during inspiration because of decreased cardiac vagal activity; thus, it is blocked by atropine but not by propranolol.P The variation in heart rate that occurs depends on the rate and depth of breathing. The test must therefore be standardized if it is to be used for clinical purposes. Normal values are affected by age, which must also be taken into account. The difference between the maximum and minimum heart rate during breathing decreases with increasing age and is diminished or absent in diabetes and other disorders that affect central or peripheral autonomic pathways.r" as shown in Figure 19-3. For clinical purposes, the recumbent patient is asked to rest quietly for 5 minutes, and is then asked to take deep breaths at the rate of six per minute, for I minute. The timing of the breaths can be directed verbally or by any other convenient means. The heart rate can be measured with a rate monitor or by recording the RR intervals on an electrocardiogram (ECG). The ECG may be displayed on a chart recorder or on standard electromyographic equipment. If the heart rate is measured directly, the difference between the highest and lowest rate during the minute of deep breathing is determined. When the ECG is recorded, several different measurements of RR variation may be made. 5 .6 The measurements made most commonly are of (1) the difference between the longest and the shortest RR interval during the period
Evaluation ofthe Autonomic Nervous System
411
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of deep breathing; and (2) the expiratory/inspiratory (E/I) ratio, which is the ratio of the mean of the maximum RR intervals in expiration to the mean of the minimum RR intervals in inspiration." The normal range of heart rate variation is agedependent.t-' but normal subjects generally have differences in heart rate exceeding 15 beats per minute. Values of less than 10 beats per minute are abnormal. From a review of the existing literature, Freeman indicated a likely decline in heart rate variability of 3 to 5 beats per minute per decade in normal subjects." The use of a single normal value regardless of age therefore reduces the utility of the test, leading to false-negative results in younger patients and false-positive results in older subjects." The E/I ratio decreases with age, but up to the age of 40 years, ratios less than 1.2 may be regarded as abnormal."
Other factors affecting the results in normal subjects include the time of the test (with increased heart rate variability occurring at night), body weight, physical fitness, medication, and body position."
Heart Rate Response to Change in Posture Immediate Increase in Heart Rate with Standing Heart rate and blood pressure responses to postural change can be measured conveniently on a tilttable. The patient lies supine until consistent values are obtained for at least 5 (preferably 10) minutes, The patient is then tilted so that he or she is in a 60degree head-up position and the heart rate and blood pressure are monitored. The normal decline in systolic and diastolic pressures should not exceed 25 and 10 mmHg, respectively. The heart rate normally
412
ELECTRODIAGNOSIS IN CLINICAL NEUROLOGY
increases by about 10 to 30 beats per minute, but the response declines with age. 4 ,9 30:15 Ratio
On changing from a recumbent to a standing position, a tachycardia normally occurs and is followed after about 20 seconds by a bradycardia that reaches a relatively stable rate at about the 30th beat after standing (Fig. 19-4). The ratio of the RR intervals that correspond to the 30th and 15th heartbeats has therefore been used as a measure of parasympathetic function.l" This 30:15 ratio decreases with age, but in young adults a ratio of less than 1.04 is regarded as abnormal. The ratio of the absolute maximum to minimum RR interval is sometimes preferred. Atropine blocks the heart rate response to standing, indicating that it depends on vagal innervation of the heart.!" The biphasic response is not present with passive tilting. Power Spectral Analysis of Heart Rate
Various modifications of heart rate testing have been described but are not in widespread use. Power spectral analysis has been described of the heart rate at rest and after postural change. Two major peaks of interest on the power spectrum occur at rest: a high-frequency peak (greater than 0.15 Hz) representing heart rate changes with respiration (parasympathetic activity), and a lowfrequency peak (at 0.05 to 0.15 Hz) that reflects sympathetic and parasympathetic activity.6.11.12 Another component, at very low frequency (less than 0.05 Hz), also
-
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96
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92
occurs, but its physiologic origin is unclear." A shift in the power spectrum from high to low frequencies occurs with a change in posture to the upright position and may reflect sympathetic activatlon." Although the results of power spectral analysis correlate with the results of other tests of autonomic function, the clinical role of such an approach remains to be defined. RESPONSE TO THE VALSALVA MANEUVER
The Valsalva maneuver consists of a forced expiration against a closed glottis or mouthpiece with a calibrated air-leak. Characteristic changes in heart rate and blood pressure occur during and after performance of the maneuver and relate to changes in cardiac vagal efferent and sympathetic vasomotor activity as a result of stimulation of carotid sinus and aortic arch baroreceptors and other intrathoracic stretch receptors. For clinical purposes, it may be adequate simply to record the heart rate responses with a heart rate monitor (Fig. 19-5) or an ECG. For more detailed information of the changes in heart rate and blood pressure, however, it is necessary to use a servo-plethysmomanometer device (Finapres) or record from an intra-arterial needle (Fig. 19-6). The test is performed with the subject in a semirecumbent position with a rubber clip over the nose. The subject is then required to blow into a mouthpiece (with a calibrated air-leak) connected to a mercury manometer and to maintain an expiratory pressure of
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TIme (seconds) FIGURE 19·4 • Heart rate response to standing in a normal subject, showing an initial tachy-
cardia that is maximal at about the 15th beat after standing, and a subsequent bradycardia.
Evaluation ofthe Autonomic Nervous System
413
110
FIGURE 19-5 II Normal heart rate response to the Valsalva maneuver, recorded with a heart rate monitor. A tachycardia occurs during the forced expiration, and a bradycardia occurs on release of the maneuver.
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40 mmHg for 15 seconds while the heart rate is recorded. The normal response has four stages. Stages 1 and 3 are artifactual and are characterized by an increase (stage 1) or a decline (stage 3) in blood pressure because of the increase or decrease, respectively, in intrathoracic pressure at the beginning and end of the maneuver. In stage 2, the reduction in venous return
leads to a progressive decline in systolic, diastolic, and pulse pressure, accompanied by a tachycardia resulting from increased cardiac sympathetic activity. The decline in blood pressure is arrested after about 5 to 8 seconds by a reflex vasoconstriction. With release of the blow at the end of the maneuver, the artifactual decline in mean blood pressure as a result of the release
Intraarterial Pressure
(mmHg)
FIGURE 19-6 II Valsalva response as recorded intra-arterially. A, Normal response. B, Abnormal response in a patient with multisystem atrophy. (From Amiuoff MJ: Electromyography in Clinical Practice. 3rd Ed. Churchill Livingstone, New York, 1998, with permission.)
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
of intrathoracic pressure (stage 3) is followed by a rebound in blood pressure to above resting levels because of the persisting peripheral vasoconstriction and the increased cardiac output that follows the increased venous return to the heart. This overshoot in the blood pressure, which varies in extent depending upon age, is accompanied by a compensatory, vagally induced bradycardia. Abnormalities of the Valsalva response in dysautonomic patients may take the form of a loss of the tachycardia in stage 2 or of the bradycardia in stage 4; or a lower heart rate in stage 2 than in stage 4. Other abnormalities include a decline in mean blood pressure in stage 2 to less than 50 percent of the resting mean pressure or loss of the overshoot in systolic pressure in stage 4 (see Fig. 19-6). With isolated impairment of efferent sympathetic vasoconstriction, the blood pressure fails to show an overshoot in stage 4, and consequently there is no compensatory bradycardia despite otherwise intact baroreflex pathways. When the response to the Valsalva maneuver is studied simply by recording the ECG, the Valsalva ratio is calculated by dividing the longest interbeat interval occurring after the maneuver by the shortest interbeat interval during it. The highest ratio from three successive attempts, each separated by 2 minutes, is recorded." The ratio reflects both parasympathetic (vagal) and sympathetic function. The normal range of values depends on age, the duration of the forced expiration, and the extent to which intrathoracic pressure is increased. A value of 1.1 or less is commonly regarded as abnormal and a value greater than 1.2 as normal, but in normal subjects younger than 40 years the ratio usually exceeds 1.4. 16 Low values are sometimes recorded in patients with heart and lung disease. The Valsalva ratio is sometimes normal when the blood pressure response is abnormal. 15 BLOOD PRESSURE VARIATION
Change in Posture The effect of postural change on blood pressure is important. The blood pressure is recorded with the subject supine and at rest for at least 10 minutes. The patient than stands with the arm held horizontally to avoid the hydrostatic effect of the column of blood in the dependent ann leading to a falsely elevated blood pressure. The blood pressure is taken immediately on standing and then at l-minute intervals for 5 minutes. In normal subjects a slight decline in systolic pressure may occur, and diastolic pressure typically increases slightly. A decline that is greater than 20 mmHg in systolic pressure or 10 mmHg in diastolic pressure is generally regarded as abnormal. A tilt-table can also be used to evaluate postural changes in blood pressure, but the response may dif-
fer from that obtained by standing because there is less enhancement of the venous return to the heart by contraction of leg and abdominal muscles, and thus greater peripheral pooling of blood. After the patient has been supine for 10 minutes, the table is tilted to an angle of at least 60 degrees, and the patient remains in this upright position for 10 minutes. Blood pressure can be measured with a sphygmomanometer or by continuous recordings from digital arteries using the Finapres device mentioned earlier, which accurately records pressure changes. 17 Prolonged testing (for up to 60 minutes) on a tilttable at an angle of at least 60 degrees is being used increasingly to evaluate patients with suspected syncope. Many studies have shown that blood pressure changes with posture are unrelated to age, but there is no agreement on this point and asymptomatic postural hypotension is common in elderly patients. Postural hypotension occurs in a variety of medical contexts including cardiac disease; endocrine disorders; hypovolemia; and in patients taking medications such as antihypertensive drugs, dopaminergic medication, and CNS depressants. Thus, detailed investigation may be necessary to clarify its cause, including other tests of autonomic function such as the response to the Valsalva maneuver.
Isometric Exercise Sustained handgrip increases heart rate and blood pressure," partly by central command and partly by changes in contracting muscles that activate fibers subserving the afferent limb of the reflex arc." The semirecumbent subject is required to maintain a pressure of 30 percent of maximal handgrip pressure for 5 minutes. The change in diastolic blood pressure is defined as the difference between the last value recorded before release of handgrip pressure and the mean resting value over the 3 minutes of recording preceding the isometric exercise.P An increase in diastolic pressure of at least 15 mmHg is normal and is not dependent on age. The test is not widely used, however, because the results are not as reproducible as the response to postural change. CUTANEOUS VASOMOTOR CONTROL
Cutaneous blood flow is altered by stimuli such as a sudden inspiratory gasp, mental stress, startle, or alteration in temperature of another part of the body. Such changes in blood flow can be examined by plethysmography or laser Doppler velocimerry.?' as illustrated in Figure 19-7. In normal subjects, an inspiratory gasp leads to a digital vasoconstriction through a spinal or brainstem reflex. The response is
Evaluation ofthe Autonomic Nervous System
415
Sudden inspiratory
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Time (seconds) FIGURE 19-7 II Effect of a sudden deep inspiration on blood volume of the index finger, recorded photoplethysmographically by an infrared emitter and detector on the pad of the finger. The upper trace shows the amplitude of each pulse in relative units. The lower trace is the sensor output after amplification and reflects absolute blood volume in the finger. Each wave represents a heartbeat, and the amplitude of the waves reflects blood volume in the region of the sensor. The apparent shift of the DC signal component results from the long time-constant used to prevent loss of signal information.
lost in the presence of a cord lesion or dysfunction of sympathetic efferent fibers to the digit under study, such as in patients with a polyneuropathy or entrapment neuropathy.22,23 A cold stimulus to the opposite hand, such as water at 4°C, similarly leads to reflex vasoconstriction. The digital vasoconstriction that occurs in response to mental stress (e.g., performing mental arithmetic despite distraction, or startle from a sudden loud noise) causes a transient increase in sympathetic vasomotor activity without involving a reflex arc and thus evaluates sympathetic efferent pathways directly. Normal subjects sometimes have no response, however, leading to false-positive results. TESTS OF BAROREFLEX SENSITIVITY AT REST
The relationship between heart rate and blood pressure can be analyzed on a beat-to-beat basis, quantifying the mathematical relationship between increase in systolic pressure and decline in heart rate, and vice versa. The slope of the regression between spontaneous increments or decrements in blood pressure and alterations in heart rate or RR interval will provide a measure of baroreflex sensitivity. Values in the order of 6 to 8 msec per mmHg have been calculated." and correlate with values obtained by phenylephrine infusion.P At present, the method is more of academic interest than practical relevance.
Sweat Tests Disturbances of sweating are common in dysautonomia and can be evaluated by several different approaches. Techniques that have not gained widespread acceptance (e.g., the sweat imprint technique/") will not be discussed. THERMOREGULATORY SWEAT TEST
The thermoregulatory sweat test evaluates central and efferent sympathetic sudomotor function. The patient is warmed with a radiant heat cradle so as to increase the body temperature by 1°C. The skin is covered with a powder that changes color when moist, the most commonly used being alizarin red. This permits the presence and distribution of sweating to be characterized. Disturbances may reflect preganglionic or postganglionic lesions. A symmetrical distal loss is suggestive of a polyneuropathy. Patchy or segmental anhidrosis may suggest a disorder such as leprosy'? or Ross (Ross-Adie) syndrome.P' The procedure is somewhat time-eonsuming, messy, and requires the patient to be unclothed. SYMPATHETIC SKIN RESPONSE AND RELATED RESPONSES
A simple test of sudomotor function is the so-called galvanic skin response. A reduction in the electrical
416
ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
resistance of the skin occurs in response to a deep inspiration or noxious stimulus. It is related to increased sudomotor activity. This can be detected as a voltage or current change between the region under study and an indifferent area (Fig. 19-8). The sympathetic skin response (SSR) represents the change in voltage measured at the skin surface following a single electrical stimulus. It depends in part on the electrical activity arising from sweat glands and is conveniently and quickly recorded in a clinical neurophysiology Iaboratory-? Pairs of surface electrodes are placed on the hands and feet, with the active electrodes on the palmar or plantar surface and the remote electrodes placed dorsally; limb temperature is maintained at 32 to 34°e. The electrical stimulus has a duration of 0.1 msec and an intensity of 5 to 20 rnA and is delivered randomly to a mixed or cutaneous nerve at the contralateral wrist or ankle. I? The interstimulus interval should be at least 30 seconds. The response is filtered at a bandpass of 0.1 or 0.5 to 1,000 or 2,000 Hz. A response can be obtained in normal subjects, but at present only its absence and not the absolute values of latency or amplitude are held to be of pathologic significance for clinical purposes. The latency in the upper limb is in the order of 1.5 sec and in the lower limb is about 2 sec. This long latency reflects the slow conduction velocity of postganglionic e fibers (approximately 1 m/sec). Abnormalities in the SSR correlate reasonably well with other sweat tests. 30 Although useful and simple to perform, the SSR is variable and habituates rapidly and is nonquantitative in nature." The SSR is absent in some patients with axonal
neuropathies but is generally preserved m those with demyelinative neuropathies. SUDOMOTOR AXON REFLEX TESTING
The intradermal injection of acetylcholine (5 to 10 mg) causes local sweating and piloerection if the postganglionic sympathetic fibers are intact. This provides a simple, nonquantitative test of sudomotor and pilomotor functions. Sweat output in response to an axon reflex can be measured directly and accurately in a specially designed chamber placed on the skin. Iontophoresed acetylcholine activates axon terminals, generating impulses that pass antidromically to a branch point and then are conducted orthodromically down another axon to its terminals, where acetylcholine is released, generating a sweat response. Quantitative sudomotor axon reflex testing (QSART) is a sensitive means of assessing postganglionic sympathetic function'< and yields reproducible results. It requires sophisticated and expensive equipment, however, so that it is used only in specialized centers.
Plasma Catecholamine Levels and Infusions The resting plasma norepinephrine level provides a useful index of sympathetic function. The main utility of this measurement is to indicate whether a sympathetic
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Evaluation of theAutonomic Nervous System
lesion is preganglionic, postganglionic, or both, because this is of pharmacologic importance. The level is diminished with postganglionic but not with preganglionic lesions. The plasma norepinephrine level normally increases on changing from a supine to standing position, but this increment may be markedly attenuated or absent in patients with either pre- or postganglionic lesions. The infusion of pressor drugs also helps to localize sympathetic lesions by demonstrating the presence and severity of denervation supersensitivity. Exaggerated pressor responses and a lower response threshold to sympathomimetic drugs (e.g., phenylephrine, norepinephrine, or epinephrine) are characteristic of degeneration of postganglionic sympathetic fibers. The blood pressure and heart rate are recorded with the patient at rest and then after intravenous infusion of the pressor agent at different doses. For example, an increase in systolic pressure of 40 mmHg usually requires norepinephrine to be infused at a rate of 15 to 20 /lg per minute in normal subjects, 5 to 10 /lg per minute in patients with multisystem atrophy, and 2.5 /lg per minute in pure autonomic failure." With infusion of graded doses of pressor drugs having 110 direct effect on heart rate, baroreflex sensitivity may be measured by the relationship between changes in heart rate and blood pressure. As mentioned earlier, the baroreflex sensitivity is indicated by the slope of the line obtained by plotting the rate of each heartbeat against the systolic pressure of the preceding beat, and is a measure of vagal activity and baroreflex afferents.
Tests of Pupillary Fundion A sympathomimetic agent applied topically leads to dilatation of denervated pupils at concentrations that are ineffective in normal pupils because of denervation sensitivity. For example, 0.1 percent epinephrine, applied to the conjunctival sac, does not affect the normal pupil but leads to dilatation when postganglionic sympathetic fibers are affected. Cocaine hydrochloride (4 percent) instilled into the conjunctival sac normally causes pupillary dilatation, but the response is reduced or absent with lesions of the oculosympathetic pathways. Thus, in Horner's syndrome occurring from an interruption of peripheral sympathetic pathways, the response to cocaine is lost. The responses to 6-hydroxyamphetamine distinguish preganglionic from postganglionic oculosympathetic lesions because pupillary dilatation occurs only when postganglionic sympathetic fibers are intact. There is usually no response of normal pupils to the instillation of very weak solutions of parasympathomimetic agents (e.g., methacholine 2.5 percent or pilocarpine 0.125 percent), but pupillary constriction
417
occurs when parasympathetic innervation is impaired because of denervation supersensitivity.
Intraneural Recordings Intraneural recording of postganglionic sympathetic activity in humans has been important in adding to understanding about the operation of the autonomic nervous system in health and disease.:H-~ti The topic is considered further in Chapter 14. At present. however, such approaches do not have a major role in diagnosing dysautonomias for clinical purposes and are therefore not considered further.
Other Investigative Techniques Radiologic studies and urologic procedures such as uroflowmetry and measurement of urethral pressure profiles are not the province of clinical neurophysiologists and are not considered further. The postganglionic sympathetic innervation of the heart has been studied by recording the myocardial concentration of radioactivity after injection of the marker iodine-123-metaiodobenzylguanidine, which accumulates presynaptically in norepinephrine storage granules. Again, this is not the province of the clinical neurophysiologists and further me thodologie details will not be provided here, but the findings in certain parkinsonian syndromes are considered later in this chapter. Sphincteric electromyography,"? pudendal and perineal nerve conduction studies, and evaluation of certain pelvic reflexes have also been used as a means of evaluating autonomic function. Those techniques useful in evaluating sacral function are considered further in Chapter 30.
SELECTION OF TESTS No full comparative study of autonomic function tests has been reported, but certain general comments can be made. Adequate assessment of autonomic function requires tests of the control of heart rate, blood pressure, and sweating, with evaluation of both sympathetic and parasympathetic pathways." Five simple noninvasive tests of cardiovascular reflexes have been deemed adequate for assessment of diabetic autonomic neuropathy'": the heart rate responses to (1) the Valsalva maneuver, (2) standing (30:15 ratio), and (3) deep breathing; and the blood pressure responses to (4) standing and (5) sustained handgrip. Definite autonomic neuropathy is indicated by an abnormality in two or more tests.
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ELECTRODIAGNOSIS IN CLINICAL NEUROLOGY
After a study involving QSART and the heart rate responses to deep breathing and the Valsalva maneuver, Low and co-workers found that abnormalities of vagal function and postganglionic sympathetic function occurred with a similar frequency in patients with diabetic neuropathy.t" They therefore concluded that these tests of parasympathetic and sympathetic function are a sensitive index of autonomic dysfunction and are adequate for investigating patients with suspected dysautonomias. Abnormalities in two or more ofa range of tests (i.e., cardiovascular responses to postural change, isometric exercise, deep breathing, and the Valsalva maneuver; thermoregulatory sweat tests; and plasma norepinephrine levels) correlate well with abnormal responses to the Valsalva maneuver as recorded intra-arterially." This suggests that abnormalities in two or more of such tests are adequate to confirm the presence of a dysautonomia.
TEST FINDINGS IN SPECIFIC DISORDERS The pattern of autonomic abnormalities may help to suggest certain disorders, even though both sympathetic and parasympathetic functions eventually come to be affected.
Central Nervous System Disorders of the CNS associated with autonomic failure include multisystem atrophy (MSA) , pure autonomic failure (PAF) , and Parkinson's disease. Multisystem atrophy is a progressive neurodegenerative disorder characterized by autonomic dysfunction; parkinsonism; upper motor neuron deficits; ataxia; and, sometimes, by lower motor neuron signs. Depending on the predominant clinical feature, the disorder may be designated the Shy-Drager syndrome (dysautonomia), stnatonigral degeneration (parkinsonism), or olivopontocerebellar atrophy (ataxic syndrome). In pure autonomic failure, orthostatic hypotension, commonly associated with bladder dysfunction, impotence, and impaired sweating, is not accompanied by clinical evidence of CNS involvement. In MSA, pathologic changes in the autonomic nervous system involve predominantly the preganglionic neurons, whereas in PAF the sympathetic ganglia and postsynaptic neurons are affected more severely. In both MSA and PAF, postural hypotension is often dramatic. Impaired thermoregulatory sweating and abnormal heart rate responses to deep breathing, the Valsalva maneuver, and postural change are also found. Resting plasma norepinephrine levels are reduced in
PAFbut not in MSA; in both disorders there is no increment with head-up tilt, and standing levels are low.42 In Parkinson's disease, postural hypotension has often been reported and, when present, may be iatrogenic. The literature is conflicting, but in the author's experience the cardiovascular reflexes are usually preserved." However, several recent studies have suggested that many patients with Parkinson's disease have cardiac sympathetic denervation that accounts for postural hypotension.r'-f In such patients, responses to the Valsalva maneuver are also abnormal. Abnormalities of the sympathetic skin response 46,47 and of heart rate variation'" have been found, but others have reported normal heart rate variability." Other dysautonomic symptoms (e.g., disturbances of bladder or gastrointestinal function and excessive salivation) are relatively common. Minor abnormalities of autonomic function may occur in patients with progressive supranuclear palsy and Huntington's disease." In patients with the rare syndrome of congenital deficiency of dopamine-/3-hydroxylase, there is pure sympathetic failure but normal cholinergic function, including sweating. Postural hypotension is an early feature.
Peripheral Nervous System Autonomic disturbances are an expected accompaniment of many peripheral neuropathies even though they have received far less attention than the motor and sensory disturbances that occur. Such a dysautonomia may be an incidental finding that is more of academic interest than clinical relevance, as in certain entrapment neuropathies. It may be a minor feature of neuropathies such as chronic inflammatory demyelinating neuropathy (ClOP) or that associated with acquired immunodeficiency syndrome (AIDS); and a major factor of others, such as the Cuillain-Barre syndrome or diabetic neuropathy. The dysautonomia may be the presenting feature of the neuropathy or simply an inconsequential accompaniment, its most disabling (even lifethreatening) feature or an asymptomatic manifestation recognized only by laboratory investigations. It may develop acutely, reaching a maximum within 4 weeks, or evolve more insidiously. Clinically, the dysautonomia may involve sympathetic or parasympathetic fibers, or both (pandysautonomia); similarly, an adrenergic or cholinergic predominance may occur. With generalized sympathetic involvement, postural hypotension and anhidrosis are conspicuous, whereas with parasympathetic involvement there is a fixed heart rate, xerostomia, xerophthalmia, gastrointestinal dysfunction (e.g., colicky abdominal pain, nausea, vomiting, satiety, bloating, gastric fullness, and diarrhea, sometimes alternating with constipation), bladder dysfunction, and-in men-
Evaluation of theAutonomic Nervous System
sexual disturbances such as impotence. With localized involvement, the site of the pathologic process governs manifestations. ACUTE AUTONOMIC NEUROPATHIES
Idiopathic Autonomic Neuropathies
Patients present with an acute, monophasic autonomic neuropathy but little if any somatic disturbance. There may be evidence of preceding viral infection, or the neuropathy may represent a paraneoplastic disorder. Such associations suggest an underlying immunologic disturbance; this is supported by studies showing high titers of ganglionic acetylcholine receptor antibody in 40 to 50 percent of patients.i? In patients with a paraneoplastic etiology, other autoantibodies may be found as well or instead, including antineuronal nuclear antibodv I (ANNA-lor anti-Hu) or 2 (ANNA-2), Purkinje cell antibody 2 (PCA-2), and collapsin response-mediator protein 5 antibody (CRMP-5). Such antibodies may be im portan t in suggesting the likely site of any underlying primary tumor. Patients with a pandysautonomia typically complain of dizziness, lightheadedness, visual blurring or fading out, near-syncope, or even loss of consciousness on standing (from postural hypotension); heat intolerance, anhidrosis, or hypohidrosis; and gastrointestinal disturbances. Clinical examination generally confirms the presence of postural hypotension, but repeated examination is sometimes necessary to do so. Other common findings include a fixed heart rate, dry skin, dilated pupils, urinary retention, and paralytic ileus. Autonomic function tests are abnormal and reflect these clinical findings. In addition, thermoregulatory sweat tests or QSART are abnormal, nerve biopsy may show perivascular round cell infiltration, and skin biopsy reveals loss of epidermal C fibers. Nerve conduct ion studies are usually normal; mild sensory changes are sometimes found. The prognosis is variable, with only about 30 percent making a good recovery, usually within 1 year of onset.?" Treatment is supportive, but immunomodulating therapy may be worthwhile in those with a progressive or life-threatening disorder. Paraneoplastic dysautonomia may remit with treatment of the underlying malignancy. Guillain-Barre Syndrome
The somatic features of the Guillain-Barre syndrome are well recognized, but it is the autonomic disturbances that generally are responsible for the fatal outcome that sometimes occurs. Cardiac arrhythmias (most commonly a sinus tachycardia), paroxysmal hypotension or hypertension, and postural hypotension are the most disabling features." Disturbances of bladder or gastrointestinal function also occur. The
419
postural hypotension is multifactorial and may relate to inactivity and bedrest, efferent sympathetic denervation, baroreceptor deafferentation, volume depletion, cardiac abnormalities, or some combination of these and other factors. Autonomic function studies reveal an abnormal Valsalva response, abnormal heart rate responses to induced hypertension or deep breathing, and abnormal sweat tests. 52,53 The dysautonomia is treated symptomatically and supportively. This may require adrenergic blockade for hypertension or a demand pacemaker for bradyarrhythmias. The dysautonomia typically recovers without long-term sequelae. The acute dysautonomia of Cuillairi-Barre syndrome is distinguished by its somatic accompaniments from the acute dysautonomia that sometimes arises as an isolated phenomenon. This latter disorder may be a variant of Cuillain-Barre syndrome, but this remains to be established. Botulism
Botulism, which typically occurs within 36 hours of the ingestion of contaminated food, results from the toxin produced by the type B strain of Clostridium botulinum, which impairs acetylcholine release from nerve terminals. It is characterized initially by the development of blurred vision, ptosis, dysphagia, and weakness of the extraocular muscles; and then by facial and more widespread weakness associated with cholinergic failure. Autonomic involvement is signaled by xerophthalmia, xerostomia, anhidrosis, constipation, paralytic ileus, and urinary retention, and studies indicate the presence of significant postural hypotension. The electrophysiologic features resemble those of the Lambert-Eaton syndrome. Single-fiber electromyography is abnormal, indicating a disorder of neuromuscular transmission that is presynaptic in nature. In the absence of associated muscle weakness, it is sometimes difficult to distinguish the disorder clinically from acute idiopathic cholinergic autonomic neuropathy. Other Causes of Acute Dysautonomia
Dysautonomic symptoms may accompany the acute motor neuropathy of porphyria, and are a feature of certain iatrogenic and toxic neuropathies (e.g., related to use of cisplatin.v' vinca alkaloids.t" paclitaxel [Taxo!] ;'>6 or amiodarone; or following exposure to organic solvents or acrylamide). The circumstances in which they develop usually suggest the underlying etiology, and treatment is supportive, combined with avoidance of the offending agent. In most instances, autonomic function studies have not been undertaken and would anyway add little to the evaluation and management of patients. Abnormalities of postganglionic sympathetic efferent fibers have been found in patients
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
receiving vincristine.F' Organic solvent exposure has been associated with abnormalities in heart rate variation with respiration and the Valsalva ratio.P? CHRONIC AUTONOMIC NEUROPATHIES
Autonomic involvement occurs most commonly in axonal (as opposed to demyelinating) neuropathies, and especially in small-fiber neuropathies. Such smallfiber neuropathies are often difficult to recognize clinically or electrophysiologically. Patients typically present with pain, dysesthesias, and allodynia beginning in the feet and then extending proximally in the legs before coming to involve the upper limbs. Evidence of sympathetic involvement is also present. Clinical examination reveals normal power and tendon reflexes, and the only sensory deficit is an impaired appreciation of pinprick and temperature in the legs. Sudomotor abnormalities may be detected by thermoregulatory sweat tests or QSART.fiR The autonomic nervous system is affected in many peripheral neuropathies, although the clinical manifestations may be mild. Autonomic dysfunction is clinically important in neuropathies associated with diabetes, primary amyloidosis, and familial amyloid polyneuropathy, and in some cases of hereditary sensory neuropathy, particularly the Riley-Day syndrome, as well as in the acute disorders discussed in the preceding section. In most other neuropathies, autonomic dysfunction is usually of only minor clinical importance. In entrapment neuropathies, for example, postganglionic sympathetic fibers mediating the cutaneous vasoconstrictor response to an inspiratory gasp may be involved." indicating that small- and large-diameter fibers are affected, but this is of little diagnostic relevance.
Diabetes
Autonomic neuropathy occurs in about 20 percent of diabetic patients, sometimes as an isolated neurologic finding but more commonly as part of a more widespread neuropathic process. It may present with impotence, postural lightheadedness, postprandial bloating, early satiety, gastrointestinal motility disturbances, impaired bladder control, and disturbances of sweating. Abnormalities in tests of parasympathetic function (heart rate response to breathing, change of posture, and the Valsalva maneuver) occur early, whereas abnormalities of sympathetic efferent function (blood pressure response to change in posture and isometric exercise) generally develop at a later stage. Abnormalities of sudomotor function are well described. The QSART is commonly abnormal and indicates involvement of distal postganglionic sympathetic fibers.t"
Amyloid Neuropathy
Primary amyloidosis and familial amyloid polyneuropathy of Portuguese type (FAP type 1) are often complicated by autonomic failure resulting from loss of predominantly unmyelinated and small myelinated peripheral fibers and cell loss in the intermediolateral columns of the cord" Postural hypotension and impotence are common early symptoms; alternating constipation and diarrhea, distal anhidrosis, urinary retention, and cardiac arrhythmias are also common. Tests of sympathetic and parasympathetic function are typically abnormal. 50 Familial Dysautonomia
Familial dysautonomia (Riley-Day syndrome or hereditary sensory and autonomic neuropathy type III) is manifest in childhood. Autonomic disturbances include impaired lacrimation, hyperhidrosis, postural hypotension, and poor temperature control. Widespread abnormalities of autonomic function may be detected on testing." Postural Orthostatic Tachycardia Syndrome
This syndrome is characterized by postural intolerance accompanied by an increase in heart rate of at least 30 beats per minute on standing or tilt-testing. Postural hypotension does not occur. The disorder is often preceded by a viral illness. Accompanying features include xerostomia, xerophthalmia, nausea, and postprandial bloating. The response to head-up tilt is characterized by a marked tachycardia within about 2 minutes. The response to the Valsalva maneuver indicates impaired peripheral vasoconstriction, but cardiovagal responses are normal/" Thermoregulatory sweat tests commonly reveal distal impairment, and the QSART shows that the lesion is postganglionic. 53 The disorder may result from partial sympathetic denervation in the legs, as suggested by studies of norepinephrine spill-over into the venous circulation of the limbs in response to various stimuli. 54
Other Autonomic Neuropathies
In Adie's syndrome (tonic pupils with areflexia), sympathetic failure is sometimes present and segmental anhidrosis (Ross syndrome) may occur. Pathologic studies have indicated reduced cholinergic sweat gland innervation in areas of hypohidrosis, implying a selective degenerative process of cholinergic sudomotor neurons." A Horner's syndrome is sometimes encountered, however, and other dysautonomic symptoms may also be present, suggesting a generalized abnormality of ganglion cells or their projections.t"
Evaluation of the Autonomic Nervous System
Dysautonomic manifestations other than impaired sweating distally are uncommon in alcoholic peripheral neuropathy except when the neuropathy is severe or coexists with Wernicke's encephalopathy, which is accompanied by central autonomic dysfunction. Abnormalities of cardiovascular parasympathetic function occur before blood pressure control mechanisms are involved." Abnormalities in sudomotor function are common." In patients with chronic renalfadure, the degree of autonomic dysfunction relates to the impairment of nerve conduction.v? Parasympathetic cardiovascular abnormalities are more common than sympathetic abnormalities such as postural hypotension and abnormalities of the SSR. The baroreceptor reflexes may also be impaired. Alcohol-dependent patients admitted to a psychiatric department were found to have a higher incideuce than normal subjects of parasympathetic (vagal) disturbances of cardiovascular function as measured by heart rate variability?" Cardiovascular autonomic dysfunction may occur in alcoholic and nonalcoholic chronic liver disease. In nonalcoholic disease, parasympathetic abnormalities are more common than sympathetic changes. il Autonomic neuropathy signifies a worse prognosis than otherwise.?" In rheumatoid arthritis, involvement of postganglionic sympathetic efferent fibers leads to impaired sweating, and vagal involvement leads to abnormalities in the heart rate response to standing, the Valsalva maneuver, and respiration, especially in patients with peripheral neuropathy. i3 Autonomic abnormalities may occur in other connective tissue diseases including systemic lupus ersihematosus. mixed connective tissue disease, and Sjogren's syndrome. 1~I'Prosy has been associated with autonomic dysfunction. i4 Patchy anhidrosis is the most common finding, but cardiovascular abnormalities including postural hypotension also occur. Abnormalities in cardiovascular parasympathetic tests are more common and occur earlier than cardiovascular sympathetic abnormalities. Nevertheless, abnormalities of cutaneous vasomotor reflexes may be found in patients with leprosy?" and in the apparently healthy contacts of such patients?" and, when combined with electrophysiologic testing of peripheral nerve function, may provide a means of determining the spectrum of involved fibers. rt Syncope, impotence, bladder and bowel dysfunction, and anhidrosis are common in patients with human immunodeficiency virus infection. Abnormal autonomic function test results become more common and more severe in patients with AIDS: up to 80 percent of patients with AIDS have abnorrnalities.P'?" Diphtheria sometimes causes a demyelinating motor polyneuropathy, and this may be associated with abnor-
421
malities in parasympathetic cardiovascular function; sympathetic abnormalities are not found.f" During the chronic phase of Chagas' disease, which is widespread in South America, the gastrointestinal tract and heart may be affected. Clinical manifestations include cardiac arrhythmias, sudden death, and postural hypotension, with abnormal cardiovascular reflexes." It is generally believed that only minor, infrequent disturbances in autonomic function occur in CIDP,82 but a recent study found a variety of abnormalities, including SSR abnormalities, in 50 percent of patients. 83 The abnormalities may involve sympathetic or parasympathetic components; in the former, both vasomotor and sudomotor fibers may be affected. In patients with hereditary neuropathies, pupillary reflexes may be abnormal and sweating is sometimes impaired distally, but cardiovascular reflexes are usually preserved in patients with hereditary motor and sensory neuropathy types I and II. R4 In hereditary sensory and autonomic neuropathies other than Riley-Day syndrome (discussed earlier), anhidrosis is the most common dysautonomic feature. The dysautonomic manifestations of Fabry's disease include hypohidrosis or anhidrosis and gastrointestinal dysfunction with indigestion, nausea, belching, esophageal reflux, abdominal pain, flatus, and diarrhea. Autonomic tests reveal pupillary abnormalities, abnormal tear and saliva production, widespread anhidrosis, reduced cutaneous flare response to scratch and intradermal histamine, and abnormal colonic motility.'" Cardiovascular autonomic tests are normal. Enzyme replacement therapy may lead to improvement or normalization of sweating, as shown by QSART or thermoregulatory sweat tests."
REFERENCES 1. Aminoff Mj: Autonomic nervous system. p. 93. In Fogel BS, Schiffer RB, Rao SM (eds): Neuropsychiatry. Williams & Wilkins, Baltimore, 1996 2. Wallin BG, Elam M: Microneurography and autonomic dysfunction. p. 243. In Low PA (ed): Clinical Autonomic Disorders. Little, Brown, Boston, 1993 3. Wheeler T, Watkins PJ: Cardiac denervation in diabetes. BMj, 4:584,1973 4. Ingal! T], McLeodjG, O'Brien PC: The effect of ageing on autonomic nervous system function. Aust N Z .I Med, 20:570, 1990 5. Stalberg EV, Nogues MA: Automatic analysis of heart rate variation. I. Method and reference values in healthy controls. Muscle Nerve, 12:993, 1989 6. Linden D, Diehl RR: Comparison of standard autonomic tests and power spectral analysis in normal adults. Muscle Nerve, 19:556, 1996 7. Sundkvist G, Almer L-O, Lilja B: Respiratory influence on heart rate in diabetes mellitus. BMj, 1:924, 1979
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8. Freeman R: Autonomic testing. p. 483. In Brown WF, Bolton CF, Aminoff MJ (eds): Neuromuscular Function and Disease. WB Saunders, Philadelphia, 2002 9. Vita G, Princi P, Calabro R et al: Cardiovascular reflex tests. Assessment of age-adjusted normal range. J Neurol Sci, 75:263, 1986 10. Ewing OJ, Campbell IW, Murray A et al: Immediate heart rate response to standing: simple test for autonomic neuropathy in diabetes. BMJ, 1:145, 1978 II. Freeman R, Cohen RJ, Saul JP: Transfer function analysis of respiratory sinus arrhythmia: a measure of autonomic function in diabetic neuropathy. Muscle Nerve, 18:74, 1995 12. Freeman R, Saul JP, Roberts MS et al: Spectral analysis of heart rate in diabetic autonomic neuropathy. Arch Neurol, 48:185, 1991 13. Pomeranz B, Macaulay RJ, Caudill MA et al: Assessment of autonomic function in humans by heart rate spectral analysis. AmJ Physiol, 248: H151, 1985 14. Hilz MJ: Quantitative autonomic functional testing in clinical trials. p. 1899. In Brown WF, Bolton CF, Aminoff MJ (eds): Neuromuscular Function and Disease. WB Saunders, Philadelphia, 2002 15. Low PA, WalshJC, Huang CYet al: The sympathetic nervous system in diabetic neuropathy: a clinical and pathological study. Brain, 98:341,1975 16. Ewing OJ, Campbell IW, Clarke BF: Assessment of cardiovascular effects in diabetic autonomic neuropathy and prugnostic implications. Ann Intern Med, 92:308, 1980 17. Molhoek GP, Wesseling KH, Settels lJM et al: Evaluation of the Penaz servo-plethysmo-manometer for the continuous, noninvasive measurement of finger blood pressure. Basic Res Cardiol, 79:597, 1984 18. Ewing OJ, Campbell IW, Kerr F et al: Cardiovascular responses to sustained handgrip in normal subjects and in patients with diabetes mellitus: a test of autonomic function. Clin Sci, 46:295, 1974 19. Hulteman E, Sjoholm H: Blood pressure and heart rate response to voluntary and non-voluntary static exercise in man. Acta Physiol Scand, 115:499, 1982 20. McLeodJG: Evaluation of the autonomic nervous system. p. 381. In Aminoff MJ (ed): Electrodiagnosis in Clinical Neurology. 4th Ed. Churchill Livingstone, New York, 1999 2 L. Low PA, Neumann C, Dyck PJ et al: Evaluation of skin vasomotor reflexes by using laser Doppler velocimetry. Mayo Clin Proc, 58:583, 1983 22. Aminoff MJ: Involvement of peripheral vasomotor fibres in carpal tunnel syndrome. J Neurol Neurosurg Psychiatry, 42:649, 1979 23. AminoffM]: Peripheral sympathetic function in patients with a polyneuropathy.J Neurol Sci, 44:213,1980 24. Parati G, DiRienzo M, Bertinieri G et al: Evaluation of the baroreceptor-heart rate reflex by 24-hour intra-arterial blood pressure monitoring in humans. Hypertension, 12:214, 1988 25. Pitzalis MY, Matropasqua F, Passantino A et al: Comparison between noninvasive indices of baroreceptor sensitivity and the phenylephrine method in post-myocardial infarction patients. Circulation, 97:1362, 1998
26. Kennedy WR, Sakuta M, Sutherland 0 et al: Quantitation of the sweating deficiency in diabetes mellitus. Ann Neurol, 15:482, 1984 27. Kyriakidis MK, Noutsis CG, Robinson-Kyriakidis CA et al: Autonomic neuropathy in leprosy. Int J Lepr, 51:331, 1983 28. Fealey RD: Thermoregulatory sweat test. p. 245. In Low PA (ed): Clinical Autonomic Disorders. 2nd Ed. LippincottRaven, Philadelphia, 1997 29. Shahani B, Halperin lJ, Boulu PJ et al: Sympathetic skin response: a method of assessing unmyelinated axon dysfunction in peripheral neuropathies.J Neurol Neurosurg Psychiatry. 47:536, 1984 30. Maselli RA, Jaspan JB, Soliven BC et al: Comparison of sympathetic skin response with quantitative sudomotor axon reflex test in diabetic neuropathy. Muscle Nerve, 12:420, 1989 31. Toyokura M, Murakami K: Reproducibility of sympathetic skin response. Muscle Nerve, 19:1481, 1996 32. Low PA, Caskey PE, Tuck RR et al: Quantitative sudomotor axon reflex test in normal and neuropathic subjects. Ann Neurol, 14:573, 1983 33. Polinsky RJ: Multiple system atrophy: clinical aspects, pathophysiology, and treatment. Neurol Clin, 2:487,1984 34. Fagius J, Wallin BG: Long-term variability and reproducibility of testing human muscle nerve sympathetic activity at rest, as re-assessed after a decade. Clin Autonom Res, 3:201, 1993 35. Wallin BG, Elam M: Microneurography and autonomic dysfunction. p. 233. In Low PA (ed): Clinical Autonomic Disorders. 2nd Ed. Lippincott-Raven, Philadelphia, 1997 36. Dotson R, OchoaJ, Marchettini P et al: Sympathetic neural outflow directly recorded in patients with primary autonomic failure: clinical observations, microneurography, and histopathology. Neurology, 40:1079,1990 37. Nahm F, Freeman R: Sphincter electromyography and multiple system atrophy. Muscle Nerve, 28:18, 2003 38. American Academy of Neurology: Assessment: clinical autonomic testing report of the Therapeutic and Technology Assessment Sub-Committee of the American Academy of Neurology. Neurology, 46:873, 1996 39. Ewing DJ: Recent advances in the non-invasive investigation of diabetic autonomic neuropathy. p. 667. In Bannister R (ed): Autonomic Failure. 2nd Ed. Oxford University Press, Oxford, 1987 40. Low PA, Zimmerman BR, Dyck PJ: Comparison of distal sympathetic with vagal function in diabetic neuropathy. Muscle Nerve, 9:592, 1986 41. McLeod JG, Tuck RR: Disorders of the autonomic nervous system, Parts I and II. Ann Neurol, 21:419, 519,1987 42. Low PA, Bannister R: Multiple system atrophy and pure autonomic failure. p. 555. In Low PA (ed): Clinical Autonomic Disorders. 2nd Ed. Lippincott-Raven, Philadelphia, 1997 43. Aminoff MJ: Other extrapyramidal disorders. p. 577. In Low PA (ed): Clinical Autonomic Disorders. 2nd Ed. Lippincott-Raven, Philadelphia, 1997 44. Goldstein OS: Dysautonomia in Parkinson's disease: neurocardiological abnormalities. Lancet Neurol, 2:669, 2003
Evaluation ofthe Autonomic Nervous System
45. Goldstein DS, Holmes CS, Dendi R et al: Orthostatic hypotension from sympathetic denervation in Parkinson's disease. Neurology, 58:1247, 2002 46. Zakrzewska-Pniewska B,Jamrozik Z: Are electrophysiological autonomic tests useful in the assessment of dysautonomia in Parkinson's disease? Parkinsonism Relat Disord, 9:179, 2003 47. Haapaniemi TH, Korpelainen JT, Tolonen U et al: Suppressed sympathetic skin response in Parkinson disease. Clin Auton Res, 10:337, 2000 48. Holmberg B, Kallio M, Johnels B et al: Cardiovascular reflex testing contributes to clinical evaluation and differential diagnosis of parkinsonian syndromes. Mov Disord, 16:217,2001 49. Vernino S, Low PA, Fealey RD et al: Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N EnglJ Med, 343:847, 2000 50. Suarez GA, Fealey RD, Camilleri M et al: Idiopathic autonomic neuropathy: clinical, neurophysiologic, and followlip studies on 27 patients. Neurology, 44:1675, 1994 51. Zochodne DW: Autonomic involvement in Guillain-Barre syndrome: a review. Muscle Nerve, 17:1145,1996 52. Tuck RR, McLeod JG: Autonomic dysfunction in Cuillain-Barre syndrome.J Neurol Neurosurg Psychiatry, 44:983,1981 53. Persson A, Solders G: R-R variation in Guillain-Barre syndrome. Acta Neurol Scand, 67:294,1983 54. Rosenfeld CS, Broder LE: Cisplatin-induced autonomic neuropathy. Cancer Treat Rep, 68:659, 1984 55. Hancock BW, Naysmith A: Vincristine-induced autonomic neuropathy. BMJ, 3:207,1975 56. Jerian SM, Sarosy GA, Link CJ et al: Incapacitating autonomic neuropathy precipitated by taxo!' Gynecol Oncol, !11:277,1993 57. Matikainen E, Juntunen J: Autonomic nervous system dysfunction in workers exposed to organic solvents. J Neurol Neurosurg Psychiatry, 48:1021,1985 58. Stewart JD, Low PA, Fealey RD: Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes. Muscle Nerve, 15:661, 1992 59. Ando Y, Suhr OB: Autonomic dysfunction in familial amyloidotic polyneuropathy (FAP). Amyloid, 5:288, 1998 60. Bernardi L, Passino C, Porta C et al: Widespread cardiovascular autonomic dysfunction in primary amyloidosis: does spontaneous hyperventilation have a compensatory role against postural hypotension? Heart, 88:615, 2002 61. Axelrod FB: Familial dysautonomia. Muscle Nerve, 29:352, 2004 62. Sandroni P, Novak V, Opfer-Gehrking TL et al: Mechanism of blood pressure alterations in response to the Valsalva maneuver in postural tachycardia syndrome. Clin Auton Res, 10:1, 2000 63. Low PA, Vernino S, Suarez G: Autonomic dysfunction in peripheral nerve disease. Muscle Nerve, 27:646, 2003 64. Jacob G, Costa F, ShannonJR et al: The neuropathic postural tachycardia syndrome. N Engl J Med, 343:1008, 2000 65. Sommer C, Lindenlaub T, Zillikens D et al: Selective loss of cholinergic sudomotor fibers causes anhidrosis in Ross syndrome. Ann Neurol, 52:247, 2002
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66. Shin RK, Galetta SL, Ting TY et al: Ross syndrome plus: beyond Horner, Holmes-Adie, and harlequin. Neurology, 55:1841,2000 67. Duncan G,Johnson RH, Lambie DG et al: Evidence of vagal neuropathy in chronic alcoholics. Lancet, 2:1053, 1980 68. Low PA, WalshJC, Huang C-Yet al: The sympathetic nervous system in alcoholic neuropathy: a clinical and pathological study. Brain, 98:357, 1975 69. Wang SJ, Liao KK, Liou HH et al: Sympathetic skin response and R-R interval variation in chronic uremic patients. Muscle Nerve, 17:4Il, 1995 70. Rechlin T, Orbes I, Weis M et al: Autonomic cardiac abnormalities in alcohol-dependent patients admitted to a psychiatric department. Clin Auton Res, 6:Il9, 1996 71. Thuluvath PJ, Triger DR: Autonomic neuropathy in chronic liver disease. QJ Med, 72:737, 1989 72. Hendrickse MT, Thuluvath PJ, Triger DR: Natural history of autonomic neuropathy in chronic liver disease. Lancet, 339:1462,1992 73. Edmonds ME, Jones TC, Saunders WA et al: Autonomic neuropathy in rheumatoid arthritis. BMJ, 2:173, 1979 74. Ramachadran A, Neelan PN: Autonomic neuropathy in leprosy. IndianJ Lepr, 59:277,1987 75. Wilder-Smith EP, Wilder-Smith AJ, Nirkko AC: Skin and muscle vasomotor reflexes in detecting autonomic dysfunction in leprosy. Muscle Nerve, 23:1105, 2000 76. Wilder-Smith E, Wilder-Smith A, Egger M: Peripheral autonomic nerve dysfunction in asymptomatic leprosy contacts. J Neurol Sci, 150:33, 1997 77. Abbot NC, BeckJS, Mostofi S et al: Sympathetic vasomotor dysfunction in leprosy patients: comparison with electrophysiological measurement and qualitative sensation testing. Neurosci Lett, 206:57, 1996 78. Ruttimann S, Hilti P, Spinas GA et al: High frequency of human immunodeficiency virus-associated autonomic neuropathy and more severe involvement in advanced stages of human immunodeficiency virus disease. Arch Intern Med, 151:2441, 1991 79. Welby SB, Rogerson SJ, Beeching NJ: Autonomic neuropathy is common in human immunodeficiency virus infection. J Infect, 23:123, 1991 80. Idiaquez J: Autonomic dysfunction in diphtheritic neuropathy.J Neurol Neurosurg Psychiatry, 55:159,1992 81. Fernandez A, Hontebeyrie M, Said G: Autonomic neuropathy and immunological abnormalities in Chagas' disease. Clin Autonom Res, 2:409, 1992 82. Ingall TJ, McLeod JG, Tamura N: Autonomic function and unmyelinated fibers in chronic inflammatory neuropathy. Muscle Nerve, 13:70, 1989 83. Lyu RK, Tang LM, Wu YRet al: Cardiovascular autonomic function and sympathetic skin response in chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve, 26:669, 2002 84. Ingall TJ, McLeodJG: Autonomic dysfunction in hereditary motor and sensory neuropathy (Charcot-Marie-Tooth disease). Muscle Nerve, 14:1080, 1991 85. Cable \\1L, Kolodny EH, Adams RD: Fabry disease: impaired autonomic function. Neurology, 32:498, 1982 86. Schiffmann R, Floeter MK, Dambrosia JM et al: Enzyme replacement therapy improves peripheral nerve and sweat function in Fabry disease. Muscle Nerve, 28:703, 2003
CHAPTER
21
Visual Evoked Potentials in Clinical Neurology GASTONE G. CELESIA
BASIC TECHNOLOGY
MULTIFOCAL VEPs
NORMATIVE DATA
CONCLUDING COMMENTS
ABNORMAL VEPs Retinopathies and Maculopathies Disorders of the Optic Nerve and Chiasm Retrochiasmatic Disorders
Electrophysiologic recording of visual evoked potentials (VEPs) has been very useful in evaluating visual function.v" Evoked potential techniques are noninvasive and have excellent temporal resolution (in the range of milliseconds), thus permitting the study of dynamic changes occurring in the nervous system.l-! It is important to review some of the fundamental characteristics of visual function before discussing the clinical applications ofVEP studies. The visual system processes information along multiple parallel channels.r" Separation of visual information starts at the neuronal circuitry of the retina, where particular features such as color, contrast, luminance, and other parameters of the stimulus are extracted and processed.l" It has been suggested that at least seven parallel channels of ganglion cells process visual information in the primate retina.'? Recent work has demonstrated several classes of neurons that differ in their visual properties and roles. These retinal neurons send central projections to the lateral geniculate body (LGB). Two separate classes of ganglion cells have been described in the macaque monkey: (1) P cells (also called midget cells); and (2) M cells (also called parasol cells)." These two neuronal groups in the retina have distinct physiologic properties and project separately to segregated brain regions. 7,9- 11 M (magnocellular) pathways can be activated independently ofP (parvocellular) pathways. P cells send their projections to the parvocellular laminae of the LGB, whereas M cells project to the magnocellular laminae." From the LGB, visual information is transmitted to striate area 17. Several projections link area 17 with areas 18, 19, and MT (midtemporal)."!! The output from areas 19 and MT goes to visual areas in the posterior parietal cortex.9,12-18
The magnocellular system is involved primarily with motion analysis. The parvocellular system is associated with color selectivity and shows a preference for high spatial-frequency stimuli l4-18; it overlaps, however, with the magnocellular system in selectivity for orientation. The parvocellular system projects heavily to the inferior temporal cortex. The two major processing systems, directed toward posterior parietal and inferior temporal cortex, exist in all primates. 9,1l,14-18 It is presumed that a similar organization of the visual system exists in humans. At least 10 cortical visual areas have been described in humans,12,13,16 with over one-third of the cerebral cortex devoted primarily to visual function. 12,13 An interesting explanation for the multiplicity of visual cortical areas has been proposed by Marr.I? He suggested that any large computation should be broken down into a collection of smaller independent modules. The multiplicity of cortical representations may provide the structural modules on which new information capabilities have developed in the course of evolution. 12,13,20,21 Thus, increasing the number of visual areas may increase the number of visual abilities and simplify the problem of interconnecting functionally related groups of neurons.s' This brief summary of present knowledge of the visual pathways emphasizes the extent to which the neocortex is involved in parallel visual processing. It also offers opportunities for evaluating the system. Two pragmatic principles can be derived from the data just presented: 1. Visual stimuli not only activate the occipital lobes
but also involve large areas of the temporal and parietal lobes. 453
454
ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
2. Different structures of the retina and visual pathways can be preferentially activated by changing the characteristics of the visual stimulus.f The first principle indicates that YEPs can be recorded from a large region of the scalp, essentially from the vertex to the inion. Accordingly, the referential electrode should be located anterior to the vertex or distant from these active regions. The second principle indicates the importance of selecting the proper visual stimulus for the specific clinical problem to be addressed. The use of selective visual stimulation and recording techniques permits the analysis of specific functions within the visual pathways.2,22,23 Selection of the appropriate test requires an understanding of the suspected site of pathology. For instance, if a patient has been referred because of difficulty with night vision and suspected retinopathy, the rod retinal receptor system requires assessment and the appropriate test is full-field flash electroretinography (ERG; discussed in Chapter 20). Conversely, a patient with suspected retrobulbar neuritis should first undergo a pattern-reversal YEP, the most sensitive electrophysiologic test to assess dysfunction of the optic nerve. Only a logical approach to specific diagnostic questions will permit proper utilization of a variety of electrophysiologic tests.
BASIC TECHNOLOGY To improve clinical care and allow comparison between different laboratories it is recommended that a standardized methodology be used. The recommended standards of the International Federation of Clinical Neurophysiology (IFCN) and the International Society for Clinical Electrophysiology ofVision (ISCEV) are followed in this brief description of the basic technology for recording YEPs. The principles of recording the YEP are simple. A visual stimulus is presented to the subject for a selected number of times, and the cerebral responses are amplified, averaged by a computer, and displayed on an oscilloscope screen or printed out on paper. For neurologic purposes, YEPs are generally elicited by monocular stimulation of each eye while the other is covered with a patch. Visual stimuli can be either patterned or unpatterned. Unpatterned stimuli most commonly consist of stroboscopic flashes. Patterned stimuli consist of a specific pattern (e.g., checks or bars) on which the subject is required to fixate. Whenever a pattern stimulus is used, it is important to define the type of pattern, size of the pattern elements, total field size, method of presentation of the pattern, rate of presentation of the pattern, stimulus intensity or luminance, background luminance, and contrast. Any change in these parame-
ters may profoundly modify the response. I- 3,22-25 The two most commonly used patterns are checks and gratings. The pattern should be achromatic (black and white). The size of the individual checks should be expressed in terms of visual angle. The visual angle p is expressed as
P= tan"! (
;
) x 120
where P is the visual angle in minutes of are, W is the width of the checks in millimeters, and D is the distance of the pattern from the corneal surface in millimeters (Fig. 21-1). Although checks are customarily reported in minutes of arc ('), gratings are usually reported in cycles per degree. Measurements in cycles per degree (abbreviated as c/deg) define the spatial frequency of the stimulus. Measurements of the visual angle in minutes of arc can be converted to cycles per degree by the formula 30 c/deg=-W where W is the width of the grating in minutes. In the case of checks, however, W represents the diagonal measure of the checks in minutes of arc. The most common method of presentation of the stimulus is by reversal of a checkerboard pattern; the black checks become white, and vice versa, so there is no change in total luminance (isoluminance) of the pattern. Isoluminance is important in preventing light scatter in the retina. The YEP is affected by the stimulus intensity. The intensity of a visual stimulus is defined as luminance. Luminance is measured by a photometer and is expressed in candela per square meter (cdz'm"). The mean luminance of the field of stimulation is expressed by the formula Lmax + Lmin
2 where Lmax indicates the maximum and Lmin the minimum luminance of the field. A desirable mean field luminance is at or above 100 cd/m 2. Another important parameter that may modify the YEP is contrast. Contrast is defined as the difference between the bright and dark portions of a pattern. It is expressed by the formula C = Lmax - Lmin x 100 Lmax+Lmin where C is the contrast in percent and Lmax and Lmin are the maximum and minimum luminance of the pattern.
Visual Evoked Potentials inClinical Neurology
455
Smm
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= Tan- 1(S/(2X1000))x120 = 27' .50 = 27' 30"
w= Tan- 1(S/(2X500)) X 120 = 54' .99 = 54' 59"
III Geometry of the visualangle and the relationship between absolute object size and distance. The size of the field (in this example a field containing four checks and having a width of 8 mm) is expressed as visual angle ~ or W. Note that although the absolute size of the field remains 8 mm, the size of the image on the retina changes with the distance. This relationship is reflected by the value of the visual angle, which changes from 27'30" at 1 m to 54'59" at 0.5 m. Further details are provided in the text.
FIGURE 21-1
The reader is referred to the recent guidelines of ISCEV for further information on measurements and calibration of visual stimuli.P" The IFCN recommends that a minimum of three stimuli be used for testing, and suggests the following parameters: 1. Pattern stimuli consisting of either checks or
gratings 2. Size of the pattern elements: 14' to 16',28' to 32', and 56' to 64' 3. Full-field size of at least 8 degrees (l degree = 60 minutes) 4. Contrast between 50 and 80 percent 5. Rate of presentation of 1 Hz (producing a reversal every 500 msec) 6. Mean luminance of the center field of at least 100 cd/m2 7. Background luminance under photopic conditions of at least 30 to 50 cd/m2 A variety of montages have been advocated for recording VEPs. The IFCN suggests a two-channel montage, Oz-Fpz and Oz-A1-A2 (linked ears), with the ground placed at Cz. Reproducible VEPs are ensured with this montage even in cases with a prominent potential gradient at the vertex. The bandpass should be 1 to 250 or 300 Hz. The subject fixates on the center of the pattern during stimulation. The responses are recorded at least twice to ensure their replicability.
NORMATIVE DATA The issue of normative data is a complex one, and two aspects merit particular attention because of their importance and clinical relevance: (1) whether it is appropriate to use the normative data obtained by others; and (2) the effect of changes in stimulus parameters on the responses. VEPs are electric potentials evoked from visual stimuli and recorded from the human scalp. Therefore, if the same stimulation and recording parameters are used, the same response will be recorded. The normative data obtained in one laboratory can be used in another, provided that the physical characteristics of the visual stimulus and the recording arrangements are identical or equivalent in the two laboratories. It may, however, be desirable to verify the validity of the adopted normal values by testing at least 10 normal subjects. The values of the new data should fall within the boundary of normality of the adopted data. VEPs to a pattern-reversing checkerboard (the most commonly used stimulus in clinical laboratories) consist of a set of sequential waveforms (Fig. 21-2). The waveforms are alternately positive and negative and are designated in accordance with their polarity and latency. Positive waves are designated P, followed by a number indicating the peak latency in milliseconds (e.g., P60 and PlOO); negative waves are designated N, followed by a number indicating the peak latency
456
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subjects with 20/20 visual acuity. The visualstimulus consisted of pattern-reversing checks subtending 31' at the eye. The total field of the stimulus subtended 22 degrees and had a mean luminance of 116 cd/m 2• The most frequent morphology is shown in A, B, and C. Less common variations are shown in D, E, and F. Note that P50 and even N70 may be absent in normal subjects. The morphology of the response shown in E and F is often referred to as a W configuration. In this and all other illustrations, two trials are superimposed to demonstrate the reproducibility of the potentials.
(e.g., N70 and NI45). There is considerable variation in the morphology of normal VEPs, but the dominant wave is the PIOO component. Figure 21-2 shows the variations in VEP morphology observed in 150 normal subjects. It can be seen that in some subjects the initial negativity (N70) is absent, whereas in other subjects N70 is as large as PIOO. In fewer than 0.5 percent of normal cases, PlOO has a W-shaped configuration (i.e., PIOO is subdivided into two peaks). In these normal subjects, both peaks have latencies within the boundaries of normality. The best way to determine which peak corresponds to PIOO is to obtain VEPs to patterns of three different sizes. Usually the larger checks will yield only one PIOO peak. What is not sufficiently appreciated is the need to maintain constant the luminance, contrast, patternreversal rate, and size of the pattern elements to obtain reproducible and reliable VEPs. Any change in these parameters will inevitably affect the VEPs. As shown in Figure 21-3, a reduction in the amount of light reach-
checks and their relationship to pupil diameter and retinal illuminance. The effect of changes in retinal illuminance is shown in the left column and that of pupil diameter on the right. Note the increase in latency ofPI00 and the change in morphology of N70 with a decline in retinal illuminance or pupillary constriction.
ing the retina will produce a reduction in amplitude and a prolongation in latency of the response. Retinal illuminance (I) is measured in trolands and is calculated by the formula
I=LxA where L is the mean luminance in cd/m 2 and A is the pupil area in mm". Pupil constriction affects the amplitude and the latency of N70 and PIOO in the same manner as decreased luminance of the stimulus does.i? In Figure 21-3, the dilated pupil had a diameter of 7.5 mm with an area of 44.17 mm", whereas the constricted pupil had a diameter of 1.8 mm with an area of 2.54 mm", The stimulus luminance was 26.9 cd/m 2 for both conditions. The variation in pupil size had drastic effects on retinal illuminance, which was 1188.2 trolands with the dilated pupil and 68.3 trolands with the constricted pupil. The latency of PIOO changed from 96 to 107.5 msec, depending on pupillary size. Check size also influences the latency and amplitude of the responses.Pv" A decrease in check size is usually associated with a prolongation ofN70 and PIOO latency. However, the relationship between pattern size and PIOO latency is not linear; certain studies suggest that as check size increases above 30', the latency of PlOO also increases.P This complex relationship indicates the need to establish normative data for every check size used. Age is another important variable that influences the VEP.30 As shown in Figure 21-4, PIOO latency increases
457
Visual Evoked Potentials inClinical Neurology
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* •• * 90 • * U o • * I · * * • *. a:: 85 • *• * ** * 80 '=----::J=----::"::--'*""-~-_=_=-~--= 10
20
30
40 50 Age in years
60
70
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FIGURE 21·4 • Effect of age and gender on PlOD latency. Visual evoked potentials were elicited by pattern reversal in 112 normal subjects. There was no statistically significant difference between sexes for responses to 15' checks; thus both men and women are represented by dots. Gender was a significant influence on responses to 31' checks; asterisks refer to women and squares to men. In the upper graph the solid line represents the weighted regression line, and the dashed line the 98 percent confidence boundary calculated so that the probability that the next observation will fall below the boundaries is 0.98. In the lower graph the dashed line and the dotted line represent the weighted regression line for men and women. The dot-dash line and the solid line are the 98 percent confidence boundary for women and men, respectively. The women have shorter latencies than the men.
in older normal subjects. Celesia and co-workers simultaneously recorded pattern ERGs and VEPs in 112 normal subjects and demonstrated that aging influenced the responses at the retinal level.30 The increased latency of the B wave in the pattern ERG was mostly caused by ocular changes related to senescence and only partially caused by aging of the neuronal circuitry in the retina. The effect of aging was more prominent when small checks were used to elicit the responses. There was also an increase in latency of the N70 and PIOO components of the VEP, and this change was not
simply a result of the delayed retinal response. The retinocortical time, expressed as the interpeak interval between the B wave of the pattern ERG and either the N70 or the P100 peak of the VEP, reflects events occurring outside the retina and at some point in the optic nerve, optic pathways, or visual cortices. The retinocortical time was prolonged for responses evoked with 15' checks, but not by 31' checks. The age-related increase in latency of VEP was therefore related to changes in the visual pathways or cortex. Ganglion cell loss,31 dysmyelination, axonal swelling, and nerve fiber loss have been described in the optic nerve. 31.32 Shorter-latency (see Fig. 21-4) and larger-amplitude VEPs than in males have been described in females. 30,33,34 Whether these changes are related to the smaller anatomic size of the head of females or to hormonal factors is unclear. Uncorrected refractory errors may affect the amplitude and latency of the VEP, especially for patterns of small size. 35,36 The effect of defocusing on the VEP is shown in Figure 21-5. Blurring of the pattern stimulus not only prolongs PlOO latency but often drastically changes VEP morphology, with elimination of N70 and broadening of the PlOO wave. Two diopters of blur reduces Snellen visual acuity from 20/20 to 20/120.:17 Patients to be tested not infrequently have 1 or 2 diopters of uncorrected myopia. Certain precautions must be taken in the laboratory before and during the recording of VEPs to prevent changes in the amplitude and latency of VEPs because of ocular factors. Caution should be taken to prevent misinterpretation ofVEP abnormalities resulting from
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25 msec/div FIGURE 21·5 • Effect of optic blur on pattern-reversal visual evoked potentials in a normal subject with 20/20 vision. In the left columns are responses to 15' checks and in the right columns are responses to 31' checks. 00 indicates no blur; +20 and +30 indicate that a lens of +2 or +3 diopters was placed in front of the subject's eye to cause visual blurring. The blurring influenced both the latency and morphology of the response. Note the destructive effect of blur on the N70 wave.
458
ELEGRODIAGNOSIS INCLINICAL NEUROLOGY
refractive errors, pupillary changes, and lens opacities as related to pathology in the visual pathways. The following precautions are recommended: (1) the pupil diameter and the visual acuity of each eye should be measured; (2) corrective lenses should be worn to compensate for refractive errors; (3) if a deficit in visual acuity greater than 20/100 is present, the technologist should determine whether it can be corrected with a "pinhole"; and (4) the pupils should not be dilated with mydriatics to prevent interference with accommodation.
sometimes be associated with decreased amplitude. The most severe abnormality is an absent YEP. In patients with small monocular delays in N70 and PIOO, it is useful to look at the intereye latency differ-
Checks 15'
ERG
ABNORMAL VEPs Abnormalities of YEPs have been described in many disorders of the optic nerve, chiasm, and retrochiasmatic visual pathways. 1-~,22-25,28,37-42 The YEP can be considered abnormal when the latency of the PIOO wave is outside the 95th to 99th percentile boundaries established for normal individuals or when the PIOO is absent. Delay or absence of the N70 peak is more difficult to evaluate because this component is so variable in different subjects. Various YEP abnormalities are shown in Figure 21-6. The most common abnormality is characterized by a normal amplitude but prolonged latency of N70 and PIOO, but a prolonged latency may
as
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25 msec/div FIGURE 21·6 • Different types of abnormality of pattern-reversal visual evoked potentials. In the left column are responses to 15' checks and in the right column are responses to 31' checks. A, Delayed PIOO of normal amplitude. B, Prolonged latency and small amplitude to 15' checks, but normal amplitude and prolonged latency of PIOO to 31' checks. C, Very delayed and small responses. D. Absent responses.
VEP~
r
RCT = 45.5 P85.5
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256 msec FIGURE 21·1 • Electrophysiologic studies in a 35-year-old man with central serous choroidopathy of the right eye. He has normal pattern electroretinograms (ERGs) and visual evoked potentials (VEPs) to stimulation of the unaffected eye (OS). Stimulation of the right eye (OD) shows absent pattern ERG to 15' checks and a delayed PIOO response in the VEP. Stimulation with 31' checks evokes an abnormal pattern ERG with a delayed B wave and mildly delayed PIOO. The retinocortical time (RCT) , however, remains within normal limits at 47 msec, thus indicating that the pathology is at the retinal level. Calibration bar represents 5 uv for ERGs and 10 uv for VEPs.
Visual Evoked Potentials in Clinical Neurology
ence. A latency difference between the two eyes greater than 10 msec is clearly indicative of pathology on the side with the longer latency.
as
00
VA= 20 20
VA = finger counting only
459
Checks 15'
Retinopathies and Maculopathies Diseases of the retina, especially diseases affecting the macular region, are associated with abnormal VEPs,38,43-47 VEPs to pattern-reversal stimulation are evoked predominantly from the central 10 degrees of the visual field and therefore reflect the function of the macular area and related pathways.I-3,7,22,23,25 Maculopathies, including macular edema, central serous choroidoparhy," Stargardt's disease, vitelliruptive macular degeneration.t" and age-related macular degeneration (senile macular degeneration) ,38,43,45,46 affect the VEPs because they disrupt vision. Similarly, diffuse retinopathies, when they involve the macular and perimacular region, are associated with abnormal VEPs. Retinal infarcts and scars involving the macular region, cone dystrophy, diabetic retinopathy with macular edema, cancer-associated retinopathy, and retinitis pigmentosa with paracentral scotoma have all been reported to affect VEPs.38,43,46,47 Celesia and co-workers have shown that in maculopathies, simultaneous recording of pattern ERGs and VEPs may be diagnostically useful in differentiating between involvement of the macula and the optic nerve.i" In maculopathies and in retinopathies involving the macular region, pattern ERGs (Figs. 21-7 and 21-8) are absent or have a prolonged latency of the B wave (often referred as P50). The retinocortical time (see p. 457) remains within normal boundaries, thus indicating that the PI00 delay occurs at the retinal levep8,43 In optic nerve diseases, VEPs may be absent or prolonged, but pattern ERGs are normal; the retinocortical time is thus prolonged, indicating that the pathology is postretinal. Only in cases of optic nerve disorder with large central scotoma or optic atrophy are both pattern ERGs and VEPs absent. In these cases it is not possible to distinguish electrophysiologically between maculopathy and optic nerve disease (Fig. 21-9). Several authors have suggested that the pattern ERG is useful in the assessment of macular and retinal ganglion function. 4B-50 Holder has shown that pattern ERG B-wave (or P50) abnormalities may be present in the absence of "significant ophthalmoscopic changes."50 He further noted that reduction in pattern ERG N95 with preservation of P50 suggests dysfunction of the optic nerve. This brief review supports the statement of Celesia and Brige1l22 that "electrophysiological responses evoked by visual stimuli cannot and should not be interpreted in isolation or be the sole methodology to assess the function of the visual system." VEPs need to be interpreted in the clinical context in which they were
ERG
P99.5
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256 msec FIGURE 21.. • Electrophysiologic studies in a 68-year-old man with senile macular degeneration of the right eye (OD). Pattern electroretinograms (ERGs) are normal on stimulation of the left eye (OS), but visual evoked potentials (VEl's) to 31' checks are small, with a W morphology and a prolonged latency of PlOD (115.5 msec). Pattern stimulation of the affected eye shows an absent ERG and a small, slightly delayed PlOO. Absence of the ERG with preservation of the VEP suggests that the VEP was evoked from stimulation of the perimacular region.
460
ELEaRODIAGNOSIS INCLINICAL NEUROLOGY
Disorders of the Optic Nerve and Chiasm
250 31' checks v
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Time in msec 00 FIGUIE11-t. Scatterplot of latency of the PlOOcomponentof
pattern-reversal visual evoked potentials elicited by monocular stimulation of the right (OD) and left (OS) eyes with 31' checks in patients with maculopathies (open circles) and multiple sclerosis (triangles). The findings are compared with those of agematched controls (not shown in the scatter to avoid cluttering, but all falling inside the shaded rectangle). The solid line of the shaded rectangle represents the boundaries of normality. The open rectangle at 145 msec represents the boundary that separates maculopathies from optic nerve demyelination. Note that although J45 msec seems to separate the two groups, there is considerable overlap. The PlOD latency of the patients with multiple sclerosis falls in all three groups.
obtained and correlated with the funduscopic and visual field examination. Abnormalities of VEPs in patients with a normal funduscopic examination (including a normal macula) suggest dysfunction in the optic nerve or visual pathways.
Halliday's group was the first to indicate the sensitivity of pattern-reversal VEPs in the diagnosis of demyelination of the optic nerve." The ability of VEPs to detect clinically silent optic nerve lesions remains a very useful tool for the diagnosis of multiple sclerosis. In a review of 180 patients with multiple sclerosis (Fig. 21-10), 73 percent had abnormal VEPs; more importantly, VEPs were abnormal in 54 percent of the patients without any symptoms or signs referable to the visual system. Such patients are often in the early stages of the disease, when diagnosis is difficult even with modern neuroimaging techniques. Several studies have compared VEPs and magnetic resonance imaging (MRI) of the optic nerve in optic neuritis. 51-53 MRI demonstrated high-signal lesions in 84 to 88 percent of symptomatic patients,52.53 whereas VEPs were abnormal in 100 percent of cases. Miller and colleagues compared the frequency of abnormalities of the optic nerve elicited by MRI and by VEPs in 30 asymptomatic eyes of patients with a recent or past attack of optic neuritis. MRI lesions were present in 20 percent and VEP abnormalities were present in 27 percent of cases. 52 They concluded that "visual evoked potentials were even more sensitive than MRI in detecting lesions and are still the investigation of choice in suspected demyelinating diseases involving the optic nerve." The incidence of reported VEP abnormalities in studies of patients with multiple sclerosis varies from 75 to 97 percent. 54-56 Although there is a consensus that VEPs are very sensitive in detecting clinically silent lesions of the optic nerve, two issues pertaining to the
Percent
o
20
60
40
80
100 FIGURE 11-10 • Results of visual
evoked potential studies with pattern-reversing 31' checks in 180 patients with multiple sclerosis. With indicates patients with visual dysfunction either at the time of testing or in the past medical history. Without indicates patients without visual complaints and with normal findings on neuro-ophthalmologic examination. Total indicates the sum of both groups of patients.
With
Without
Total
•
Abnormal
o
Normal
Visual Evoked Potentials inClinical Neurology
diagnosis of multiple sclerosis are still unresolved: (l) the problem of incorrect diagnosis; and (2) the issue of VEP specificity. No specific laboratory tests can confirm the diagnosis of multiple sclerosis, and the disorder may be missed or diagnosed incorrectly. Rudick and associates identified five features that should suggest the possibility of an alternative diagnosis in patients with suspected multiple sclerosis.57 Among these features was the absence of ocular (including VEP) abnormalities. No adequate study has defined the frequency with which the diagnosis of multiple sclerosis is missed or made erroneously. Some authors suggest that an abnormal VEP in a clinical setting suggestive of multiple sclerosis is sufficient to classify a patient as definitely having that disorder, but a prolonged PlOD latency may lead to the error of overlooking another diagnosis. Tartaglione and co-workers compared 38 patients with multiple sclerosis and 52 patients with neurologic disorders usually not associated with optic pathway involvement and concluded that there was a 30 percent chance of error in attributing a delayed PlOD to multiple sclerosis.P A delayed PlOD or absent VEPs have been reported in many other disorders involving the optic nerve (e.g., systemic lupus erythematosus.t" sarcoidosis.v" vitamin B I2 deficiency,6l,62 neurosyphilis." tropical spastic paraparesis.P' and spinocerebellar ataxia65,66). The initial reports that temporal dispersion of the YEP (defined as the difference in latency between N70 and N135) was characteristic of optic nerve compression'V? were not confirmed. Bodis-Wollner and Onofrj" and the author's group'" have shown that temporal dispersion can be found in both compression and demyelination of the optic nerve. Abnormal VEPs also occur in ischemic optic neuropathy and in toxic optic neuropathy.W? YEPs are useful in determining the diagnosis in patients presenting with transverse myelitis. They can determine whether the disorder is limited to the spinal cord or is multifocal, thus suggesting that the process is probably a form of multiple sclerosis. The Transverse Myelitis Consortium Group of the American Academy of Neurology?" stated: "Brain MRI with gadolinium and visual evoked potentials will determine if there is demyelination elsewhere in the neuraxis, therefore defining the process as multifocal." VEPs have been retained as the only useful sensory evoked potentials in the revised diagnostic criteria for multiple sclerosis." McDonald and colleagues pointed out that VEPs are not necessary in the diagnosis if the patient has had two or more attacks and has evidence of multiple lesions on magnetic resonance imaging." Although a delayed PlOD is not specific for any disease, and any pathologic process involving the optic nerve can produce similar physiologic disturbances,
461
the clinical context in which an abnormal YEP is obtained will have important diagnostic implications. Electrophysiologic studies should also take advantage of the parallel processing of vision by using a variety of visual stimuli. Pathologic processes may interfere with the normal functioning of only some of the parallel channels. A more comprehensive use of VEPs elicited by different stimuli may therefore assess more effectively any visual deficits and at the same time increase the diagnostic yield. Regan and colleagues have identified a group of patients with multiple sclerosis who, despite normal visual acuity, had difficulty in detecting objects of medium size under certain conditions. 72-74 They showed that these patients had a loss of contrast sensitivity limited to midspatial-frequency stimuli. It has also been shown that in patients with multiple sclerosis or optic neuritis, VEPs may be abnormal only to a specific pattern orientation (horizontal versus vertical);" again suggesting that deficits may be limited to selected processing channels. Porciatti and Sartucci compared VEPs to chromatic and luminance stimuli in patients with multiple sclerosis and in patients with unilateral optic neuritis.F" The amplitude losses and latency delays were greater for chromatic than luminance VEPs. This dissociation between luminance and color suggests that the parvocellular pathway is more impaired than is the magnocellular pathway in optic neuritis. Although it is evident that testing the patient with a variety of visual stimuli (e.g., different size patterns or different orientation) increases the number of abnormalities detected, pragmatically it is necessary to "limit the testing sequence to a tolerable duration for the patient. "22 Among the various techniques devised to speed the gathering of data has been the utilization of steady-state VEPs. Steady-state VEPs are responses to visual stimuli of relatively high frequency (usually greater than 3.5 Hz). These responses resemble quasi-sinusoidal oscillations and therefore can be analyzed by fast Fourier analysis. 1,2,76 The response at the frequency of the stimulus is the fundamental or first harmonic, whereas the response component at twice the stimulus frequency is called the second harmonic (2F). Fourier analysis provides the amplitude and phase of each harmonic response. Phase can be used as a measurement similar to latency for transient VEPS.77,78 The author has used steady-state evoked potentials analyzed by fast Fourier transform both in normal subjects?" and in patients with optic neuropathy or multiple sclerosis."? Visual stimuli were computer generated and interfaced with the recording system. The recorded visual spectrum array is shown in Figure 21-11. It took less than 3 minutes to characterize the spatial frequency function to five spatial frequencies. Phase abnormalities, defined as a phase lag outside the mean phase ± 2 circular
462
ELECTRODIAGNOSIS IN CLINICAL NEUROLOGY
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Frequency (6.1 Hz/div) FIGURE 21·11 • Amplitude spectra of steady-state visual
evoked potentials at various spatial frequencies. The stimulus consisted of vertical gratings reversing at 4 Hz with a mean luminance of 90 cd/m 2• 2F indicates the second harmonic response (at 8 Hz) and 4F the fourth harmonic response (at 16 Hz).
standard deviations, were noted in 18 (75 percent) of 24 eyes examined in patients with multiple sclerosis (Fig. 21-12). The phase abnormalities were of two types: type 1 abnormality consisted of phase lag present at all spatial frequencies tested, whereas type 2 abnormality consisted of phase lag present only at selected spatial frequencies. Type 2 abnormality could be further subdivided depending on whether phase lag was present at the lower, middle, or higher part of the spatial frequency tested. This technology offers promise in the assessmen t of visual dysfunction and can be used to study amplitude/temporal frequency functions and contrast functions. Another method used to speed the recording and assessment of the visual system is the "sweep technique." With this technique, during repetitive stimulation, rather than averaging each single point in a graphic function under study, a running average is implemented to plot the whole graph. A limited number of single sweeps are then summated to estimate the shape of the curve in the graph. 8o-82 The speed of this technique in comparison to conventional averaging is increased by a factor greater than 15.80 Sweep techniques have been used to study contrast sensitivity'S and to rapidly determine the visual acuity of infants. 83.84
Further studies are needed to confirm the reliability of these newer technologies. Conventional VEPs have been correlated with clinical findings to determine whether a relationship exists between VEP abnormalities and clinical progression or improvement. Although some authors have reported that visual acuity improved in parallel with improvement in latency of the VEP in patients with multiple sclerosis,85-87 others have found no relationship between clinical status and VEPs.sS The author has been impressed by the persistence of prolonged VEP latency following optic neuritis, even when vision has returned to normal. To address the possibility that abnormal pattern ERGs and VEPs may have prognostic usefulness, a prospective study was carried out on 20 patients with optic neuritis.t" The patients were monitored for 12 months and a complete neuro-ophthalmologic examination (i.e., funduscopy, Goldmann perimetry, measurement of visual acuity, pupil evaluation, contrast sensitivity testing, and pseudoisochromatic plate evaluation) was performed together with recording of pattern ERGs and VEPs at the onset and 1, 2, 4, 6, and 12 months later. At the onset of optic neuritis, VEPs to 15' checks were abnormal in all patients, whereas VEPs to 31' and 60' checks were abnormal in 89 and 95 percent of cases, respectively. Color vision was also abnormal in all patients; contrast sensitivity was abnormal in 95 percent and visual acuity in 90 percent. Complete recovery of visual function occurred in 65 percent of cases. Different measures of vision returned to normal in different patients, but visual acuity, color vision, and visual
200 A
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100 A
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s:
x
0
x
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x
-100 -200
0
2
3
4
5
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7
8
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FIGURE 21·12 • Phase/spatial frequency function in a patient
with multiple sclerosis. Triangles indicate responses from the right eye (OD) and crosses indicate responses from the left eye (OS). The two solid lines above and below the zero line indicate the boundary of normality. Note the normal response for the left eye and very delayed responses from the right eye at most, but not all, spatial frequencies tested.
Visual Evoked Potentials inClinical Neurology
fields returned to normal in 80 percent of patients; contrast sensitivity returned to normal in 79 percent. In contrast to the recovery of vision, VEPs remained abnormal in all patients tested (Fig. 21-13) with stimuli of 15' and in 18 of 19 patients tested with checks of 60'. As shown in Figure 21-13, although considerable improvement in VEPs occurred in a subset of patients with absent VEPs during the acute phase of optic neuritis, VEPs usually remained greatly delayed. Once a well-formed VEP can be recorded, N70 and P100 generally remain unchanged in latency (Fig. 21-14) for many years. The author has recorded a delayed P100 (latency of 133 msec with 15' checks, and 230 msec with 31' checks) in a patient with
463
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1 month 20 20 P144
2 months P100 15' checks 200
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25 msec/div FIGURE 21-14 .. Pattern-reversal visual evoked potentials
(VEPs) from the left eye in a 36-year-old woman with optic neuritis in that eye. During the acute phase no VEPs were recordable (see also Fig. 21-15). At 1, 2, and 4 months the responses remained prolonged, although her vision had returned to normal.
150
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en E .5 100 (;'
~
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Onset
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FIGURE 21-13 .. Histograms of PI00 latencies in the pattern-
reversal visual evoked potentials (VEPs) elicited by (A) 15' and (B) 60' checks in patients with optic neuritis. The dark bars represent PIOO at the onset of the optic neuritis, and the lighter bars indicate P100values 12 months later. Barsclose to the zero line indicate that no response was present. The solid line at around 100 msec indicates the boundary of normality. At the onset of optic neuritis, many patients had absent VEPs. In most of these patients the VEPlater returned, but it usually remained abnormally delayed.
normal vision who had a well-documented attack of optic neuritis 37 years earlier. Thus, the VEP can be used as a marker of a past episode of optic neuritis. The author's study did not confirm previous reports that absence of pattern ERGs in the acute phase of optic neuropathy is a poor prognostic indicator for visual recovery.SO,90 Three patients had absent VEPs and pattern ERGs, yet two recovered normal vision (Fig. 21-15) and one regained nearly normal vision. It was concluded that the absence ofVEPs and pattern ERG in acute optic neuritis is compatible with full visual recovery. Brusa and colleagues monitored VEPs for 2 years following an episode of optic neuritis.f! They demonstrated an improvement in the latencies ofVEPs in the affected eye, but also noted a significant prolongation of VEP latencies in the asymptomatic fellow eye. This study suggests that optic nerve demyelination is a dynamic process and that demyelination/remyelination may be active even when the patient appears clinically stable.
464
ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
Initial
1 month
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is detected by either Goldmann perimetry or Octopus or Humphrey computerized perimetry, approximately 20 to 40 percent of the ganglion cells have been destroyed. 92 •93 VEPs may be smaller in amplitude, and PlOO may be delayed (Fig. 21-16) in glaucoma. Bray and co-workers prospectively studied 49 patients with verified ocular hypertension by recording transient VEPs, visual fields (Octopus perimetry), and intraocular pressure.f" They monitored their patients for an average of 3.2 years. Of the 24 patients with VEP abnormalities at the onset of the study, glaucoma later developed in 7, but it developed in none of the 25 patients with normal VEPs. Horn and co-workers suggested that the blue-sensitive pathways are more susceptible to damage by glaucoma than are other pathways." They evaluated with disc photography, and VEPs to blue-on-yellow pattern, 161 patients with perimetric and 118 patients with preperimetric chronic glaucoma. The patients were followed for a mean of 24 months. They found significantly prolonged VEP peak times in both glaucoma groups compared with the control group and concluded that VEPs to blue-on-yellow pattern may be a useful method to monitor progression of the disease.
P121.5 I
,
I
,
,
I
I
I
,
I
I
25 msec/div FIGURE 21-15 • Left-eye findings in the same patient as in
Figure 21-14. The left column represents the state of the patient during the acute phase of optic neuritis, and the right column showsthe findings 1 month later. At the onset, acuity wasreduced to the detection of hand motion (HM), there was a large central scotoma on Goldmann perimetry, and pattern electroretinograms (ERGs) and visual evoked potentials (VEPs) to 15' and 30' checks were absent. One month later, visualacuity was normal at 20/20, visualfield was normal, pattern ERG had returned to normal, but the VEP, although it had returned and was of normal morphology, was very prolonged in latency to both 15' and 30' checks.
Although VEPs have no prognostic significance in optic neuritis, there is evidence that they may have prognostic value in progressive disorders of the visual system (e.g., ocular hypertension). Ocular hypertension, defined as an intraocular pressure greater than 21 mmHg, is a benign condition until it damages the retinal ganglion cells and becomes glaucoma. It is estimated that glaucoma eventually develops in 35 percent of patients with increased intraocular pressure. Glaucoma can definitely be diagnosed when a visual deficit is documented; however, by the time a visual loss
00
P117.5
as
+ 2.5 j.LV
1 .
I
I
I
25 msec/div FIGURE 21-16 • Pattern-reversal visual evoked potentials
(VEPs) elicited by 15' checks in a 60-year-Qld man with glaucoma of the right eye (documented by arcuate scotoma on Goldmann perimetry) and ocular hypertension (30 mmHg) in the left eye. VEPs have normal morphology, but N70 and PlOD are clearly prolonged bilaterally. (Normal values for age are shown in Fig. 21-4.) The VEP from the symptomatic eye is more abnormal than that from the nonsymptomatic eye.
Visual Evoked Potentials inClinical Neurology
These data suggest that VEPs have a role in determining which patients with increased intraocular pressure are at risk of developing glaucoma, and therefore who requires aggressive therapy. Abnormalities of VEPs have been reported in patients with lesions of the optic chiasm, especially when caused by compression from pituitary tumors40,41,69 or by direct invasion of gliomas. 96,97 Most of the VEP abnormalities were observed with full-field stimulation and probably indicated involvement of the optic nerve either by direct compression or by involvement of the vascular supply of the nerve and chiasm. It is still unclear whether the utilization of half-field stimulation increases the yield of abnormalities. 41,69,98,GG The issue in compressive chiasmatic lesions is to determine when there is danger to the visual system requiring neurosurgical intervention. At present the accepted approach is periodically to assess the visual fields with Goldmann perimetry or with computerized Octopus or Humphrey perimetry. No prospective study has determined whether VEPs can be used in patients with chiasmatic and perichiasmatic lesions as a prognostic indicator for the risk of visual impairment.
Retrochiasmatic Disorders The reliability of VEPs in the diagnosis of retrochiasmatic lesions remains questionable. VEPs to full-field pattern stimulation are usually normal in patients with unilateral hemispheric lesions, even in the presence of a dense homonymous hemianopia. There have been many studies ofVEPs elicited by hemifield stimulation, with various claims of diagnostic reliability made. 98-104 Blumhardt and co-workers detected 18 of 25 (72 percent) cases of homonymous field defects.l'" A slightly better rate for the detection of homonymous field defects by hemifield VEP abnormalities has been reported by others. 98,103 Abnormalities in these studies consisted of either absent potentials to stimulation of the affected hemifield or gross distortion of the normal amplitude distribution over the scalp, In the author's laboratory, 50 consecutive patients with verified ischemic infarcts of the occipital or temporoparietal lobes and homonymous field defects were tested. 101,I02 The relative values of confrontation field examination, Goldmann perimetry, VEPs to hemifield pattern stimulation, and VEPs to steadystate flash stimulation were compared.l'" Visual field examination by confrontation at the bedside demonstrated the field defect in 96 percent of cases, and Goldmann perimetry did so in 100 percent of cases, whereas VEPs to hemifield stimulation were abnormal in only 79 percent of cases and steady-state VEPs to flash were abnormal in 67 percent (Fig. 21-17). Clearly, VEPs to either flash or hemifield pattern stim-
465
ulation were not sufficiently sensitive to be useful in clinical practice. It has been suggested that VEP amplitude distribution based on multiple scalp recordings (19 derivations) during hemifield stimulation (also referred to as topographic mapping) may be a better method to evaluate patients with retrochiasmatic lesions.!" The author has studied the scalp distribution of VEPs to hemifield stimulation in 14 normal subjects and compared the configuration of the topographic maps with the equivalent dipole underlying the surface evoked potentials as estimated by dipole source localization methods.l'" The stimuli consisted of pattern reversal with 60' checks presented in a hemifield pattern. Normal subjects showed considerable variability in the scalp distribution of the major positive peak (PI 00), with either paradoxical localization of the response over the ipsilateral occipital region or more conventional contralateral occipital localization (Fig. 21-18). Dipole source localization, however, always localized the source of the PlOO over the correct hemisphere. Amplitude distribution over the scalp may provide incorrect information about the underlying cortical generators and cannot be used reliably for diagnostic purposes. Most of the explanations regarding the generator source of VEPs are oversimplifications presuming sequential activation of one or two cortical areas. In reality, as was discussed at the beginning of this chapter, once visual information reaches area 17 it is distributed in parallel to at least 10 cortical areas involving the temporal and the parietal lobes, 12-21 Furthermore, whereas processing is implemented in extrastriate cortices, area 17 still remains active. It is therefore not surprising that the complexity of visual processing receives little clarification from the analysis ofVEPs. Bilateral retrochiasmatic lesions, if sufficiently extensive, will produce cortical blindness.105-107 However, in spite of the severity of clinical dysfunction, VEPs are often preserved. 107-110 The VEP to pattern was preserved in 5 of 7 cortically blind patients studied in the author's laboratory.I'" including 1 patient with total blindness. The VEP waveforms were normal, but in some patients P100 was delayed. VEPs were also normal in morphology and latency in cases of bilateral hemianopia (Fig. 21-19). There are two possible explanations for the preservation ofVEPs in patients with cortical blindness and bilateral occipital lobe lesions: VEPs are either generated in extrastriate visual cortex or originate in remnants of cortical area 17. VEPs were correlated with regional cerebral blood flow and/or regional glucose metabolism with positron emission tomography or single-photon emission computed tomography in 5 patients.l"? All 4 patients with preserved VEPs had some spared cerebral activity in area 17, whereas the patient without a recordable VEP had
466
ElEGRODIAGNOSIS INCLINICAL NEUROLOGY
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RO LO RP LP FIGURE 21-17 • Visual evoked potentials (VEPs) to pattern-reversal stimulation and amplitude spectra to repetitive flash stimu-
lation in a 57-year-old man with an ischemic infarct of the left occipital lobe and isolated right homonymous hemianopia. Goldmann perimetry delineated the extent of the visual field defect. The lower half of the figure illustrates the VEP to hemifield stimulation. Note the absence of response to stimulation of the affected hemifield. Stimulation of the intact left hemifield yielded responses with a contralateral occipital distribution and prominent negative response (represented by an upward deflection in this illustration). The right half of the figure illustrates amplitude spectra to flashes at increasing frequency from 8 to 22 per second. Each spectrum represents the average of a 4-second epoch of electroencephalography. Note the greatly depressed spectra over the left occipital and parietal regions. OS, left eye; RT, right temporal; RO, right occipital; MO, midoccipital; LO, left occipital; LT, left temporal; RP, right parietal; LP, left parietal. The amplitude ratio between the right and left occipital and parietal regions is shown in the graphs. Equal amplitude would yield a number close to 1. (From Celesia GG, Meredith JT, Pluff K: Perimetry, visual evoked potentials and visual spectrum array in homonymous hemianopia. Electroencephalogr Clin Neurophysiol, 56:16,1983, with permission.)
no activity in either occipital lobe. It was concluded that VEPs in cortically blind subjects originate in remnants of area 17. These studies further emphasize that there is a dissociation between the pattern VEP and visual function. Consequently, it is unwise to compare visual perception with VEPs. VEPs are electrical phenomena to a visual stimulus, and although they test some of the function of the visual pathways, they should not be confused with the conscious perception of visual stimuli.
MULTI FOCAL VEPs A new technique has shown promise in the study of the visual function: the multifocal VEP.lJI.Jl2 With this technique, VEPs can be recorded simultaneously from many regions of the visual field. The patient views a display containing about 60 sectors, each with a checkerboard pattern. To assess local defects in the visual field, the multifocal VEP responses must be compared with
Visual Evoked Potentials inClinical Neurology
467
FIGURE 21·18 • Topographic distribution of the major positive wave (P90 and P102, respectively) in the visual evoked potential of two normal subjects. Stimuli consisted of 60' checks reversing at 1 Hz. The left hemifield was stimulated in subject 91-7 and the right hemifield in subject 91-4. Recordings were from 20 scalp electrodes. A, Sample ofVEPs from five scalp derivations. B, The topographic map obtained by using a Hjorth derivation. C, The dipole of the plOO for each subject. Note that in case 91-7 both the topographic mapping and the dipole correctly localize PIOOin the right occipital lobe. However, in case 91-4 the topographic mapping suggests paradoxical localization in the right occipital lobe, whereas the dipole is correctly placed in the left hemisphere with the vector toward the right hemisphere. These complex interactions make interpretation of hemifield stimulation very difficult.
normal controls. These comparisons require relatively sophisticated analyses and software. The multifocal VEP has been used for excluding nonorganic visual loss, diagnosing and following patients with optic neuritis/multiple sclerosis, and following disease progression. It can be combined with multifocal ERG, with the hope of differentiating diseases of the macula and retina from diseases of the ganglion cells and optic nerve. The technique is still in its infancy and there are as yet no studies to determine its reliability and sensitivity compared with other methods of investigation. However, it remains a promising methodology.
CONCLUDING COMMENTS In conclusion, VEPs to patterned stimuli are a reliable and sensitive test in the evaluation of macular and optic nerve function but are of questionable value in the assessment of retrochiasmatic disorders. Future work will require the utilization of variable and complex visual stimuli to test selectively the function of the different parallel channels involved in visual processing. The technique of VEPs is a promising methodology that may permit processing of the evoked biologic signals in a wider and yet still reliable way.
468
ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
OD~
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FIGURE 21-11 • A 61-year-old man with bilateral hemianopia. Note the normal visual acuity and normal visual evoked potential
(YEP) to 30' checks. RO, MO, and LO refer to right, middle, and left occipital electrode placements. Replication ofYEPs was carried out with stimulation of only the right eye (OD). On the right half of the illustration are drawings of the patient's computed tomographic scan. The right side of the brain is shown on the right side of the template. On the upper left of the illustration are the Goldmann visual fields. (From Celesia GG, Bushnell D, Cone Toleikis S et al: Cortical blindness and residual vision: is the "second" visual system in humans capable of more than rudimentary visual perception? Neurology, 41:862, 1991, with permission.)
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33. Allison T, Wood CC, Goff WR: Brain stem auditory, pattern-reversal visual, and short-latency somatosensory evoked potentials: latencies in relation to age, sex, and brain and body size. Electroencephalogr Clin Neurophysiol, 55:919, 1983 34. La Marche JA, Dobson WR, Cohn NB et al: Amplitudes ofvisually evoked potentials to patterned stimuli: age and sex comparisons. Electroencephalogr Clin Neurophysiol, 65:81, 1986 35. Collins DWK, Carroll WM, BlackJL et al: Effect ofrefractive error on the visual evoked response. BMJ, 1:231, 1979 36. Van Lith GHM: The application of visually evoked cerebral potentials in ophthalmological diagnosis. Clin Neurol Neurosurg, 82:85, 1980 37. Thorn F, Schwartz F: Effects of dioptric blur on Snellen and grating acuity. Optom Vis Sci, 67:3, 1990 38. Celesia GG, Kaufman D: Pattern ERGs and visual evoked potentials in maculopathies and optic nerve diseases. Invest Ophthalmol Vis Sci, 26:726, 1985 39. Celesia GG, Kaufman D, Cone SB: Simultaneous recording of pattern electroretinography and visual evoked potentials in multiple sclerosis. A method to separate demyelination from axonal damage to the optic nerve. Arch Neurol, 43:1247,1986 40. Gott PS, Weiss MH, Apuzzo M et al: Checkerboard visual evoked response in evaluation and management of pituitary tumors. Neurosurgery, 5:553, 1979 41. Halliday AM, Halliday E, Kriss A et al: The patternevoked potential in compression of the anterior visual pathways. Brain, 99:357, 1976 42. Halliday AM, McDonald WI, Mushin J: Delayed visual evoked response in optic neuritis. Lancet, 1:982, 1972 43. Kaufman D, Celesia GG: Simultaneous recording of pattern electroretinogram and visual evoked responses in neuro-ophthalmologic disorders. Neurology, 35:644, 1985 44. Arden GB, Hamilton AMP, Wilson-Holt J et al: Pattern electroretinograms become abnormal when background diabetic retinopathy deteriorates to a pre-proliferative stage: possible use as a screening test. Br J Ophthalmol, 70:330, 1986 45. Fish GE, Birch DG, Fuller DG et al: A comparison of visual function tests in eyes with maculopathy. Ophthalmology, 93:1177,1986 46. Lennerstrand G: Delayed visual evoked cortical potentials in retinal disease. Acta OphthalmoI60:497, 1982 47. Thirkill CE, Roth AM, Keltner JL: Cancer-associated retinopathy. Arch Ophthalmol, 105:372, 1987 48. Bach M, Hawlina M, Holder GE et al: Standard for pattern electroretinography. Doc Ophthalmol, 101:11, 2000 49. Celesia GG, Brigell MG: Recommended standards for pattern electroretinograms and visual evoked potentials. Electroencephalogr Clin Neurophysiol Suppl, 52:53, 1999 50. Holder GE: Pattern ERG and an integrated approach to visual pathway diagnosis. Prog Retin Eye Res, 20:531, 2001 51. Ormerod IEC, Miller DH, McDonald WI et al: The role of NMR imaging in the assessment of multiple sclerosis and isolated neurological lesions. Brain, 110:1579, 1988
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52. Miller DH, Newton MR, van der PoeljC et al: Magnetic resonance imaging of the optic nerve in optic neuritis. Neurology, 38:175, 1988 53. Filippini G, Comi GC, Cosi V et al: Sensitivities and predictive values of paraclinical tests for diagnosing multiple sclerosis.] Neurol, 241:132, 1994 54. Matthews WB, Small DG, Small M et al: Pattern reversal evoked visual potential in the diagnosis of multiple sclerosis.] Neurol Neurosurg Psychiatry, 40:1009,1977 55. Becker V\]", Richards 1M: Serial pattern shift visual evoked potentials in multiple sclerosis. Canj Neurol Sci, 11:53,1984 56. Bottcher j, Trojaborg W: Follow-up of patients with suspected multiple sclerosis: a clinical and electrophysiological study.] Neurol Neurosurg Psychiatry, 45:809,1982 57. Rudick RA, Schiffer RB, Schwetz KM et al: Multiple sclerosis: the problem of incorrect diagnosis. Arch Neurol, 43:578, 1986 58. Tartaglione A, Oneto A, Bandini F et al: Electrophysiological detection of "silent" plaques in the optic pathways. Acta Neurol Scand, 76:246, 1987 59. jabs DA, Miller NR, Newman SA et al: Optic neuropathy in systemic lupus erythematosus. Arch Ophthalmol, 104:564, 1986 60. Streletz L], Chambers RA, Bae SH et al: Visual evoked potentials in sarcoidosis. Neurology, 31:1545, 1981 61. Fine E;J, Hallett M: Neurophysiological study of subacute combined degeneration.j Neurol Sci, 45:331,1980 62. Krumholtz A, Weiss HD, Goldstein Pj et al: Evoked responses in vitamin B12 deficiency. Ann Neurol, 9:407, 1981 63. Conrad B, Benecke R, Musers H et al: Visual evoked potentials in neurosyphilis.] Neurol Neurosurg Psychiatry, 46:23,1983 64. Newton M, Cruikshank K, Miller D et al: Antibody to human T-Iymphotropic virus type 1 in West-Indian-born UK residents with spastic paraparesis. Lancet, 1:415, 1987 65. Pedersen L, Trojaborg W: Visual, auditory and somatosensory pathway involvement in hereditary cerebellar ataxia, Friedreich's ataxia and familial spastic paraplegia. Electroencephalogr Clin Neurophysiol, 52:283, 1981 66. Livingstone IR, Mastaglia FL, Edis R et al: Pattern visual evoked responses in hereditary spastic paraplegia. J Neurol Neurosurg Psychiatry, 44:176, 1981 67. Holder GE: Pattern visual evoked potential in patients with posteriorly situated space-occupying lesions. Doc Ophthalmol, 59:121, 1985 68. Bodis-Wollner I, Onofrj M: System diseases and visual evoked potential diagnosis in neurology: changes due to synaptic malfunction. Ann N YAcad Sci, 388:327, 1982 69. Celesia GG, Daly RF: Visual electroencephalographic computer analysis (VECA): a new electrophysiologic test for the diagnosis of optic nerve lesions. Neurology, 27:637,1977 70. Transverse Myelitis Consortium Group: Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology, 59: 499, 2002. 71. McDonald WI, Compston A, Edan Get al: Recommended diagnostic criteria for multiple sclerosis: guidelines from
the International Panel on the Diagnosis of Multiple Sclerosis. Ann Neurol, 50:121, 2001 72. Regan D, Raymond ], Ginsburg AP et al: Contrast sensitivity, visual acuity and the discrimination of Snellen letters in multiple sclerosis. Brain, 104:333, 1981 73. Regan D: Visual information channeling in normal and disordered vision. Psychol Rev, 89:407, 1982 74. Neima D, Regan D: Pattern visual evoked potentials and spatial vision in retrobulbar neuritis and multiple sclerosis. Arch Neurol, 41:198, 1984 75. Coupland SG, Kirkham TH: Orientation-specific visual evoked potential deficits in multiple sclerosis. Can j Neurol Sci, 9:331,1982 76. Strasburger H, Scheidler W, Rentschler I: Amplitude and phase characteristics of the steady-state visual evoked potential. Appl Opt, 27:1069, 1988 77. Tobimatsu S, Tashima-Kurita S, Nakayama-Hiromatsu M et al: Clinical relevance of phase of steady-state VEPs to P100 latency of transient VEPs. Electroencephalogr Clin Neurophysiol, 80:89, 1991 78. Tomoda H, Celesia GG, Cone Toleikis S: Effect of spatial frequency on simultaneous recorded steady-state pattern electroretinograms and visual evoked potentials. Electroencephalogr Clin Neurophysiol, 80:81, 1991 79. Celesia GG: Visual evoked potentials. p. 45. In Barber C, Taylor Mj (eds): Evoked Potentials Review. IEPS, Nottingham, 1991 80. Regan D: Rapid objective refraction using evoked brain potentials. Invest Ophthalmol, 12:669, 1973 81. Regan D: Colour coding of pattern responses in man investigated by evoked potential feedback and direct plot techniques. Vision Res, 15:175, 1975 82. Seiple W, Kupersmith M, Nelson ] et al: The assessment of evoked potential contrast thresholds using real-time retrieval. Invest Ophthalmol Vis Sci, 25:627, 1984 83. Tyler CW, Apkarian P, Levi DM et al: Rapid assessment of visual function: an electronic sweep technique for the pattern visual evoked potential. Invest Ophthalmol Vis Sci, 18:703, 1979 84. Norcia AM, Tyler CW: Spatial frequency sweep VEP: visual acuity during the first year of life. Vision Res, 25:1399, 1985 85. Matthews WB, Small DG: Serial recording of visual and somatosensory evoked potentials in multiple sclerosis. J Neurol Sci, 40:11, 1979 86. Diener HC, Scheibler H: Follow-up studies of visual potentials in multiple sclerosis evoked by checkerboard and foveal stimulation. Electroencephalogr Clin Neurophysiol, 49:490, 1980 87. Nuwer MR, PackwoodJW, Myers LW et al: Evoked potentials predict the clinical changes in a multiple sclerosis drug study. Neurology, 37:1754, 1987 88. Aminoff M], Davis SL, Panitch HS: Serial evoked potential studies in patients with definite multiple sclerosis. Arch Neurol, 41:1197, 1984 89. Celesia GG, Kaufman DI, Brigell M et al: Optic neuritis: a prospective study. Neurology, 40:919, 1990 90. Porciatti V, von Berger GP: Pattern electroretinogram and visual evoked potential in optic nerve disease: early diagnosis and prognosis. Doc Ophthalmol Proc Ser, 40:101,1984
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91. Brusa A, Jones SJ, Plant GT: Long-term remyelination after optic neuritis. A 2-year visual evoked potential and psychophysical serial study. Brain, 124:468, 2001 92. Quigley HA, Addicks EM, Green WR: Optic nerve damage in human glaucoma. III. Quantitative correlation of nerve fiber loss and visual field defect in glaucoma, ischemic neuropathy, papilledema, and toxic neuropathy. Arch Ophthalmol, 100:135, 1982 93. Quigley HA, Dunkelberger GR, Green WR: Retinal ganglion cell atrophy correlated with automated perimetry in human eyes with glaucoma. Am J Ophthalmol, 107:453, 1989 94. Bray LC, Mitchell KW, HoweJW: Prognostic significance of the pattern visual evoked potentials in ocular hypertension. Br J Ophthalmol, 75:79, 1991 9!i. Horn FK, Jonas JB, Budde WM et al: Monitoring glaucoma progression with visual evoked potentials of the blue-sensitive pathway. Invest Ophthalmol Vis Sci 43:1828, 2002 96. Kupersmith MJ, Siegel 1M, Carr RE et al: Visual evoked potentials in chiasmal gliomas in four adults. Arch Neurol, 38:362, 1981 97. Groswasser Z, Kriss A, Halliday AM et al: Pattern and flash evoked potentials in the assessment and management of optic nerve gliomas. J Neurol Neurosurg Psychiatry, 48:1125, 1985 98. Maitland CG, Aminoff MJ, Kennard C et al: Evoked potentials in the evaluation of visual field defects due to chiasmal or retrochiasmal lesions. Neurology, 32:986, 1982 99. Muller-jensen A, Zschocke S, Dannheim F: VER analysis of the chiasmal syndrome. J Neurol, 225:33, 1981 100. Blumhardt LD, Barrett G, Kriss A et al: The pattern evoked potential in lesions of the posterior visual pathways. Ann N YAcad Sci, 388:264, 1982 101. Kuroiwa Y, Celesia GG: Visual evoked potentials with hemifield pattern stimulation: their use in the diagnosis of retrochiasmatic lesions. Arch Neurol, 38:86, 1981
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102. Celesia GG, Meredith JT, Pluff K: Perimetry, visual evoked potentials and visual evoked spectrum array in homonymous hemianopsia. Electraencephalogr Clin Neurophysiol, 56:16,1983 103. Haimovic lC, Pedley TA: Hemi-field pattern reversal visual evoked potentials. 11. Lesions of the chiasm and posterior visual pathways. Electraencephalogr Clin Neurophysiol, 54:121,1982 104. Onofrj M, Bodis-Wollner I, Mylin L: Visual evoked potential diagnosis of field defects in patients with chiasmatic and retrochiasmatic lesions.J Neural Neurosurg Psychiatry, 45:294, 1982 105. Onofrj M: Generators of pattern visual evoked potentials in normals and in patients with retrachiasmatic lesions. p. 87. In Desmedt JE (ed): Visual Evoked Potentials. Elsevier, Amsterdam, 1990 106. Brigell M, Rubboli G, Celesia GG: Application of a single equivalent dipole model to the hemifield pattern VEP. Invest Ophthalmol Vis Sci, 32: Suppl, 910, 1991 107. Celesia GG, Bushnell D, Cone Toleikis S et al: Cortical blindness and residual vision: Is the "second" visual system in humans capable of more than rudimen tary visual perception? Neurology, 41:862,1991 108. Bodis-Wollner I, Atkin A, Raab E et al: Visual association cortex and vision in man: patterned evoked potentials in a blind boy. Science, 198:629, 1977 109. Celesia GG, Archer CR, Kuroiwa Yet al: Visual function of the extrageniculo-calcarine system in man. Arch Neurol, 37:704, 1980 110. Spehlmann R, Grass RA, Ho SU et al: Visual evoked potentials and postmortem findings in a case of cortical blindness. Ann Neurol, 2:531,1977 111. Hood DC, Odel JG, Winn BJ: The multifocal visual evoked potential.J Neuro-ophthalmol, 23:279, 2003 112. Balachandran C, Klistorner AI, Graham SL: Effect of stimulus check size on multifocal visual evoked potentials. Doc Ophthalmol, 106:183,2003
CHAPTER
Visual Evoked Potentials in Infants and Children
22
EILEEN E. BIRCH and RAIN G. BOSWORTH
TRANSIENT LUMINANCE (FLASH) VEPs PATTERN ONSET/OFFSET VEPs PATTERN-REVERSAL VEPs NORMAL MATURATION OFVEPs Amplitude and Latency of Transient Luminance (Flash) VEPs Amplitude and Latency of Pattern VEPs Acuity Development CLINICAL USE OFTHE VEP IN INFANTS AND CHILDREN Patient and Technical Issues
Visual evoked potentials (VEPs) are massed electrical signals generated by occipital cortical areas 17, 18, and 19 in response to visual stimulation. VEPs differ from the electroencephalogram (EEG) in that the EEG represents ongoing activity of wide areas of the cortex, whereas the VEP is primarily a specific occipital lobe response triggered by a visual stimulus. Thus, VEPs can be used to assess the integrity or maturational state of the visual pathway in infants and preverbal children. The basic methodology for recording VEPs is straightforward and is described in the standard developed by the International Society for Clinical Electrophysiology of Vision (ISCEV). lOne or more active electrodes are placed over the occipital lobes. A reference electrode and a ground electrode are also placed on the scalp. Signals are led from the electrodes through a preamplifier that is located near the infant to boost signal amplitude before further contamination by outside noise sources. The preamplifier also typically acts as a bandpass filter (e.g., between 1 and 30 Hz) to eliminate most of the 60-Hz noise that may contaminate the VEP at the electrode sites. From the preamplifier the signal is led into a device capable of averaging VEPs (e.g., a dedicated microprocessor or a personal computer equipped with appropriate hardware and software). The main purpose of filtering and signal averaging is to improve the
Disorders of the Optic Nerve, Chiasm, and Tract Cortical Visual Impairment Perinatal Asphyxia Delayed Visual Maturation Antiepileptic Medications Cerebral White Matter Disorders Phenylketonuria Prenatal Substance Exposure Diverse Neurologic Disorders Visual Loss of Unknown Etiology and Malingering
signal-to-noise ratio. The VEP is contaminated by EEG as well as by outside noise sources. However, because the VEP in response to a given pattern is fairly constant in amplitude and latency (or phase), whereas the EEG occurs randomly with respect to the visual stimulus, stimulus averaging will decrease the unwanted contamination by EEG and other noise sources in proportion to the square root of the number ofVEPs averaged. For some stimulus conditions, digital filtering using computer software can further improve the signal-to-noise ratio. Most commercial equipment for recording the VEP is not specifically designed for use with infants and young children and therefore requires several modifications for use in this patient population. Because it is important that the infant be visually alert and attentive to patterned stimuli, it is helpful to have some small toys that can be dangled in front of the video display when collecting pattern VEPs. The majority of the VEP response is generated by the cortical projection of the macular area (i.e., the central 6 to 8 degrees of the visual field)2.3; therefore, the toys must be very small or open in the center so as not to block the stimulus from reaching the macula. Infants cannot be instructed to attend to the pattern, and an observer must therefore watch the infant and signal to the averaging equipment when the infant is looking at the pattern and when the
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
infant is looking elsewhere. Both hand-held buttons and foot pedals can be constructed for this purpose. Sudden head and body movements (e.g., yawns, crying, or vigorous sucking) can produce large-amplitude broadband electrical artifacts. Accordingly, the averaging or analysis equipment often contains hardware or software to reject these artifacts because averaging alone is not sufficient to eliminate their contribution to the recorded response. Alternatively, trials containing artifacts can be deleted manually from the signal average. Minimum standards for reporting VEPs have been published. 1 At least two averages should be obtained to demonstrate reproducibility of waveforms. Traces of VEP recordings should have a clear indication of polarity, time in milliseconds, and amplitude in microvolts. The ISCEV recommends that VEP traces be presented as positive upwards, although in many clinical neurophysiology laboratories the traces are presented with a downward deflection representing positivity at the active electrode. Normative values and normal tolerance limits for amplitude and latency should be reported along with the results. Because VEP latency, amplitude, and waveform change with age, comparison to same-age normative values is useful in clinical practice. VEPs are elicited by a temporal change in visual stimulation. Three types of visual stimuli are commonly used to elicit VEPs: (1) luminance (light) flashes; (2) pattern onset/offset; and (3) pattern contrast reversal. Each of these stimuli may be presented as a single event or in a repetitive manner. When the light flash, pattern onset/offset, or contrast reversal occurs infrequently (i.e., at 1 Hz or less), the entire VEP waveform can be seen; this is called a transient response. Peak-to-peak amplitudes and latencies of several major peaks can be measured (Fig. 22-1). When the light flashes or when pattern reversals are repeated frequently at regular intervals (i.e., at 10 Hz or higher), a simpler periodic waveform is seen; this is called a steady-state response. Response amplitude and phase are measured.
TRANSIENT LUMINANCE (FLASH) VEPs Transient luminance VEPs are obtained in response to a strobe light or a flashing light-emitting diode (LED) display or goggles. The flash should subtend at least 20 degrees and should have a stimulus strength of 1.5 to 3 cd/m 2 . 1 The transient luminance flash VEP is a complex waveform with multiple negative and positive changes in voltage. Various approaches have been taken to naming the peaks and troughs in this response, which has led to some difficulty in interpreting differences among studies. Recently, recommendations for standardized reporting ofVEP data have been made by ISCEV.1 As shown in Figure 22-1, peaks are
10 IJV
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FIGURE ]2·1 • Visual evoked potentials. A, Normal transient flash. B, Transient pattern onset/offset. C, Transient patternreversal. The standardization for naming of positive and negative peaks proposed by the International Society for Clinical Electrophysiology of Vision is indicated.
designated as positive and negative in numerical sequence (PI, P2, P3 and NI, N2, N3). The most commonly reported amplitude is the N2-P2 peak-to-peak amplitude. Using both source localization techniques in humans and intracortical recording in primates, several recent studies suggest that the transient luminance flash VEP primarily reflects the activity of striate and extrastriate cortex.r" In addition, some wavelets in the VEP appear to be subcortical in origin.5- 7 These subcortical wavelets are not major components of the flash VEPs obtained from patients with healthy striate and
Visual Evoked Potentials in Infants and Children
extrastriate cortical areas. However, flash YEPs have been recorded in newborns who lack functional striate and extrastriate cortex.s" These VEPs may have reflected subcortical function that was more apparent in the YEP when the cortical components of the response were missing. Thus, the presence of a flash YEP response cannot be taken as unequivocal evidence of cortical function.
PAnERN ONSET/OFFSET VEPs Pattern onset/offset YEPs are obtained in response to a pattern abruptly exchanged with a diffuse background. The pattern should subtend at least 15 degrees, and the pattern and diffuse fields should be well matched in mean luminance.' In most cases, a minimum of two pattern element sizes should be included, 1 degree and 15 minutes, 1 but normal newborns may not respond to the 15-minute pattern element size. Pattern VEPs primarily reflect activity of the striate and extrastriate cortex. 1O- 13 The pattern onset/offset VEP contains three peaks in adults: a positive peak followed by a negative peak and a second positive peak. As shown in Figure 22-1, ISCEV proposes that these components be termed Cl, C2, and C3. Amplitude is measured from the preceding negative peak. Using MRI in humans, a recent study located the source of the C1 peak in striate cortex."
PAnERN-REVERSAL VEPs The pattern-reversal YEP is less variable in appearance than the pattern onset/offset or transient luminance VEP, In adults, the transient pattern reversal VEP typically contains a small negative peak followed by a large positive peak and a second negative peak. As shown in Figure 22-1, ISCEV proposes that these components be termed N75, PlOD, and N135 to indicate their polarity and their approximate latency (in milliseconds) in normal adults. The most commonly reported amplitude is the N75-PIOO peak-to-peak amplitude. The steady-state pattern-reversal VEP has a relatively simple, almost sinusoidal waveform; amplitude and phase of the response are typically reported. Because the mean luminance of the pattern remains constant throughout the contrast reversals, pattern-reversal YEPs reflect pattern sensitivity rather than light sensitivity. Using intracerebral recording in awake humans, Ducati and co-workers" found that PlOD appears to be generated by the pyramidal cells in layer IV of area 17. However, imaging studies in humans point to the source of the early phase of the PIOO peak as being in dorsal extrastriate cortex of the middle occipital gyrus, whereas the late phase of PlOD appears to be generated by the ventral extrastriate cortex of the fusiform
475
gyrus." There have been no reports of pattern-reversal VEPs being recorded in newborns who lack functional striate and extrastriate cortex. Thus, the presence of a pattern-reversal VEP response may be a good indicator of the integrity of cortical function.
NORMAL MATURATION OF VEPs Visual responses have been documented in preterm infants as young as 24 weeks gestational age (GA), but these responses are rudimentary. Infants tested at 22 to 23 weeks GA had very poor or absent VEPs.14 Considerable visual development occurs during the third trimester of gestation and the first post-term year. Although on funduscopic examination the fovea appears mature soon after term birth, detailed anatomic studies have shown that neither the migration of cone photoreceptors toward the foveal pit nor the movement of ganglion cells away from the foveal pit is complete during the first months of life. 15 Moreover, the fine anatomic structure of the foveal cone photoreceptors, which subserve fine-detail vision, is not mature until at least 4 years of age. 15 Myelination of the optic nerve and tract is incomplete at term birth and continues to increase for 2 years postnatally!" Although the number of cells in the primary visual cortex appears to be complete at birth. considerable increases in cell size, synaptic structure, and dendritic density take place during the first 6 to 8 months oflife.l7· 18 One approach to monitoring the progress of anatomic maturation has been to evaluate developmental changes in the VEPs of healthy alert infants. These data also provide a baseline for assessment of the degree of visual impairment in pediatric patients. Flash VEP amplitudes may be influenced by arousal state, but latency is less affected.P:" The mean latency of N3 across various arousal states (awake, drowsy, active sleep, and quiet sleep) was within 15 msec in preterm infants at 30 to 37 weeks GA, but sleep significantly reduced N3 amplitude.V Similarly, the mean latencies of PI for the alert state and the sleep state were within 15 msec at 40 weeks GA.23 Pattern VEPs are affected by arousal state; good quality pattern YEP recordings require an alert, attentive infant whose eyes are focused on the pattern.
Amplitude and Latency of Transient Luminance (Flash) VEPs Flash YEPs can be recorded from preterm infants as early as 24 weeks GA. In preterm infants less than 30 weeks GA, a single long-latency (about 300 msec) negative peak is the most prominent component of the flash VEP (Fig. 22-2) .14.23-28 This peak has been
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
400 31
• Pike et al • Shepherd et al23 • Kraemer et al24 + Tsuneishi et al20 • Harding et al34 21 I) Groseet al " Pryds et al1 21 v Tayloret al1 4 \J Ellingson et al35 • Engel & Fay122 o Ferriss et al1 23
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FIGURE 11·1 • Latency of the major negative components of the flash visual evoked potential in preterm and term infants. Age at 0 weeks corresponds to 40 weeks gestational age (term). Two exponential decay fits are plotted; the solid line summarizes the maturational trend for N3 latency. Note that, in the study of Tsuneishi and colleagues.s" the initial negative peak was bifid in many infants and the latency of each component is reported separately. The dotted line summarizes the maturational trend for what is believed to be earlier components Nl or N2 starting at 34 weeks GA.
Adult
Age (weeks)
identified by some authors as Nl because it is the earliest negative peak observed in young infants. However, other authors have suggested that this peak corresponds to the N3 component of the mature waveform and that the Nl and N2 peaks are "missing. "14.29 Some difficulty in establishing correspondence between peaks in infant and adult waveforms occurs because the early negative peak in young infants is often bifid, with two sub-peaks that mayor may not be symmetrical in amplitude. 14.22.24.30 In Figure 22-2, flash YEP latencies from various studies are plotted to show the maturation of the early negative peak, which appears to correspond to the adult's N3 (adult latency, 150 msec). Tsuneishi and colleagues20. 30 assessed changes in the early negative peak longitudinally and found that latency decreased at a rate of 4.6 msec per week between 30 and 40 weeks GA. Pike and colleagues" report a similar rate of 5.5 msec per week between 28 and 42 weeks GA. There is some evidence that the change in latency does not occur smoothly but instead occurs in "spurts" of at least 6 msec,20.30 possibly reflecting the myelination process in the visual pathway. At term (40 weeks GA), earlier negative components are present in the waveform that shorten in latency with age; these appear to correspond to N2 (adult latency, 75 msec) and Nl (adult latency, 40 msec). As seen in Figure 22-2, Pike and associates'" report the earliest negative components, including an NO wave at about 85 msec and Nl at about 155 msec, can be obtained from infants as young as 34 weeks GA, whereas all other studies indicate that these components arise at term (40 weeks GA). Yet, even in the study of Pike and co-
workers." only at term age did all infants simultaneously have both an early NO and Nl. One possible explanation for this finding is that Pike and colleagues" included only infants who later had normal neurologic examinations over the first 2 years of life. The youngest infants reported to show an early positive peak with a latency of approximately 200 msec were between 30 and 35 weeks GA.29.32 This positive peak likely corresponds to the P2 peak in the adult waveform (latency, 100 msec). P2 is consistently present in all normal neonates from 37 weeks GA on, and is present in 90 percent of neurologically normal infants by 35 to 36 weeks GA.33 When present, the latency of the positive component decreases from about 220 msec at 34 weeks GA to 150 to 190 msec at term and to 100 msec by 8 to12 weeks post-term age (48 to 52 weeks GA)20.21.24,34.35 (Fig. 22-3). The P2 peak is clearly identifiable in the YEPs of healthy infants by 6 weeks post-term (46 weeks GA), and its amplitude exceeds that ofN3 by 8 weeks postterm (48 weeks GA).29.32.35 A rapid increase in the amplitudes of most of the flash YEP peaks occurs during early childhood, with the largest amplitudes present at about 6 years of age. Amplitudes of the various peaks reach adult levels by about 16 years of age. The maturational changes in amplitude, however, are age trends that are present despite very large individual differences in amplitude within any given age group. This variability limits the utility of flash YEP amplitude in detecting developmental visual abnormalities. Clinical evaluation has largely focused on the latency of the negative component and appearance of the first positive peak (which
Visual Evoked Potentials inInfants andChildren
477
250 • Shepherd et al23 ~ Pike et al31 • Kraemer et al24 • Tsuneishi et al20 6. Harding et al34 o Grose et al21 o Taylor et aj14 'V Ellingson et aj35 [] Ferriss at al123
200 FIGURE
]2.] • Latency of the major positive component of the transient flash visual evoked potential in preterm and term infants. Age at 0 weeks corresponds to 40 weeks gestational age (term). An exponential decay fit summarizes the mean maturational trend.
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Birch 45 - Monocular Birch 45 - Binocular Hamer et al. 127 - Monocular Norcia & Tyler46 - Binocular Norcia et al. 128 - Binocular Orel-Bixler & Norcia 129 - Binocular Orel-Blxler & Norcia 129 - Pattern onset/offset Birch 45 - Preterm monocular
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Age (weeks)
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II Monocular (open symbols) and binocular (filled symbols) sweep visual evoked potential (YEP) acuity as a function of age in weeks.45,46,127- 129 Age at 0 weeks corresponds to 40 weeks gestational age (term) . All researchers used pattern-reversal except Orel-Bixler and Norcia.l'" who used pattern onset!offset (thick line). Exponential decay fits are plotted for monocular (dotted line) and binocular (thin line) sweep YEP acuity. Note that binocular sweep YEP acuity is slightly better (lower log MAR) than monocular sweep YEP acuity after 15 weeks of age. Preterm monocular acuity (shaded diamonds) development matches term infant acuity development when age is adjusted for pre term birth.
FIGURE 21·7
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479
Adult
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
After 15 weeks of age, mean binocular sweep VEP acuity is better than mean monocular sweep VEP acuity by about 0.03 10gMAR (equivalent to about a half-line on an eye chart). The variability of binocular sweep VEP acuity within an age group (e.g., 17-week-old infants), defined as 95 percent of the normal distribution, is about ±0,23 10gMAR around the mean. Variability is slightly greater for monocular sweep VEP acuity at ±0,29 10gMAR. Within the normative sample, mean interocular acuity differences are small in each age group, averaging less than 0.1 10gMAR (equivalent to about 1 line on an eye chart). However, the range of interocular differences covering 95 percent of the normal distribution varies with age. At 6 weeks, 95 percent of interocular differences fall within ±0.29 10gMAR (equivalent to about 3 lines on an eye chart), whereas by 46 weeks post-term age (86 weeks GA), 95 percent of interocular differences fall within ±0.18 10gMAR (equivalent to about 2 lines on an eye chart). Normative longitudinal measurements of sweep VEP acuity over the first 18 months of life have also been reported for preterm and full-term infants. 49 ,5o These data have direct clinical utility in that they provide a method for determining whether a change in an individual's acuity over time represents a significant change. In other words, such data provide a baseline for the evaluation of progression, recovery, or response to treatment in individual patients. The rate of sweep VEP acuity development (slope) ranged from -0.34 to -0.89 10gMAR/log weeks in a normative sample of 53 healthy term infants tested on 5 occasions during the first 18 months of life. Preliminary studies have suggested that the rate of acuity development during infancy may be more predictive oflong-term visual acuity outcome than is the infant's acuity determined from a single acuity test."!
CLINICAL USE OF THE YEP IN INFANTS AND CHILDREN With few exceptions, the clinical value of VEP testing does not lie in the detection or differential diagnosis of pediatric diseases. 52 Instead, the strength of VEP assessment lies in the quantitative measurement that it provides of the degree of visual impairment. Determination ofVEP visual acuity is of great value in establishing eligibility for educational and social services, for providing parents with a clear picture of their child's abilities, and for defining baseline visual function before progression or intervention. The VEP may be especially useful in conditions where the ophthalmoscopic appearance of the fundus is variable. Especially in very young infants, the optic disc may appear pale or the macular reflex may appear indistinct, so that it may be
difficult to distinguish normal variants from signs of optic nerve or retinal disorders. VEP responses also may provide prognostic information in several pediatric visual disorders. In some limited cases, it is useful to conduct both VEP and electroretinographic (ERG) testing to clarify the differential diagnosis. In particular, tandem VEP and ERG testing may be helpful in establishing whether the visual dysfunction is attributable to a retinal or an optic nerve disorder. One such case is the distinction between optic nerve hypoplasia and Leber's amaurosis. In optic nerve hypoplasia, the ERG is completely normal, whereas the VEP is abnormal or absent. In Leber's amaurosis, by contrast, severely abnormal ERGs are found or, more often, the ERG is absent. In other cases, the VEP may provide an important adjunct to the ophthalmologic examination, In cases of oculomotor apraxia, for example, the classic compensatory head thrusting may not be present during early infancy. Instead, the infant may simply be unable to fixate or track and appear blind. The VEP can document normal acuity in this condition.
Patient and Technical Issues In the projection from the retina to the occipital cortex, the central 10 degrees of the visual field is predominant, with the peripheral visual field more sparsely represented. The electrical signals recorded from the scalp over the occipital lobe even more strongly reflect this central visual field area because the central projection is on the exposed surface of the occipital cortex, whereas the peripheral projection lies deep within the calcarine fissure. This situation enhances the sensitivity ofVEP protocols to disruption of central vision, which subserves the ability to fixate and to perform the many finely detailed visual tasks that make up daily life (e.g., reading or face recognition). However, a child with poor central vision or noncentral fixation may fail to produce a reliable VEP response despite substantial residual visual function. Several patient characteristics limit the ability to obtain VEPs. In general, patients must be alert and quiet, able to look at the center of the stimulus, and able to focus on the stimulus. Sleepy or sedated patients, as well as patients under anesthesia, produce poor or variable VEP results at best and paradoxical and misleading VEP results at worst. Head and body movements (e.g., yawning, crying, and vigorous sucking) can lead to muscle artifacts in the VEP records, which are sometimes so large that the VEP signal cannot be recognized. Patients who are unable to maintain gaze at the center of the stimulus have variable or absent VEP responses even when significant visual function is present. Nystagmus is a particular problem
Visual Evoked Potentials in Infants and Children
481
because central fixation is impaired and the involuntary eye movements themselves may generate electrical artifacts. Failure to accommodate to bring pattern stimuli into focus on the retina or uncorrected refractive error substantially reduces the amplitudes of pattern VEP responses and may lead to nondetectable VEPs in children who see quite well when the stimuli are in proper focus. Patients with neurologic diseases present some additional problems for VEP testing. Gross disorganization of the EEG (e.g., hypsarrhythmia) or critical electrolyte imbalances usually preclude successful VEP testing. 52.53 Accurate electrode placement, which is accomplished by careful measurement relative to skull landmarks, may not be possible in patients with abnormal brain anatomy. Artificial alterations in brain anatomy (e.g., the placement of shunts) may interfere with the ability to record a signal at some sites on the scalp.
dren with neurofibromatosis type 1 is an annual ophthalmologic examination, this method is often unreliable and inaccurate in young children. Magnetic resonance imaging is very sensitive, but cost and the need for sedation preclude its routine use. VEPs have been proposed as a possible alternative or aid in identitying which patients need MRI examinations. Ng and North 58 found 100 percent sensitivity of the VEP for optic gliomas. Specificity of the VEP ranges from 60 to 83 percent.58-62 Multiple sclerosis (MS) in children is rare, but VEPs may be helpful in diagnosis. Abnormal VEPs typical of MS, delayed but well preserved in waveform, have been reported in all children with MS and optic neuritls.f" Among children diagnosed with MS but without symptoms of optic neuritis, changes in the VEP indicating clinically silent lesions of the visual pathway were found in 86 percent.63
Disorders of the Optic Nerve, Chiasm, and Trad
Cortical Visual Impairment
Optic nerve hypoplasia is an ocular malformation diagnosed clinically on the basis of an abnormally small optic nerve head, optic nerve pallor, the "double-ring sign," and tortuous retinal vessels. Functional vision outcome varies widely in this group, and outcome is not always clearly associated with the appearance of the optic nerve head. Weiss and Kelly» have shown that visual outcome in infants with bilateral optic nerve hypoplasia can be predicted from a weighted combination of initial acuity measurement and estimated optic disc diameter, and that the prediction is improved by waiting until 6 months of age when the possible impact of visual immaturity and delayed visual maturation is decreased. Colobomas of the optic nerve are a rare malformation in which the optic disc is excavated. Like optic nerve hypoplasia, visual function outcomes with coloboma are highly variable. Transient pattern-reversal VEPs appear to be more suitable for analyzing vision in these patients than flash VEPs are in predicting functional vision, although flash VEPs are also altered in cases of serious malformation. 55 The carrier state of Leber's hereditary optic neuropathy, a maternally inherited disease associated with mitochondrial point mutations that leads to profound visual impairment, may be detectable via transient pattern VEPS.56 Prolonged PlOO and Nl35 latencies for 15-minute checks and N135 latencies for 60-minute checks have been reported in asymptomatic carriers. VEPs become abnormal immediately after the onset of acut.e visual loss, and may even be abnormal before symptoms appear in some patients.f? Although the current recommendation for screening and monitoring of optic pathway gliomas in chil-
Cortical visual impairment, often referred to as "cortical blindness" before residual visual function was established in many patients.P' is characterized by severe visual impairment, normal pupillary responses, normal fundus, and no nystagmus. Cortical visual impairment rarely occurs in isolation; almost all patients have developmental delays and neurologic abnormalities. In early VEP studies of cortical visual impairment, VEPs ranged from normal to nondetectable, which suggested that VEP testing was of little use in evaluating this group of children. These wide-ranging results were probably caused by differences in stimulation and recording protocols, in eligibility criteria for the patient cohort, and in timing of the test relative to the onset of visual loss. More recent studies document that virtually all children with carefully defined cortical visual impairment have either abnormal flash or pattern VEPs, or both, and that topographic recording can further increase the sensitivity of VEP protocols in this context. 65,66 A recent study showed that VEP acuity could be measured reliably in a cohort of children with moderate to severe cortical visual impairment, and that the acuity test result was correlated with the Huo scale (a clinical scale of visual funcnonr." Nonetheless, two-thirds of infants showed improved acuity with increasing age. The catchup phase was short and highly accelerated in some infants, but for other infants improvement was protracted. 68 ,69 It should be noted that there are also reports of abnormal VEPs in children who recover;" of behaviorally blind children with normal VEPs who show recovery,71·72 and of patients with normal VEPs who remain blind because of damage at higher levels of the visual system beyond area 17. 73.74 VEP testing may also be
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
useful in distinguishing gaze disturbances that limit the infant's ability to fix and follow a visual stimulus (e.g., oculomotor apraxia) from cortical visual impairment.59 In infants with shaken baby syndrome, abnormal flash VEPs are common at presentation, even in the absence of retinal hemorrhages'"; however, these abnormalities are not prognostic because many infants with visual impairment have normal VEPs and show visual recovery on a later visit. Flash VEPs are prognostic in cases of acute-onset cortical blindness following surgery, trauma, infectious disease, or hypoxia. 7l>-78 Within this carefully defined subset of patients with cortical visual impairment, tested immediately after the onset of visual impairment, over 90 percent with normal transient flash VEPs recovered normal visual function. Among those with abnormal or absent transient flash VEPs, over 90 percent had longterm visual impairment or blindness. Thus, unlike the diverse outcomes found in the broader context of cortical visual impairment, traditional flash VEPs may provide clinically useful information concerning outcome when recorded immediately after acute onset of cortical visual loss in pediatric patients.
use of pattern VEPs in delayed visual maturation is not diagnostic but as a method to monitor visual acuity development during the first year of life.
Antiepileptic Medications In epileptic patients receiving different antiepileptic drugs, VEPs are used widely for the evaluation of sensory pathways.84-87 It has been suggested that some antiepileptic drugs can significantly affect VEPs,87,88 although other authors did not find any difference in evoked potentials between epileptic patients and controls. 84 The controversy may arise from the study ofvery different cohorts, with some authors examining patients who have just started therapy, but the large majority examining adult patients who have received poly therapy for a long time. Infants with infantile spasms treated with vigabatrin may suffer visual loss because of retinal toxicity. When tested with VEPs, treated infants show reductions in peak contrast sensitivity'" and visual field defects.?" Specialized VEP methods for assessing contrast sensitivity and visual fields in preverbal children may be especially useful in assessing drug toxicity.90
Perinatal Asphyxia Serial measurements of transient flash VEPs during the first week of life may have prognostic value in cases of perinatal asphyxia. McCulloch and colleagues'? reported that neonates with normal flash VEPs or only transient abnormalities during the first week of life had no long-term visual dysfunction. Among neonates who had no recordable flash VEP response during the first week of life, only I achieved normal vision, whereas 3 were blind and 2 had significant visual impairment.
Delayed Visual Maturation In many cases of delayed visual maturation, transient flash VEPs are reduced in amplitude and delayed in timing. 26,80.81 Because these findings are also characteristic of infants with permanent cortical visual impairment, it is not possible to use the flash VEP to distinguish infants who will recover from those who will have long-term visual impairment. Delayed myelination of the optic nerves may underlie the flash VEP abnormalities.F Pattern VEPs are normal in cases of delayed visual maturation and may provide an avenue for establishing prognosis.I" Caution is needed when in terpreting normal pattern VEPs as good prognostic indicators in a child who appears blind, however, because there are rare reports of children with normal pattern VEPs who are blind because of dysfunction of higher visual areas beyond area 17. 73 Perhaps the best
Cerebral White Matter Disorders Cerebral white matter disorders include demyelination, hypomyelination, and dysmyelination of white matter from neurodegenerative, metabolic, inflammatory, or developmental disorders. Flash VEP abnormalities (e.g., increased latencies or generally altered waveforms) are present in many but not all children with cerebral white matter disorders." Very few patients with progressive disease have shown a normal flash VEP. In general, increased latency correlates with progressive disease, and highly abnormal or non-recordable flash VEPs are associated with severe disability and a poor prognosis."
Phenylketonuria Most studies of children and adolescents with phenylketonuria report increased latency of the PIOO wave, either in terms of mean latency relative to age-matched controls or in terms of a higher frequency of abnormalities in patients with phenylketonuria, or both. 92-98 There are some reports of associations between prolonged PlOD latency and recent exposure to high phenylalanine levels, the mean phenylalanine level during the first decade of life, the level of phenylalanine measured on the day of the VEP recording, and the age at discontinuation of dietary therapy for phenylketonuria. However, others have found no association
Visual Evoked Potentials in Infants and Children
with clinical or metabolic measures. Correlations between prolonged latency and severity of cerebral white matter abnormalities on MRI are also controversial. An alternative hypothesis for the pathogenesis of the VEP abnormality is that it may be related to sensitivity of retinal dopaminergic neurons to increased phenylalanine levels.P?
Prenatal Substance Exposure Alterations in the flash or pattern VEPs of children prenatally exposed to moderate levels of alcohol, marijuana, tobacco, or other illicit drugs have been noted.I?" Most striking is a delay in PI latency during the first weeks following birth. Methylmercury can produce Widespread adverse effects on the development and functioning of the human central nervous system, especially in some fishing- communities where infants are exposed prenatally or during early childhood.!" Prolonged PlOO latency has been reported, 102,103 and neuropathologic studies confirm that lesions affect the visual cortex. 104,105 VEP abnormalities have also been associated with prenatal exposure to organic solventsl'" and with chronic exposure to toxic molds!"? and lead. lOS
Diverse Neurologic Disorders Routine behavioral assessment of visual capacity in infants and children with neurologic disorders is often complicated by motor abnormalities that limit their ability to fix and follow. Although the caveats discussed earlier urge caution in the interpretation of VEP responses in such cases, VEPs can nevertheless provide useful information about visual cortical function. Pattern-reversal VEPs are small and irregular in infants with hypsarrythmia. However, with medical therapy to normalize the EEG, good-quality VEPs can be recorded from pediatric patients with infantile spasms, and preliminary evidence suggests that pattern VEPs show abnormalities only with moderate patternelement sizes.l?" Flash VEPs have been used to assess the degree of visual impairment in high-risk neonates. Abnormalities in nash VEPs have been demonstrated in infants with grade III intraventricular hemorrhage but not in infants with milder hemorrhage; the abnormal responses may reflect subcortical rather than cortical visual function.P Abnormal flash VEPs are common in infants with periventricular low-density masses'"; absence of one or more components of the flash VEP or increased latency of the components has been found in all infants with periventricular leukomalacia. Normal flash VEPs were found in 88 percent of very low birth-
483
weight infants with normal computed tomographic scans.!? O'Connor and colleagues reported that sweep VEP acuity at 7 to 12 months, but not at I to 6 months, was predictive of acuity outcome at age 4 to 8 years in a cohort of children with birth weights less than 2000 grams. I 10 Infants with posthemorrhagic hydrocephalus may have delays in latency of the primary positive peak of the flash VEP; these delays increase with increasing intracranial pressure. Jll 113 Some evidence suggests that the changes in latency occur only in hydrocephalic infants with brain damage and not in those who are neurologically normal. 113 Vertical nystagmus and asymmetric nystagmus are commonly associated with serious intracranial pathology and are considered indications for neuroimaging. Visual evoked potentials, together with electroretinography, are also useful tools for evaluating such cases because vertical or asymmetric nystagmus may be associated with hereditary retinal dystrophies, albinism, or spasmus nutans.114.115
Visual Loss of Unknown Etiology and Malingering VEPs can be a useful acljunct in evaluating children with visual loss of unknown etiology, particularly in distinguishing visual impairment from malingering in children who have a normal ophthalmologic examination. ll6.l 17 Children who are familiar with eye charts are unfamiliar with striped patterns on video displays and often provide evidence of normal visual acuity in a VEP protocol. Abnormal VEP responses are not necessarily indicative of visual impairment because patients can willfully degrade VEP responses by defocusing the patterns. 118-120
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6. Ducati A, Fava E, Motti EDF: Neuronal generators of the visual evoked potentials: intracerebral recording in awake humans. Electroencephalogr Clin Neurophysiol, 71:89,1988 7. Schanel-Klitsch E, Siegfried JB, Kavanagh V: Developmental differences in visual evoked potential slow waves and high frequency wavelets across the lifespan: effects ofluminance variation of flash and background. p. 198. In Barber C, Blum T (eds): Evoked Potentials III. Butterworth, Boston, 1987 8. Snyder R, Hata SK, Brann BS et al: Subcortical visual function in the newborn. Pediatr Neurol, 6:333, 1990 9. Dubowitz LMS, Mushin J, DeVries L et al: Visual function in the newborn infant: is it cortically mediated? Lancet, 1:1139, 1986 10. Spekreijse H, Dagnelie G, Maier Jet al: Flicker and movement constituents of the pattern reversal response. Vision Res, 25:1297, 1985 11. Dagnelie G, DeVries M, Maier J et al: Pattern reversal stimuli: motion or contrast? Doc Ophthalmol, 31:343, 1986 12. Schroeder CE, Tenke CE, Givre SJ et al: Striate cortical contribution to the surface-recorded pattern-reversal VEP in the alert monkey. Vision Res, 31:1143, 1991 13. Di Russo F, Martinez A, Sereno MI et al: Cortical sources of the early components of the visual evoked potential. Hum Brain Map, 15:95, 2001 14. Taylor MJ, Menzies R, MacMillan LJ et al: VEPs in normal full-term and premature neonates: longitudinal versus cross-sectional data. Electroencephalogr Clin Neurophysiol, 68:20, 1987 15. Hendrickson A: Morphological development of the primate retina. p. 287. In Simons K (ed): Early Visual Development: Normal and Abnormal. Oxford University Press, New York, 1993 16. Magoon EH, Robb RM: Development of myelin in human optic nerve and tract. A light and electron microscope study. Arch Ophthalmol, 99:655, 1981 17. Huttenlocher PR, de Courten C: The development of synapses in striate cortex of man. Hum Neurobiol, 6:1, 1987 18. Garey LJ: Structural development of the visual system of man. Hum Neurobiol, 3:75,1984 19. Kurtzberg D, Vaughan HG: Electrophysiological assessment of auditory and visual function in the newborn. Clin Perinatol, 12:277, 1985 20. Tsuneishi S, Casaer P, FockJM et al: Establishment of normal values for flash visual evoked potentials (VEPs) in preterrn infants: a longitudinal study with special reference to two components of the Nl wave. Electroencephalogr Clin Neurophysiol, 96:291, 1995 21. Grose J, Harding GFA, Wilton AYet al: The maturation of the pattern reversal VEP and flash ERG in pre-term infants. Clin Vision Sci, 4:239, 1989 22. Whyte HE, Pearce JM, Taylor MJ: Changes in the VEP in preterm neonates with arousal states, as assessed by EEG monitoring. Electroencephalogr Clin Neurophysiol, 68:223, 1987 23. Shepherd AJ, Saunders KJ, McCulloch DL et al: Prognostic value of flash visual evoked potentials in preterm infants. Dev Med Child Neurol, 41:9, 1999
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81. Mellor DH, Fielder AR: Dissociated visual development: electrodiagnostic studies in infants that are slow to see. Dev Med Child Neurol, 22:327, 1980 82. Baker RS, Schmeisser ET, Epstein AD: Visual system electrodiagnosis in neurologic disease of childhood. Pedriatr Neurol, 12:99, 1995 83. Lambert SR, Kriss A, Taylor D: Delayed visual maturation: A longitudinal clinical and electrophysiological assessment. Ophthalmology, 96:524, 1989 84. Harding GF, Herrick CE,]eavons PM: A controlled study of the effect of sodium valproate on photosensitive epilepsy and its prognosis. Epilepsia, 19:555, 1987 85. Cosi V, Callieco R, Galimberti CA et al: Effect of vigabatrin on evoked potentials recordings in patients with epilepsy. Br] Clin Pharmacol, 27: Suppll, 61S, 1989 86. Drake ME ]r, Pakalnis A, Padamadan H et al: Effect of anti-epileptic drug monotherapy and polypharmacy on visual and auditory evoked potentials. Electromyogr Clin Neurophysiol, 29:55, 1989 87. Martinovic Z, Ristanovic D, Dokic-Ristanovic D et al: Pattern reversal evoked potentials recorded in children with generalized epilepsy. Clin Electroencephalogr, 21:233, 1990 88. Cosi V,Callieco R, Galimberti C et al: Effect of vigabatrin: on visual, brainstem auditory, and somatosensory evoked potentials in epileptic patients. Eur Neurol, 28:42, 1988 89. Morang SE, Westall CA, Buncic R] et al: Sweep visual evoked potentials in infants with infantile spasms before and during vigabatrin treatment. Invest Ophthalmol Vis Sci, 44:E-Abstract 2720, 2003 90. Harding GF, Robertson K, Spencer EL et al: Vigabatrin: its effect on the electrophysiology of vision. Doc Ophthalmol, 104:213, 2002 91. Kristjansdottir R, Sjostrom A, Uverbrant P: Ophthalmological abnormalities in children with cerebral white matter disorders. Eur j Pediatr Neurol, 6:25, 2002 92. Jones Sj, Turano G, Kriss A et al: Visual evoked potentials in phenylketonuria: association with brain MRl, dietary state, and IQ. j Neurol Neurosurg Psychiatry, 59:260, 1995 93. LeuzziV,Cardona F,Antonozzi I et al: Visual, auditory, and somatosensorial evoked potentials in early and late treated adolescents with phenylketonuria. j Clin Neuraphysiol, 11:602, 1994 94. Ludolph AC, Ullrich K, Nedjat S et al: Neurological outcome in 22 treated adolescents with hyperphenylalaninemia. A clinical and electrophysiological study. Acta Neurol Scand, 85:243, 1992 95. Ludolph AC, Vetter U, Ullrich K; Studies of multimodal evoked potentials in treated phenylketonuria: the pattern of vulnerability. Eur J Pediatr, 155: Suppl I, S64, 1996 96. Cleary MA, Walter jH, Wraith jE et al: Magnetic resonance imaging of the brain in phenylketonuria. Lancet, 344:87, 1994 97. Giovannini M, Valsasina R, Villani R et al: Pattern reversal visual evoked potentials in phenylketonuria.] Inherit Metab Dis, ll:416, 1986 98. Korinthenberg R, Ullrich K, Fullenkemper F: Evoked potentials and electroencephalography in adolescents with phenylketonuria. Neuropediatrics, 19:175, 1988
99. Leuzzi V,Rinaldussi S, Chiarotti F et al: Subclinical visual impairment in phenylketonuria. A neurophysiological study (VEP-P) with clinical, biochemical, and neuroradiological (MRl) correlations. J Inherit Metab Dis, 21:351, 1998 100. Scher MS, Richardson GA, Robles Net al: Effects of prenatal substance exposure: altered maturation of visual evoked potentials. Pediatr Neurol, 18:236, 1998 101. Igata A: Epidemiological and clinical features of Minamata disease. Environ Res, 63:157, 1993 102. Murata K, Weihe P, Renzoni A et al: Delayed evoked potentials in children exposed to methylmercury from seafood. Neurotoxicol Teratol, 21:343, 1999 103. Inayoshi S, Okajima T, Imai H: Electrophysiological studies on Minamata disease. jpn] EEG EMG, 16:48, 1988 104. Choi BH: The effects of methylmercury on the developing brain. Prog Neurobiol, 32:447, 1989 105. Tokuomi H, Uchino M, Imamura S et al: Minimata disease (organic mercury poisoning): neuroradiologic and electrophysiologic studies. Neurology, 32:1369, 1982 106. Till C, Rovet]F, Koren G et al: Assessment of visual functions following prenatal exposure to organic solvents. Neurotoxicology, 24:725, 2003 107. Anyanwu EC, Campbell AW, Vojdani A: Neurophysiological effects of chronic indoor environmental toxic mold exposure on children. Sci World], 3:281, 2003 108. Altmann L, Sveinsson K, Kramer U et al: Visual functions in 6-year-old children in relation to lead and mercury levels. Neurotoxicol Teratol, 20:9, 1998 109. Taddeucci G, Fiorentini A, Pirchio M et al: Pattern reversal evoked potentials in infantile spasms. Hum Neurobiol 3:153,1984 llO. O'Connor AR, Birch EE, Leffler] et al: Infant visual evoked potential (VEP) and preferential-looking (PL) grating acuity as predictors for recognition acuity in low birth weight children. Invest Ophthalmol Vis Sci, 44: E-Abstract 2712, 2003 Ill. Coupland SG, Cochrane DD: Visual evoked potentials, intracranial pressure and ventricular size in hydrocephalus. Doc Ophthalmol, 66:321,1987 112. Desch LW: Longitudinal stability of visual evoked potentials in children and adolescents with hydrocephalus. Dev Med Child Neurol, 43:ll3, 2001 113. Guthkelch AN, Sclabassi R], Hirsch RP et al: Visual evoked potentials in hydrocephalus: relationship to head size, shunting, and mental development. Neurosurgery, 14:283, 1984 114. Shawkat FS, Kriss A, Thompson D et al: Vertical or asymmetric nystagmus need not imply neurological disease. Br J Ophthalmol, 84:175, 2000 115. Shaw FS, Kriss A, Russel-Eggitt I et al: Diagnosing children presenting with asymmetric pendular nystagmus. Dev Med Child Neurol, 43:622, 2001 ll6. Sokol S: The pattern visual evoked potential in the evaluation of pediatric patients. p. ll5. In DesmedtjE (ed): Visual Evoked Potentials. Elsevier, Amsterdam, 1990 ll7. Holder G: Electrodiagnostic testing in malingering and hysteria. p. 573. In Heckenlively]R, Arden GB (eds): Principles and Practice of Clinical Electrophysiology. Mosby Year Book, St. Louis, 1991
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11S. Morgan RK, Nugent B, Harrison]M et al: Voluntary alteration of pattern visual evoked responses. Ophthalmology, 92:1356, 1985 I 19. Chiappa KH, Yiannikas C: Voluntary alteration of visual evoked potentials. Ann Neurol, 12:496, 1982 120. Baumgartner F, Epstein CM: Voluntary alteration of visual evoked potentials. Ann Neurol, 12:475, 1982 121. Pryds 0, Trojaborg W, Carlsen] et al: Determinants of visual-evoked potentials in preterm infants. Early Human Dev 19:117,1989 122. Engel R, Fay W: Visual evoked responses at birth, verbal scores at 3 years, and IQ at 4 years. Dev Med Child NeuroI14:283,1972 123. Ferriss GS, Davis DD, Dorsen MM et al: Changes in latency and form of the photically induced average evoked responses in human infants. Electroencephalogr Clin Neurophysiol, 22:305, 1967 124. Fiorentini A, Trimarchi C: Development of temporal properties of pattern electroretinogram and
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CHAPTER
Brainstem Auditory Evoked Potentials: Methodology, Interpretation, and Clinical Application
23
ALAN D. LEGATT
OVERVIEW OF AEPs STANDARD BAEP RECORDING TECHNIQUES Stimulation Recording Waveform Identification and Measurement Patient Relaxation and Sedation MODIFICATIONS TO BAEP RECORDING TECHNIQUES Reducing the Stimulus Artifact Improving the Resolution of Specific Components Stimulation at Several Intensities Rapid Stimulation Alternative Auditory Stimuli BAEPs to Electrical Stimuli EFFECTS OF VARYING STIMULUS PARAMETERS Stimulus Polarity Stimulus Intensity Stimulus Rate GENERATORS AND SCALP TOPOGRAPHIES OF BAEPs Wave I Wave IN Wave II Wave liN Wave III Wave IV
Following a transient acoustic stimulus, such as a click or a brief tone pip, the ear and parts of the nervous system generate a series of electrical signals with latencies ranging from milliseconds to hundreds of milliseconds. These auditory evoked potentials (AEPs) are conducted through the body tissues and can be recorded from electrodes placed on the skin to evaluate noninvasively the function of the ear and portions of the nervous system activated by the acoustic stimulation. These short-latency or brainstem auditory evoked potentials (BAEPs) have proven to be valuable tools for hearing assessment, diagnosis of neurologic disorders, and intraoperative monitoring.
Wave Wave Wave Wave
V VI VII VN
CLINICAL INTERPRETATION OF BAEPs Normative Data Delay Versus Absence of Components Significance of Specific BAEP Abnormalities Abnormalities of Wave I Abnormalities of the I-III Interpeak Interval Abnormalities of the III-V Interpeak Interval Abnormalities of the IVIV:I AmplitudeRatio Portion of the Auditory System Assessed by BAEPs Functional Subsets Crossed and Uncrossed Pathways Rostrocaudal Extent Role of Descending Pathways Relationship Between BAEPs and Hearing Categorization of Abnormalities Peripheral Hearing Loss Central AuditoryPathway Abnormalities BAEPs in Specific Neurologic Conditions Acoustic Neuroma Other Posterior Fossa Tumors Cerebrovascular Disease Demyelinating Disease Coma and Brain Death
OVERVIEW OF AEPs Auditory evoked potentials have been divided into short-latency components, with latencies of under 10 msec in adults; long-latency AEPs, with latencies exceeding 50 msec; and middle-latency AEPs, with in termediate latencies (Fig. 23-1). The earliest components derive from electrical processes within the inner ear and action potentials in the auditory nerve. AEP components generated within the brainstem may reflect both action potentials and postsynaptic potentials. Auditory-evoked neural activity becomes increasingly affected by temporal dispersion as the poststimulus latency increases and as the contribution of
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II
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and analyzing stimulus features (Fig. 23-2). They have therefore been used as probes of cognitive processes, but their variability as well as uncertainly about the precise identity of their cortical generators limit their utility for neurologic diagnosis. Middle-latency AEPs are small; are subject to contamination by myogenic signals; and are rather variable from subject to subject, which also limits their clinical application. Both middleand long-latency AEPs are affected prominently by surgical anesthesia. Short-latency AEPs have achieved the greatest clinical utility because they are relatively easy to record and their waveforms and latencies are highly consistent across normal subjects. They are unaffected by the subject's degree of attention to the stimuli and are almost identical in the waking and sleeping states.' aside from minor differences related to changes in body ternperature.!
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0.5 sec Short-latency (top), middle-latency (middle), and long-latency (bottom) auditory evoked potentials (AEPs) elicited by monaural click stimuli and recorded in a vertexmastoid channel with vertex positivity plotted as a downward deflection. Note the differing epoch durations of the three AEPs. (From Picton TW, Hillyard SA, Krausz HI et al: Human auditory evoked potentials. 1. Evaluation of components. Electroencephalogr Clin Neurophysiol, 36:179, 1974, with permission.) ' - - _ - ' " - _ - - " -_ _. L - -........-
FIGURE 23-1
........
II
short-duration electrical phenomena (e.g., action potentials) is eliminated. Thus, AEP components that are longer in latency are also wider, and the middleand long-latency AEP components are predominantly generated by postsynaptic potentials within areas of cerebral cortex that are activated by the acoustic stimulus. AEP components are also increasingly affected by the state of the subject and by anesthesia as their latency increases. Long-latency AEPs are profoundly affected by the degree to which the subject is attending to the stimuli
~
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_
FIGURE 23-2 • Effect of attention on auditory evoked poten-
tials. Trains of clicksthat were occasionally lower in intensity were presented, and the subjectwasasked to either ignore the clicks (left) or to attend to them and count the number of softer ones (right). Recording conditions were otherwise the same as Figure 23-1. (From Picton TW, Hillyard SA: Human auditory evoked potentials. II: Effects of attention. Electroencephalogr Clin Neurophysiol, 36:191, 1974, with permission.)
Brainstem Auditory Evoked Potentials
Sedation also produces only minor changes in BAEPs,3 and has been employed during BAEP recordings. However, the use of sedation for evoked potential recordings has been markedly reduced owing to concerns about monitoring and the care of patients during conscious sedation." Because a typical surgical level of anesthesia produces only minor alterations in BAEP S5.6 (Fig. 23-3), they can be used for intraoperative monitoring of the ears and the auditory pathways. The earliest electrical signals produced by the auditory system in response to a transient stimulus, constituting the electrocochleogram (ECochG), were initially recorded by electrodes placed directly in the middle ear. 7 Extratympanic recordings of the ECochG8 yielded smaller signals that required signal averaging to achieve an adequate signal-to-noise ratio. Signal averaging also permitted recording of small time-locked signals originating from other locations. Additional deflections with latencies of several milliseconds after auditory stimulation were first recorded in humans during signal-averaged ECochG studies by Sohmer and Feinrnesser," Jewett and co-workers'P-'! identified the short-latency scalprecorded AEPs as far-field potentials volume-conducted from the brainstem, described the components and their properties, and established the Roman numeral labeling of the peaks that is used in most laboratories (Fig. 23-4). A far-field potential is a potential (voltage) recorded at a sufficiently large distance from its source that small movements of the recording electrode have no significant effect on the waveform. Although short-latency AEPs are commonly called brainstem auditory evoked potentials, this term is not completely accurate because the roster of generators clearly includes the distal (with respect to the brainstem) cochlear nerve and may also include the thalamocortical auditory radiations, neither of which is within the brainstem. Nonetheless, the designation EAEP is used in this chapter because it is the most widely used and
491
Fp1-C3 - - - - - - - - - - C3-01 Fp2-C4 - - - - - - - - - - C4-02 - - - - - - - - - - T3-Cz - - - - - - - - - - Cz-T4 EMG/ECG - - - - - - - . . -_ _~_ _
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msec Brainstem auditory evoked potentials recorded during surgery in a patient anesthetized with isoflurane at a concentration sufficient to render the electroencephalogram isoelectric. Although the amplitudes of waves IV, V, VI, and VII were reduced by anesthesia, the latencies of waves I through V were not significantly different from those recorded in this patient in the unanesthetized state. (From Stockard Il- Pope-Stockard JE, Sharbrough FW: Brainstem auditory evoked potentials in neurology: methodology, interpretation, and clinical application. p. 514. In Aminoff MJ [ed]: Electrodiagnosis in Clinical Neurology. 3rd Ed. Churchil\ Livingstone, New York, 1992, with permission.) FIGURE
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FIGURE 13-4 II Normal brainstem auditory evoked potential recorded between the vertex (Cz) and the right earlobe (A2) following right ear stimulation in a 23-year-old woman. Two averages of 2,000 sweeps each are superimposed. Vertex-positive peaks, shown here as upward deflections, are labeled with Roman numerals according to the convention of Jewett and Williston."! Downgoing peaks after waves I and V are labeled IN and VN, respectively. An electrical stimulus artifact appears at the beginning of the tracings.
O.2.VL IN
VN
1 msec
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
understood term. Other synonyms or related designations include auditory brainstem response, far-field electrocochleography, and brainstem audiometry.
STANDARD BAEP RECORDING TECHNIQUES This section describes the standard techniques used to record BAEPs in adult subjects. BAEP recording techniques for infants and children are described in Chapter 24, and intraoperative BAEP monitoring is discussed in Chapter 29. The American Electroencephalographic Society (now the American Clinical Neurophysiology Society) has published guidelines for clinical'! and intraoperativel'' BAEP recordings.
tralateral stimulation from occurring and possibly being misinterpreted as a BAEP arising from stimulation of the ipsilateral ear, the contralateral ear is masked with continuous white noise at an intensity 30 to 40 dB below that of the BAEP stimulus. Acoustic crosstalk also occurs with ear-insert transducers, though the signal reaching the opposite ear is attenuated to an even greater extent, typically 70 to 100 dB.15 If the electrical square pulse causes the diaphragm of the acoustic transducer to move toward the patient's ear, a propagating wave of increased air pressure, termed a compression click (also called a condensation click) is produced. Reversing the polarity of the electrical square pulse that activates the transducer produces a rarefaction click. BAEPs to rarefaction and compression clicks may differ16 ,17 (most prominently in patients with
Stimulation BAEPs are most commonly elicited by brief acoustic click stimuli that are produced by delivering monophasic square pulses of 100-Ilsec duration to headphones or other electromechanical transducers at a rate of about 10 Hz. A rate of exactly 10 Hz or another submultiple of the power line frequency should be avoided; otherwise, the inevitable line frequency artifact will be timelocked to the stimuli and will not be removed by the averaging process. Audiometric headphones having a relatively flat frequency response are desirable so that "broad-band" clicks, whose energy is spread over a wide frequency range, will be produced. The stimulus intensity should be loud enough to elicit a clear BAEP waveform without causing discomfort or ear damage; 60 to 65 dB HL is a typical level. If hearing loss is present, stimulus intensity may be acljusted accordingly so that stimulation is at 60 to 65 dB SL. (It should be noted that dB HL is decibels relative to the threshold of a normal population, dB SL is decibels relative to the threshold of the ear being tested, and dB nHL is decibels relative to the threshold of the specific control population used to establish a laboratory's normative database.) Reduced stimulus intensities are also useful during BAEP recordings, as discussed later in this chapter. The subjective click threshold should be measured in all subjects in whom this is possible, to recognize hearing loss and to determine the stimulus level corresponding to 0 dB SL. Stimuli are delivered monaurally, so that a normal BAEP to stimulation of one ear does not obscure the presence of an abnormal response to stimulation of the other ear. An acoustic stimulus delivered to one ear via headphones can reach the other ear via air and bone conduction with a volume attenuation of 40 to 70 dB14,15 and generate an evoked potential by stimulation of the contralateral ear (Fig. 23-5). To prevent this con-
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5 msec FIGURE U·5 • Brainstem auditory evoked potentials to monaural stimulation from a patient with one nonfunctioning ear. A, Stimulation of the unaffected ear elicits a normal BAEP. B, When contralateral noise masking is not used, stimulation of the nonfunctioning ear produces a delayed wave V because of air and bone conduction of the stimulus to the other ear, e, When masking noise is delivered to the unaffected ear, stimulation of the nonfunctioning ear does not elicit any reproducible BAEPs. (Modified from Chiappa K, Gladstone Kj, Young RR: Brain stem auditory evoked responses. Studies of waveform variations in 50 normal human subjects. Arch Neurol, 36:81, 1979, with permission.)
Brainstem Auditory Evoked Potentials
a cochlear high-frequency hearing loss), and averaging the responses to the two click polarities together may produce a composite waveform with less diagnostic utility. Therefore, a single stimulus polarity should be used unless alternating polarities are necessary for canceling the electrical stimulus artifact or cochlear microphonic. Rarefaction clicks are generally preferable because they tend to yield BAEPs with better definition of the components; this may be because the initial cochlear movement.s produced by rarefaction clicks are in a direct.ion that depolarizes the hair cells.'? In evaluat.ing a patient's BAEPs, the normative data used should have been acquired with the same stimulus polarity used to test the patient.
Recording Recording electrodes are typically placed at t.he vertex (location Cz of the International 10-20 System) and at both earlobes (the earlobes ipsilateral and contralateral to the stimulated ear are labeled Ai and Ac, respectively). Electrodes at the mastoids (labeled Mi and Mc) may be substituted for the earlobe placements, although wave I tends to be smaller. Such placement, in combination with increased pickup of muscle noise, yields a poorer signal-to-noise ratio for wave I with mastoid leads than with earlobe leads. The ground electrode is often placed on the forehead, but its precise location is not critical. Metal cup or pellet electrodes may be used; needle electrodes should be avoided. Electrode impedance should be less than 5 kohm. Optimally, the same type of electrode should be used at all recording positions, and electrode impedance should be as consistent as possible across all recording electrodes because mismatched electrode impedance can increase the amount of noise in the BAEP data. 18 BAEPs should be recorded between Cz and either Ai or Mi. A minimum of a two recording-channel system, with Cz-Ac or Cz-Mc in the second channel, has been recommended 12 because this channel may aid in the identification of waves IV and V, which may be fused in the channel 1 waveform. An Ac-Ai or Mc-Mi channel may assist in the identification of wave I, and can be substituted in channel 2 when necessary, or can be recorded as a standard part of all tests if more than two recording channels are available. The raw analog data are amplified by high inputimpedance differential amplifiers with a common mode rejection ratio of at least 80 dB (10,000:1).J2 A typical analog filter bandpass is 100 Hz or 150 Hz to 3,000 Hz (-3 dB points). The analog gain depends on the input window of the analog-to-digital converter; a value of approximately 100,000 is typical. Data are typically digitized over an epoch durat.ion or analysis time of approximately 10 msec (the analysis
493
time in some recording systems is actually 10.24 msec). However, a longer analysis t.ime of 15 msec may be required for recording pathologically delayed BAEPs, BAEPs to lowered stimulus intensities (as when recording a lat.ency-intensity study), BAEPs in children, and BAEPs during intraoperative monitoring. The Nyquist criterion requires analog-to-digital conversion with a sampling rate of at least 6,000 Hz (2 x 3,000 Hz) in each channel to avoid aliasing, but higher sampling rates are required for accurate reproduction of the BAEP waveshape and precise measurement of peak latencies. The an alog-to-digital conversion should use at least 256 points per epoch; sampling of a 10.24-msec epoch at 256 time points corresponds to a sampling interval of 0.4 msec and a sampling rate of 25,000 Hz. Far-field BAEPs are too small to be visible in unaveraged raw data, and so signal averaging is required. The improvement in the signal-to-noise ratio is proportional to the square root of the number of data epochs included in the average. Automatic artifact rejection is used to exclude sweeps with high-amplitude noise from the average. The number of epochs per trial is typically 2,000, although a larger number may be required if the signal-to-noise ratio is poor (usually reflecting a lowamplitude BAEP or noisy raw data). At least two separate averages should be recorded and superimposed to assess reproducibility of the BAEP waveforms. Latency replication to within 1 percent of the sweep time and amplitude replication to within 15 percent of the peakto-peak amplitude have been recommended as standards for adequate reproducibility.!"
Waveform Identification and Measurement When recording far-field potentials such as the BAEPs, the two electrodes connected to the inputs of a differential amplifier cannot be considered active and reference electrodes. The voltage distributions of the BAEPs extend over most, if not all, of the head, and no cephalic electrode can be considered to be truly inactive for all components. For example, wave V in the Cz-Ai BAEP waveform largely reflects positivity at the vertex, whereas wave I is derived from a negativity around the stimulated ear that is picked up by the Ai electrode. 19 .20 Thus, both input. electrodes must be specified when describing a BAEP waveform. The Cz-Ai BAEP is typically displayed so that positivity at the vertex relative to the stimulated ear is displayed as an upward deflection, and the upward-pointing peaks are labeled with Roman numerals according to the convention established by Jewett and Williston II (see Fig. 23-4; Fig. 23-6). The downward-pointing peaks are labeled with the suffix N according to the peak that they follow; for example, downward peak IN follows
494
ElECTRODIAGNOSIS IN ClINICAL NEUROlOGY
Cz-Ai III Brainstem auditory evoked potentials recorded simultaneously from three different recording electrode linkages following monaural stimulation. The vertical dashed lines indicate the peak latenciesof waves IVand Yin the Cz-Ai waveforms. Note the decreased wave IVlatencyand the increased wave V latency in the Cz-Acwaveforms.
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upward wave I. The downward deflection following wave V, which has also been labeled the slow negativity (SN), is typically wider than the positive components and the earlier negative peaks. Recognition and identification of the components in BAEP waveforms obtained with standard recording techniques will now be described. Modifications in the recording paradigm that can be used to enhance specific BAEP components are discussed later in this chapter. The BAEP waveform typically begins with an electrical stimulus artifact that is synchronous with stimulus production at the transducer. Wave I is the first major upgoing peak of the Cz-Ai BAEP. It appears as an upgoing peak of similar amplitude in the Ac-Ai waveform and is markedly attenuated or absent in the Cz-Ac waveform (see Fig. 23-6). The cochlear microphonic may be visible as a separate peak preceding wave I, especially if the stimulus artifact is small. Its scalp distribution is similar to that of wave I. They may be distinguished by reversing the stimulus polarity, which will reverse the polarity of the cochlear microphonic; wave I may show a latency shift, but will not reverse polarity. A bifid wave I is occasionally present and represents contributions to wave I from different portions of the cochlea. The earlier of the two peaks, which reflects activation of the base of the cochlea, corresponds to the single wave I that is typically present in the Cz-Ai waveform. Reversal of stimulus polarity can be used to distinguish a bifid wave I from a cochlear microphonic followed by (a single) wave I. In contrast to wave I, wave IN is present at substantial amplitude in the Cz-Ac channel (see Fig. 23-6). This downgoing deflection is usually the earliest BAEP component in that waveform.
Wave II is typically the first major upward deflection in the Cz-Ac waveform because wave I is markedly attenuated or absent there. When present, wave II is usually of similar amplitude in the Cz-Ai and Cz-Ac channels (see Fig. 23-6). However, wave II may be small and difficult to identify in some normal subjects. A substantial wave III is usually present in both the Cz-Ai and Ac-Ai channels. Wave III in the Cz-Ac waveform is usually substantially smaller than that in the Cz-Ai waveform (see Fig. 23-6). This difference helps to distinguish it from wave II, whose amplitude is little changed by the change in the ear electrode. The peak latency of wave III decreases slightly, whereas that of wave II increases slightly when the inverting amplifier input is changed from Ai to Ac; thus, the Cz-Ai waveform tends to give better separation of waves II and III than does the Cz-Ac waveform. A bifid wave III is occasionally observed as a normal variant (Fig. 23-7); the wave III latency in such waveforms can be scored as midway between the peak latencies of the two subcomponents. Rarely, wave III may be poorly formed or absent in a patient with a clear wave V and a normal I-V interpeak interval; this finding is best interpreted as a normal variant waveform. Waves IV and V are often fused into a IVIV complex whose morphology varies from one subject to another, and may differ between the two ears in the same person (Fig. 23-8). The IVIV complex is often the most prominent component in the BAEP waveform. It is usually followed by a large negative deflection that lasts several milliseconds and brings the waveform to a point below the pre-stimulus baseline. Occasionally, the most negative point in the waveform follows waveVI (see Fig. 23-7), which could lead to misinterpretation of wave VI as an abnormally delayed wave V. The identity of wave V
Brainstem Auditory Evoked Potentials
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6 10 8 msec FIGURE 11·7 Ii Brainstem auditory evoked potentials recorded from a normal subject following stimulation with compression (C) and rarefaction (R) clicks. Prominent differences in wave shape are evident between the two stimulus polarities. The latency ofwave VI and the relative amplitudes ofwaves IV and V are markedly affected by the click polarity. The lowest point in the waveform after wave V precedes wave VI with compression clicks and follows wave VI with rarefaction clicks. A bifid wave III is present in the Cz-Ai waveform elicited by compression clicks. (By permission of the Mayo Foundation.) 2
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can be clarified by changes in recording montage or click polarity (see Figs. 23-6 and 23-7) or by reducing the stimulus intensity and/or increasing the stimulus rate to attenuate wave VI relative to wave V. In distinguishing between a totally fused IVIV complex and a single wave IV or V, Epstein notes that the former has a "base" that is greater than 1.5 msec in duration, whereas the width of a single wave is less than 1.5 msec." When waves IV and V overlap in the Cz-Ai waveform, the wave V latency measurement used for BAEP interpretation should be taken from the second subcomponent of the IVIV complex even if this is not the highest peak (in contrast to the amplitude measurement used to calculate the IVIV:I amplitude ratio, which is taken from the highest point in the complex). Measurement of the peak latency of wave V may be inaccurate if V appears only as an inflection on the falling edge of wave IV (see Fig. 23-8) and it may be impossible if they are smoothly fused. Two approaches may be used in such cases. The first involves measure-
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ment of wave V latency in a Cz-Ac recording channel. The overlapping peaks are more clearly separated there because the latency of wave IV is typically earlier, and that of wave V is later, than in the Cz-Ai waveform (see Fig. 23-6). However, because of these latency shifts, wave V latency values measured in a Cz-Ac waveform should be compared with normative data in which the latency of wave V was also measured in a Cz-Ac recording. The other approach is to reduce the stimulus intensity to attenuate wave IV relative to wave V and permit accurate measurement of the peak latency of wave V. That latency value cannot be compared with normative data obtained at a higher stimulus intensity, but the I-V interpeak interval can be evaluated because it is minimally affected by changes in stimulus intensity. It is important to distinguish wave V from wave IV. If wave V were abnormally delayed, but an earlier and larger wave IV (which dominated the IVIV complex) was mistaken for wave V, the BAEP abnormality might be missed. If the latency of an apparent wave V is abnormally short, efforts should be made to determine whether this peak is in fact a dominant wave IV. Lesions that affect wave V almost always also affect wave IV,22-24 but rarely wave IV may be unaltered (Fig. 23-9).
496
ELECTRODIAGNOSIS IN CUNICAL NEUROLOGY
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FIGURE 23·1 • BAEPs to left ear stimulation recorded (Cz-Ai) during surgery for a basilar artery aneurysm. The aneurysm ruptured and the basilar artery was transiently dipped to control the bleeding. The patient suffered a brainstem infarct. A, Clear waves I through VI were present in these BAEPs recorded just before the aneurysm ruptured. B, BAEPs recorded after the clip was removed show a loss of wavesV and VI. Waves I through IV were unaffected. (Modified from Legatt AD, Arezzo JC, Vaughan HG Jr: The anatomic and physiologic bases of brain stem auditory evoked potentials. Neural CIin, 6:681,1988, with permission.)
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Clinical interpretation of BAEPs is based predominantly on the latencies ofwaves I, III, and V. Once these peaks have been identified and their latencies measured, the I-III, III-V, and I-V interpeak intervals are calculated. The latency of wave I has also been labeled the peripheral transmission time (PTT) and the I-V interpeak interval has been called the central transmission time (CTT). Differences of component latencies and interpeak intervals with stimulation of the right and left ears are also calculated. The amplitudes of waves I and the IVIV complex are measured, each with respect to the most negative point that follows it in the waveform (I to IN and IVIV to VN), and their ratio is calculated. An excessively small IVIV:l amplitude ratio can identify as abnormal some BAEP waveforms in which all component latencies and interpeak intervals are normal (Fig. 23-10). It has sometimes been called the V:I amplitude ratio. However, most studies establishing the value of this quantity24-26
measured the amplitude from the highest peak of the IVIV complex to VN, not from the wave V peak to VN. Measuring the latter may give an abnormally small ratio in normal waveforms in which the peak of wave IV is much higher than that of wave V.
Patient Relaxation and Sedation The amplifier bandpass used for BAEP recordings filters out all of the delta, theta, alpha, and beta bands of the electroencephalogram, and the biologically derived noise in the recordings is predominantly derived from muscle activity. Therefore, patient relaxation during the recording session is essential to get "clean" waveforms with a good signal-to-noise ratio. Patients are usually tested while lying comfortably so that their neck musculature is relaxed. Patients should be requested to let their mouth hang open if the muscles of mastication
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FIGURE :Z:S·IO • Brainstem auditory evoked potential (Cz-Ai) in a 27-year-oldwoman with probable multiple sclerosis. The IVIV:I amplitude ratio is 0.28; all absolute latencies and interpeak intervals are normal. The stimulus intensity was 65 dB nHL.
Brainstem Auditory Evoked Potentials
are tensed. They are encouraged to sleep during testing because this aids relaxation and will not alter the BAEPs.27 If the patient cannot relax sufficiently, sedation can be induced with agents such as chloral hydrate, a shortacting barbiturate, or a benzodiazepine; these have little or no effect on BAEPs in the usual sedative doses."
MODIFICATIONS TO BAEP RECORDING TECHNIQUES Reducing the Stimulus Artifad The transient electrical current in the transducer that generates the acoustic stimulus produces a transient electromagnetic field, which in turn induces a voltage in the patient and in the recording leads. This voltage creates an electrical stimulus artifact that, if large and prolonged, may overlap with wave I and impair the identification and measurement of that component. Using shielded headphones and headphones with piezoelectric transducers/" instead of voice coil transducers can reduce this artifact. Transducers that are connected to an ear insert by flexible plastic tubing several centimeters in length may also be used to mitigate this problem. The BAEPs, including wave I, are delayed by the time required for the acoustic stimulus to propagate through the plastic tube, but the electrical stimulus artifact remains simultaneous with transducer activation; the increased temporal separation between them permits greater decay of the electrical artifact before wave I. The greater distance between the transducer and the earlobe or mastoid recording site also serves to reduce the amplitude of the electrical stimulus artifact. The delay introduced by the plastic tube must be considered when one interprets BAEP latencies; passage through the tube may also change the acoustic properties of the stimulus. Ideally, the normative data used for BAEP interpretation should have been acquired with the same techniques that are used to test the patients. When ear inserts are used, they may be covered with metal foil to serve as near-field recording electrodes for wave I, thereby yielding a larger wave I. Responses to compression and rarefaction clicks may be averaged together to reduce the electrical stimulus artifact by cancellation. Most evoked potential recording svstems have an option for alternating the click polarity during stimulus delivery. This option should be avoided if possible during diagnostic testing because the BAEPs elicited by the two click polarities may differ.!""? Stimulus artifact is usually more of a problem in the operating room environment, and alternating click polarity is often necessary during intraoperative BAEP monitoring. In this setting, the BAEPs are being compared with signals recorded earlier in the same patient
497
with the identical stimulus paradigm, so the admixture of responses to the two stimulus polarities is less of a problem.
Improving the Resolution of Specific Components Wave I may be small and difficult to record in some patients, especially if hearing loss is present. Several techniques can be used to obtain a clearer wave I. Because wave I is a near-field potential, relatively small movements of the Ai/Mi recording electrode can have a substantial effect on its amplitude. Thus, alternative electrode positions around the stimulated ear can be used. An electrode within the external auditory canal yields an even larger wave I, and may take the form of a metal foil covering on an ear insert or a spring-leaf electrode that makes contact with the wall of the canal. Although wave I appears predominantly because of the presence of a near-field negativity at the Ai electrode, the horizontal orientation of its dipole projects a small positivity to the contralateral ear. Accordingly, an Ac-Ai recording channel can yield a somewhat larger and clearer wave I than that in the standard Cz-Ai recording. Modifications in stimulus parameters are also useful in obtaining a clearer wave l. Alternating stimulus polarity can be useful by attenuating a large stimulus artifact that is obscuring wave I or by helping to differentiate wave I from the cochlear microphonic. A reduction in the stimulus repetition rate may yield a clearer wave I. Increasing the stimulus intensity is particularly helpful in improving the clarity of wave I and may be used if that peak is not clearly identifiable at standard intensities in the presence of hearing loss. One caveat is that in patients with a high-frequency hearing loss of cochlear origin, this maneuver yields interpeak intervals that are shorter than those of normal subjects.F' This difference in interpeak intervals probably reflects contributions to wave I from different portions of the cochlea. At normal intensities, the earliest peak, which reflects activation of the base of the cochlea, predominates. At higher intensities, a somewhat longer-latency component becomes increasingly prominent. If the earlier component is missing because of high-frequency hearing loss, and if stimulus intensity is increased, the wave I that appears may predominantly reflect the longer-latency contribution; the I-III and I-V interpeak intervals are thus shorter than those that would have been measured from the usual wave I. Measurement of the PTT from this longer-latency subcomponent would decrease the sensitivity of the test for recognition of prolonged I-III or I-V interpeak intervals. Wave V is often fused with wave IV into a IVIV complex in the Cz-Ai BAEP waveform. A Cz-Ac recording
498
ELECTRODIAGNOSIS IN CLINICAL NEUROLOGY
channel helps to identify wave V by increasing the sep· aration between the peaks of these two components; the latency of wave IV is shorter and that of wave V is longer than in the Cz-Ai recording (see Fig. 23-6). Because of this latency shift, the latency of wave V in a patient's Cz-Ac waveform should be compared with normal values derived from Cz-Ac recordings in control subjects. Modifications of the stimulus parameters can also be used to identify wave V if it is unclear when standard recording techniques are used. Wave V is the BAEP component most resistant to the effects of decreasing stimulus intensity (Fig. 23·11) or increasing stimulus rate. If either of these stimulus modifications is performed progressively until only one component remains, that peak can be identified as wave V and then traced back through the series of waveforms to identify wave V in the BAEP recorded with the standard stimulus. Occasionally, wave V may be present following stimulation with one click polarity but not the other (Fig. 23-12). Therefore, recording a BAEP with the opposite stimulus polarity may be useful if wave V is not identifiable with the standard laboratory protocol.
Stimulation at Several Intensities In a patient with a conductive hearing loss, the stimulus intensity reaching the cochlea is less than that delivered to the external ear, and an abnormal BAEP with a delayed or absent wave I may result. If the stimulus intensity is increased to compensate for the conductive hearing loss, and no coexisting sensorineural hearing loss is present, a normal BAEP will be recorded. In contrast, BAEPs that are delayed as a result of abnormally slowed neural conduction do not normalize when the stimulus intensity is increased (Fig. 23·13). Thus, increasing the stimulus intensity can help to differentiate peripheral from neural abnormalities, especially when wave I is not clear. The degree of hearing loss can be estimated by the elevation of the subjective auditory click threshold; increasing the stimulus intensity to compensate for this elevation is thus equivalent to stimulating at a specific intensity above that threshold (e.g., at 60 to 65 dB SL rather than at 60 to 65 dB HL). The normative data to which such recordings are compared should also have been recorded at a specific intensity in dB SL, rather than db HL.
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5 FIGURE 23-11 • Brainstem auditory evoked potentials (BAEPs) recorded at progressively lower stimulus intensities are shown on the left. Wave V latencies (arrows) are measured and then plotted as a function of stimulus intensity to give the latency-intensity curve on the right. This 35-year-old woman with dizziness and tinnitus had normal BAEPs and normal magnetic resonance imaging findings.
Brainstem Auditory Evoked Potentials
499
AD
R 70 dB SL
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FIGURE 23-12 • Brainstem auditory evoked potentials elicited by rarefaction (R) and compression (C) clicks of several different intensities. Wave V is absent following left ear stimulation with 70 dB SL rarefaction clicks but appears when the stimulus intensity is decreased to 55 dB SL or when stimulus polarity is reversed. A clear wave V is present following right ear stimulation with 70 dB SL clicks of either polarity. The calibration bars are 0.25 IlVand 1.0 msec. (From Emerson RG, Brooks EB, Parker SW et al: Effects of click polarity on brainstem auditory evoked potentials in normal subjects and patients: unexpected sensitivity ofwave V. Ann NY Acad Sci, 388:710,1982, with permission.)
If each ear is stimulated at several different in tensities, and the latency of wave V is graphed as a function of stimulus intensity, a latency-intensity curve is produced (see Fig. 23-11). Examination of latencyintensity curves may help to classify a patient's hearing loss.t" A shift of the curve to a higher intensity level without a change in its shape suggests conductive hearing loss, whereas a change in the shape of the curve with an increased slope suggests sensorineural hearing loss. Latency-intensity curves may also reveal abnormalities that are not demonstrated by BAEP recordings at the standard, relatively high stimulus intensity typically used in BAEP studies performed for neurologic diagnosis."
Rapid Stimulation A stimulus rate of approximately 10 Hz is used for routine clinical testing; this is because some of the BAEP components become attenuated and less clearly defined and the interpeak intervals lengthen as the rate is increased substantially above this. Measurement of the BAEP threshold is based solely on the presence or absence of wave V because it is the last BAEP component to disappear as the stimulus intensity is reduced. Because wave V is relatively resistant to the effects of rapid stimulation, recordings made solely for threshold
measurement can be accomplished more rapidly by increasing the stimulus rate to 50 to 70 Hz. However, rapid stimulation can make BAEPs undetectable, especially in premature infants. Thus, infants who appear to have a hearing loss on BAEP screening using rapid stimulation should be retested using a slower stimulation rate. 32 When stimuli are delivered at a rate of about 10 Hz, the neural elements generating the BAEPs have approximately 100 msec to recover after responding to one stimulus before they must respond to the next. It has been speculated that in some pathologic states, action potential propagation or synaptic transmission occurs normally with recovery times of this magnitude but is delayed when recovery times are shorter. If this were the case, more rapid stimulation would demonstrate BAEP abnormalities in some patients with normal BAEPs to the standard stimuli, thus increasing the sensitivity of the test. Rapid stimulation has been reported to increase the test sensitivity of BAEPs in patients with neurologic abnormalities in some, but not all, studies. 33.34
Altemative Auditory Stimuli The standard BAEP stimulus is a "broad-band" click produced when an electrical square pulse is delivered
500
ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
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D FIGURE 2:1-15 • Brainstem auditory evoked potentials (BAEPs) elicited by two different stimulus intensities in
two patients and recorded in Cz-Ai montage. A, Left ear stimulation at 70 dB nHL elicits an abnormally delayed wave V in a 3&-year-old woman with a peripheral hearing loss in the left ear. Wave I is not visible. B, When the stimulus intensity is increased to 85 dB nHL, wave I becomes identifiable and the latency of waveV is markedly decreased. Interpeak intervals are normal. C, Left ear stimulation at 65 dB nHL in a 14-year-old boy with a fourth ventricular tumor elicits clear BAEPswith a normal wave I latency and an abnormally delayed waveV.The I-III and I-V interpeak intervals are both abnormally prolonged. D, An increase in the stimulus intensity to 85 dB nHL causes a slight decrease in all component latencies. Wave V remains abnormally delayed, and the I-III and I-V interpeak intervals remain abnormally prolonged.
to the headphone or other electromechanical transducer. It is generated predominantly by the region of the cochlea responding to 2000- to 4000-Hz sounds,35,36 although wave V may also receive contributions from lower-frequency regions of the cochlea. BAEPs have also been recorded following stimulation with brief tone pips, in an effort to probe specific parts of the cochlea. This method can be used to determine thresholds at different frequencies for BAEP audiometry. Tone pips are most often generated with stimuli consisting of brief bursts of sine waves. The burst cannot be abruptly stopped and started because an audible "click" containing many frequencies would be produced. Instead, the sine wave stimulus is amplitude-modulated with a rise time, plateau, and fall time to reduce (although not eliminate) the energy content of the stimulus at other frequencies. A filtered click, which is obtained by passing a broad-band click through a bandpass filter, has also been used as a frequency-specific stimulus. Another technique that can be used to obtain frequency-specific information from BAEPs is acoustic
masking. In one approach, the broad-band clicks used to elicit the BAEPs are superimposed on white noise that has been highpass-filtered by using different cutoff frequencies in different runs. Each BAEP waveform is generated predominantly by the unmasked region of the cochlea and represents a response to frequencies lower than the cutoff frequency used during that run. Subtraction of one such response from another yields a "derived" response that estimates the response to the frequency band between the cutoff frequencies of the two runs (Fig. 23-14). The subtraction process yields waveforms with relatively poor signal-to-noise ratios,
however." Frequency-specific stimuli and frequency-specific masking can be combined by embedding tone pips in continuous notched noise. The latter is white noise that has been notch-filtered to remove the basic frequency of the tone pip. Shaping a pure tone into a pip with an onset and an offset introduces power at other frequencies into its frequency spectrum, which would impair the frequency specificity of the test, but the notched noise masks the responses to frequencies other than
Brainstem Auditory Evoked Potentials Click • high-pass noise
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to 15 msec each) produces an evoked potential that contains oscillatory components at the frequency of the tone (Fig. 23-15). Intracranial recordings in animals'" have shown that this frequencyfollowing response does reflect neuronal activity in the brainstem, although care must be taken to avoid contamination by the cochlear microphonic.P? The frequency-following response and the BAEPs do not appear to have the same neural generators.t? Whereas the BAEPs reflect activity originating in the base of the cochlea,35,36 the frequency-following response predominantly reflects activity originating in lower-frequency regions of the cochlea.t'. o
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Stimulus intensity, dB nHL Stimulus intensity, dB nHL FIGURE U·30 • (Left) Latency-intensity curves to left ear (solid line) and right ear (dashed line) stimulation recorded before surgery in a 52-year-old woman with a left-sided intracanalicular acoustic neuroma. The wave V latencyto 70-
Brainstem Auditory Evoked Potentials in Infants and Children
543
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FIGURE 24·16 II Brainstem auditory evoked potentials (BAEPs) from three different children with Hurler's syndrome. The responses were elicited by 70-dB nHI. clicks presented at I I Hz. The top three recordings were obtained before bone marrow transplantation. The recordings illustrate the types of BAEP abnormalities found in these children. The top trace shows delayed waves beginning at wave I, probably caused by conductive hearing loss (seen in two cases). The second trace shows a complete absence of waves that could represent both hearing loss and brainstem dysfunction (seen in two cases). The third trace shows a prolonged interpeak latency indicating brainstem dysfunction (seen in three cases). The fourth trace shows a normal BAEP following bone marrow transplantation in the same child as in the top trace.
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~0.5~V 1 msec
the rate of progression and the severity of Friedreich's ataxia.F" Certain disorders such as kernicterus have a specific predilection for the auditory pathways.l'" In acute bilirubin encephalopathy, BAEPs are absent or severely abnormal. BAEP abnormalities vary with the "bilirubin toxicity," an index that takes into account serum bilirubin, albumin binding, and pH. 153 The BAEP is a good technique for detecting and monitoring the hearing loss that is so often a part of chronic bilirubin encephalopathy. This hearing loss is usually an auditory neuropathy (see p. 534). In general, BAEP abnormalities increase with progression of the degenerative diseases. Repeated tests can therefore help to quantify the rate of progression, a measurement that is often difficult in young children. The BAEP interpeak latencies can improve during the treatment of certain metabolic disorders. For example, BAEPs improve in infants with hyperbilirubinemia after exchange transfusions'Pr "? or phototherapy.157.158 BAEPs have also been used to monitor the neurologic status of children with metabolic disorders who are treated with peritoneal dialysis and dietary restrictions (Fig. 24-18).
BAEPs can help to demonstrate the neurologic effects of environmental tox.ins such as lead and mercury.159-161 The effects are usually small and are demonstrated mainly by comparisons with normal children and by correlations with serum levels of the toxin. Although they cannot clearly demonstrate abnormalities in individual children, they can demonstrate the deleterious neurologic effects of a population's exposure to the toxins. Malnutrition sufficient to cause marasmus or kwashiorkor causes abnormalities of the BAEP, particularly increasing the I-V interpeak latency.162,163 Long-term effects and the relation of BAEP abnormalities to treatment and to other evidence of neurologic abnormality remain to be determined.
Anoxia The BAEPs recorded in infants and children with anoxic brain damage are often abnormal. Prolonged anoxia caused by congenital cardiac disease results in increased I-V interpeak latencies.l'" BAEPs are perhaps
544
ELECTRODIAGNOSIS IN CLINICAL NEUROLOGY
Age
Duration
8
3
I I
2wk
3wk 10
6 1 yr
18
8
+0.5 ""V + 0.5l!V ] ' -........~.........---'----'_~-'--~---'-_ 10 msec FIGURE 14-17 • Friedreich's ataxia. The brainstem auditory evoked potentials (BAEPs) to 8o-dB nHL clicks presented at the rate of 11 Hz are shown for three different patients. For simplicity, only responses obtained from one ear are shown in each case. The first tracing is from an 8-year-old child with a mild ataxia of 3 years' duration, areflexia, posterior column signs, and extensor plantar reflexes. The second tracing is from a 100year-old patient who had been ataxic for 6 years and who also had cord signs and cardiomyopathy. The third tracing is from a patient aged 18 years who had been ataxic for 8 years. This patient had severe ataxia, spinal cord signs, cardiomyopathy, dysarthria, and peripheral neuropathy. The BAEPs show a progressive attenuation of the later components of the response with increasing duration and severity of the disease process. The arrows indicate the identified waves. The first tracings show normal waves I to VI, the second tracings show only waves I to III, the third tracings show no recognizable components after wave 1.
yr
yr
more clinically helpful in evaluating the effects of a specific anoxic episode or period to determine the extent of the anoxic damage and the prognosis for recovery.165-169 The most common abnormalities are attenuation and delay of the later components of the response (Fig. 24-19). The significance of the abnormality depends on the age of the child, the persistence of the abnormality over repeated testing, and the clinical findings. In infants and young children, the abnormal BAEPs that follow an anoxic episode are prognostically less significant than in older children or adults. Severely abnormal BAEPs have been recorded in asphyxiated premature infants who develop normally despite persistence of the BAEP abnormality.l'" In older children, the central nervous system is less resilient than it is in neonates, and abnormal BAEPs following an anoxic episode are more likely to indicate irreversible damage. The BAEP may then be helpful in predicting long-term neurologic sequelae after hypoxia. An abnormally small V/1 amplitude ratio is a particularly bad prognostic
] '---'-.........---''--''''---'----'_"''------'---"''__ 10 msec FIGURE 14·18 • Monitoring the treatment of a metabolic disorder. This child was seen at 2 weeks of age with seizures progressing to coma. The tracings at the top of the figure represent the brainstem auditory evoked potentials (BAEPs) to 80-dB nHL stimuli presented to the right ear at a rate of II Hz. There were no recognizable components. At that time, the serum ammonia level was markedly elevated. A diagnosis of proprionic acidemia was made, and the patient was treated with peritoneal dialysis and dietary restrictions. The second tracing, done 1 week later, showed recognizable waves I, III, and V (arrows) at normal latencies for her age. Since then the patient has continued with a diet low in methionine, isoleucine, valine, and threonine. At the age of 1 year, the BAEPs have shown the normal maturational decrease in latency.
indicator. In asphyxiated children who were not born prematurely, an abnormally small wave V in the presence of normal or only mildly attenuated waves I and III is associated with severe neurologic abnormalities on follow-up examination.P" Such a pattern is likely caused by anoxic damage in the midbrain. When measurements of the V/1 ratio are made, care must be taken not to attenuate wave V by using clicks with too high an intensity or amplifiers with too high a low-frequency cutoff. Abnormal BAEPsrecorded on only one occasion are not very helpful in predicting the long-term neurologic sequelae of anoxia at any age. Although normal responses are usually positive prognostic signs, and absent responses are usually negative signs, BAEPs that are absent or abnormally delayed must be repeated until they stabilize. The resilience of the child's brain is such that absent BAEPs can return to normal within a few weeks.F? The BAEPs may also deteriorate in the first day or two after an anoxic episode. Improvement or deterioration of the BAEP may occur before or in parallel with clinical changes. When BAEPs remain persistently abnormal or absent after an anoxic episode, infants do not do well. The BAEP examines function only in the auditory pathways and cannot evaluate
Brainstem Auditory Evoked Potentials in Infants and Children
545
+3d
L ..... ~=
=c
R
o
Time (msec)
10
0
Time (msec)
10
FIGURE 14·19 • Effects of anoxia on the brainstem auditory evoked potential (BAEP). These tracings were obtained from a 2-year-old who had a cardiac arrest after asphyxia caused by acute epiglottitis. The initial EEG showed a burst-suppression pattern. On the second day of hospitalization, the EEG showed electrocerebral inactivity. The BAEPs at that time (+2 d) showed a normal wave I with severely attenuated or absent later components. The responses to left (L) ear stimulation with 90-dB nHL clicks are shown at the top, and the responses to right (R) ear stimulation are shown at the bottom. On the third day (+3 d), the BAEP to left ear stimulation showed an absence of all waves. The EEG continued to show electrocerebral inactivity. There were no spontaneous respirations, and the patient died on the fourth day of hospitalization.
anoxic damage in other areas of the brain. The prognosis after asphyxia depends on the results of many clinical and laboratory tests, of which the BAEP is only one. Later auditory evoked potentials and responses in other sensory modalities may provide important additional information about the extent of neurologic damage. The effects of anoxia on the BAEP may be more evident when stimuli are presented at rapid rates. The neurologic effects of perinatal anoxia may be detected and followed using BAEPs that are recorded using maximum length sequences that allow stimuli to be presented at rates of several hundred per second. 17J.1 72 Because anoxia can damage the cochlea as well as the brain, it is important to assess the BAEP at threshold as well as at high intensity. In the authors' experience, anoxia can cause a profound hearing loss or a moderate hearing loss with recruitment. In the latter cases, responses at high intensity may be normal. BAEPs in infants who have apneic episodes and are at risk for sudden infant death are usually normal. 173. 174 Abnormalities reported in earlier studies were small and were probably the result of the apneic episodes rather than a sign of a brainstem cause for them.F" We have found the BAEP to be so consistently normal in
these children that its use is not recommended in screening infants who may be at risk for sudden infant death. During a routine follow-up examination of infants who were in the NICU, we recorded completely normal BAEPs in a baby who died without obvious cause on the night after the recording.
Head Injury, Coma, and Brain Death BAEPs in children with head injuries provide information similar to those recorded in adults. 167.l7!'l-178 In general, absent or abnormal BAEPs in a comatose child are a bad prognostic sign. This is particularly true if the BAEPs are persistently abnormal and no peripheral hearing loss is present. A normal BAEP is not necessarily a good prognostic sign because the cerebral cortex can be extensively damaged without affecting the BAEP. The authors have often seen normal BAEPs in comatose children who died within a day. SEPs have been found to be more useful as a general prognostic indicator.179.180 Localization of the brain damage in head-injured children is better determined from the combined recording of evoked potentials to auditory, somatosensory, and visual stimuli than from BAEPs alone.l'"
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ELECTRO DIAGNOSIS IN CLINICAL NEUROLOGY
Peripheral hearing loss is not uncommon after head injury. Unilateral absence ofBAEPs suggests the possibility of a temporal bone fracture with damage to the cochlea or auditory nerve. Endotracheal intubation can result in middle ear effusions, which will delay all components of the BAEP. In these children, high-intensity clicks are often necessary to elicit a recognizable wave 1. The BAEPs may be a helpful adjunct in the clinical diagnosis of brain death. BAEPs in 51 pediatric patients with clinically established brain death (following head injury and other causes) showed a recognizable wave I was present in about a third of the patients (an incidence higher than in adults) but no waves III or V.182 The BAEPs were more compatible with the clinical diagnosis of brain death than the EEG, which often showed residual activity.
Cognitive Disorders Several studies have found abnormal BAEPs in patients with autismYl3-IS6 The findings have included abnormally delayed interpeak latencies or raised thresholds. The abnormalities are not pathognomonic for autism because a group of autistic patients without mental retardation or epilepsy showed completely normal BAEPs.18? The auditory abnormalities that they represent are probably part of a diffuse or multifocal brain dysfunction and are not directly related to the autistic behavior. Nevertheless, distorted auditory input could certainly exacerbate the underlying disorder and further impede normal development. Some work has suggested that BAEP abnormalities may serve as a marker for an autistic phenotype.l'" Rett syndrome is a disorder in girls characterized by mental retardation, autistic behavior, ataxia, and stereotyped hand movements. The EEG is quite abnormal, with multifocal spike discharges and slowing. Some researchers have found that BAEPs show a specific delay in the III-V interval in certain patients.18B.189 However, we have found BAEPs to be normal in 15 of 16 cases of Rett syndrome (the only abnormal case having a delayed III-V interpeak interval), which is consistent with other recent reports that the BAEP is usually normal in this disorder.P" BAEPs with abnormal waveforms and raised thresholds have also been found in mentally retarded children. 191,J92 Patients with Down syndrome show an interesting decrease in interpeak latencies that is not related to head size or hearing loss. Although some studies have reported smaller BAEP waves in undifferentiated mental retardation.P" such has not been our experience. Neurologic damage in infancy can go undetected because the infant has not yet developed to a stage
where the damaged tissue is used. BAEPs may be helpful in documenting brain damage in the perinatal period. 194,195 An extensive study of the development of the BAEP in infancy differentiated a group of infants at risk for central nervous system damage from a group of healthy infants on the basis of the amplitudes of waves III and V.195 The at-risk infants failed to show the normal maturational increase in amplitude of these waves. Unfortunately, because of the large intersubject variability in amplitude measurements, it is impossible to make any definite comments about individual babies. Furthermore, it is as yet uncertain whether the BAEP abnormalities are related to the actual neurologic and intellectual outcome of the high-risk infants. Because the BAEPs were evoked by binaural stimuli, their small amplitude in some children may have related to unilateral conductive hearing loss. A common reason for BAEP referral in childhood is a delay in the development of speech and language. After mental retardation, a hearing impairment is the most common cause of delayed speech and language. Many mentally retarded children have a hearing impairment in addition to their neurologic disorder. Children with delayed speech and language who have normal intelligence and no peripheral hearing loss may have a central auditory dysfunction. Some of these children have abnormalities of the BAEP.196,197 More extensive studies of auditory evoked potentials at all latenciesl'" and of the auditory steady-state responses'P" may help to classify these abnormalities of Auditory perception.
CONCLUDING COMMENTS The BAEP can provide important information about a child's cochlear and brainstem function. The results of BAEP testing must be interpreted cautiously. It is particularly difficult to evaluate hearing when neurologic abnormalities are present and to evaluate brainstern function when peripheral hearing is impaired. Furthermore, the BAEP must never be considered in isolation. It can indicate dysfunction but cannot determine the specific etiology of this dysfunction. Its great advantages are that it does not require the cooperation of the child and that it provides replicable measurements oflatency, amplitude, and threshold. BAEPs are therefore an essential part of the audiologic test battery and a helpful adjunct to the neurologic examination.
ACKNOWLEDGMENTS We appreciate the financial support of the Medical Research Council, the National Health Research and Development Program, the Ontario Deafness Research Foundation, the Research Foundation of the Hospital
Brainstem Auditory Evoked Potentials in Infants and Children
for Sick Children, and the Research Institute of the Children's Hospital of Eastern Ontario. Richard Mowrey, Chris Edwards, Linda Moran, Janice Pearce, Lynn MacMillan, Nancy Keenan, Patricia Van Roon, and Sandra Champagne helped with the recordings.
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107. Sininger YS: Auditory neuropathy in infants and children: implications for early hearing detection and intervention programs. Audiology Today, 14:16, 2002 108. Shallop ]K, Peterson A, Facer GW et al: Cochlear implants in five cases of auditory neuropathy: postoperative findings and progress. Laryngoscope, 111:555, 2001 109. Mason ]C, De Michele A, Stevens C et al: Cochlear implantation in patients with auditory neuropathy of varied etiologies. Laryngoscope, 113:45, 2003 110. Taylor M]: Evoked potentials in paediatrics. p. 489. In Halliday AM (ed): Evoked Potentials in Clinical Testing. 2nd Ed. Churchill Livingstone, Edinburgh, 1993 111. Taylor M], Saliba E, Laugier J: Use of evoked potentials in preterm neonates. Arch Dis Child (Fetal Neonatal Ed), 74:F70, 1996 112. Frank Y, Vishnubhakat SM, Pahwa S: Brainstem auditory evoked responses in infants and children with AIDS. Pediatr Neurol, 8:262, 1992 113. Brivio L, Tornaghi R, Musetti L et al: Improvement of auditory brainstem responses after treatment with zidovudine in a child with AIDS. Pediatr Neurol, 7:53,1990 114. Hecox KE, Cone B, Blaw ME: Brainstem auditory evoked response in the diagnosis of pediatric neurologic diseases. Neurology, 31:832, 1981 115. Davis SL, Aminoff M], Berg BO: Brain-stem auditory evoked potentials in children with brain-stem or cerebellar dysfunction. Arch Neurol, 42:156, 1985 116. Pikus AT: Pediatric audiologic profile in type 1 and type 2 neurofibromatosis.] Am Acad Audiol, 6:54, 1995 117. Evans DG, Newton V, Neary W et al: Use of MRI and audiological tests in presymptomatic diagnosis of type 2 neurofibromatosis (NF2).] Med Genet, 37:944, 2000 118. Nodal' RH, Hahn ]F, Erenberg G et al: Improvement of brainstem auditory evoked potential test results following intervention for brainstem tumors. p. 228. In Nodal' RH, Barber C (eds): Evoked Potentials II. Butterworths, Boston, 1984 119. Pensak ML, Keith RW, Digman PS et a1: Neuroaudiologic abnormalities in patients with type 1 neurofibromatosis. Laryngoscope, 99:702, 1989 120. Duffner PK, Cohen ME, Seidel FG et al: The significance of MRI abnormalities in children with neurofibromatosis. Neurology, 39:373, 1989 121. Edwards CG, Durieux-Srnith A, Picton TW: Auditory brainstem response audiometry in neonatal hydrocephalus.] Otololaryngol, 14:SuppI14, 40,1985 122. Kraus N, Ozdamar 0, Heydemann PT et al: Auditory brain-stem responses in hydrocephalic patients. Electroencephalogr Clin Neurophysiol, 59:310,1984 123. McPherson DL, Amlie R, Folta E: Auditory brainstem response in infant hydrocephalus. Childs Nerv Syst, 1:70,1985 124. Liitschg], Meyer E, ]eanneret-Iseli C: Brainstem auditory evoked potentials in meningomyelocele. Neuropediatrics, 16:202, 1985 125. Stone .JL, Bouffard A, Morris R et al: Clinical and electrophysiologic recovery in Arnold Chiari malformation. Surg Neurol, 20:313, 1983 126. Docherty TB, Herbaut AG, Sedgwick EM: Brainstem auditory evoked potential abnormalities in myelomeningo-
coele in the older child.] Neurol Neurosurg Psychiatry, 50:13, 1987 127. Taylor M], Boor R, Keenan NK et al: Brainstem auditory and visual evoked potentials in infants with myelomengingocele. Brain Dev, 18:99, 1996 128. Anderson RC, Dowling KC, Feldstein NA et al: Chiari I malformation: potential role for intraoperative electrophysiologic monitoring. J Clin Neurophysiol, 20:65, 2003 129. Lott IT, McPherson DL, Starr A: Cerebral cortical contributions to sensory evoked potentials: hydranencephaly. Electroencephalogr Clin Neurophysiol, 64:218, 1986 130. Kaga K, Yasui T, fuge T: Auditory behaviors and auditory brainstem responses of infants with hypogenesis of cerebral hemispheres. Acta Otolaryngol, 122:16,2002 131. Garg BP, Markand ON, DeMyer WE: Usefulness of BAEP studies in the early diagnosis of Pelizaeus-Merzbacher disease. Neurology, 33:955, 1983 132. Kaga M, Murakami T, Naitoh H et al: Studies on pediatric patients with absent auditory brainstem response (ABR) later components. Brain Dev, 12:380, 1990 133. Yamanouchi H, Kaga M, Iwasaki Yet al: Auditory evoked responses in Krabbe disease. Pediatr Neurol, 9:387, 1993 134. Nezu A: Neurophysiological study in PelizaeusMerzbacher disease. Brain Dev, 17:175, 1995 135. Wang P], Young C, Liu HM et al: Neurophysiologic studies and MRI in Pelizaeus-Merzbacher disease: comparison of classic and connatal forms. Pediatr Neurol, 12:47, 1995 136. Kaga K, Tokoro Y, Tanaka Y et al: The progress of adrenoleukodystrophy as revealed by auditory evoked responses and brain stem histology. Arch Otorhinolaryngol, 228:17, 1980 137. De Meirleir L], Taylor M], Logan V\]: MuItimodal evoked potential studies in leukodystrophies of children. Can] Neurol Sci, 15:26, 1988 138. Garg BP, Markand ON, DeMyer WE et a1: Evoked response studies in patients with adrenoleukodystrophy and heterozygous relatives. Arch Neurol, 40:356, 1983 139. Schmidt S, Traber F, Block W: Phenotype assignment in symptomatic female carriers of X-linked adrenoleukodystrophy.] Neurol, 248:36, 2001 140. Guilhoto LM, Osorio CA, Machado LR et al: Pediatric multiple sclerosis: report of 14 cases. Brain Dev, 17:9, 1995 141. Markand ON, Garg BP, Brandt lK: Nonketotic hyperglycinemia: electroencephalographic and evoked potential abnormalities. Neurology, 32:151, 1982 142. Brin MF, Pedley TA, Lovelace RE et al: Electrophysiologic features of abetalipoproteinemia. Neurology, 36:669, 1986 143. Fagan ER, Taylor MJ: Longitudinal multimodal evoked potential studies in abetalipoproteinemia. Can] Neurol Sci, 14:617, 1987 144. Kaga M, Naitoh H, Niher K: Auditory brainstem response in Leigh's syndrome. Acta Paediatr Jpn, 29:254, 1987 145. Taylor M], Robinson BH: Evoked potentials in children with oxidative metabolic defects leading to Leigh's syndrome. Pediatr Neurol, 8:25, 1992
Brainstem Auditory Evoked Potentials in Infants and Children 14(;. Lacey DJ. Terplan K: Correlating auditory evoked and brainstem histologic abnormalities in infantile Gaucher's disease. Neurology, 34:539, 1984 147. Aisen M, Rapoport S, Solomon G: Brainstem auditory evoked potentials in two siblings with Niemann-Pick disease. Brain Dev, 7:431,1985 148. Kaga K, Marsh RR, Fukuyama Y: Auditory brain stem responses in infantile spasms. Int J Pediatr Otorhinolaryngol, 4:il7, 1982 149. Hsu YS, Chang YC, Lee WT et al: The diagnostic value of ~ensory evoked potentials in pediatric Wilson disease. Pediatr Neurol, 29:42, 2003 150. Taylor MJ, McMenamin JB, Andermann E et al: Electrophysiological investigation of the auditory system in Friedreich's ataxia. CanJ Neurol Sci, 9:131, 1982 151. Cassandro E, Mosca F, Sequino L et al: Otoneurological findings in Friedreich's ataxia and other inherited neuropathies. Audiology, 25:84, 1986 152. Taylor M], Chan-Lui WY, Logan WJ: Longitudinal evoked potential studies in hereditary ataxias. Can] Neurol Sci, 12:100, 1985 15:j. Esbjorrner E, Larsson 1', Leissner I' et al: The serum reserve albumin concentration or monoacetyldiaminodiphenyl sulphone and auditory evoked responses during neonatal hyperbilirubinaemia. Acta Paediatr Scand, 80:406, 1991 1M. Chin KC, Taylor MJ, Perlman M: Improvement in audiLOry and visual evoked potentials in jaundiced preterm infants after exchange transfusion. Arch Dis Child, 60:714, 1985 I5il. Wennberg RP, Ahlfors CE, Bickers R et al: Abnormal auditory brainstern response in a newborn infant with hyperbilirubinemia: improvement with exchange transfusion.] Pediatr, 100:624, 1982 150. Perlman M, Fainmesser P, Sohmer H et al: Auditory nerve-brainstem evoked responses in hyperbilirubinemic neonates. Pediatrics, 72:658, 1983 157. Hung KL: Auditory brainstem responses in patients with neonatal hyperbilirubinemia and bilirubin encephalopathy. Brain Dev, 11:297, 1989 158. Tan KL, Skurr BA, Yip W: Phototherapy and the brainstem auditory evoked response in neonatal hyperbilirubinemia.J Pediatr, 120:306, 1992 159. Rothenberg ~J, Poblano A, Garza-Morales S: Prenatal and perinatal low-level lead exposure alters brainstem auditory evoked responses in infants. Neurotoxicology, l5:695,1994 160. Rothenberg SJ, Poblano A, Schnaas L: Brainstem auditory evoked response at five years and prenatal and postnatal blood lead. Neurotoxicol Teratol, 22:503, 2000 161. Counter SA: Neurophysiological anomalies in brainstem responses of mercury-exposed children of Andean gold miners.] Occup Environ Med, 45:87, 2003 lfj\!. Bartel PR, Robinson E, Conradie JM et al: Brainstem auditory evoked potentials in severely malnourished children with kwashiorkor. Neuropediatrics, 17:178, 1986 163. Durmaz S, Karagol U, Deda G et al: Brainstem auditory and visual evoked potentials in children with proteinenergy malnutrition. Pediatr Int, 41:615, 1999
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164. Sunaga Y, Sone K, Nagashima K et al: Auditory brainstem responses in congenital heart disease. Pediatr Neurol, 8:437, 1992 165. Hecox KE, Cone B: Prognostic importance of brainstern auditory evoked responses after asphyxia. Neurology, 31:1429,1981 166. Stockard ]E, Stockard lJ, Kleinberg F et al: Prognostic value of brainstem auditory evoked potentials in neonates. Arch Neurol, 40:360, 1983 167. LiitschgJ, PfenningerJ, Ludin HI' et al: Brain-stem auditory evoked potentials and early somatosensory evoked potentials in neuro-intensively treated comatose children. AmJ Dis Child, 137:421, 1983 168. Majnemer A, Rosenblatt B, Riley 1': Prognostic significance of the auditory brainstem evoked response in high-risk neonates. Dev Med Child Neurol, 30:43, 1988 169. Kaga K, Ichimura K, Kitazumi E et al: Auditory brainstem responses in infants and children with anoxic brain damage due to near-suffocation or near-drowning. Int J Pediatr Otorhinolaryngol, 36:231, 1996 170. Taylor MJ, Houston BD, Lowry NJ: Recovery of auditory brainstem responses in severe hypoxic-ischemic insult. N EnglJ Med, 309:1169,1983 171. Jiang ZD, Brosi DM, Shao XM et al: Maximum length sequence brainstem auditory evoked responses in term neonates who have perinatal hypoxia-ischemia. Pediatr Res, 48:639, 2000 172. Jiang ZD, Brosi DM, WangJ et al: Time course of brainstem pathophysiology during first month in term infants after perinatal asphyxia, revealed by MLS BAER latencies and intervals. Pediatr Res, 54:680, 2003 173. Kileny 1', Finer N, Sussman I' et al: Auditory brainstem responses in sudden infant death syndrome: comparison of siblings, "near-miss," and normal infants. J Pediatr, 101:225, 1982 174. Stockard lJ: Brainstem auditory evoked potentials in adult and infant sleep apnea syndromes. including sudden infant death syndrome and near-miss for sudden infant death. Ann N YAcad Sci, 388:443, 1982 175. De Meirleir LJ, Taylor MJ: Evoked potentials ill comatose children: auditory brainstem responses. Pediatr Neurol, 2:31, 1986 176. Ottaviani F, Almadori G, Calderazzo AB et al: Auditory brainstem (ABRs) and middle latency auditory responses (MLRs) in the prognosis of severely headinjured patients. Electroencephalogr Clin Neurophysiol, 65:196, 1986 177. Bosch Blancafort J, Olesti Marco M, Poch Puig JM et al: Predictive value of brain-stem auditory evoked potentials in children with post-traumatic coma produced by diffuse brain injury. Childs Nerv Syst, 11:400, 1995 178. Butinar D, Gostisa A: Brainstem auditory evoked potentials and somatosensory evoked potentials in prediction of posttraumatic coma in children. Eur ] Physiol, 43l:Suppl 2, R289, 1996 179. De Meirleir LJ, Taylor MJ: Prognostic utility of SEPs in comatose children. Pediatr Neurol, 3:78, 1987 180. Becca ], Cox PN, Taylor M] et al: Somatosensory evoked potentials for prediction of outcome in acute severe brain injury.J Pediatr, 126:44, 1995
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181. Goodwin SR, Friedman WA, Bellefleur M: Is it time to use evoked potentials to predict outcome in comatose children and adults? Crit Care Med, 19:518, 1991 182. Ruiz-Lopez MJ, Martinez de Azagra A, Serrano A et al: Brain death and evoked potentials in pediatric patients. Crit Care Med, 27:412, 1999 183. Taylor MJ, Rosenblatt B, Linschoten L: Auditory brainstem response abnormalities in autistic children. Can J Neurol Sci, 9:429, 1982 184. Tanguay PE, Edwards RM, Buchwald J et al: Auditory brainstem evoked responses in autistic children. Arch Gen Psychiatry, 39:174, 1982 185. Maziade M, Merette C, Cayer M et al: Prolongation of brainstem auditory-evoked responses in autistic probands and their unaffected relatives. Arch Gen Psychiatry, 57:1077, 2000 186. Rosenhall V, Nordin V, Brantberg K et al: Autism and auditory brain stem responses. Ear Hear, 24:206, 2003 187. Courchesne E, Courchesne RY, Hicks G et al: Functioning of the brainstem auditory pathway in nonretarded autistic individuals. Electroencephalogr Clin Neurophysiol, 61:491, 1985 188. Bader GG, Witt-Engerstrom I, Hagberg B: Neurophysiological findings in the Rett syndrome, II: visual and auditory brainstem, middle and late evoked responses. Brain Dev, 11:110, 1989 189. Pe1son RO, Budden SS: Auditory brainstem response findings in Rett syndrome. Brain Dev, 9:514, 1987 190. Verma Np, Nigro MA, Hart ZH: Rett syndrome a gray matter disease? Electrophysiologic evidence. Electroencephalogr Clin Neurophysiol, 67:327,1987
191. Squires N, Ollo C, Jordan R: Auditory brainstem responses in the mentally retarded: audiometric correlates. Ear Hear, 7:83, 1986 192. Jiang ZD, Wu YY, Liu XV: Early development of brainstem auditory evoked potentials in Down's syndrome. Early Hum Dev, 23:41, 1990 193. Karmel BZ, Gardner JM, Zappulla R et al: Brainstem auditory evoked responses as indicators of early brain insult. Electroencephalogr Clin Neurophysiol, 71:429, 1988 194. Kitamoto 1, Kukita], Kurukawa T et al: Transient neurologic abnormalities and BAEPs in high-risk infants. Pediatr Neurol, 6:319,1990 195. Salamy A, Mendelson T, Tooley WH et al: Differential development of brainstem potentials in healthy and high-risk infants. Science, 210:553, 1980 196. Maison S, Duclaux R, Ferber-Viart C et al: Clinical interest of brainstem auditory evoked potentials in 72 children with inadequate language development. Int J Neurosci, 88:261, 1996 197. Blegvad B, Hvidegaard T: Hereditary dysfunction of the brainstem auditory pathways as the major cause of speech retardation. ScandAudiol, 12:179, 1983 198. Mason SM, Mellor DH: Brain-stem, middle latency and late cortical evoked potentials in children with speech and language disorders. Electroencephalogr Clin Neurophysiol, 59:297, 1984 199. Stefanatos GA,Foley C, Grover Wet al: Steady-state auditory evoked responses to pulsed frequency modulations in children. Electroencephalogr Clin Neurophysiol, 104:31, 1997
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CHAPTER
27 Motor Evoked Potentials NICHOLAS M. F. MURRAY
PHYSIOLOGIC ASPECTS Facilitation Repetitive Firing METHODS Electrical Stimulation of the Cortex Magnetic Stimulation of the Cortex Determination of Central Motor Conduction Time Spinal Cord and Brainstem Stimulation NORMATIVE DATA PATHOPHYSIOLOGY OF ABNORMALITIES IN CENTRAL MOTOR CONDUCTION Triple-Stimulation Technique Paired-Pulse Stimuli Silent Period Repetitive Transcranial Magnetic Stimulation FINDINGS IN NEUROLOGIC DISORDERS Multiple Sclerosis
The term motor evoked potentials (MEPs) refers to the electrical potentials recorded from muscle, peripheral nerve, or spinal cord in response to stimulation of the motor cortex or the motor pathways within the central nervous system (CNS) . For most clinical and research purposes, transcutaneous magnetic stimulation of the motor cortex is used with recording of the compound muscle action potential (CMAP).I Transcutaneous electrical stimulation of the cortex- has a more restricted clinical application because, in contrast to the magnetic technique, it may be painful. Both techniques provide important insights into motor control in normal subjects and disease states. Until quite recently, direct noninvasive investigation of conduction in central motor pathways has not been possible, although a variety of indirect methods have been used for clinical purposes. Transcutaneous electrical stimulation of the motor cortex of animals was reported in the 1870s when Fritsch and Hitzig in Germany and Ferrier in England showed that muscle twitches could be caused by the application of electrical
Motor Neuron Disease Cervical Spondylosis Stroke Miscellaneous Hereditary, Ataxic, and Peripheral Nerve Disorders Movement Disorders Epilepsy Functional Weakness INTRAOPERATIVE MONITORING STIMULATION OF PERIPHERAL NERVES AND ROOTS STIMULATION OF CRANIAL NERVES DEPRESSION SAFETY CONSIDERATIONS MAPPING AND PLASTICITY CONCLUDING COMMENTS
stimuli to relevant areas of the scalp, but subsequent studies in humans proved unacceptably painful.v' The recording of MEPs became a viable proposition in 1980 when Merton and Morton devised an electrical stimulator that could excite the motor cortex transcutaneously by single shocks of short duration (10-llsec timeconstant of decay) and high voltage (up to 2,000 V).2 The threshold for excitation was lower with anodal than with cathodal stimuli. A moderate voluntary contraction of the target muscle reduced the latency and increased the amplitude of the MEP elicited by cortical stimulation but had no effect on the muscle response evoked by similar stimuli over the cervical spine." It was subsequently shown that electrical stimuli delivered by this device over the lower cervical region activated the C8 and T1 motor roots in the region of the intervertebral foramina to produce responses in small muscles of the hand, and that stronger spinal stimuli could also excite descending tracts to lower-limb and sphincter muscles.v" Stimulation at the level of the pyramidal decussation has also been reported."
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Clinical studies in patients with multiple sclerosis revealed a high incidence of abnormalities, consisting either of a prolonged central motor conduction time (CMCT) or of absent responses to cortical stimulation. 1D-12 Studies on patients, however, have been limited because of discomfort resulting from the high current density at the scalp, although this may be reduced by modifications to the pulse duration and to the type of cathode. 13 Magnetic stimulation of the cortex was introduced in 1985; this procedure relies on Faraday's principle of mutual induction, whereby a current-carrying primary circuit will cause current to flow in an adjacent secondary circuit.v' A strong time-varying magnetic field produced by passing a current through a coil can induce stimulating currents in nearby neural tissue such as peripheral nerve or brain. A magnetic stimulator was devised by Barker with the aim of achieving painless excitation of peripheral nerves, and this device was subsequently shown to be capable of noninvasive and painless stimulation of the motor cortex, the first subject being P.A. Merton at the National Hospital, London.lt" The magnetic stimulator devised by Barker consists of a copper coil that generates a brief but intense magnetic field when a large current pulse is passed through it. A capacitor charged up to 4 kV is discharged and a current of up to 5,000 A passes through the coil, causing a magnetic pulse of up to 2 Tesla, peaking at l6011sec (Fig. 27-1). When the coil is placed over the vertex of the scalp, the magnetic field passes unattenuated through the skin and skull, inducing stimulating electrical eddy currents in underlying motor cortex. In striking contrast to transcutaneous electrical stimulation, current density at the surface is low and no pain is caused. Various modifications have been introduced without affecting the basic principles of magnetic stim-
l-----l
200 usee FIGURE 27-1 • Time-courses of the magnetic field generated by passage of an inducing current through Barker's stimulat-
ing coil and the induced current under the coil center.
ulation. Perhaps the most important of these was the introduction of a figure-of-eight coil configuration instead of the original circular shape; this increased precision of stimulation because activation occurs beneath the site of intersection rather than under the annulus.'? The coil does not have to be in physical contact with the skin. In addition to stimulating the brain, it is capable of exciting deep-seated peripheral nerves and roots, but not the spinal cord. Magnetic stimulators have since been devised that employ multiple capacitors, discharging through a single coil to deliver stimuli at up to 100 Hz. These frequencies may cause heating of the coil sufficient to endanger both the subject and the equipment, so that a water or oil cooling system is essential for repetitive transcranial magnetic stimulation (rTMS).
PHYSIOLOGIC ASPECTS When a brief, low-intensity, anodal electrical stimulus is delivered to the exposed motor cortex of a monkey, the axons of pyramidal tract neurons are activated in the region of the axon hillock or the first internode, and a single descending volley is recordable in the pyramidal tract. 18 ,19 This wave was termed the D wave, or direct wave, because its latency (0.4 to 0.6 msec in the monkey) is too short to allow for an interposed synapse. At higher intensities of stimulation a series of descending volleys can be recorded, following the D wave at intervals of about 2 msec. These have been termed I waves to indicate their indirect origin, and they appear to require intact gray matter; they are probably caused by transsynaptic activation of the same corticospinal neurons but through intracortical neural elements (Fig. 27-2). The I waves are abolished if the cortex is cooled or ablated, but the initial D wave remains. Cathodal shocks are less effective than are anodal shocks for producing motor responses. This is probably because during surface anodal stimulation, current flows into the dendrites of the pyramidal tract cells and exits at the axon hillock or first internode, causing an action potential that produces the D wave. With higher intensities of stimulation, other cortical elements are activated, including interneurons or afferents to the cortex; transsynaptic excitation of pyramidal output neurons results in I waves in the pyramidal tract. During cathodal surface stimulation, current flows in the wrong direction to depolarize the axon hillock; accordingly, the threshold for D-wave activation is high and there is emphasis on I waves, the relative threshold for indirect transsynaptic excitation being 10W. 20,21 Studies of single motor unit behavior and direct recordings of descending volleysin the spinal cord during neurosurgical procedures indicate that similar phenomena occur in humans during transcranial stimulation.P Motor
Motor Evoked Potentials
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Motor Evoked Potentials ~ Magnetic Field Lines
---Inducing Current
-Coil
--Induced Current FIGURE 27-2 II Schematic representation of the multiple descending volleys evoked by a single transcutaneous stimulus to the motor cortex. Anodal electrical stimulation activates the corticomotoneuron in the region of the axon hillock, causing an initial D wave and subsequent series of I waves. Magnetic stimulation activates the corticomotoneuron transsynaptically, causing a volley of I waves but no D wave. A high-intensity stimulus, of either type, may cause repetitive firing of the anterior horn cell.
unit studies depend on the construction of a peristimulus time histogram (PSTH) of motor unit firing probability to show how the firing behavior of a voluntarily activated motor unit has been altered by randomly timed cortical shocks. With low-intensity electrical stimuli, a single peak is discernible in the histogram; this probably reflects the excitatory postsynaptic potential at the spinal motor neuron resulting from a single D-wave volley in the pyramidal tract. With higher intensities of stimulation, there are multiple peaks that relate to both D- and I-wave volleys in the pyramidal tract. With transcranial electrical stimuli of increasing intensity, direct recordings from the cervicomedullary junction (exposed during surgery) show an initial wave with a latency of about 2 msec and later waves with stronger stimuli (Fig. 27-3). It seems likely that these are also the equivalent of the D and I waves recorded in primates.
With magnetic stimulation at the vertex in humans, responses from small muscles of the hand have longer onset latencies (by about 2 msec) than do the responses induced electrically.P CMAPs to magnetic stimulation are also of rather simpler waveform, shorter duration, and larger amplitude (Fig. 27-4). The latency difference is consistent with the time interval between the D wave and the first I wave, and it is likely that magnetic stimulation preferentially excites corticomotoneurons transsynapticaIIy, resulting in descending volleys composed mostly of! waves.v' It should be noted, however, that with certain lateral coil placements and the use of stimuli of very high intensity, the latency of the response may shorten slightly, consistent with D-wave generation. Supportive evidence has been provided by single motor unit studies, which have also been used to examine the effects of the direction of current flow in
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D
D
6.6 msec 4.9 msec 3.6 msec
A
1.8 msec 15 msec
I5.2 6.8 msec msec
B
FIGURE 27-3 • Cervicomedullary potentials to high-intensity electrical stimulation of the motor cortex during light anesthesia; a D wave is followed by a series of I waves. A, Differential of recordings and omission of stimulus artifact demonstrates waves more clearly than (B) raw traces.
I 4 msec 1.9 msec 15 msec
the magnetic coiI.25 Responses in muscles of the right hand to anticlockwise stimulation (current direction being defined according to the flux of negativity) are of slightly shorter latency than are those with clockwise stimulation, the difference being comparable to that between succeeding I waves or peaks in a PSTH. It seems that the direction of current flow induced in the cortex affects the activation of synaptic inputs to the corticomotoneuron responsible for generating the various I waves. Responses from lower-limb muscles are of similar latency with electrical and magnetic stimuli. This indicates that both methods have the same activation site caused by D-wave activity initiated in the rostal pyramidal axons as they leave the cortex."
Facilitation Voluntary activation of a muscle has a considerable effect on both the amplitude and the latency of the responses evoked in that muscle by cortical stimulation, a phenomenon known as facilitation (Fig. 27_5).23.27 The threshold for activating a muscle is reduced by voluntary contraction, and the amplitude of the CMAP is much larger for a given stimulus intensity than when the muscle is relaxed; the onset latency of the CMAP is reduced in the contracting muscle by 2 to 4 msec. The relationship between background force and CMAP amplitude is approximately linear with electrical stimulation, whereas during magnetic stimulation a small background contraction (about 5 percent of maximum)
Wrist el.
C7-T1 el.
Scalp mag.
Scalp el.
-y-
-f\v----Pv--~-
FIGURE 27-4. Responses from abductor digiti minimi muscle in two healthy subjects to electrical stimulation (el.) of the ulnar nerve at the wrist and over the C7-Tl interspace and to anodal electrical and magnetic (mag.) stimulation of the motor cortex. Responses to magnetic cortical stimulation are larger and of slightly longer latency than those evoked by electrical stimuli.
Motor Evoked Potentials
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Repetitive Firing
12% force 3% force 1.5% force Relaxed
I
I
10 msec FIGURE 17-5 • Effect of voluntary contraction on motor evoked potentials to 20 percent suprathreshold magnetic stimulation, recording from the abductor digiti minirni muscle. From bottom: Muscle relaxed and contraction force of 1.5 percent, 3 percent, and 12 percent maximum. The latency decreases and the amplitude increases with voluntary contraction.
has a marked effect on both amplitude and latency of the response. Contraction of the same muscle on the opposite side (so-called contralateral facilitation) has a similar effect on latency but only a moderate effect on amplitude; activation of more distant muscles has relatively little influence. It would appear that several physiologic mechanisms, both cortical and spinal, affect facilitation. Single motor unit studies suggest that some of the facilitatory effect during voluntary contraction occurs at the level of the anterior horn cell; if the motor neuron threshold is lowered by voluntary activation, neuronal discharge can occur on an earlier descending volley. Thus, with electrical stimulation the initial D wave may be insufficient to discharge the motor neuron, and summation with a following I wave may be required; during voluntary contraction, there may be sufficient motor neurons near threshold for activation to occur with the D wave, causing a shortening of latency. Summation of the first or second and later I waves is probably responsible for a similar phenomenon with magnetic stimulation. The size principle of Henneman may also operate: the first corticomotoneurons to fire during a voluntary contraction are those with axons conducting slowly, and larger, faster-conducting neurons are recruited with increasing contraction. The first motor units to be stimulated magnetically are also the first to fire under voluntary control and are of relatively long latency." Later, larger units with faster-conducting axons have shorter latencies.
With higher-intensity electrical or magnetic stimuli, multiple firing may occur at the level of the anterior horn cell (see Fig. 27-2). The duration and complexity of the evoked CMAP continue to increase with increasing stimulus intensity even after the peak-to-peak amplitude has saturated; twitch force also increases, so that the force generated by a single maximal cortical stimulus may exceed that evoked by a supramaximal stimulus to the peripheral nerve. Collision studies have confirmed that this is caused by multiple repetitive firing of alpha motor neurons in response to a descending volley, a phenomenon with important implications for clinical studies relying on amplitude or twitch tension, at least at high stimulus intensities.20.21.23 More detailed reviews of physiologic mechanisms and activation sites with magnetic and electrical stimulation are provided elsewhere. 26,2R
METHODS Recordings for clinical purposes are usually made with a conventional electromyograph connected to the stimulator and with surface electrodes fixed to the target muscle. CMCT is estimated by subtracting the time for conduction along the peripheral portion of the motor pathway to the muscle from the total latency of the electromyographic (EMG) response following cortical stimulation.
Eledrical Stimulation of the Cortex For most clinical purposes, electrical stimulation of the cortex has long been superseded by magnetic stimulation; however, it has an important role in certain physiologic studies, where a modification of the apparatus devised by Merton and Morton is used. Usually, a single stimulus is delivered, of up to 700 V with a half-time for discharge of 50 or 100 usee. For bipolar stimulation the anode is placed over the relevant area of the motor cortex, with the cathode at the vertex. 10,1 I Electrical stimulation is particularly useful for intraoperative monitoring of MEPs, the stimulator being modified to deliver short trains of stimuli at 1- to 6-msec intervals rather than single shocks.s?
Magnetic Stimulation of the Cortex For investigation of conduction to small hand muscles, a circular coil is used, centered at the vertex; precise coil position is not critical and movements of a centimeter or so away from the vertex have little effect on
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ELEaRODIAGNOSIS INCLINICAL NEUROLOGY
responses. The left hemisphere is preferentially activated when the inducing current travels in an anticlockwise direction as viewed from above; the coil is turned over to reverse the direction of the current and to stimulate the opposite side. Responses can be recorded with the target muscle either relaxed or modestly contracted; there are advantages and disadvantages to each approach, but the state of activity must be specified in view of the known effects on amplitude and latency. If facilitatory contraction is used, it should be in the range of 10 to 20 percent of a maximal contraction. With very weak contractions, small inconsistencies will affect response latency, whereas with strong contractions the background EMG is excessive. The ongoing muscle activity of a facilitatory contraction may make measurement of onset-latency difficult when responses are small because of pathology in the eNS; in such circumstances, complete relaxation of the target muscle, but moderate contraction of the homologous contralateral muscle, results in the same reduction of latency and a useful increase in amplitude.F This technique may also be useful in patients with anterior horn cell disease in whom early recruitment of giant units can make it difficult to determine response onset. The routine testing of muscles in the relaxed state provides a "cleaner" baseline, but the responses are smaller, and in pathologic states the incidence of unobtainable responses is relatively high. A stimulus intensity that is about 20 percent higher than the threshold for evoking muscle responses usually produces fairly reproducible responses, but some variability in onset latency and amplitude is inevitable regardless of whether the target muscle is relaxed or contracted; this is a function of summating descending volleys and spontaneous fluctuations in corticospinal excitability. The effect of variability can be minimized by taking the shortest onset-latency and the largest amplitude from a series of four or five consecutive responses. Amplitude may be expressed in absolute terms but, at least for the small muscles of the hand, it may be expressed more meaningfully as a percentage of the CMAP evoked by peripheral nerve stimulation.t" Caution is required for studies of twitch tension and of the duration and area of the CMAP in view of the possibility of repetitive firing of anterior horn cells with stimuli of high intensity. Proximal muscles in the upper limbs generally require stimuli of a rather higher intensity than hand muscles. The phenomenon of facilitation has been investigated less thoroughly in them, but for clinical purposes the procedures used can be similar to those used for the hand muscles. Muscles in the lower limbs may be studied using either a circular coil or a coil with a figure-of-eight configuration. Depending on the magnetic stimulator in use, lower-limb responses may not be obtained in up to
10 percent of normal subjects with a circular coil, whereas the figure-of-eight coil is almost always successfu1. 3 ,31- 33 The disadvantage of the figure-of-eight coil is that very precise placement may be required because excitation occurs quite focally beneath the site of intersection. A similar technique may be used for recording from the bulbocavernosus, sphincter, and pelvic floor muscles.r' Voluntary contraction of muscles in the lower limb affects response onset and amplitude, whereas "postural facilitation," the normal activation of distal leg muscles during stance, enhances the amplitude of CMAPs without affecting their latency."
Determination of Central Motor Condudion Time Various techniques are available for estimating the peripheral segment of the motor pathway so that CMCT can be measured.l'' In the case of distal muscles of the upper and lower limbs, F waves can be evoked by peripheral nerve stimulation. The formula (F + M - 1) .;. 2 may be used to calculate the conduction time from the alpha motoneuron to the muscle; F is the F-wave latency (shortest of 12 F waves), M is the latency of the direct M wave, and 1 msec is allowed for turn-around time at the spinal cord. High-voltage electrical or magnetic stimulation over the spinal column provides an alternative means of assessing peripheral conduction time. Using the low output-impedance electrical stimulator devised for cranial stimulation, and with the cathode placed over the C7-T1 interspinous space and the anode 6 cm rostral or lateral, excitation of the C8 and T1 cervical roots takes place in the region of the intervertebral foramina, rather than within the cervical cord itself." Percutaneous stimuli of the order of 300 or 400 V are required for cervical root excitation by this method, and there is moderate local discomfort (but much less than that incurred by transcranial electrical stimulation). Responses in the abductor digiti minimi muscle of the hand evoked by cervical stimulation are of similar morphology and of only slightly smaller amplitude than those obtained by routine electrical stimulation of the ulnar nerve at the wrist or elbow. Therefore, in addition to its use for estimation of central motor conduction, the technique may also be used to assess the degree of proximal conduction block in the motor roots in cases of Cuillain-Barre syndrome (Fig. 27-6) .37 However, attempts to obtain responses of maximal amplitude by increasing the stimulus intensity will eventually lead to a decrease in onset-latency of the response because the site of activation moves distally along the motor root. For the same reason, care must be taken when assessing CMCT by this means in patients with hypoexcitable nerves (e.g., in patients with chronic demyelinating neuropathy).
Motor Evoked Potentials
595
Wrist FIGURE 27. . . Acute Cuillain-Barre syndrome. Compound muscle action potentials (CMAPs) elicited from the abductor digiti minirni muscle with electrical stimuli to the ulnar nerve at the wrist, elbow, and axilla, and over the C7-TI interspace. Proximal conduction block in the motor roots is demonstrable by the abnormal decrement in CMAP amplitude and area to cervical stimulation despite normal motor conduction velocity and a retained F wave in response to wrist stimulation. AMP, amplitude.
Elbow
Axilla
Site AMP Area mV mV.msec Wrist
A'o
10
The magnetic coil can also be used to excite the cervical motor roots, and this occurs at approximately the same site as with electrical stimulation." Responses can most readily be obtained when the coil is centered over the (;7 spinous process and when current flows clockwise as viewed from behind. By this means, discomfort is rather less than with electrical stimulation, though there is a pronounced jerk of the affected limb and there may also be a hiccup caused by phrenic nerve excitation. Responses are of similar latency but smaller amplitude than with electric stimulation, and the technique is not a reliable means of assessing proximal conduction block. When peripheral conduction time is assessed by either electrical or magnetic stimulation over the cervical spine, the CMCT (total latency minus peripheral latency) includes time for excitation of the corticospinal pathways and transmission along those tracts, 0.5- to l-msec synaptic delay, and approximately O.4--msec conduction time along the proximal cervical roots. Therefore, a substantial portion (perhaps up to 25 percent) of the normal CMCT of approximately 6 msec obtained by magnetic stimulation of the cortex is not caused by conduction down the corticospinal tracts, and some of this time is for conduction within the peripheral nervous system. Thus, measures of conduction velocity in the corticospinal tract are only approximations. When peripheral neuropathy causes diffuse slowing of motor conduction, a correction factor must be added to the CMCT to reflect the increased time for conduction in the proximal roots (e.g., 0.46 msec at 30 m/sec and 0.89 msec at 20 m.'sec'").
msec
30
40
CV m/sec
7.6
22.4
~
Elbow 5.9
22.4
f----
Axilla
5.1
19.2
2.5 mV] Cord
1.8
10.5
-61.1
~_--....;...~ Cord C7
20
f----
49.8 54.4
-
50
Electrical and magnetic stimuli can be used to estimate the peripheral component of conduction to the lower-limb muscles. 40.41 When the stimulating cathode or the magnetic coil is placed over the conus medullaris, intradural motor roots are excited close to the cord. If the cathode or coil is placed more caudally, the motor roots are stimulated in the region of the intervertebral foramina. Therefore, as with upper-limb studies, the CMCT determined by these techniques includes a certain amount of time taken by peripheral conduction, and neither technique is reliable for quantification of conduction block to lower-limb muscles.
Spinal Cord and Bralnstem Stimulation If sufficiently large stimuli are used, transcutaneous electrical stimulation of the spinal cord can be achieved using the same device as that for cortical stimulation.v" Saline-soaked pad surface electrodes mounted a few centimeters apart are placed over the spinal column at cervical or thoracic levels or over the lumbar enlargement; single shocks of 800 to 1500 V, decaying with a time-constant of 50 or 100 usee, are required to obtain CMAPs from lower-limb or sphincter muscles. The level of discomfort is considerable and inappropriate for routine clinical studies. In contrast to brain stimulation, however, this technique allows true measurement of motor conduction velocity in the corticospinal tracts. Stimuli are delivered at two levels along the spinal column. The distance between the two sites of stimulation
596
ElECTRODIAGNOSIS INCLINICAL NEUROLOGY
and the difference in latency of the responses are measured, and conduction velocity is calculated in the same way as in peripheral motor conduction studies. High-voltage electrical stimulation across the base of the skull may be used to activate the descending motor tracts at a point midway between the cortex and the cervical enlargement." The posterior aspects of the mastoid processes are used as anode and cathode. Evoked EMG responses are larger when the target muscle is preactivated by a small voluntary contraction than with complete relaxation. The latency difference between cortical and brainstem stimulation is 1.5 msec, the latency difference between cervical and brainstem stimulation being 3.9 msec for the first dorsal interosseous and 2.6 msec for the tibialis anterior muscles. The findings suggest that brainstem stimulation occurs approximately at the level of the pyramidal decussation at the cervicomedullary junction. In contrast to responses evoked by electrical cortical stimulation, latency of the responses to brainstem stimulation is not affected by contraction of the target muscle, and responses are also simpler in form, suggesting that brainstem stimulation evokes a single descending volley larger than the multiple volleys produced by cortical stimulation. The clinical value of this technique for localizing dysfunction within the corticospinal pathways is limited by the discomfort that it causes, but it is of interest as a research procedure. The magnetic stimulators presently available can excite corticospinal pathways at the foramen magnum level42 but are unable to stimulate the spinal cord more distally, at least with single pulses.
NORMATIVE DATA Normative data for central motor conduction studies are influenced considerably by the apparatus and technique used, and to a lesser degree are influenced by the nature of the control population. CMCT is greatly affected by the choice of electrical or magnetic stimulation, but there is relatively little difference between the various types of magnetic stimulator now commercially available. As previously noted, total conduction time is shorter with a background voluntary contraction, and peripheral conduction time is shorter with percutaneous stimulation of the motor roots than when estimated by F waves. When acquiring normative data the target muscle, coil position, coil size, and direction of current flow must all be kept constant, as must the approximate stimulus intensity in relation to threshold. Illustrative normative data for conduction to some upper- and lower-limb muscles are provided in Table 27-1. For abductor digiti minimi (ADM), using magnetic cortical stimulation, electrical stimulation of the cervical roots, and a facilitatory background contraction, mean
TABLE 27-' • Transcranlal Magnetic Stimulation: lI\ustrative Latencies and Central Motor Conduction Times (CMCT) to Various Muscles Latency (msec) (eortex - muscle)
Muscle Nasalis Tongue Biceps Extensor digitorum communis Abductor digiti minimi Abductor pollicis brevis Diaphragm Tibialis anterior
9.9 8.7 9.7 19.4 19.7 20.1 16.2 27.2
eMeT (msec) 5.1' 6.3 t 6.1 6.4 6.3 6.7 8.4 12.5
Latencies represent conduction time from cortex tomuscle, with responses being obtained with afacilitatory contraction; CMCT was determined utiliziing F·wave studies unless otherwise stated. 'Magnetic transcranial stimulation offacial nerve. tElectrical stimulation oflingual nerve atmandibular angle.
CMCT is around 6 msec, the lower limit of normal amplitude being taken as 15 percent of that evoked by ulnar nerve stimulation at the wrist (Table 27-2). The relationship between the amplitudes of the MEP and the CMAP to peripheral nerve stimulation is dependent on the muscle; MEPs (but not CMAPs) recorded with electrodes on abductor pollicis brevis (APB) may have a contribution from thenar muscles supplied by the ulnar nerve, whereas for ADM there is no significant contribution from non-ulnar fibers with either cortical or peripheral stimulation. CMCT would be shorter by approximately 0.7 msec if F waves are used to estimate peripheral conduction instead of cervical root stimulation, and shorter by 1.5 to 2.0 msec with electrical instead of magnetic cortical stimulation. The normal CMCT to tibialis anterior, using magnetic stimulation of the motor cortex and electrical stimulation over the lumbar enlargement, with background voluntary
TABLE 27-2 • Magnetic Brain Stimulation: Normative Data for Conduction to Abdudor Diliti Minimi Muscle·
Conduction time from C7-Tl (msec) Conduction time from scalp (msec) Central motor conduction time (msec) Amplitude as percent of amplitude fromwrist 'N =36 sides.
Mean + 2.5SD
Mean
SD
Range
13.60
1.35
10.9-16.0
16.97
19.73
1.25
17.5-23.1
22.85
6.13
0.89
4.7-7.7
8.35
18.6-96.6
Motor Evoked Potentials
contraction, is ofthe order of 12.5 msec'"; this is clearly influenced by height, and there is also a sex difference that probably simply reflects differences in height between men and women. Age affects MEPs at both ends of the spectrum. In children, MEP latency does not attain adult values until about 11 years of age. The threshold for magnetic stimulation is markedly increased in infancy, decreasing to the adult level at about the age of 8 years." It has been reponed that MEP latency increases in a linear fashion with age from the second to the ninth decade, and that the conduction slowing occurs in both central and peripheral portions of the motor pathway." The amplitude of the response to cortical stimulation appears to decline gradually with increasing years.
PATHOPHYSIOLOGY OF ABNORMALITIES IN CENTRAL MOTOR CONDUOION MEP abnormalities are limited in type 45 ,46 ; the abnormalities encountered consist of a prolonged onset latency, reduction in amplitude or absence of the response to brain stimulation, abnormal corticomotor threshold (defined as the minimal stimulus intensity to evoke an MEP),47.48 abnormal complexity of the response, and abnormal trial-to-trial variability in amplitude or onset latency.t? In addition, changes in responses to paired stimuli at differing intervals, and in the duration of the silent period to cortical stimulation, occur in various disease states. These abnormalities are
597
not independent of one another, and various combinations can occur (Table 27-3). Very different disorders may produce identical abnormalities, and no abnormality appears specific for a single pathophysiologic process, which is not surprising when the normal mechanisms of central motor conduction and the nature of the response to brain stimulation are considered. Latency prolongation is a typical feature of slowing of conduction velocity caused by demyelination of large-diameter fibers; it is used in routine peripheral nerve conduction testing to delineate demyelinating neuropathy. Prolongation of central motor conduction may well be caused by demyelination, but conduction may also be slowed when corticospinal fibers are degenerating because of primary dysfunction of the axon or cell body. Failure of conduction in large myelinated fibers as a result of degeneration or conduction block may allow transmission via small myelinated fibers conducting relatively slowly or by some other oligosynaptic pathway. All of these processes will result in prolongation of CMCT. Because both temporal and spatial summation of the impulses reaching the alpha motor neuron are required before it depolarizes, any reduction in the descending volley through loss of fibers by degeneration or compression or as a result of conduction block will lead to delayed excitation of the anterior horn cell, and it may prolong the CMCT by up to 4 msec. CMCT will also be prolonged if a disease process results in failure of activation of large, fast-conducting spinal motor neurons by the cortical stimulus, but these fibers are still excitable by cervical stimulation.t''
TABLE 27-3 • Diagnostic Applications of Transcranial Magnetic Stimulation TMS Measure
Abnormal Findings
Diseases and Symptoms
CMCT MEP
Long Dispersed Small or absent Large Central conduction failure
MS, MND, stroke, secondary parkinsonism, secondary dystonia, brain injury, SCI, CS MS, stroke MS, MND, stroke, brain injury, SCI, CS Parkinson's disease, dystonia MS, MND (with upper motor neuron damage), stroke, secondary parkinsonism, brain injury, SCI, CS, hydrocephalus MS, stroke, brain injury, SCI, CS, epilepsy, demyelinating neuropathy MND, Parkinson's disease, dystonia, agenesis of corpus callosum SCI, CS MS, stroke, brain injury (with transcallosal lesion), dysgenesis of corpus callosum MS,MND Stroke (with transcallosal lesion), dysgenesis of corpus callosum MS, stroke, agenesis of corpus callosum, brain injury, spinal cord injury, CS MND, epilepsy Early MND Parkinson's disease, SCI, CS, epilepsy Dystonia
MEP with triple-stimulation technique Silent period
Interhemispheric conduction
Motor cortex excitability
Long Short Absent Long latency Reduced interhemispheric inhibition Interhemispheric inhibition absent High motor threshold Low motor threshold Increased intracortical inhibition Decreased intracortical inhibition Enlarged cortical representation
CMCT, central motor conduction time; CS, cervical spondylosis; MEP, motor evoked potential; MND, motor neuron disease; MS, multiple sclerosis; SCI, spinal cord injury. Adapted from Kobayashi M, Pascual-leone A: Transcranial magnetic stimulation in neurology. lancet Neurology, 2:145, 2003, with permission.
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
The amplitude of the response to brain stimulation may be reduced because of conduction block or degeneration of corticospinal fibers; dispersion of the MEP because of differential slowing, as in demyelination, is associated with further amplitude reduction caused by phase cancellation among components. Another important feature of demyelination is failure of transmission of trains of impulses, so that trains of I waves may not be conducted and the spinal motor neuron may fail to fire. Depression of spinal motor neuron excitability and increased presynaptic inhibition of corticospinal terminals in the spinal cord are other possible mechanisms for reduction in amplitude of the MEP. Corticomotor threshold may be abnormal (usually elevated) because of dysfunction of intracortical or spinal excitatory or inhibitory mechanisms.v-"
Triple-stimulation Technique The value of MEP amplitudes is limited in clinical practice; not only are they variable from stimulus to stimulus, but they are normally smaller than the responses to peripheral stimuli, either because of central conduction failure (in disease) or from dispersal of the descending volley resulting in phase cancellation (a normal phenomenon, exacerbated by disease). This has been addressed by the triple-stimulation technique (TST) devised by Magistris and colleagues.51 Recording from the APB hand muscle, a suitably timed peripheral stimulus to the median nerve at the wrist collides with the descending volley to cortical stimulation, so there is no direct APB response to the cortical stimulus. A third stimulus, to Erb's point, results in an orthodromic volley that obliterates any uncollided impulses from the wrist stimulus. The final CMAP recorded from this third stimulus thus indicates the number of peripheral fibers activated by the original brain stimulus. The results are compared with a control test in which the cortical stimulus is replaced by Erb's point stimulation. This method eliminates desynchronization effects on MEP amplitude and is significantly more sensitive than conventional MEP measures to detect corticospinal conduction failure.P It is, however, a technically complex procedure, albeit usually welltolerated by the subject.
Paired-Pulse Stimuli Responses to pairs of magnetic stimuli provide information on the intrinsic circuitry of the motor cortex and other areas of the brain. The interaction of a subthreshold conditioning impulse and a second, suprathreshold test impulse are examined; effects depend on the intensity of the stimuli and the interval between them.
Maximum inhibitory effects on the test response by the conditioning pulse are seen with short interstimulus intervals of 1 to 4 msec, where it appears that interaction between I-wave impulses to corticospinal neurons is tested. Facilitatory effects occur at intervals of 7 to 20 msec and can be used to investigate excitability in corticocortical inhibitory and facilitatory circuits. 53,54 The pairedpulse technique can be used to study interhemispheric interactions, the conditioning stimulus being applied to one hemisphere and the test pulse to the other. 55,56
Silent Period A stimulus to the motor cortex will arrest ongoing voluntary activity for several hundred milliseconds after the MEP. This silent period is attributed primarily to cortical inhibitory mechanisms, with spinal inhibitory processes also probably contributing during the first 50 to 60 msec. Silent period studies have the technical drawback of difficulty in endpoint measurement, but they offer another way of examining excitatory or inhibitory activity in health and disease.3.46,57
Repetitive Transcranial Magnetic Stimulation The effects of rTMS depend on stimulus frequency: low-rate stimuli at around 1 Hz produce relatively longlasting inhibition of the cortex associated with a reduction in cerebral blood flow, whereas high-frequency stimuli at around 10 to 20 Hz cause an increase in cortical excitability and cerebral metabolism.vv-" The precise mechanisms for these effects, which are not restricted to the motor cortex, are unclear at present.
FINDINGS IN NEUROLOGIC DISORDERS Multiple Sclerosis Early studies using electrical stimulation of the brain and spinal cord showed marked prolongation of CMCT in multiple sclerosis (MS) entirely consistent with a demyelinating process. 10- 12 These findings have been confirmed by several studies using magnetic stimulation, the chief difference between the techniques being the much lower incidence of absent responses to brain stimulation with the magnetic method. 49,50,57-62 This may reflect the fact that it is easier to confirm the presence of small, delayed but reproducible responses when brain stimulation does not cause discomfort. An early study involving magnetic stimulation of 15 patients showed that the degree of prolongation in
Motor Evoked Potentials
CMCT to upper- and lower-limb muscles was related to the clinical deficit.F CMCT was prolonged to small hand muscles on one or both sides in 72 percent of 83 patients (Fig. 27-7) .59 In 10 percent of abnormal sides, the CMCT was more than three times the normal mean; in others, the prolongation was just slightly beyond the upper limit of normal. The amplitude of the MEP response was reduced in half of the patients with a prolonged CMCT; small responses rarely occurred without CMCT prolongation, being found on only seven sides. There was only one side of one patient in which brain stimulation evoked no muscle action potential. A much higher incidence of unobtainable responses to brain stimulation has been demonstrated in lower-limb studies. Britton and co-workers have highlighted the usefulness of measuring onset-latency variability, which may occasionally be the only abnormal neurophysiologic parameter." Increased corticomotor threshold usually correlates with CMCT but may also occur as an isolated abnormality.'? When the target muscle is weak or when there are pyramidal signs in the limb, central motor conduction is almost always abnormal, and there is a strong inverse correlation between central conduction time and phasic muscle strength.P In the upper limbs, central motor conduction abnormalities correlate well with brisk finger flexor reflexes; when this sign is absent, CMCT is
Wrist R
Jv----
C7R
Soalp
~--------
'-----~~...---
Wrist l ~_----
_
C7l
~
Soalp
-----~----
_
5mVJ
o
20
40
msec
60
80
599
usually normal.r'' Increased onset-latency variability also correlates well with the presence of pathologic finger reflexes and with impairment of fine finger movements. Subclinical abnormalities have been demonstrated in 20 percent of neurologically normal limbs in one series'f and in 24 percent of patients in another."! Lower-limb abnormalities of central motor conduction correlate particularly well with the presence of extensor plantar responses.P? Use of the triple-stimulation technique to eliminate discharge desynchronization effects on MEP amplitude results, as expected, in a considerable increase in the rate of detection of central conduction failure and better correlation with the clinical deficit." When this technique is used in conjunction with conventional CMCT studies, the pattern of abnormality (amplitude attenuation versus conduction slowing) appears to differ in relapsing-remitting disease and in chronic primary or secondary progressive MS.64 The incidence of upper-limb MEP and visual evoked potential (VEP) abnormalities is broadly similar in multiple sclerosis, abnormalities of upper-limb somatosensory evoked potentials (SEPs) being rather less common and abnormal brainstem auditory evoked potentials (BAEPs) being much less common. VEPs and SEPs are, however, probably superior to MEP studies for demonstrating subclinical lesions of their respective pathways. When magnetic resonance imaging (MRI) and cerebrospinal fluid studies are suggestive of multiple sclerosis, MEPs add little to the security of the diagnosis, but they may be more helpful when other investigations prove equivocal.65 Serial studies of central motor conduction have shown a high degree of reproducibility in patients with stable multiple sclerosis, as well as in normal subjects." Changes in central motor conduction may follow the clinical course in patients with unstable MS, including those treated with steroids for acute relapse.v" These findings suggest that MEPs may be a useful tool for quantification of motor disability and for monitoring the response to new treatments. Studies with pairedpulse stimuli in MS patients with prominent fatigue have failed to provide evidence for frequency-dependent conduction block in corticomotor pathways as the cause of this symptom, though their decrease in force production during a fatiguing muscle contraction appeared to originate centrally''?
100
FIGURE 27·7 • Multiple sclerosis. Compound muscle action
Motor Neuron Disease
potentials (CMAPs) from right (R) and left (L) abductor digiti minimi muscle evoked by electrical stimuli at the wrist and C7-Tl interspace and by magnetic stimulation of the motor cortex (two responses superimposed). Central motor conduction time is grossly prolonged (greater than 20 msec) bilate-rally and responses are of prolonged duration on the right. although of normal amplitude.
In one of the earliest clinical studies of magnetic brain stimulation, the findings were normal in five patients with motor neuron disease (MND), but other studies have shown a high incidence of abnormality:'i7,6H-70 In contrast to multiple sclerosis, MEPs tend to be small or unobtainable, with only minor prolongations in latency
600
ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
(Fig. 27-8). Two-thirds of patients in one study showed abnormalities of central motor conduction to a small hand muscle; subclinical abnormalities were demonstrable in 4 of the 22 patients, but MEPs were normal despite clinical evidence for central motor involvement in 5 patients.P? Abnormalities are not specific, but the technique may be particularly useful in the investigation of patients in whom the lower motor neuron deficit is so severe that an associated upper motor neuron lesion could be masked. Eisen and co-workers found abnormalities in almost all of their 40 patients when they recorded MEPs from three upper-limb muscles, and 75 percent showed abnormalities of MEPs from small hand muscles.58 Corticomotor threshold is typically reduced early in the course of the disease, the cortical silent period is shortened, and intracortical inhibition is reduced, all suggesting cortical hyperexcitability. As the disease progresses, the corticomotor threshold becomes pathologically elevated. These studies provide a clue to possible pathophysiologic mechanisms in amyotrophic lateral sclerosis (e.g., glutamateinduced excitotoxicity) .71.72 Some but not all patients with familial amyotrophic lateral sclerosis show striking prolongation of CMCT, much more than is normally encountered in sporadic motor neuron disease. The reason for this is unclear, but it is consistent with disease heterogeneity." In seven patients with primary lateral sclerosis, four showed no response in either upper- or lower-limb muscles to brain stimulation; in the remaining three, CMCT was grossly prolonged." Loss of anterior horn cells alone might theoretically cause a prolongation of CMCT because of reduced Wrist
C7rr1
Scalp
AU\r--4r--~
Bhr-~b----f\j
c Jl---~f'.--10 msec
FIGURE 27·8 • Motor neuron disease. Compound muscle action potentials (CMAPs) from the abductor digiti minimi muscle evoked by electrical stimuli at the wrist and C7-Tl interspace, and magnetic stimulation of the motor cortex in (A) a healthy subject, and (B and C) patients with motor neuron disease. Central motor conduction time is 5.6 msec in trace A, 11.3 msec in B, and there is no response to cortical stimulation in C. Calibration 10 mV except for the scalp response in trace B. (From Schriefer TN, Hess CW, Mills KR et al: Central motor conduction studies in motor neuron disease using magnetic brain stimulation. Electroencephalogr Clin Neurophysiol, 74:431, 1989, with permission.)
temporospatial summation of the descending volley, but studies of MEPs in patients with pure spinal muscular atrophy and with an terior horn cell loss from poliomyelitis have revealed normal CMCTs.50
Cervical Spondylosis Several studies have shown that CMCT is often prolonged in patients with cervical spondylotic myelopathy.51,74-75 Abnormalities are more common in the lower than in the upper limbs; upper-limb abnormalities are more common distally than proximally. MEPs are more sensitive than SEPs for demonstrating abnormality but seem to be of less value for documenting progression of the disease." There may be minor slowing of the peripheral as well as the central portion of the motor pathway when radiculopathy coexists with spondylotic myelopathy. Overall, central motor conduction studies have a modest role in patient management, being useful in providing objective evidence for myelopathy but oflittle value in distinguishing between possible causes, and sometimes helpful when imaging studies are normal or equivocal.
Stroke Studies of central motor conduction in cerebrovascular disease66.78.79 indicate that the more severe the clinical deficit, the more likely it is that there will be no response in the paretic muscle to brain stimulation. If responses are recordable, their latency is usually normal or delayed only slightly. Rather infrequently, motor responses are absent or delayed despite normal strength. Hemispheric lesions tend to show absent rather than delayed MEPs, the response pattern being more variable with subcortical strokes. When central motor conduction studies are performed within 3 or 4 days of an acute stroke, complete absence of response to brain stimulation portends pOQr functional outcome at 1 year.80.81 In patients in whom the initial response is normal, progressive improvement in function and power is likely. Those with a delayed but preserved MEP recover more slowly than do those with normal MEPs, but these groups are similar at 12 months. The technique seems a moderately helpful adjunct to well-validated clinical indicators of prognosis after an acute stroke.
Miscellaneous Hereditary, Ataxic, and Peripheral Nerve Disorders Rather characteristic MEP findings occur in the pure form of hereditary spastic paraplegia (HSP).39 Lowerlimb responses are almost always abnormal, being
Motor Evoked Potentials
either absent or very small with only minor prolongation in latency. In contrast, upper-limb responses are usually normal (but occasionally are mildly prolonged) despite clear clinical evidence of upper-limb pyramidal involvement. These findings are very different from those that are characteristic of multiple sclerosis, and they are consistent with the known pathologic finding of degeneration of corticospinal tracts, especially to the lower limb. In Friedreich's ataxia, central motor conduction to upper-limb muscles is almost always abnormal; responses are of low amplitude, dispersed, and moderately delayed.V Electrophysiologic abnormalities worsen in line with clinical progression.P In late-onset cerebellar ataxias, central motor conduction abnormalities are still less common and may be strikingly asymmetric; they appear unrelated to disease duration and suggest a heterogeneous disorder. Central motor conduction studies have proved normal in cases of chronic fatigue syndrome, both at rest and after a prolonged fatiguing muscle conrraction" Upper-limb central motor conduction studies are usually normal in patients with hereditary motor and sensory neuropathy (HMSN) type I and HMSN type II when CMCT is corrected for slowing of conduction in proximal motor roots.t" Six of 18 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) were found to have abnormalities of central motor conduction.f" Abnormalities were unilateral in four patients and typically consisted of a moderate prolongation of latency. These patients were part of a larger series of 30, of whom 5 had clinical evidence and 14 had imaging evidence for CNS involvement. In very severe demyelinating neuropathy with extreme hypoexcitability, peripheral nerves may be electrically inexcitable despite the presence of voluntary activity in relevant muscles. In such circumstances, magnetic stimulation of the cortex (but not the nerves) may evoke a response and thus allow a rough estimate of peripheral slowing that is otherwise not measurable by standard conduction studies. The use of high-voltage electrical stimulation to demonstrate and quantify proximal conduction block in Guillain-Barre syndrome.'? was referred to earlier; both magnetic and electrical stimulators may be used to measure conduction time from the intervertebral foramina to target muscles and thus to confirm and localize conduction slowing in demyelinating neuropathy
Movement Disorders In Parkinson's disease, CMCT is normal both to electrical and to magnetic cortical stimuiationf-'": however, some studies have demonstrated abnormally large MEPs to magnetic stirnulation.t'v" The pathophysio-
601
logic significance of this observation is unclear, but monitoring of the MEP amplitude may provide an objective measure of response to therapy. In Guamanian Parkinson's disease, MEP amplitude is commonly reduced, even in the absence of associated amyotrophic lateral sclerosis.V Central motor conduction times have been normal in Huntington's chorea and in dystonia; studies during sleep in torsion dystonia suggest that the inhibitory centers in the region of the locus ceruleus and their descending pathways to spinal alpha motor neurons are in tact. 88,89 Abnormal corticomotoneuronal projections have been demonstrated using magnetic stimulation in some but not all patients with congenital mirror movements; the normal relationship between direction of current flow and preferential hemisphere activation may be reversed, suggesting abnormal ipsilateral prcjections.P" More sophisticated studies of cortical inhibitory and excitatory processes in movement disorders that use, for example, paired-pulse stimuli and the cortically evoked silent period have produced variable and often rather nonspecific findings to date, similar abnormalities being found in dystonia and Parkinson's disease. The clinical role of these techniques remains unclear but in due course they may provide useful insights into disease processes and therapeutic agents."!
Epilepsy Single-pulse magnetic stimulators currently in use stimulate at most at around 0.3 Hz. The theoretical risk of kindling an epileptic focus in the brain is therefore extremely small, animal studies having shown that a much higher frequency of stimulation is necessary.92 There have been occasional reports of focal seizures occurring during or immediately after magnetic stimulation in patients with ischemic lesions of the cortex and also in multiple sclerosis. 93,Y4 A study of transcranial magnetic stimulation in 58 patients with partial or generalized epilepsy showed no change in seizure pattern or in the EEG, and early reports suggesting that patients with epilepsy may have their seizure activity triggered by magnetic stimuli have not been confirrned.F'P" Classen and associates reported that focal seizures similar to spontaneous seizures were triggered reliably by single stimuli." Dhuna and colleagues." using a high-frequency magnetic stimulator that could deliver trains of 8- to 25-Hz stimuli, were unable to trigger seizures or to induce epileptiform discharges arising from the epileptic focus in any of eight patients. They did, however, induce a partial motor seizure from the contralateral hemisphere to the temporal focus in the only patient stimulated with 100 percent maximal stimuli.
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
Steinhoff and co-workers also failed to activate epileptic foci using single stimuli, noting instead a decrease in spike frequency when stimuli were applied contralateral to the epileptic focus.P? It has been shown that anticonvulsant medication affects MEPs elicited by magnetic stimulation, generally raising cortical threshold intensity and prolonging peripheral latency, but MEPs are less affected by duration of epilepsy, location of the epileptic focus, or type of seizure. 100 In patients being evaluated for epilepsy surgery, rTMS is a reliable method of temporarily arresting speech when applied to the dominant hemisphere, and the findings correspond well with the results of the Wada test. 101 The dominant hemisphere may also be identified using single-pulse stimuli to measure the increase in motor cortical excitability of the dominant (but not of the nondorninant) hemisphere during language tasks. 102 Motor cortex mapping studies using magnetic stimulation may also be of value in epilepsy surgery candidates. 103
Fundional Weakness The recording of normal MEPs from a muscle that is apparently very weak does not exclude a structural lesion, but it is certainly a cause for suspicion that symptoms have a nonorganic basis. The finding of an absent or delayed response when functional weakness is suspected suggests that there is an organic component to the problem.l'" Care must be taken to monitor the degree of voluntary muscle contraction during testing (particularly when activation is erratic) and to ensure that the appropriate normative data on response amplitudes and latencies (i.e., for "relaxed" or "facilitated" target muscles) are used.
INTRAOPERATIVE MONITORING Transcutaneous motor cortical stimulation is potentially of great value for monitoring motor tracts during surgery on the brain and spinal cord. 105 As long as muscle relaxants are not administered in such large doses that neuromuscular transmission is completely blocked, MEPs may be recorded from muscles distal to the surgical site. Electrical stimulation of the cortex has several advantages over magnetic stimulation. First, the stimulating electrodes are much smaller than the magnetic coils currently in use, and they are more readily placed for focal activation of the required muscle groups. Second, MEPs elicited by electrical stimuli are less subject to the depressant effects of anesthetic agents, reflecting the different sites of activation by electrical and magnetic stimulators. Finally, the lack of pain with magnetic (as opposed
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FIGURE 17-' • Intraoperative recording of MEPs from left abductor hallucis muscle to multipulse transcranial electrical stimulation at an intensity of 700 V. There is no response to single pulses or to trains of 2 or 3 pulses with an interpulse interval of 2 msec. MEPs of consistent latency but variable amplitude and morphology are elicited by trains of 4, 5, or 6 pulses. (From Jones 8J, Harrison R, Koh KF et al: Motor evoked potential monitoring during spinal surgery: responses of distal limb muscles to transcranial cortical stimulation with pulse trains. Electroencephalogr Clin Neurophysiol, 100:375, 1996, with permission.)
to electrical) stimulation confers no advantage during surgery under anesthesia. MEPs are much more readily obtained in anesthetized patients if, rather than a single stimulus, a train of three to six stimuli at in tervals of 2 msec is used; this is because of the temporal stimulation produced at spinal motor neuron level by a volley of impulses (Fig. 27-9). Multipulse transcranial electrical stimulation allows simultaneous recording from a number of muscle groups, both above and below the operative site in the case of spinal surgery, and it appears to be both practical and sensitive.P However, given the very low incidence of anterolateral cord damage sustained during spinal cord surgery with SEP monitoring and stable responses, the advantages of MEP monitoring over tried and tested SEP techniques are limited. MEP monitoring is particularly worth considering for anterior spinal surgery and in the relatively few cases in which SEPs are unrecordable from the onset. 106
STIMULATION OF PERIPHERAL NERVES AND ROOTS As previously noted, both electrical and magnetic stimulators can excite the motor roots in the region of the intervertebral foramina. The magnetic stimulator can also activate deep-seated nerves and plexuses without
Motor Evoked Potentials
causing pain; indeed, it was for this reason that the magnetic stimulator was originally devised. 107-109 The present role of magnetic stimulation of nerves and roots is limited by uncertainty about the precise activation site and by difficulty in achieving supramaximal stimulation without exciting neighboring structures.107-111 It is likely that advances in coil design will gradually improve the precision and thus the utility of the technique, though the probability of magnetic stimulation actually replacing standard electrical stimulation for the commonly tested, readily accessible peripheral nerves is low. Magnetic lumbar root stimulation, with activation at the intervertebral forum, may be used in conjunction with F-wave measurements, giving conduction time to the anterior horn cells, to estimate motor root conduction time. This measure may be pathologically increased in compressive and especially in inflammatory radiculopathies. J 12
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of delivering rapid trains of impulses was soon followed by studies in patients with psychiatric disorders. Higher frequencies of rTMS can upregulate and low frequencies downregulate cortical activity, leading to numerous studies in depressed patients. There is certainly evidence that high-frequency left prefrontal rTMS and low-frequency right hemisphere stimulation have a measurable if relatively transient moodenhancing effect in psychotically depressed subjects I 18.119; however, meta-analysis of these studies suggests that the clinical significance of this new treatment is modest. 120 Treatment protocols are continually being refined, but at present there is little to suggest that rTMS, given either unilaterally or bilaterally, has a major therapeutic effect in isolation or as adjunctive treatment for depression.l'" Other psychiatric disorders are also under investigation, both to establish more clearly the clinical role of rTMS and to increase the understanding of brain processes in psychiatric disease.F"
STIMULATION OF CRANIAL NERVES SAFETY CONSIDERATIONS A magnetic coil can also be used to stimulate cranial nerves. The facial nerve can be excited intracranially in the region of its labyrinthine segment by magnetic coil placement over the temporal region; this has some rather limited clinical applications, particularly in the case of facial nerve trauma. 113.114 Hopes that the method would provide a way of quantifying facial nerve conduction block in early Bell's palsy have not been fulfilled. There is often no response to intracranial facial nerve stimulation in Bell's palsy, even when considerable clinical recovery has occurred, perhaps because the stimulus is applied at the site of demyelination of the nerve. The method can be used to demonstrate slowed conduction over a short segment of the facial nerve in demyelinating neuropathies such as Guillain-Barre syndrome. The trigeminal, vagus, accessory, and hypoglossal nerves can also be stimulated intracranially with the magnetic coil. 33.111 Most studies to date have concentrated on anatomic aspects such as laterality of pathways rather than on clinical questions, but some studies have suggested that the magnetic stimulation of cranial nerves and their central pathways may be helpful in demonstrating subclinical upper or lower motor neuron involvement of bulbar muscles in motor neuron disease. I 15-117
DEPRESSION High-frequency transcranial magnetic stimulation has some obvious parallels with electroconvulsive therapy, and the development of magnetic stimulators capable
Adverse effects of single-pulse magnetic stimulation of the motor cortex are extremely rare. The potential adverse effect that has caused most concern until now has been epilepsy, though on theoretical grounds the risk of kindling is remote. Many thousands of patients have now undergone electrical or magnetic stimulation, but only isolated reports of focal seizures occurring around the time of stimulation have been published.Pv'" In contrast, there is no question that rapid-rate transcranial magnetic stimulation can evoke seizures in normal subjects as well as in patients with neurologic diseases. Evaluation of stimulus parameters relevant to seizure induction (e.g., stimulus intensity and frequency, and train duration and frequency) has led to specific recommendations and guidelines for rTMS.123-J26 Theoretically, implanted metal structures within the skull (e.g., aneurysm clips) are susceptible to movement by the mechanical force from the induced current, though this is most unlikely. It is reasonable to regard both epilepsy and previous neurosurgery as relative rather than absolute contraindications to brain stimulation; caution should particularly be exercised in the case of cochlear implants. It has been suggested that the acoustic artifact of the magnetic stimulating coil may cause hearing loss, and the use of ear-plugs has been recommended.F? There is some disagreement about the necessity for this precaution in adult subjects.!" but it seems wise to use earplugs when testing small babies, in whom the coil-to-ear distance is small.
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ELEaRODIAGNOSIS INCLINICAL NEUROLOGY
MAPPING AND PLASTICITY The processes by which the cortex is reorganized to compensate for injury or environmental changes may be investigated by noninvasive mapping of the cortex with magnetic stimulation. 4,129,130 Two methods are used: the easier and more popular is to keep the stimulus intensity constant and plot response amplitude (the optimal site produces the largest response). The alternative is to map threshold intensities (at the optimal site, the intensity required to produce a threshold response is least). For both methods, attention to technique, coil configuration, and orientation is essential for reliable results. 131,132 As well as mapping normal cortex, short-term and long-term changes can be demonstrated. For example, piano practice for a few days tends to increase the size of the cortical motor area for relevant muscles.l'" Spinal cord injury increases cortical representation of muscles rostral to the lesion, whereas cervical root avulsion causes gradual change in cortical arm representation to improve motor control of surviving units. 134,135 The reading finger of the blind Braille reader has a larger representation than the same finger in the opposite hand.P" The ability of rTMS to modulate cortical activity in different ways at different frequencies can be utilized in conjunction with mapping studies for therapeutic purposes. Studies in stroke and head-injured patients have demonstrated that some symptoms reflect changes in activity in surviving undamaged brain rather than loss of tissue at the lesion site. Thus, contralateral neglect after stroke is primarily caused by hyperactivity of the intact hemisphere, and there is overactivity of Brodmann's area 45 in patients with Broca's aphasia. After appropriate mapping, low-frequency rTMS may be used to reduce this maladaptive cortical plasticity46,137,13R and thus aid rehabilitation.
CONCLUDING COMMENTS Single-stimulus magnetic stimulation of the motor cortex is easy to perform, well tolerated, and apparently safe. MEP abnormalities have been demonstrated in many neurologic disorders; these abnormalities are virtually never specific to a single disease process, but they may be more typical of one than another. The technique is capable of demonstrating subclinical abnormalities, although with limited success, in part because the motor system (unlike the sensory system) is relatively easily examined by the clinician. The role of magnetic brain stimulation for quantification of abnormalities and for follow-up purposes is restricted because of the numerous physiologic variables affecting the descending volley in the corticospinal tract, most of
which may alter central conduction time by a few milliseconds. Refinements such as the triple-stimulation technique will lead to some enhancement of the role of MEPs in diagnosis and quantification. Magnetic stimulation will undoubtedly become more important in the next few years because of developing methodologies (especially rTMS) to investigate and to modulate excitatory and inhibitory mechanisms in health and disease. Candidate fields for these potentially exciting changes include neurorehabilitation, epilepsy, movement disorders, and psychiatry.
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66. Kandler RH: Magnetic Stimulation in Neurological Practice. Thesis. University of Sheffield, Sheffield, England, 1989 67. Sheean GL, Murray NMF, Rothwell]C et al: An electrophysiological study of the mechanism of fatigue in multiple sclerosis. Brain, 120:299, 1997 68. Eisen A, Shytbel W, Murphy K et al: Cortical stimulation in amyotrophic lateral sclerosis. Muscle Nerve, 13:146, 1990 69. Schriefer TN, Hess CW, Mills KR et al: Central motor conduction studies in motor neurone disease using magnetic brain stimulation. Electroencephalogr Clin Neurophysiol, 74:431, 1989 70. Mills KR: Motor neuron disease studies of the corticospinal excitation of single motor neurones by magnetic brain stimulation. Brain, 118:971, 1995 71. Mills KR, Nithi KA: Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis. Muscle Nerve, 20:1137, 1997 72. Nakajima M, Eisen A, Stewart H: Diverse abnormalities of corticomotoneuronal projections in individual patients with amyotrophic lateral sclerosis. Electroencephalogr Clin Neurophysiol, 105:451, 1997 73. Brown WF, Veitch], Ebers GC et al: Electrophysiologic features of primary lateral sclerosis. Muscle Nerve, 14:876,1991 74. Jaskolski D], Jarratt ]A, Jakubowski J: Magnetic stimulation in cervical spondylosis. Br] Neurosurg, 3:541,1989 75. Abbruzzese G, Dall'Agata D, Morena M et al: Electrical stimulation of the motor tracts in cervical spondylosis. J Neurol Neurosurg Psychiatry, 51:796, 1988 76. Tavy DLJ, Wagner GL, Keunen RWM et al: Transcranial magnetic stimulation in patients with cervical spondylotic myelopathy: clinical and radiological correlations. Muscle Nerve, 17:235, 1994 77. Maertens de Noordhout A, Myressiotis S, Delvaux V et al: Motor and somatosensory evoked potentials in cervical spondylotic myelopathy. Electroencephalogr Clin Neurophysiol, 108:24, 1998 78. Dolce G: Cortical and cervical stimulation after hemisphere infarction. ] Neurol Neurosurg Psychiatry, 50:861,1987 79. Bridgers SL: Magnetic cortical stimulation in stroke patients with hemiparesis. p. 233. In Chokroverty S (ed): Magnetic Stimulation in Clinical Neurophysiology. Butterworths, London, 1990 80. Heald A, Bates D, Cartlidge NEF et al: Longitudinal study of central motor conduction time following stroke: 1. Natural history of central motor conduction. Brain, 116:1355, 1993. 81. Heald A, Bates D, Cartlidge NEF et al: Longitudinal study of central motor conduction time following stroke: 2. Central motor conduction measured within 72 hours after stroke as a predictor of functional outcome at 12 months. Brain, 116:1371, 1993. 82. Claus D, Harding AE, Hess CW et al: Central motor conduction in degenerative ataxic disorders: a magnetic stimulation study. ] Neurol Neurosurg Psychiatry, 51:790,1988 83. Cruz-Martinez A, Palau F: Central motor conduction time by magnetic stimulation of the cortex and peripheral
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119, Pascual-Leone A, Rubio B, Pallardo F et al: Beneficial effect of rapid-rate transcranial magnetic stimulation of the left dorsa-lateral prefrontal cortex in drug-resistant depression. Lancet, 348:233, 1996 120. Burt T, Lisanby SH, Sackeim HA: Neuropsychiatric applications of transcranial magnetic stimulation: a meta analysis. IntJ Neuropsychopharmacol, 5:73, 2002 121. Hausmann A, Kemrnler G, Walpoth M: No benefit derived from repetitive transcranial magnetic stimulation in depression: a prospective, single centre, randomised, double blind, sham controlled "add on" trial.J Neurol Neurosurg Psychiatry, 75:320, 2004 122. Fitzgerald PB, Brown TL, Daskalaksis ~: The application of transcranial magnetic stimulation in psychiatry and neurosciences research. Acta Psychiatr Scand, 105:324, 2002 123. Wassermann EM: Safety and side effects of transcranial magnetic stimulation and repetitive transcranial magnetic stimulation. p. 39. In Pascual-Leone A, Davey Nj, Rothwell J et al (eds): Handbook of Transcranial Magnetic Stimulation. Arnold, London, 2002 124. Wassermann EM: Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation. Electroencephalogr Clin Neurophysiol, 108:1, 1998 125. Chen R, Gerloff C, Classen J et al: Safety of different inter-train intervals for repetitive transcranial magnetic stimulation and recommendations for safe ranges of stimulation parameters. Electroencephalogr Clin Neurophysiol, 105:415, 1997 126. jahanshahi M, Ridding MC, Limousin P et al: Rapid rate transcranial magnetic stimulation-a safety study. Electroencephalogr Clin Neurophysiol, 105:422, 1997 127. Counter SA, Borg E, Lofqvist L et al: Hearing loss from the acoustic artifact of the coil used in extracranial magnetic stimulation. Neurology, 40:1159, 1990 128. Boyd SG, Kandler RH, Stevens WR: A comparison of noise levels produced by different magnetic stimulators. .J Physiol, 438:368P, 1991
129. Cohen LG, Mano Y: Neuroplasticity and transcranial magnetic stimulation. P: 346. In Pascual-Leone A, Davey NJ, Rothwell J et al (eds): Handbook of Transcranial Magnetic Stimulation. Arnold, London, 2002 130. Thickbroom GW, Mastaglia FL: Mapping studies. p. 127. In Pascual-Leone A, Davey NJ, Rothwell J et al (eds): Handbook of Transcranial Magnetic Stimulation. Arnold, London, 2002 131. Brasil-NetoJP, Cohen LG, Panizza M et al: Optimal focal transcranial magnetic activation of the human motor cortex: effects of coil orientation, shape of the induced current pulse, and stimulus intensity. J Clin Neurophysiol, 9:132, 1992 132. Brasil-Neto JP, McShane LM, Fuhr P et al: Topographic mapping of the human motor cortex with magnetic stimulation: factors affecting accuracy and reproducibility. Electroencephalogr Clin Neurophysiol, 85:9, 1992 133. Pascual-Leone A, Nguyet D, Cohen LG et al: Modulation of muscle responses evoked by transcranial magnetic stimulation during the acquisition of new fine motor skills.] Neurophysiol, 74:1037,1995 134. Topka H, Cohen LG, Cole RA et al: Reorganization of corticospinal pathways following spinal cord injury. Neurology, 41:1276, 1991 135. Mano Y, Nakamuro T, Tamura R et al: Central motor reorganization after anastomosis of the musculocutaneous and intercostal nerves following cervical root avulsion. Ann Neurol, 38:15, 1995 136. Pascual-Leone A, Wassermann EM, Sadato N et al: The role of reading activity on the modulation of motor cortical outputs to the reading hand in Braille readers. Ann Neurol, 38:910, 1995 137. Oliveri M, Bisiach E, Brighina F et al: rTMS of the unaffected hemisphere transiently reduces contralesional visuospatial hemineglect. Neurology, 57:1338, 2001 138. Martin PI, Naeser MA, Theoret H et al: Transcranial magnetic stimulation as a complementary treatment for aphasia. Semin Speech Lang, 25:181, 2004
CHAPTER
28 Event-Related Potentials DOUGLAS S. GOODIN
DESCRIPTION OF EVENT-RELATED (ENDOGENOUS) POTENTIALS
Fitness Other Factors
RECORDING ARRANGEMENTS NONNEUROLOGIC FACTORS INFLUENCING THE P3 COMPONENT Age Sex Drugs Sleep Deprivation
Averaged evoked potentials have been widely used to record the changes in electrical potential that occur within the nervous system in response to an external stimulus. I For clinical purposes, the short-latency brainstem auditory evoked potential (BAEP) , somatosensory evoked potential (SEP) , and visual evoked potential (VEP) are recorded. In general, these evoked potentials represent an obligate neuronal response to a given stimulus, and both their amplitude and latency depend on the physical characteristics of the eliciting stimulus (see Chapters 21 to 26). Such "exogenous" or "stimulus-related" potentials (SRPs) are independent of whether the subject is attentive to or interested in the stimulus. Indeed, BAEPs, SEPs, and flash VEPs can be recorded even when the subject is asleep. There is, however, another distinct class of evoked potential: the "endogenous" or "event-related" potentials (ERPs) that can be recorded in response to an external stimulus or event.v" These potential changes, unlike the SRPs just described, occur only when the subject is selectively attentive to the stimulus and are elicited only in circumstances in which the subject is required to distinguish one stimulus (the target) from a group of other stimuli (the nontargets). They depend primarily on the setting in which the target stimulus occurs and are relatively independent of the physical characteristics of that stimulus.v" Thus, ERPs seem to be related to some aspect of the cognitive events associated with the distinction of target from nontarget stimuli. Attempts have even been made to relate ERPs to presumed stages of information processing (e.g., sen-
CLINICAL APPLICATIONS Dementia Other Disease States DIFFICULTY IN ERP INTERPRETATION CONCLUDING COMMENTS
sory discrimination or response selection) that must be successfully completed before a person can selectively respond to a target stimulus.vP The precise relationship between any such stages and the individual components of the ERP is, however, uncertain. Indeed, it seems most likely that the ERP reflects activity in distributed parallel networks that are responsible for the discriminative behavior.l1.12.14 Because of this relationship between ERPs and cognitive behavior, considerable interest has developed in the possible clinical use of these potentials in the evaluation of patients who suffer from disorders of cognition. This interest has focused principally on disorders that affect brain function diffusely (e.g., AJzheimer's disease, frontotemporal dementia, schizophrenia, or metabolic encephalopathies).
DESCRIPTION OF EVENT-RELATED (ENDOGENOUS) POTENTIALS Several components of the ERP have been identified; these include Nd 4; the processing negativity (PN)4; the mismatch negativity (MMN)4; P165 15; N2 12; P3a 4,16,17; P3 (or P3b)4,16.17; N400 18; and the error negativity (ERN or Ne ) .19,20 With the exception of P3 (which is also referred to as the P300 component because of its polarity and latency), these components have not been found consistently in different recording situations. Much of this apparent inconsistency probably relates to two factors. First, these other ERP components are of
609
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ELECTRODIAGNOSIS IN CLINICAL NEUROLOGY
relatively small amplitude compared with the P3 component and are thus more difficult to separate from background noise when only a few trials are averaged. Second, most of these components occur at relatively short latencies and overlap considerably with the simultaneously occurring SRPs. As a consequence, special procedures such as the subtraction of one waveform from another-!" are often required for demonstrating them (Fig. 28-1). Most clinical studies have therefore
Rarestimulus
Frequent stimulus
P3 P2
Count
Ignore Countignore
~~~V o
350
700
a
350
700
Latency (msec) FIGURE 18·1 • Long-latency evoked potentials recorded from an electrode at the vertex (Cz) and referred to linked mastoids. The waveforms on the left show the response to a frequent (l,OOO-Hz) tone that occurred on 85 percent of the trials. The average of 340 trials is shown. The waveforms on the right show the response to a rare (2,OOO-Hz) tone that occurred on 15 percent of the trials. The average of 60 responses is shown. The sequence of rare and frequent tones (5Q-msec duration, 60 dB HL, l.5-second interstimulus interval) was pseudorandom, with the constraint that no two rare tones occurred consecutively. The top row of waveforms represents the response to the rare and frequent stimuli when the subject is required to count the rare tones as they occur. With the frequent stimulus, a negative (Nl)-positive (P2) vertex potential is seen. With the rare stimulus, a negative (Nl )-positive (apparent P2)-negative (N2)-positive (P3) complex representing, in part, the event-related response is seen. The middle row of waveforms represents the response to the same stimuli when the subject ignores the tone sequence and reads a magazine during the test procedure. The response to both stimuli consists of only the stimulus-related vertex potential. The bottom row of waveforms was obtained by subtraction of the "ignore" waveform from the "count" waveform for the rare and frequent tones, respectively. For the frequent tone, this difference waveform is a flat line because in both conditions only a stimulus-related response is obtained. For the rare tone, the stimulus-related response has been similarly subtracted out and the event-related response (PI65, N2, P3) can be seen clearly. (Modified from Goodin DS, Squires KC, Henderson BH et al: An early event-related cortical potential. Psychophysiology, 15:360, 1978, with permission.)
been concerned primarily with the more easily identified Nl and P2 components in response to the frequent tone and the P3 component in response to the rare tone (see Fig. 28-1). For this reason, attention is confined to a discussion of these components of the ERP in the remainder of this chapter. The simplest experimental design that is used to elicit the P3 response is the so-called oddball paradigm. 2-4 In this design, the subject is presented with a sequence of two distinguishable stimuli, one of which occurs frequently (the frequent stimulus) and the other infrequently (the rare stimulus). The subject is required to count mentally or otherwise respond to one of the two stimuli. Cerebral responses to the rare and frequent stimuli are recorded and averaged separately. The response to the frequent stimulus consists of a series of waves (the stimulus-related components) that relates, for the most part, to the sensory modality stimulated. For example, to an auditory stimulus this response has been divided into three sequential time periods: (1) early-latency, (2) mid-latency, and (3) longlatency responses (Fig. 28-2). The early-latency (less than 10 msec) response (BAEP) reflects activity in the peripheral and brainstem auditory structures (see Chapter 23). The mid-latency (10 to 50 msec) response is thought to reflect a combination of muscle reflex activity and neural activity that may arise in the thalamocortical radiations, primary auditory cortex, and early association cortex. The neural generators of the longlatency (greater than 50 msec) response are uncertain, although probably the ERP reflects overlapping neural activity from multiple neocortical and limbic regions." This response consists of a large negative (Nl)-positive (P2) complex referred to as the ''vertex potential" because it has the largest amplitude at the vertex." At least part of this vertex potential seems to reflect activity in neural areas that can be activated by more than one sensory modality. Thus, a similar negative-positive complex is elicited by auditory, visual, and somatosensory stimuli (Fig. 28-3). This response is nevertheless an obligate response of the nervous system to the stimulus and is largely independent of the subject's attention or level of arousal. 4,21 It is, therefore, like the early-latency and mid-latency components, a stimulus-related response. In contrast, the long-latency response to the rare auditory stimulus is considerably different and consists of a negative (NI)-positive (apparent P2)-negative (N2)-positive (P3) complex (see Fig. 28-1). The first positive wave is termed apparent P2 because it represents the sum of the stimulus-related P2 and the eventrelated P165. This response is quite consistent, in both amplitude and latency, in the same subject performing the same task 14 ,22,23 even when measured on several different occasions over a period of months (Fig. 28-4). The P3 component of this response has a latency-to-
611
Event-Related Potentials Early-latency response
Mid-latency response
Long-latency response
P2 FIGURE :18·:1 • Evoked potentials recorded from the vertex (Cz) in response to an auditory stimulus during three sequential time periods show the earlylatency (BAEP), mid-latency, and long-latency responses.
N1
o
5
10
o
25
o
50
400
800
Latency (msec)
peak of approximately 300 to 400 msec following onset of the rare stimulus; it is of positive polarity and is of maximal amplitude in the midline over the central and parietal regions of the scalp. An evoked potential component with a similar scalp distribution can be recorded to stimuli in any of the sensory modalities (see Fig. 28-3) and can even be recorded (without asso-
Frequent stimulus
P2
ciated SRPs) when an anticipated stimulus is unexpectedly omitted.F" The neural generators of this P3 response are unknown although, as mentioned earlier, some evidence has suggested multiple neocortical and subcortical locations. 14,25-30 Several variables alter the amplitude and latency of the SRPs without appreciably affecting the ERPs, and
Rare stimulus P3
P300 Auditory
P3 Visual
Somatosensory
[~fLV
o
400
800 0
400
800
Latency (msec) FIGURE :18-3 • Long-latency potentials elicited by auditory (top row), visual (middle row), and somatosensory (bottom row) stimuli. The responses to rare and frequent stimuli in each modality are shown. In each case, the frequent stimulus elicited a negative (Nl )-positive (P2) response, and the rare stimulus elicited, in addition, an event-related response.
o
350
700
Latency (msec) FIGURE :18-4 • Event-related potentials recorded from the vertex in response to a rare tone on several occasions over a 2-month period in the same subject. Each trace represents the difference waveform obtained by subtracting the rare-tone "ignore" waveform from the rare-tone "count" waveform (see Fig. 28-1). The event-related response is quite stable in both amplitude and latency over time. (Modified from Goodin DS, Squires KC, Henderson BH et a1: An early event-related cortical potential. Psychophysiology, 15:360, 1978, with permission.)
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ElECTRODIAGNOSIS INCLINICAL NEUROLOGY
vice versa. For instance, a change in the intensity of stimulation has relatively little effect on the P3 component (Fig. 28-5) but has a major influence on the associated SRPs (see Chapters 21 to 26). Conversely, the P3 is influenced by changes in the ease with which targets can be distinguished from nontargets (Fig. 28-6), by alterations in the ratio of target to nontarget stimuli (Fig. 28-7), or by shifts in the attention of the subject (see Fig. 28-1), whereas SRPs are not,4,6,8.17,31-33
P3 ,"\ \
\ \ \ \
\
\
'-.., \ \
\ \
N2
\
'-- ,
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RECORDING ARRANGEMENTS To record ERPs it is necessary to be able to deliver both frequent and rare stimuli and to average separately the cerebral response to each. Any sensory modality can be used, although in clinical practice an auditory stimulus is most common. The stimuli are generally two or three differently pitched tones (see Fig. 28-1) delivered binaurally with a relatively long interstimulus interval (i.e., greater than I second) because of the long refractory period of the vertex potential. The amplitude of the P3 response is quite large (i.e., 50 to 100 times the amplitude of the BAEP), and therefore an average of the cerebral response to a relatively
--20dB -- -- 3 dB
-\
\
\
\ \
,, ,
\
\ \ \
\ \ \
o
400
800
Latency (msec) FIGURE :18·6 • Event-related potentials (ERPs) (plotted as dif-
ference waveforms: see Fig. 28-1) obtained from two subjects at two different levels of task difficulty. In the easy condition (solid lines) the subjects were required to distinguish two tones that differed in intensity by 20 dB, whereas in the difficult condition (dashed lines) the two tones differed in intensity by only 3 dB. The peak latencies of the different components of the ERP are longer in response to the difficult task than to the easy one. (Modified from Goodin DS, Squires KC, Starr A: Variations in early and late event-related components of the auditory evoked potential with task difficulty. Electroencephalogr Clin Neurophysiol, 55:680, 1983, with permission.)
I P3 I
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25dB 15 dB
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-
400
800
msec FIGURE :1..5 • Event-related potentials recorded from the ver-
tex of a 30-year-old subject in response to rare auditory stimuli of different stimulus intensities (measured in dB HL). A reduction in stimulus intensity did not influence the amplitude or latency of the P3 response (despite an increase in the latency of the stimulus-related Nl component) until a stimulus of 5 dB HL was used, at which point the stimuli were barely perceptible to the subject.
few number of rare tones is generally sufficient to improve the signal-to-noise ratio to the point that the P3 response can be easily seen (Fig. 28-8). Indeed, the P3 amplitude is often so large that the P3 response can be identified in single trials (see Fig. 28-8). The probability of rare tone occurrence is generally set between 10 and 30 percent, so that approximately 50 responses to the rare tone can be averaged in 10 minutes of recording time. This arrangement seems to be a good balance between the enhancement ofP3 amplitude that occurs at smaller ratios of target to nontarget stimuli, the increased response noise associated with fewer trials in the rare tone average, and the difficulty of keeping the subject's attention for longer recording times.
Event-Related Potentials
Response to target stimulus P3
Response to nontarget stimulus % Targets
Individual responses
613
Averaged responses
3%
22%
o B
50%
400
800
Latency (msec) Signal: noise ratio with averaging
100
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Latency (msec) FIG. .E 21-7 • Long-latency evoked potentials recorded from
the vertex in response to target and nontarget stimuli (tones) when the probability of target stimulus occurrence is altered. With increasing probability that a target stimulus will occur, there is a progressive decrement in the P3 response evoked by target stimuli and a progressive increment in that elicited by nontarget stimuli.
Optimally, multiple recording channels (a minimum of four) are used. Responses are recorded from Fz, Cz, and Pz electrode placements on the scalp referenced to an indifferent (although not necessarily inactive) scalp location such as the mastoids or ear lobe. Eye movements may contaminate the ERP recordings; therefore, at least one channel is usually devoted to monitoring them. Depending on the recording apparatus used, it may be possible to reject automatically trials containing eve movement or to remove digitally eye blink artifacts from the responses and thereby produce less noisy recordings. The electrical power in these long-latency responses is essentially confined to frequencies under 10 Hz so that the high-frequency cutoff of the filters used (down 3 dB at the cutoff frequencies; rolloff of 12 dB per octave) can be set low enough (e.g., at 40 to 50 Hz) to eliminate any 60-Hz activity that might otherwise degrade the waveforms. The best low-frequency cutoff is somewhat controversial.P'P'' although it should probably not exceed 1 Hz because much of the power in these recordings is in the 1- to 4-Hz frequency band, and a marked distortion in P3 amplitude begins to
Noise
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o
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400
800
Latency (msec)
A
c
50
100
Number of trials in averaged response
FIGURE 28-8 • A, Long-latency evoked potentials recorded
from the vertex of a subject on 12 single trials. In each trial a negative-positive-negative-positive complex can be identified, although it is somewhat variable in both amplitude and latency, presumably partly because of superimposed noise. B, Average of these 12 trials. The negative (N1)-positive (apparent P2)-negative (N2)-positive (P3) response can be seen. C, Plot showing the improvement in the signal-to-noise ratio that occurs with averaging. The noise is reduced in the average by the square root of the number of trials, whereas the time-locked signal remains constant. The P3 component generally has an amplitude ofbetween 10 and 30 !lV. The background electroencephalogram is often approximately 50 !lV; thus the initial signal-to-noise ratio in ERP recording may be as high as 0.5:1. Under such circumstances, even the averaged response to only a few trials is adequate to define the signal.
occur at this point. In addition, as will occur with any analog lowpass filter, responses will be shifted to earlier latencies at even very low filter settings, so it is important to record both normal control subjects and clinical patients at the same bandpass. 34 •35
NONNEUROLOGIC FACTORS INFLUENCING THE P3 COMPONENT Several nonneurologic factors may affect the ERP; it is essential that these factors be taken into account if ERPs are to be recorded in a clinical setting.
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ELECTRODIAGNOSIS INCLINICAL NEUROLOGY
Age Advancing age, during both maturation and senescence, has an important influence on several of the long-latency evoked potential components (Fig. 28-9 and Table 28-1). The data on maturation are limited, but they suggest that the stimulus-related Nl and P2 components have reached their adult latencies at least by the age of 5 or 6 years and perhaps well before. 36-38 The event-related N2 and P3 components, in contrast, are markedly prolonged in young children and progressively decrease in latency with increasing age until
600
10 20 30
40
50 60
70 80
Age (years) FIGURE 18·9 • Effect of age on the components of the long-
latency evoked potential. The solid lines represent the regression lines from data obtained from 50 normal subjects. Beginning at about age 15 years, each component increases in latencywith age. The rate of this change, however, becomes progressively faster for components with greater initial peak latencies. During maturation (age 6 to 15 years), the effect of age is reversed, at least for the event-related components. (Modifiedfrom Goodin DS,Squires KC, Henderson HB et al: Age-related variationsin evoked potentials to auditory stimuli in normal human subjects. Electroencephalogr Clin Neurophysiol, 44:447,1978, with permission.)
reaching adult values in the teenage years or early twenties.36-38 This apparently differential effect of maturation on the stimulus-related and event-related components may be related to the temporal evolution of cognitive development in children. 36-38 Beginning in about the midteens, a linear increase occurs in the latency of both the stimulus-related (P2) and the event-related (N2 and P3) components with advancing age (see Fig. 28-9 and Table 28-1). Several studies have corroborated these general findings (Table 28-2), although the rate of these changes has varied somewhat between reports. 16,36,39-49 Brown and associates have suggested that the age-related change in the latency of the P3 component is exponential, rather than linear.I? Similarly, highly significant curvilinear effects (P< .001) have been reported in a large series of 172 normal subjects.'? By contrast, the possibility of such a nonlinear relationship was studied in detail by Picton and colleagues, who noted no nonlinear trends either on trend analysis or on formal testing for curvilinearity." Moreover, the lack of curvilinearity in the P3 latency-age function has been the general finding of other authors. 16.36,40-46,48,49 Indeed, in a meta-analysis of the existing literature on this issue as of 1996, Polich concluded that the weight of the evidence supported a linear, and not a curvilinear, relationship between the latency ofP3 and age. 46 This has continued to the experience of others. 48,49 As a result of these discrepancies, it is unclear whether, or in what circumstances, nonlinear factors are important determinants of the P3 latency-age function. For example, even in the study of Anderer and associates.t? the significance of such curvilinear effects may have been exaggerated by the fact that the four oldest subjects (greater than 80 years) had quite deviant P3 latencies. It would be of interest to know what effect the exclusion of these four subjects from the analysis may have on the significance of the curvilinear nature of the age-latency function. Regardless, however, even based on this study, the use of linear approximation for subjects younger than 70 years of age seems appropriate. Moreover, in any case, normative values will need to be collected by individual investigators so that the presence or absence of curvilinear effects can be assessed directly in constructing their normal database. This age-related increase in latency occurs at a faster rate for components of longer initial peak latency,36,44,45,47 which suggests that a relatively uniform slowing of neural transmission occurs with advancing age. 36 There has also been speculation regarding the cause of the latency delay in demented subjects. For example, Ball and co-workers'" studied demented patients and control subjects longitudinally and found a significantly greater slope for the P3 latency-age function in demented subjects. They interpreted their
Event-Related Potentials
615
TABLE 28-1 • Age-Related Variations in the Amplitudes and Latencies of AuditoryEvoked Potential Components for Normal Subjects Aged 15to 7& Years Slope
Correlation Coefficient
Standard Error about Regression Line
0.1 mseC/yr 0.7 mseC/yr -0.2 't!Vjyr
0.228 0.560 -0.420
8 msec 19 msec 5.561!V
94 msec 168 msec 15.61!V
NS P< .001 P< .01
0.8 mseC/yr 1.6 mseC/yr -0.2I!Vjyr
0.691 0.810 -0.313
15 msec 21 msec 7.9 I!V
199 msec 310 msec 17.71!V
P< .001 P< .001 P' =- _ _.Q.=~ I -.. I I I I
I I II
I
B
-------=:..
I
, I
..l.-....--I - - .lJ - > '
MO-
a
I
I 0
I I 100
I I I I I I I I I
I I 200
I I I I I I I I
mS8C
I I II
N = 256
FIGURE :14-10 • Retinal, but no cerebral, responses to flash stimulation of (A) the left and (B) the right eye in the same patient as in Figure 34-9. Electroretinograms (ERGs) (waves a and b) were recorded between left and right infraorbital electrodes (101 and 102) and interconnected earlobe reference (AIA2). Slow downgoing potentials (open arrows) in recordings from right and left occipital electrodes (RO and LO) are ERGs detected by the AIA2 reference. (Modified from Wyrrzes LM, Chatrian G-E, Shaw C-M et al: Acute failure of forebrain with sparing of brain-stem function: electroencephalographic, multimodal evoked potentials, and pathologic findings. Arch Neurol, 46:93,1989, with permission.)
772
ELECTRODIAGNOSIS IN CLINICAL NEUROLOGY
I
Fp2-F4-.......,.-.....__----'--...--~---......
I
I
I
F4-C4 - - . - - - - - - - - - ....- - - - - - - - -
: N1 I
.~ C4-P4 ... -...- - -...- --... ""'"".......·----~...,..--------""
SP I
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:
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... ~ t F3-C3 ---"'--""---"'''''''''''''''-'''''''- -----.....-C3-P3 ...- _-~---_.---..._-~ ........_ ....-
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. ------. . . 50
P3-01 -_-'"""" ....~----':"'"+ v. ~ Pinching right leg 1 sec FIGUIE 14·12 • Eight hours after severe head injury, a 59-yearold man was unresponsive to noxious stimuli and visual threat, had rapid but deep and labored respiration, absent oculocephalic reflexes but preserved pupillary responses to light stimuli, and displayed bilateral extensor rigidity. His electroencephalogram (EEG) demonstrated a posterior alpha rhythm at 8 to 10 Hz, best developed on the right hemisphere, and scattered 2- to 7-Hz potentials, most prominent on the left side. This pattern wasunmodified by noxious stimuli. (Modified from Chatrian GE,White LEJr, ShawCM: EEG pattern resembling wakefulness in unresponsive decerebrate state following traumatic brainstem infarct. Electroencephalogr Clin Neurophysiol, 16:285, 1964,with permission.)
V
Cz-A1
EVALUATION OF BRAIN DEATH IN THE DEVELOPMENTAL PERIOD 5
B
10 msec
15
FIGUIE 14-11 • Electrocochleograms (ECochGs) (top traces) and brainstem auditory potentials (BAEPS) (bottom traces) in response to click stimulation of (A) the right and (B) the left ear. A2 and AI, right and left earlobes. EAM2 and EAMl, right and left external auditory meatuses. Cz, vertex. SP, cochlear summating potential. Nl, compound auditory nerve action potential, simultaneous with wave I. Waves ill and V, main brainstern components of BAEPs. The latency of Nl (and I) was prolonged on stimulation of the right but not of the left ear and all remaining latencies and interpeak intervals were normal. Same patient as in Figs. 34-9 and 34-10. (Modified from Wytrzes LM, Chatrian G-E, Shaw C-M et al: Acute failure of forebrain with sparing of brain-stem function: electroencephalographic, multimodal evoked potentials, and pathologic findings. Arch Neurol, 46:93,1989,with permission.)
the ventral pons bilaterally with no or variable extension into the pontine tegmentum. In these "locked-in" individuals,so VEPs are usually present, but BAEP and SEP studies give variable results, presumably reflecting the extent and indirect effects of the lesion."
Guidelines for establishing brain death in young patients, issued and widely disseminated in the United States by the Special Task Force for the Determination of Brain Death in Children,s2 warned that it was not possible to establish cessation of cerebral and brainstem functions and determine its irreversibility following severe brain insults in newborns earlier than 7 days after term. Clinical criteria of brain death applicable after this age did not differ from those recommended for adults. However, between the ages of 7 days and 1 year, the validity of these clinical standards depended on their persistence over specified periods and on their confirmation by EEG, cerebral radionuclide or contrast angiography, or both. No such constraints were advocated after the age of 1 year (Tables 34-2 and 34-3). These recommendations drew sharp criticism from some authors,s3.84 who believed that the proposed standards were based on combined clinical criteria and laboratory tests, none of which had been validated. Subsequent surveys of pediatric hospitals and neurosurgeons in the United States85•86 revealed only scant adherence to the guidelines of the Special Task Force. In the United Kingdom, a Working Party of the British Paediatric Association'" believed that the concept itself of brain ("brainstem") death was "inappropriate"
Electrophysiologic Evaluation of Brain Death: ACritical Appraisal
773
review of the literature reveals that the determination of brain death in children remains complex and controversial.
Clinical Criteria It is generally agreed that attempting to determine by
FIGURE 34-1J • Sagittal midline section of brain showing
infarct that transects the pons and lowermost portion of the midbrain (dashed line). Lesion wascaused by pinching of the basilar artery in vertical midline fracture of the clivus. Same patient as in Figure 34-12. (Modified from Chatrian GE, White LEJr, Shaw CM: EEG pattern resembling wakefulness in unresponsive decerebrate state following traumatic brainstem infarct. Electroencephalogr Clin Neurophysiol, 16:285, 1964, with permission.)
before 37 weeks' gestation, and that a confident diagnosis of this condition was "rarely possible" between the ages of 37 weeks' gestation and 2 months. For children older than 2 months, the assessment of brain death should be "approached in an unhurried manner" to ensure that all preconditions and clinical criteria are satisfied. The Working Party also denied the need to perform EEG, evoked potential, angiographic, radioisotope, and Doppler studies to confirm the diagnosis of brain death in a developing child. The present
clinical observation and ancillary methods that brain function has ceased in newborns and young infants, and establishing that this functional failure is irreversible, are associated with unique problems. In a thoughtful introductory commentary to the report of the Special Task Force." Volpe emphasized that "many of the critical functions to be assessed are either still in the process of developing or have only recently developed" and that "developing systems or recently acquired developmental functions are exquisitely vulnerable to injury by exogenous insults.Y" Rapid changes occur during the last 12 to 15 weeks of gestation in such functions as level of alertness; pupillary size and reaction to light; and the control of ventilation, eye movements, and bulbar reflexes. Some brainstem reflexes (e.g., pupillary and oculocephalic reflexes) are not fully developed before 32 weeks of gestation, and caloric stimulation is difficult to perform and assess in neonates." Even the reliability of apnea tests in this age group has been questioned.s" In addition to developmental factors, other conditions may confound the clinical assessment of brain viability in the early developmental period. Among them, profound systemic hypotension, common among newborns and young infants suspected of having dead brains, may so reduce cerebral perfusion as to cause potentially reversible clinical manifestations of loss of brain function. In addition, neonates and infants suspected of having dead brains are often treated with high-dose intravenous pentobarbital to control
TABLE 34-2 • Physkll Examination and Laboratory CriterIa for DetermlnlnlBraln DeIth In Chlldren* Physical Examination
EEG
Cerebral Angiography
1. Coma and apnea 2. Absence of brainstem function 3. Lack of significant hypothermia or hypotension for age 4. Flaccid tone and absence of spontaneous or reflex movements excluding spinal cord events such as reflex withdrawal or spinal myoclonus. The above findings should remain constant throughout the observation period.
Electrocerebral inactivity over a 3O-minute period according to American Electroencephalographic Society guidelines.!" Drug concentrations should be insufficient to suppress EEG activity.
lack of visualization of intracranial arterial circulation in cerebral radionuclide angiography or lack of blood flowto brain in contrast angiography. Value of cerebral radionuclide angiography in infants under 2 months isunder investigation.
'Summary ofReport ofSpecial Task Force on Brain Death inChildren: Guidelines for the determination ofbrain death inchildren. Pediatrics, 80:298, 1987. Note: The above guidelines have been seriously questioned, as indicated inthe text.
774
ElECTRODIAGNOSIS INCLINICAL NEUROLOGY
TABLE 34-3 • Tvpes of Studies and Observation Periods for Determining Brain Death in Children· PatIent Age
Types ofStudies and Observation Periods
7 days to 2 months 2 months to 1 year
Two physical examinations and two EEGs demonstrating Eel atleast 24hours apart Two physical examinations and two EEGs showing ECI atleast 24 hours apart; or a physical examination, an EEG demonstrating ECI, and a cerebral radionudide angiogram demonstrating nonvisualization of cerebral arteries Assuming demonstration ofirreversible cause of coma, two physical examinations 24 hours apart should fulfill the criteria of brain death when laboratory testing isnotto be performed. The period of observation should beprolonged byatleast 24 hours if the extent and irreversibility of brain damage are uncertain (especially in hypoxic-ischemic encephalopathy), or it may be reduced if the EEG demonstrates ECI or if cerebral radionudide angiography does notvisualize cerebral arteries.
Over 1 year
EEG, electroencephalogram; EO, electrocerebral inactivity. 'Summary ofReport ofSpecial Task Force onBrain Death inChildren: Guidelines for thedetermination ofbrain death inchildren. Pediatrics, 80:298, 1987. Note: The above guidelines have been seriously questioned, asindicated in thetext.
intracranial pressure or have received high-dose intravenous phenobarbital loading because of proven or suspected seizures. Barbiturates have profound depressing effects on the CNS of severely brain-damaged neonates'" and older children, and the inclusion in the treatment protocol of neuromuscular blocking agents and hypothermia further complicates the clinical assessment of these young patients. A large proportion of newborns with suspected irreversible loss of brain function suffer from hypoxicischemic encephalopathies secondary to perinatal asphyxia of unclear duration and severity. In this age group. the extent and gravity of the hypoxic-ischemic injury is inadequately assessed by clinical examination."s These factors, among others, limit the validity of the clinical criteria of deep coma, absent brainstem reflexes, and apnea as indicators of loss of brain function in neonates and young infants, and periods of observation longer than those in older patients are essential to establish their irreversibilityf'v"
The Eledroencephalogram PECULIARITIES IN THE DEVELOPMENTAL PERIOD: TECHNICAL AND INTERPRETIVE REQUIREMENTS
The EEGs of neonates and small infants have peculiar features that differ sharply from those of older children as well as adults and that evolve particularly rapidly from prematurity to 2 months after term. Specifically, neonates, especially premature infants, display characteristically discontinuous electrocerebral activity consisting of bursts of EEG potentials separated by periods of voltage attenuation that decrease in duration with increasing age. This discontinuous pattern is associated with cyclic variations in the state of consciousness of the nconate,91-94 Increasing duration of interburst intervals, widespread voltage attenuation, and, ultimately, Eel may develop under the influence of various condi-
tions (e.g., hypoxia, hypotension, hypothermia, drug intoxication, and metabolic disorders) ,91-95 Because of the small head size of neonates and other developmental factors, obtaining EEGs on neonates ranging in age from prematurity to 4 to 8 weeks after term requires the use of fewer scalp electrodes than in older children and adults. In addition, neonatal recordings must include the monitoring of measures other than the EEG (typically, eye movements, mental EMG, respiration, and ECG) to identity sleep stages and demonstrate artifacts.92,96,97 Actual recording time for these polygraphic studies should be at least 45 minutes." but longer recordings are often indicated. Recording technique in children older than 4 to 8 weeks does not differ from that recommended for similarly unresponsive adults.i" Because the EEGs of neonates and infants are extremely sensitive to a variety of endogenous and exogenous factors, recordings demonstrating Eel in these patients should best be repeated after an interval to ensure persistent lack of electrocerebral activity. A standard interval of 24 hours'" seems reasonable but is arbitrary. Also, the peculiarities of the EEG in normal neonates and infants as well as neonates and infants presumed to be brain dead require that these tests be performed by qualified technologists and interpreted by clinical neurophysiologists with special expertise in this age group. ASSESSMENT OF THE ELECTROENCEPHALOGRAM
Assessing the literature on the EEG as a confirmatory test of brain death in the developmental period is difficult because of paucity of data; common failure to separately report results in newborns, infants, and older children; and the use of EEG and evoked potential techniques that are not described or are incompletely described, or are inadequate by current standards. Provided these limitations are recognized, the following observations on the EEG of neonates with presumed brain death deserve consideration:
775
Electrophysiologic Evaluation ofBrain Death: ACritical Appraisal ..
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-746 respiratory studies in, 742-744, 7431', 743t prognosis and, 734 research uses of, 734 technical considerations in, 736-737 techniques used for, 735t, 735-736, 736t therapy evaluation using, 734 Intentional (kinetic) tremor, 391 without postural tremor, 393-394, 3941' Interference pattern, in EMG, 235, 238, 243, 245, 247, 253, 254, 655 reduction of, signal enhancement by, 30, 311' Interhemispheric synchrony, in newborn infants, EEG and, 86 International Classification of Epileptic Seizures, 113, 113t International Electrotechnical Commission (lEC) standards, 32 International Federation of Clinical Neurophysiology (lFCN) long-term monitoring for epilepsy guidelines of, 132 long-term monitoring for epilepsy standards of, 146-147 visual evoked potential standards of, 454, 455 International Society for Clinical Electrophysiology of Vision (ISCEV), visual evoked potential standards of, 4.">4,473 Interneuron(s) altered excitability of, R2 component of blink reflex and, 385f, 385-386 inhibitory, H reflex and, 358 Interosseous muscle, first dorsal, nerve conduction studies of, motor, 287 Intracerebral hematoma(s), EEG in, 70-71, 71f Intracerebral hemorrhage, quantitative electroencephalography in, 191 Intracranial aneurysm(s), EEG in, 71-72 Intracranial pressure, lowering of, digital electroencephalography in, 192 Intramedullary surgery intraoperative monitoring in, 628 somatosensory evoked potentials and, 630 Intramuscular electrodes, for compound muscle action potential recording, 636-638 Intraneural recordings, as autonomic function test, 417 Intraocular foreign bodies, electroretinography in, 443 Intraoperative electroencephalography, 207-217 during carotid endarterectomy, 209-217 anesthesia and, 209-212, 210f symmetric changes with induction and, 210, 21 If, 212 symmetric EEG patterns at subanesthetic or minimal anesthetic concentrations of, 209-210, 2lOf symmetric EEG patterns at sub-MAC concentrations of, 212,212f carotid artery clamping and EEG changes related to, 213-215, 213f-215f EEG changes unrelated to, 212, 2131' cerebral blood flow and, 215-216 EEG monitoring and, 217 methodology for, 209 significance of changes in, 216 Intraoperative monitoring, 627-642 compound muscle action potentials for, 632, 635 of cranial nerves and spinal roots, 636-638, 638f, 639f interpretation of, 636, 6371' evoked potentials for acoustic nerve and brainstem auditory pathway monitoring and,639-641,64If
836
Index
In traoperative moni toring (Continued) cranial nerve and spinal root monitoring and, 636-639 compound muscle action potential recording for, 636-638,638L639f neurotonic discharges and, 638-639, 639f, 640£ long-tract function and, 628-636 motor evoked potentials for, 632-636, 633f-635f, 637f somatosensory evoked potentials for, 628-630, 629f-631£, 632 by motor evoked potentials, 627, 628 motor evoked potentials as. SeeMotor evoked potentials (MEPs), intraoperative monitoring using. reducing risk of neurologic injury by, 627 somatosensory evoked potentials as, 584, 627, 641-642 cerebral ischemia detection by, 641-642 functional localization using, 642, 642f interpretation of, 636 of long-tract function, 628-630, 629f-631£, 632 nerve conduction studies for, 315-316 of cranial nerves, 315-316, 316f, 317f of peripheral nerves, 315, 316f Intravenous accurate control machines, artifact from, 736 Intraventricular hemorrhage positive rolandic sharp waveswith, in newborns, 95-96 visual evoked potentials in, in pediatric patients, 483 Invasive electroencephalography depth advantages of, 168 complications of, 168 definition of, 165 findings in, 166-168, 167f indications for, 165 limitations of, 168 techniques for, 165-166 in epilepsy, 163-165 electrode placement for, 164, 167f for epileptogenic zone localization, 163-164 morbidity associated with, 165 surface EEG versus, 164, 165f magnetoencephalography for guiding, 224 strip electrodes in, 168-171 advantages of, 169 complications of, 169, 171 definition of, 168 findings on, 169 indications for, 168, 170f, 171£ limitations of, 169 techniques for, 168-169 with subdural grids, 171-174 advantages of, 173 complications of, 173-174 definition of, 171 findings on, 173, 173f indications for, 171-172 limitations of, 173 techniques for, 172f, 172-173 Involuntary movement assessment of, 390-391 asterixis, 396, 396t ballism, 396, 396t, disorders of, 391-397 dystonia, 396, 396t, 397-398 myoclonus, 395, 395£,396f, 396t, 398-399 of peripheral nerve origin, disorders associated with, nerve conduction studies in, 314-315 reflex, 391, 392f, 395, 396, 396t, 397f, 398, 399 tic, 395-396, 396t
Involuntary movement (Continued) tonic, 395, 396, 396t, 397f, 403 tremor, 391-394 Isaacs'syndrome EMGin, 253 nerve conduction studies in, 314-315 ISCEV. See International Society for Clinical Electrophysiology of Vision (ISCEV), visual evoked potential standards of. Ischemia cochlear, brainstem auditory evoked potentials in, 511 paresthesia provoked by, microneurography in, 327-328, 328f Isoelectric patterns, in EEG, in newborn infants, 89-90 Isoflurane EEG and, 209, 210f somatosensory evoked potentials and, 629, 629f Isolation mode rejection ratio, signal enhancement by, 30, 30f Isoniazid, EEG and, 796
J Jansky-Bielschowsky ceroid lipofuscinosis, EEG findings in, 122 Jitter in EMG,255 single-fiber, 265, 267 in myasthenia gravis, 349 in neuromuscular transmission, 337, 339f in single-fiber EMG, 345-346, 346f-348f, 347 JND (just noticeable difference) units, 785, 785f, 786f Juvenile absence epilepsy, EEG findings in, 114 Juvenile myoclonic epilepsy, EEG findings in, 60, 114 Juvenile retinoschisis, electroretinogram of, 442, 443f
K Kandori's flecked retina syndrome, electroretinography in, 441 Kaufmann, P. Y., 11 Kcomplexes in children, 106 in sleep, 57, 703. 704f Kearns-Sayre syndrome, brainstern auditory evoked potentials in, in infants, 542 Kernicterus, brainstem auditory evoked potentials in, in infants, 543 Kidney(s), See Renal entries. Kinetic (intentional) tremor. 391 cerebellar, without postural tremor, 393-394, 394f "Kleiste Flasche," 5 Krabbe's disease brainstem auditory evoked potentials in, in infants, 540 somatosensory evoked potentials in, 583 Kratzenstein, J. H., 4 Kriiger, Gottlob, 4 Kugelberg-Welander disease, nerve conduction studies in, 312
L Labyrinthine asymmetry, 681 Lambda waves, in EEG, 48,108, 108f Lambert-Eaton myasthenic syndrome, 351-352 electrophysiologic testing in, in intensive care unit, 746 EMG in, 351-352, 352f jitter in, 266 single-fiber, 352 nerve conduction studies in, 352 overlap with myasthenia gravis, 352 Lamotrigine, EEG effects of, 64 Landau-Kleffner syndrome (acquired epileptic aphasia), 726 EEG in, in children, 116
Index Language mapping elertrocortlcography for, 174 magnetoencephalography for, 226 Larionov, V. E., 12 Laryngeal electromyography, 254 Laser stimulation, of somatosensory evoked potentials, 555 Late waveforms, in nerve conduction studies, motor, 290-291, 291f Latency(ies) of blink reflex, direct and reflex responses in, normal values for, 376-377,378t of compound muscle action potential, 289, 290 of F waves, 363 of H reflex, 357 in nerve conduction studies, motor, 287-288, 288f of pattern visual evoked potentials, in pediatric patients, 477, 478f of sensory nerve action potentials, 296 of somatosensory evoked potentials, 447 in pediatric patients, age and height effects on, 580-581 of transient luminance (flash) visual evoked potentials, in pediatric patients, 475-477, 476f, 477f of visual evoked potentials, 457 Lateral medullary syndrome blink reflex in, 379t, 382-383, 384 somatosensory evoked potentials, 569 Lead EEG and, 796 neurotoxic disorders from, 806-807 prenatal exposure to, visual evoked potentials and, 483 Leber's disease brainstern auditory evoked potentials in, in infants, 542 carrier state of, visual evoked potentials in, 481 Leigh disease brainstern auditory evoked potentials in, in infants, 542, 542t somatosensory evoked potentials in, 583 Lennox-Gastaut syndrome, 61, 62f, 66, 110-111, 112, 723 Leprosy, autonomic function tests in, 421 Leukodystrophy(ies) brainstem auditory evoked potentials in, in infants, 540 somatosensory evoked potentials in, 583 Leukoencephalopathy, posterior, EEG in, 71 Leukomalada, periventricular, visual evoked potentials in, in pediatric patients, 483 Limb-girdle muscular dystrophy, EMG in, 244 Limb-girdle myasthenia, 351 Linneaus, daughter of (Elizabeth), 3 Lipofuscinosis, ceroid, neuronal classic late infantile Oansky-Bielschowsky type), EEG in, 118 EEG in, 118-119 infantile (Santavuori-Halatia type), EEG in, 118 juvenile (Spielmeyer-Vogt-Sjogren type), EEG in, 119 Lissencephaly (agyria-pachygyria), in newborn infants, EEG in, 102 Lithium, EEG and, 76, 796 Liver. See also Hepatic entries. transplantation of, EEG following, 75 L/M-cone electroretinography, 436-437, 437f Locked-in syndrome (de-efferented state) hlink reflex in, 385 evoked potentials in, 518, 772 EEG in, 79 somatosensory evoked potentials in, 569 Long-term monitoring for epilepsy, 65, 131-147, 132t equipment for, 134-137 amplifiers as, 135-136 for clinical behavior monitoring, 137t, 137-138 electrodes as, 134£, 134-135 for recording, storage, retrieval, and review, 136-137 for transmission, 136, 147
837
Long-term monitoring for epilepsy (Continued) historical background of, 131-132 indications for, 132-134 differential diagnosis as, 132-133 epileptogenic region localization as, 133-134 seizure characterization and classification as, 133 seizure frequency and temporal pattern determination as, 133 interpretation of results in, 140-146 artifacts and, 140-141, 14lf epileptic activity and, 141-143, 142f-145f, 145 nonepileptic abnormal activity and, 145-146, 146f standards for analysis and, 147 procedures for, 138-139 for electrodes, 138 for recording, 139, 139t for recording system, 138 recommendations for, 146-147 for diagnosis of nonepileptic seizures, 147 for presurgical evaluation, 147 for quantification of electrographic abnormalities, 147 for seizure classification and characterization, 147 seizure characterization and classification using, 133 recommendations for, 147 seizure frequency and temporal pattern determination using, 133 recommendations for, 147 signs and symptoms associated with ictal discharges from specific areas and, 149-150 system configurations for, 139t, 139-140 Long-term neurodiagnostic monitoring. SeeLong-term monitoring for epilepsy. Long-tract function, intraoperative monitoring of, 628-636 motor evoked potentials for, 632-636, 633f-635f, 637f somatosensory evoked potentials for, 628-630, 629f-631£, 632 Long-tract motor dysfunction, H reflex in, 362 Lower motor neuron lesions, EMG in, 238, 239, 240, 242, 243, 244, 247,248,249,250,251,252,253,254,255 Lower-limb muscles, repetitive nerve stimulation in, 344 Low-Q filters, 18 LOW-VOltage pattern(s), in EEG, 53 with theta rhythms, in newborn infants, 92 undifferentiated, in newborn infants, 91-92 Lumbar plexopathy(ies), EMG in, 252, 752 Lumbar radiculopathy(ies) electromyography of, 249-250 nerve conduction studies of, 311, 312 somatosensory evoked potentials and, 563-565, 563f, 564f, 565f Lumbosacral fixation, pedicle screw placement for, compound muscle action potential assessment of, 638, 638f, 639f Lumbosacral plexopathy(ies), nerve conduction studies in, 311 Luminance, of stimulus for visual evoked potential, 454 Lysosomal storage diseases, brainstem auditory evoked potentials in, 542
M M cells (parasol cells), 453 M (magnetocellular) pathways, 453 M wave. See Compound muscle action potentials. Macro-EMG, 256, 269-270, 270f, 271£, 27lt electrodes for, 269-270 utility of, 270 Macular degeneration age-related (senile), visual evoked potentials in, 459 vitelIiruptive, visual evoked potentials in, 459 Macular edema, visual evoked potentials in, 459 Macular function, assessment of, by electroretinography, 444
838
Index
Maculopathy(ies) of macular region, visual evoked potentials in, 459, 459f visual evoked potentials in, 458f, 459, 459f, 460, 460£ Magnesium, neuromuscular blocking by, 353 Magnetic resonance imaging coregistration with magnetoencephalography, 219, 221-222 in multiple sclerosis, 568 Magnetic source imaging, 219 Magnetic stimulation blink reflex elicitation by, 376 cortical, for motor evoked potentials, 593-594 transcranial in head injury, in intensive care unit, 739 in intensive care unit, 736 in movement disorders, 403 repetitive for motor evoked potentials, 598 safety considerations with, 603 in spinal cord compression, in intensive care unit, 745 Magnetic stimulators, 23 Magnetocellular pathways, 453 Magnetoencephalography (MEG), 219-227, 220£ in brain tumors, 226 combined with EEG, 222 coregistration with MRI, 219, 221-222 cortical mapping and, 226 in epilepsy, partial, intractable, 224-225, 225f, 226f gradiometers for, 220 localization procedures using, 220-222 validation of accuracy of, 222-223 comparison of seizure discharges for, 223, 223f median somatosensory evoked field for, 223 phantom studies for, 222 magnets for, 219 recording technique for, 219-220, 220f superconducting quantum interference device for, 219-220, 220£ signal-to-noise ratio in, 221 volume conductor for, 221 Mains noise, 24 Maintenance of wakefulness test (MWr), 713 Malingering, visual evoked potentials in, in pediatric patients, 483 Malnutrition, brainstem auditory evoked potentials in, in infants, 543 Mangin, Abbe, 5 Maple syrup urine disease brainstern auditory evoked potentials in, in infants, 540 in newborn infants, EEG in, 103, 103f Mapping, with motor evoked potentials, 604 Marar.jean-Paul, 5 Marijuana, prenatal exposure to, visual evoked potentials and, 483 Masseter muscle, repetitive nerve stimulation in, 343, 343f Matteucci, C., 5, 9 Matthews, B. H. C., 10 Maturation, somatosensory evoked potentials and, 578-581 brainstem maturation and, 579-580, 580f hemispheric maturation and, 579-580, 580f peripheral nerve maturation and, 578 spinal cord maturation and, 578-579, 579£ McArdle's disease (phosphorylase deficiency), EMG in, 245 Mechanical safety,32 Mechanical stimulation, to elicit sacral reflexes, 656, 657 Median nerve nerve conduction studies in in median-ulnar anastomosis, 299, 300f, 30lf motor, 286 in neuropathy, 307-309, 308f, 309f
Median nerve (Continued) sensory, 294, 296, 296f somatosensory evoked potentials of, intraoperative, 642 Medications. SeeDrug(s). MEG. See Magnetoencephalography (MEG). Meissner corpuscles, 323t MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes), EEG in, 119 Meniere's disease, vestibular testing in, 689 Meningitis EEGin, 67 in intensive care unit, 740-741 hearing evaluation following, 533 Menkes' kinky hair disease, brainstem auditory evoked potentials in, in infants, 542 Mental status, change in, EEG evaluation of, 38 MEPPs. See Miniature endplate potentials (MEPPs). MEPs. See Motor evoked potentials (MEPs). Meralgia paresthetica, somatosensory evoked potentials in, 561 Mercury poisoning, EEG and, 796 Merkel disks, 323t MERRF (myoclonic epilepsy and ragged-red fibers), EEG in, 119 Metabolic disorders. See alsospecific disorders. EEG in, 74-76, 739-740, 740t, 761 in newborn infants, 102-103, 103f EMGin, 245 somatosensory evoked potentials in, 583 Methohexital, electrocorticography and, 176, 179f Methylmercury neurotoxic disorders from, 799 prenatal exposure to, visual evoked potentials and, 483 Metrics, for motor unit action potentials, 265, 266f, 267f Microelectrode recordings, in movement disorders, 177-182 advantages of, 182 complications of, 182 definition of, 178 globus palIidus identification by, 180f, 180-181 historical background of, 177-178 indications for, 178-179 limitations of, 182 subthalamic nucleus identification by, 18O£-182f, 181-182 techniques for, 179-180 thalamic, 181 Microneurography, 321-332 in autonomic failure, 326, 326f C fiber functional classification and, 322-323, 324f definition of, 321 electrodes for, 322 in hyperhidrosis, idiopathic, primary, 326-327, 327f in neuropathy, painful, hyperexcitable nociceptors and, 329-330, 330f in nociceptor sensitization, 329-330, 33Gf in paresthesias experimental, 327-328 postischemic events and, 327-328, 328f neuropathic, 329, 330f Phalen's sign and, 328-329 recording method for, 322 in reflex sympathetic dystrophy, 330-332 somatosensory function and, normal, 322, 322t Spurling's sign and, 329, 329f stimulation for, 322 sympathetic function and in autonomic failure, 326, 326f in hyperhidrosis, primary idiopathic, 326-327, 327f normal, 324-326, 325f Tiners sign and, 328, 329£
Index Mirrostimulation, intraneural, for microneurography, 322, 322t. Midhrain tumors, brainstem auditory evoked potentials in, in infants, 537 Middle ear effusions, in infants, hearing evaluation and, 533 Midget cells (P cells), 453 Midline theta activity, in EEG, 46 Mignline EEG in, 72 R2 component of blink reflex in, 386 vesubulopathy related to, vestibular testing in, 689 MiHard-Gubler syndrome, blink reflex in, 383 Miller Fisher syndrome. somatosensory evoked potentials in, 561 Miniature endplate potentials (MEPPs), 338 in congenital myasthenia, 350 Mirror movements, congenital, motor evoked potentials in, 601 Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MElAS) , EEG in, 119 Mitochondrial encephalopathy, EEG in, 119 Mitochondrial myopathy, R2 component of blink reflex in, 386 Mixed connective tissue disease, autonomic function tests in, 421 Mixe-d nerve stimulation, and somatosensory evoked potentials, 554 Miibius' syndrome, somatosensory evoked potentials in, 584 Monsch-Woltman syndrome (stiff-man syndrome), EMG in, 253-254 Mold(s), prenatal exposure to, visual evoked potentials and, 483 Monomelic amyotrophy (Sobue's disease), EMG in, 248 Mononeuropathy(ies). See also specific nerves. ek-ctrophvsiologic testing in, in intensive care unit, 752 nerve conduction st.udies of. 307-31 I somatosensory evoked potentials in, 561 Mononeuropathy multiplex, neurotoxic, 806-807 Monosynaptic reflex, in EMG, in movement disorders, 400 Momagets). See Electrode is) and individual techniques. Motor and sensory neuropathy axonal, eleet.rophysiologic studies of, 304-305, 306-307 demyelinating, electrophysiologic studies of, 305-306, 306-307 hereditary, 305, 306, 306f autonomic dysfunction in, 420, 421 blink reflex studies of, 3781., 379t, 380, 38lf motor evoked potential studies of, 600-601 nerve conduction studies of. 304-307 somatosensory evoked potential studies of, 583 tremor in, 394 in intensive care unit, 601, 745 Motor axonal neuropathyries). neurotoxic, electrodiagnostic evaluation of, 802-803 Motor conduction studies. See also Central motor conduction time (CMCT); Motor nerve conduction studies. in spinal cord compression, in intensive care unit, 744-745 Motor cortex, mapping of, magnetoencephalography for, 226 MOlor evoked potentials (MEPs), 589-604, 590£ abnormalities in, pathophysiology of, 597t, 597-598 in brain death. 766-767 suitability for confirming brain death and, 767 central motor conduction time determination and, 594-595, 595f in cerebellar ataxia, 601 in chronic fatigue syndrome, 601 in chronic inflammatory demyelinating neuropathy, 601 in congenital mirror movements, 601 D (direct) wave component of, 590. 591, 591f. 593, 632-633, 63111',634 in depression. 603 in dystonia, 60 I in epilepsy, 601-602 in Friedreich's ataxia, 601 in functional weakness, 602 in Cuillain-Barre syndrome. 601, 603
839
Motor evoked potentials (MEPs) (Continued) in hereditary motor and sensory neuropathy, 601 in hereditary spastic paraplegia, 600--601 in Huntington's chorea, 601 I (indirect) waves of, 590, 591, 59lf, 593, 598, 632-633, 633f, 634 intraoperative monitoring using, 602, 602f evoked potentials for. 602, 602f interpretation of, 636, 637f oflong-rractfiwnction, 632-636 spinal stimulation for, 632 transcranial stimulation for, 632-636. 633f-635f mapping with, 604 in motor neuron disease, 599-600, 600f in movement disorders, 601 in multiple sclerosis, 598-599, 599f normative data for, 5961., 596-597 in Parkinson's disease, 601 physiologic aspects of, 590-593, 59lf, 592f facilitation as, 592-593. 593f repetitive firing as, 593 plasticity and, 604 sacral, 659 safety considerations with, 603 silent period in, 598 in spinal cord injury, 628 in spondylosis, cervical, 600 stimulation for of brainstem, 596 cortical, 593-594 electrical, 593 magnetic, 593-594 of cranial nerves, 603 paired-pulse stimuli and, 598 of peripheral nerves and roots, 602-603 repetitive transcranial magnetic stimulation as, 598 of spinal cord, 595-596 triple-stimulation technique for, 598 in stroke, 600 in transcranial magnetic stimulation, 403 Motor mapping, e1ectrocorticography for, 174 Motor nerve conduction studies, 285-292, 286f A waves in, 291, 291f of anterior compartment muscles, 287 collision method for, 290 compound muscle action potential in, 286, 291-292, 292f amplitude of, 289, 290, 290f, 291-292, 292f area of, 289, 290, 290f latency of, 289, 290 duration in, 289-290 electrodes for, 288 locations for, 287 F waves in, 291, 291f of facial nerve, 286 of femoral nerve, 286 of first dorsal interosseous muscle, 287 of flexor carpi ulnaris muscle, 287 of hypothenar muscles, 287 latency in, 287-288, 288f measurements in, 287-292, 288f, 290f-292f collision method for, 290 of compound muscle action potential amplitude, 289, 290, 290f of conduction velocity, 288-289 of duration, 289-290 of latency, 287-288, 288f of negative phase area, 289 of median nerve, 286 of musculocutaneous nerve, 286
840
Index
Motor nerve conduction studies (Continued) of peroneal nerve, 286 of phrenic nerve, 286 of radial nerve, 286 recording in, 287 sacral,659 of spinal accessory nerve, 286 stimulation in, 286-287 of tibial nerve, 286 of ulnar nerve, 286, 286f waveforms in, late, 290-291, 29lf Motor neuron disease EMG in, 247 in intensive care unit, 745 in lower motor neuron disease, 247 lower EMG in, 247 sacral reflex evaluation in, 658 motor evoked potentials in, 599-600, 600f nerve conduction studies in, 312 in intensive care unit, 745 upper F waves in, 366 H reflexes in, 361 Motor neuropathy(ies) characterized by conduction slowing, neurotoxic, e1ectrodiagnostic evaluation of, 803-804 hereditary motor evoked potentials in, 601 somatosensory evoked potentials in, 583 Motor pathway, central, sacral, assessment of, 660 Motor point stimulation, of somatosensory evoked potentials, .554-M5 Motor unites) in EMG macro, 270 scanning, 272-273 fiber density in, in single-fiber EMG, 266-269, 268f, 269t isolation of automated, 264f, 264-265, 265t manual, 262-264, 263f recruitment pattern of inEMG of normal muscle, 237-238, 238f in pathologic states, 242f, 242-243 in normal muscle, 237-238, 238f triggering of, 263, 263f Motor unit action potentials (MUAPs), See alsoSingle motor unit potentials (S-MUPs). analysis of, 262-265 automated motor unit isolation for, 264f, 264-265, 265t manual motor unit isolation for, 262-264, 263f motor unit action potential metrics and, 265, 266f, 267f in EMG, scanning, 272 in normal muscle, 236-237, 237f amplitude of, 237 duration of, 236-237 negative spike area of, 237 physiologic factors affecting, 237 rise time of, 237 shape of, 236, 2371" parameters of, 655 in pathologic states during activity, 237f, 241-242, 242f at rest, 240-241, 24lf polyphasic, 242 satellite potentials following, 237f, 242
Motor unit action potentials (MUAPs) (Continued) in sphincter muscles, analysis of, 653f, 653-654, 654f waveforms of, 261 Motor unit number estimation (MUNE), 261, 273-282 in amyotrophic lateral sclerosis, clinical trials for, 789 compound muscle action potential and, 273 independent verification of, 275 muscles studied with, 273, 273t phase cancellation and, 274-275 S-MUP sample size and bias and, 275 S-MUPwaveforms and, 273-274, 274f techniques for, 275-282 F-wave MUNE as, 277-278, 278f incremental stimulation MUNE as, 275f, 275-276, 276f multiple-point stimulation MUNE as, 276-277, 277f spike-triggered averaging MUNE as, 280, 280£, 281f, 282 statistical MUNE as, 278-279, 279f test-retest reliability of, 275 Movement involuntary assessment of, 390-391 ballistic, 395 disorders of, 391-397 of peripheral nerve origin, disorders associated with, nerve conduction studies in, 314-315 reflex, 395 tonic,395 measurement of, 389-390, 390f accelerometer for, 390, 390f by EMC. 390-391 voluntary, assessment of, 391, 39lf Movement artifacts, in EEG, 42-43, 43f Movement disorder(s), 391-403. SeealsoDystonia(s); Myoclonus; Parkinson's disease; Tremor(s); specific disorders. asterixis as, 396, 397f athetosis as, 396 ballism as, 396, 396t chorea as, 396, 396t, 397f dyskinesia as, 396, 396t EMG in, 400-403 blink reflex and, 400 ~reflexesand,402-403,403f
electrical stimulation of mixed and cutaneous nerves and,402 flexor reflex and, 400 monosynaptic reflex and, 400 reciprocal inhibition and, 400-401 startle reflex and, 402 stretch reflexes and tone assessment by, 4Olf, 401-402, 402f EMG-EEG correlation in, 398-400 in dystonia, 399 in myoclonus, 398-399, 399f in Parkinson's disease, 399 in Tourette syndrome, 399, 399f hemiballismus as, 396 of involuntary movement, 391-397 microelectrode recordings in, 177-182 advantages of, 182 complications of, 182 definition of, 178 from globus pallidus, 180f, 180-181 historical background of, 177-178 indications for, 178-179 limitations of, 182 from subthalamic nucleus, 180f-182f, 181-182 techniques for, 179-180 thalamic, 181
Index Movement disorder(s) (Continued) motor evoked potentials in, 601 tic as, 395-396 transcranial magnetic stimulation studies in, 403 of voluntary movement, 397-398 athetosis as, 397-398 with cerebellar lesions, 397 with corticospinal tract lesions, 397 dystonia as, 397-398 parkinsonian bradykinesia as, 397, 398f Movement-related cortical potentials (MRCPs), in movement disorders, 398 MSLT. See Multiple sleep latency test (MSLT). Mu rhythm in EEC, 45, 4,lif in sleep, in children, 107 MlJAPs. See Motor unit action potentials (MlJAPs). Mucopolysaccharidosis(es) somatosensory evoked potentials in, 569 type I, brainstem auditory evoked potentials in, in infants, 542, 543f Multichannel recording, of somatosensory evoked potentials, 555 Multifocal electroretinography, 444, 445f Multifocal visual evoked potentials, 448, 466--467 Multi-infarct dementia, Alzheimer's disease differentiated from, with quantitative electroencephalography, 197 Multilobar seizures, behavioral signs and symptoms associated with, 150 Multiparametric analysis, in digital electroencephalography, 187-188 Multiple sclerosis blink reflex in, 379t, 382, 382f, 383f, 384 brainstem auditory evoked potentials in, 517, 540, 599 in children, visual evoked potentials in, 481 clinical trials for, 790-791 evoked potentials in, 790-791 pathophysiologic considerations in, 790 EEC in, 77 event-related potentials in, 620 magnetic resonance imaging in, 568 motor evoked potentials in, 598-599, 599f somatosensory evoked potentials in, 566f, 566--568, 567t~ 583, 599 visual evoked potentials in, 460f, 460--462, 462f, 599 Multiple sleep latency test (MSLT), 711-712, 712f Multiple-point stimulation motor unit number estimation, 276--277, 277f Multisystem atrophy autonomic function tests in, 418 electrodiagnostic testing in, 663 sacral electrodiagnostic studies in, 662 MlJNE. See Motor unit number estimation (MlJNE). Muscle(s). See also specificmuscles. background activity of, in nerve conduction studies, sensory, 294-295 cramps in, EMC in, 253 motor unit action potentials in. See Motor unit action potentials (MlJAPs). normal, EMC studies of, 235f, 236--238 endplate noise in, 236 insertion activity in, 236 motor unit action potentials and, 236--237, 237f motor unit recruitment pattern and, 237-238, 238f at rest, 236, 236f selection of, for repetitive nerve stimulation, 341-344, 342f, 343f studied using motor unit number estimation, 273, 273t temperature of, in repetitive nerve stimulation, 339, 339f
841
Muscle action potentials, compound, 274 Muscle artifacts, in EEG, 42-43, 43f Muscle disease (s). See also specificdiseases. primary, electrodiagnostie testing in, 238, 240, 242, 243-247, 255,664 Muscle fibers, density of, in single-fiber EMG, 255, 266--269, 268f,269t Muscle-specific tyrosine kinase (MuSK) antibodies to, myasthenia gravis, 347-348 in neuromuscular transmission, 338 Muscular dystrophy(ies) EMC in, 244 gene for, attempts to identify female carriers of, 244 repetitive nerve stimulation in, stimulation technique for, 339-340, 340f Musculocutaneous nerve, nerve conduction studies of, motor, 286 MuSK. See Muscle-specific tyrosine kinase (MuSK). MWT. See Maintenance of wakefulness test (MWT). Myasthenia, genetic forms of, 350f, 350-351 Myasthenia gravis, 347-350, 348f disorders of nerve conduction studies in, 313, 313f electrodiagnostic techniques in approach for, 348-349 comparison of, 349f, 349-350 electrophysiologic testing in, in intensive care unit, 746 EMCin jitter in, 266 needle, 241, 242, 245, 246, 247, 253, 255, 345, 346f jitter in, 349 overlap with Lambert-Eaton myasthenic syndrome, 352 repetitive nerve stimulation in, 349f, 349-350 single-fiber EMC in, 349-350 Myasthenic syndromers) congenital, 350 with episodic apnea (familial infantile myasthenia), 350, 350f disorders of nerve conduction studies in, 313, 313f Lambert-Eaton. SeeLambert-Eaton myasthenic syndrome. Myelodysplasia, somatosensory evoked potentials in, .',84 Myelomeningocele, brainstem auditory evoked potentials in, in infants, 539, 540f Myelopathy electrophysiologic testing for, in intensive care unit, 746--747 EMC in, 241, 248 motor evoked potential studies in, 600 nerve conduction studies in, 314f somatosensory evoked potentials in, 562-563, 569 visual evoked potentials in, 461 Myeloradiculopathies, cervical, F waves in, 365 Myoclonic epilepsy EEC in, 62 juvenile, 60,110,114,725 Myoclonic epilepsy and ragged-red fibers (MERRF), EEG in, 119 Myoclonic jerks, diagnosis of, 132 Myoclonic seizures, EEC in, 60-61 Myoclonic status epilepticus, in coma, 65, 738 Myoclonus EMC in, 395f, 395-396, 396f epileptic, 395f, 395-396, 396f cortical reflex, 398-399, 399f EMG-EEC correlation in, 398-399, 399f primary generalized, 399 reticular reflex, 399 nonepileptic, 395 Myokymia EMC in, 253 facial, EMC in, 253
842
Index
Myokymic discharges, in EMG, 241 Myopathy(ies). See alsospecific disorders. compound muscle action potential in, 314, 314f, 315f critical illness e1ectrophysiologic testing in, 246, 749-752 disuse (cachetic), electrophysiologic testing in, in intensive care unit, 748t, 751 electrophysiologic testing in, in intensive care unit, 746, 747f EMGin, 238, 240, 243-247,255,664 motor unit action potentials in, 237f, 242 motor unit recruitment pattern abnormalities in, 242-243 value of, 243 inflammatory, EMG in, 244-245 mitochondrial, R2 component of blink reflex in, 386 necrotizing, of intensive care, electro physiologic testing in, 748t, 751 nerve conduction studies in, 314, 314f, 315f neurotoxic, electrodlagnostic evaluation of, 808 thick-filament, electrophysiologic testing in, in intensive care unit, 751 Myositis, inclusion body, EMG in, 245 Myotonia congenita, EMG in, 240, 246, 255 Myotonic discharges, in EMG, 240, 240f Myotonic dystrophy, EMG in, 240, 246
N Naked endings, 323t Narcolepsy, polysomnography in, 720-721, 722f Narcotics, EEG and, 76 Necrotizing encephalomyelopathy, subacute, brainstem auditory evoked potentials in, in infants, 542 Necrotizing myopathy, of intensive care, electrophysiologic testing in, 748t, 751 Needle electrodes, 17 scalp, for somatosensory evoked potentials, 555 Needle electromyography. See Electromyography. Nerve conduction studies, 285-316 in amyotrophic lateral sclerosis, clinical trials for, 788 in axonal destruction, 302-303 in brachial plexus lesions, 311, 31U in calcium disorders, 314-315 in Clostridium botulinum intoxication, 313 in conduction block, 300, 302 conduction velocity in, 288-289 in continuous muscle fiber activity,314-315 in cramp-fasciculation syndrome, 314-315 in critical illness myopathy, 750 data analysis for, 298 in degenerative disorders, 312 in disorders associated with involuntary activity of peripheral nerve origin, 314-315 in facial neuropathies, 311 in focal neuropathies, 306t, 306-312, 307t in brachial plexus lesions, 311, 31U in facial neuropathies, 311 in lumbosacral plexus lesions, 311 in median neuropathies, 307-309, 308f, 309f in peroneal neuropathies, 31Of, 310-311 in radiculopathies, 312 in ulnar neuropathies, 309-310 in hereditary disorders, 314-315 in hypocalcemia, 314-315 in innervation anomalies. 299 in intensive care unit, 735 for intraoperative monitoring, 315-316 cranial nerves in, 315-316, 316f, 317f peripheral nerves in, 315, 316f
Nerve conduction studies (Continued) in Isaacs' syndrome, 314-315 in Lambert-Eaton myasthenic syndrome, 352 long-segment, 298 in lumbosacral plexus lesions, 311 in median neuropathies, 307-309, 308f, 309f of median-ulnar anastomosis, 299, 300f, 30U motor. SeeMotor nerve conduction studies. in motor neuron disease, 312 in intensive care unit, 745 in myasthenic syndrome, 313, 313f in neurapraxia, 300, 302, 302t in neuromuscular junction disorders, 313, 313f in neuromytonia, 314-315 in pathophysiologic conditions, 299-300, 302f, 302t, 302-303 axonal destruction, 302-303 conduction block, 299-300, 302, 302t diffuse peripheral damage, 302-303, 304f localized peripheral damage, 302, 303f neurapraxia, 300, 302, 302t segmental demyelination, 303, 304f patterns of abnormality in, 305t, 307t, 308t, 312-313 of perineal nerve, as autonomic function test, 417 in peripheral neuropathy, clinical trials for, 782-784 in peroneal neuropathies, 310f, 310-311 of phrenic nerve in critical illness myopathy, 750 in Culllain-Barre syndrome, in intensive care unit, 745 physiologic variables in, 297-298 proximal versus distal abnormalities in, 298 of pudendal nerve, as autonomic function test, 417 in radiculopathies, 312 risks with, 299 in sacral dysfunction, in peripheral neuropathy, 662 in segmental demyelination, 303, 304f sensory. See Sensory nerve conduction studies. in sensory nerve degeneration, 312 short-segment, 298 of superficial peroneal nerve, deep accessory branch of, 299, 3011' technical errors in, 298-299 in tetany, 314-315 in ulnar neuropathies, 309-310 Nerve injury, electrophysiologic changes with, 307, 307t Nerve roots. See alsoRadiculopathy(ies). avulsion of, somatosensory evoked potentials in, 584 dorsal, sensory root electrical responses of, sacral, 660 intraoperative monitoring of, 636-639 compound muscle action potential recording for, 636-638, 638f,639f neurotonic discharges and, 638-639, 639f, 640f sensory, dorsal, electrical responses of, 660 stimulation of, for motor evoked potentials, 602-603 Nerve stimulation, repetitive. SeeRepetitive nerve stimulation. Nerve terminals, types of, in glabrous skin, 322, 323t Neural generators, of somatosensory evoked potentials, 558t, 558-560, 559f Neuralgic amyotrophy (idiopathic brachial plexopathy or Parsonage-Turner syndrome), EMG in, 252 Neurapraxia, nerve conduction studies in, 300, 302, 3021', 302t Neuroaxonal dystrophy, infantile, EEG in, 119 Neurobehavioral disorders, EEG in, quantitative, 198t, 198-199 Neurodegenerative disorder(s). SeeDegenerative disorder(s); specific disorders. Neurodiagnostic monitoring, long-term. See Long-term monitoring for epilepsy. Neurofibromatosis, type I, in infants, brainstem auditory evoked potentials in, 537, 539f
Index Neurogenic atrophy, F waves in, 365 Neurogenic motor evoked potentials (NMEPs), 632 Neurogenic weakness, EMG in, motor unit recruitment pattern abnormalities in, 242, 242f Neuroleptic drugs. See alsospecific drug\ and drug types. FEG and, 76, 796 Neurologic disease(s). See alsospecific disorders. in infants, brainstem auditory evoked potentials for evaluating. See Infant(s), brainstern auditory evoked potentials in. negative symptoms of, 781 positive symptoms of, 781 visual evoked potentials and, 481 Neuromals) , acoustic blink reflex with, 378t, 379t, 380 brainstem auditory evoked potentials in, 506f, 511, 51 If, 512, 515-516. 516f. 538f, 539f resection of brainstern auditory evoked potentials and, 640, 64lf intraoperative monitoring of nerve, 315, 317f vestibulography and, 689 Neuromuscular blocking agents, in intensive care unit, 749 Neuromuscular disease(s). See alsospecific disorders. motor unit action potentials in. 237 Neuromuscular transmission disorders of, 335-354. See also Lambert-Eaton myasthenic syndrome; Myasthenia gravis. drug-induced, 246 electrophysiologic testing in, in intensive care unit, 746, 749t FMC in, 241, 242. 245, 246, 247. 253, 255 motor unit action potentials in. 242, 242f disorders of nerve conduction studies in, 313, 313f impaired, neurotoxic. electrodiagnostic evaluation of, 807-808 normal, 335-338, 336f-339f acetylcholine in, 335-338, 336f, 337f blocking of, 337 compound muscle action potentials and, 3311 end-plate potential in, 336 jitter and, 337, 3391' miniature endplate potentials in, 3311 muscle-specific tyrosine kinase and, 338 postactivation facilitation and. 336, 338f rapsyn and, 338 with repetitive nerve stimulation, 336. 337f Neuromyotonic discharges, in EMG. 241. 253 Neuromytonia, nerve conduction studies in, 314-315 Neuronal ceroid lipofuscinosis, f 18-1 19 classic late infantile (jansky-Bielschowsky type), EEG in, 118 infantile (Santavuori-Halatia type). EEG in, 118 juvenile (Spielmeyer-Vogt-Sjogren type), EEG in, 119 Neuronal storage diseases. somatosensory evoked potentials in. 583 Neuronopathy(ies) bulbospinal EMG in, 248 somatosensory evoked potentials in, 57] st'nsory motor, neurotoxic, electrodiagnostic evaluation of, 804-805 Neuropathic pain. microneurography and, 322 Neuropathy(ies). See also Autonomic nervous system. disorders of; Mononeuropathy(ies); Peripheral neuropathvties): Polyneuropathy(ies); specific nerves. alcoholic, autonomic function tests in. 421 amyloid, autonomic function test, in. 420 auditory, 534-536 demyelinating blink reflex in, 380. 38lf chronic inflammatory, motor evoked potentials in, 601 nerve conduction studies in, 305-306, 306-307
843
Neuropathy(ies) (Continued) diabetic, autonomic function tests in. 418. 420 EMG in, 247-253 motor unit action potentials in, 237f, 242 peripheral, 252-253 plexus lesions as, 250-252, 25lf radiculopathies as, 249-250 spinal cord pathology as. 247-249 erectile dysfunction and, 665 focal. nerve conduction studies in, 306t. 306-312. 307t in brachial plexus lesions, 311, 311f in facial neuropathies, 311 in lumbosacral plexus lesions, 311 in median neuropathies, 307-309, 3081', 3091' in peroneal neuropathies, 310f. 310-311 in radiculopathies, 312 in ulnar neuropathies. 309-310 hereditary, autonomic function tests in, 421 iatrogenic, autonomic function tests in, 419 idiopathic. autonomic function tests in, 419 motor, hereditary, blink reflex in, 379t, 380, 381f motor and sensory. axonal, electrophysiologic testing in. in intensive care unit. 745 optic, hereditary, Leber's, carrier state of. visual evoked potentials in, 481 painful, microneurography in, hyperexcitable nociceptors and, 329-330, 3301' peripheral, autonomic function tests in, 420 pudendal, 659 sensory, hereditary. blink reflex in. 379t. 380. 38If toxic, autonomic function tests in. 419 Neurophysiologic techniques. See also SPecific techniques. in amyotrophic lateral sclerosis, clinical trials for, 789-790 in peripheral neuropathy, clinical trials for, 787 Neurotoxic disorderts), 795-809 from amiodarone, 419. 803 from arsenic. 803-804. 805 from botulinum toxin, 807 from carbon disulfide. 799 from carbon monoxide, 799 of central nervous system, 796-800 EEG in, 796-797 evoked potentials in, 797-798 research studies of, 796 from specific agents, 798-800 from cholesterol-lowering medications, 808 from cisplatin, 804-805 from colchicine, 808 from corticosteroids. 808 from dapsone. 802-803. 806 from disulfiram. 803 from ethyl alcohol, 805 from n-hexane, 798, 804 from lead, 806-807 from methylmercury. 799 myopathy as. electrodiagnostic evaluation of, 808 from nitrofurantoin. 803 from nondepolarizing neuromuscular blockers. 808 from organophosphates, 799, 803, 807-808 pain tel's' encephalopathy as, 800 from penicillamine, 807 of peripheral nervous system, 800-808 clinical examination in. 800-801 CMAPs in, 801 EEG in, 798, 799. 800 electrodiagnostic evaluation of, 801-808 in impaired neuromuscular transmission, 807-808
844
Index
Neurotoxic disorder(s) (Continued) in multifocal sensorimotor neuropathy, 806-807 in myopathy, 808 in predominantly motor axonal neuropathies, 802-803 in predominantly motor neuropathies characterized by conduction slowing, 803--804 in sensorimotor axonal polyneuropathy, 805-806 in sensory motor neuronopathies, 804-805 EMG in, 801 sensory nerve action potentials in, 801 from pyridoxine, 804 from saxitoxin, 804 from styrene, 799-800, 805 from tetrodotoxin, 804 from thalidomide, 805 from thallium, 806 from toluene, 798-799 from L-tryptophan, 806 from vincristine, 803, 805 Newborn infant(s) assessment of, somatosensory evoked potentials in, 582 EEG in, 81-104 abnormal background patterns in, 89t, 89-94 amplitude asymmetry pattern as, 93, 931' burst-suppression pattern as, 90-91 diffuse slow activity as, 92, 921' electrocerebral inactivity as, 89-90 encoches frontales as, 85, 88, 93--94 excessively discontinuous background as, 91 focal abnormalities in, 93 grossly asynchronous records as, 921', 92-93 low-voltage, with theta rhythms, 92 low-voltage undifferentiated pattern as, 91-92 sleep state disturbances and, 93 abnormal transients in, 95-98 excessive fron tal sharp transien ts as, 96 periodic discharges as, 96-97, 971' positive rolandic sharp waves as, 95-96, 961' positive temporal sharp waves as, 96 rhythmic theta-alpha activity as, 97-98, 981' temporal sharp transients as, 96 in Aicardi syndrome, 102 amplitude-integrated, 103--104 analytic techniques for, 103--104 in brain death, 90 dysmature patterns in, 94 in herpes simplex encephalitis, 103, 1031' in holoprosencephaly, 102, 1021' in lissencephaly, 102 in maple syrup urine disease, 103, 1031' in metabolic disorders, 102-103, 1031' in neurologic disorders, 1021', 102-104, 1031' normal, 82-89 age-specific background patterns in, 86-88, 881' behavioral states and, 83--84 central nervous system maturation and, 82-83, 841' delta brushes as, 85 frontal sharp transients as, 85 interhemispheric synchrony and, 86 interpretation of, pitfalls in, 89 ontogenic scheduling and, 82-83, 84f rhythmic frontal delta activity as, 85 theta bursts as, 841', 84-85 trace alternant as, 86, 871' trace discontinu as, 851', 85-86, 861' in seizures, 98-102 ictal EEG as, 99, 991'-101£
Newborn infant(s) (Continued) interictal EEG as, 99-100 rhythmic discharges in, 101-102 spikes and sharp waves in, 100-101 serial in preterm infants, 94-95 in term infants, 95 technical considerations with, 82, 83t normal, brainstem auditory evoked potentials in, 527, 5271', 5281' sleep in, 706 Niacin, myositis due to, EMG in, 246 Nitrofurantoin, neurotoxic disorders from, 803 Nitrous oxide EEG and, 209, 2101' somatosensory evoked potentials and, 629 NMEPs. See Neurogenic motor evoked potentials (NMEPs). Nociceptor(s) C fiber functional classification and, microneurography in, 322-323, 324f microneurography in, in complex regional pain syndrome type I, 331-332 sensitization of, microneurography in, 329-330, 3301' Noise, 23--25 inEMG,234 impulse, 24 in-band sources of, 24 mains, 24 signal-to-noise ratio and, 24f, 24-25, 251' synchronous, 24, 26 white, 23 Nollet, Abbe, 4, 5 Nondepolarizing neuromuscular blockers, neurotoxic disorders from, 808 Nonneurogenic thoracic outlet syndrome, somatosensory evoked potentials in, 562 Non-REM sleep, 703--704, 703f-705f, 705, 706, 707, 708 in newborns, EEG in, 84 Norepinephrine in autonomic function testing, 417 plasma level of, as index of sympathetic function, 324-325, 416-417 Normative data, for motor evoked potentials, 596t, 596-597 Notch filters, 17-18, 191' Nougaret's disease, electroretinography in, 441 Number-of-turns, of motor unit action potentials, 655 Nyctalopia(s), stationary (rod dysfunction without degeneration), electroretinography in, 440-441 Nystagmus definition of, 677-678, 6781' gaze-evoked, 679, 679f optokinetic, 679 positional, testing of, 679-680, 6821', 683f positioning, testing of, 680, 6831' spontaneous, 678 vestibular, spontaneous, 678-679 visual evoked potentials in, 480-481 in pediatric patients, 483
o Observer-reporting, for monitoring clinical behavior, 137 Obstetric lesions, of brachial plexus, EMG in, 252 Obstructive sleep apnea, 714 diagnosis of, 718, 719f-721£ Occipitallobe(s), seizures arising in, behavioral signs and symptoms associated with, 150 Ocular hypertension, visual evoked potentials in, 464, 464f Ocular muscular dystrophy, EMG in, 244
Index OculopharyngeaI muscular dystrophy, EMG in, 244 Oddball paradigm, 610 Oersted, C, 9 Oguchi's disease, electroretinography in, 440-441 Olivopontocerebellar atrophy (ataxic syndrome) autonomic function tests in, 418 R:l component of blink reflex and, 386 somatosensory evoked potentials in, 569, 583 Omeprazole, for gastroesophageal reflux, 715 Ontogenic scheduling, in newborn infants, EEG and, 82-83, 84f Ophthalmic artery, occlusion of, electroretinography in, 442-443 Optic chiasm, disorders of, visual evoked potentials in, 465 in pediatric patients, 481 Optic nerve(s) delayed myelination of, visual evoked potentials in, 482 disorders of colobomas as, visual evoked potentials and, 481 electroretinography in, 443, 460f, 460-465, 462f-464f hypoplasia as, visual evoked potentials and, 481 in multiple sclerosis, 460-465 visual evoked potentials in children, 481 responses of, in electroretinography, 447-448 Optic nerve head component, 448 Optic neuritis, visual evoked potentials in, 462-463, 463f, 464f Optic neuropathy, hereditary, Leber's, carrier state of, visual evoked potentials in, 481 Optic tract disorders of gliomas as, in children, visual evoked potentials in, 481 visual evoked potentials in, 465-466, 481 microelectrode recordings to identity, 180 Optokinetic nystagmus, 679 Organic acidernias, somatosensory evoked potentials in, 583 Organic solvents neuropathy due to, 419 prenatal exposure to, visual evoked potentials and, 483 Organophosphates EEG and, 796 neuromuscular blocking by, 353-354 neurotoxic disorders from, 799, 803, 807-808 poisoning by, e1ectrophysiologic testing in, in intensive care unit, 746 Orthostatic tremor, 394 Osteomalacia, EMG in, 245 Otitis media, in infants, hearing evaluation in, 533 Otoacoustic emissions, evoking, 530 Otohara syndrome (early infantile epileptic encephalopathy with suppression-burst), EEG in, 112, 1I3f Ototoxic drug exposure in infants, hearing evaluation following, 533-534 vestibular testing and, 689-690 Overflow in athetosis, 396 in dystonia, 396
P P3, See Event-related potentials. P cells (midget cells), 453 P (parvocellular) pathways, 453 Pacini corpuscles, 323t Paclitaxel, neuropathy due to, 419 Pain. See also Headache. congenital indifference to, somatosensory evoked potentials in, 572-573 at EMG needle insertion sites, 235 neuropathic, microneurography and, 322 perception of, R2 component of blink reflex and, 385
845
Painful legs and moving toes syndrome, EMG in, 253 Painters' encephalopathy, 800 Paired-pulse stimuli, for motor evoked potentials, 598 Palatal tremor (palatal myoclonus), 394 Pandysautonomia, autonomic function tests in, 419 Paracentral scotoma, retinitis pigmentosa with, visual evoked potentials in, 459 Paralysis periodic, hypokalemic, EMG in, 245 tick bite, electrophysiologic testing in, in intensive care unit, 746 Paramyotonia congenita, EMG in, 246 Paraneoplastic dysautonomia, autonomic function tests in, 419 Paraplegia, spastic familial, somatosensory evoked potentials in, 583 hereditary motor evoked potentials in, 600-601 somatosensory evoked potentials in, 569 Parasol cells (M cells), 453 Parasomnias, 708 polysomnography in, 724 Paraspinal muscle(s), EMG of, 235 in radiculopathies, 249-250 Paraspinal stimulation, of somatosensory evoked potentials, 555 Parasympathetic nervous system, efferent pathways of, 409, 410 Paresthesias experimental, microneurography in, 327-328 postischemic events and, 327-328, 328f neuropathic, microneurography in, 329, 330f Parietal lobe (s) autonomic regulation, in 408 seizures arising in, behavioral signs and symptoms associated with, 150 Parkinsonian tremor, at rest, 391, 393f Parkinsonism autonomic function tests in, 418 sacral electrodiagnostic testing and, 663 Parkinson's disease autonomic function tests in, 418 blink reflex in, 385 deep brain stimulation for globus pallidus identification for, 180f, 180-181 subthalamic nucleus identification for, 180f-182f, 181-182 EEG in, 79 EMG-EEG correlation in, 399 event-related potentials in, 619-620 microelectrode recordings in. See Microelectrode recordings, in movement disorders. monitoring disease severity in, 403 motor evoked potentials in, 601 R2 component of blink reflex and, 385 transcranial magnetic stimulation in, 403 Paroxysmal activity, in EEG. See Electroencephalography (EEG), paroxysmal activity in. Parsonage-Turner syndrome (neuralgic amyotrophy or idiopathic brachial plexopathy), EMG in, 252 Parvocellular (P) pathways, 453 Pattern electroretinography, 444, 446f, 447f, 459 Pattern onset/offset visual evoked potentials, in pediatric patients, 475 Pattern-reversal visual evoked poten tials, in pediatric patien ts, 475 Pediatric patient(s). See also Infant(s); Newborn infant(s). blink reflex in, normal latencies of, 376--377, 378t brain death in, 770-774, 77It, 772t clinical criteria for, 771-772 EEG in, 119,772-774 assessment of, 772-774, 773f peculiarities in developmental period and, 772 evoked potentials in, 774
846
Index
Pediatric patient(s) (Continued) brainstem auditory evoked potentials in, 529, 529t EEG in, 104-119 in Angelman syndrome, 117 in brain death, 119,772-774 assessment of, 772-774, 773f peculiarities in developmental period and, 772 in cherry-red spot-myoclonus syndrome, 119 in encephalitis, herpes simplex, 116 in epilepsy and epileptic syndromes, 109-116 absence, 60, 109-110 acquired epileptic aphasia and, 116 benign syndromes of, 114-115 early-onset, associated with encephalopathy, 112, 113f febrile seizures as, 115-116 generalized, associated with encephalopathy, 110-112 partial, 112-114, 113t in genetic syndromes, 117-118 in hypnagogic hypersynchrony, 105, 105f in infantile neuroaxonal dystrophy, 119 in infectious diseases, 116-117 in mitochondrial encephalopathy, 119 in neuronal ceroid lipofuscinosis, 118-119 normal during drowsiness, 104-105, 105f after first two years, 106-108, 108f during first two years, 104-106 during sleep, 105-106 during wakefulness, 104, 104f patterns of dubious significance in, 108 in progressive neurologic syndromes, 118t, 118-119 in Rett syndrome, 117f, 117-118 in subacute sclerosing panencephalitis, 116-117 electroretinography in, 443-444 evoked potentials in in brain death, 774 brainstem auditory evoked potentials as, 529, 529t somatosensory. SeePediatric patient(s), somatosensory evoked potentials in. visual. See Pediatric patient(s), visual evoked potentials in. familial infantile myasthenia in, 350, 350f repetitive nerve stimulation in, 344-345 sleep in, 706, 707f, 707-708 somatosensory evoked potentials in, 577-584, 578t in achondroplasia, 583 in adrenoleukodystrophy, 583 in adrenomyeloneuropathy, 583 in AIDS, 582-583 in aminoacidopathies, 583 in ataxia telangiectasia, 583 brainstem maturation and, 579-580, 580f in cerebral palsy, 583 in coma, 581-582 in compressive spinal lesions, 583-584 in demyelinating diseases, 583 in Erb's palsy, 584 in familial spastic paraplegia, 583 in foramen magnum stenosis, 583 in Friedreich's ataxia, 583 in Cuillain-Barre syndrome, 584 hemispheric maturation and, 579-580, 580f in hereditary motor and sensory neuropathy, 583 intraoperative monitoring with, 584 intrauterine endocrine environment effects on, 581 in Krabbe's disease, 583 latency of, age and height effects on, 580-581
Pediatric patient(s) (Continued) in Leigh disease, 583 in leukodystrophies, 583 maturation effects on, 578-581 in metabolic diseases, 583 in Mobius' syndrome, 584 in multiple sclerosis, 583 in myelodysplasia, 584 in neurodegenerative disorders, 583 in neuronal storage diseases, 583 newborn assessment by, 582 in olivopontocerebellar atrophy, 583 in organic acidernias, 583 peripheral nerve maturation and, 578 in plexus lesions, 584 in polioencephalopathies, 583 premature infant assessment by, 582 recording, 577-578, 578f, 578t, 579f in Reye's syndrome, 582 in root avulsion, 584 sleep effects on, 581, 581£ spinal cord maturation and, 578-579, 579f in spinal dysraphism, occult, 584 in structural lesions, 584 in supratentorial brain tumors, 584 in tethered spinal cord syndrome, 584 visual evoked potentials in, 473-483 with antiepileptic medications, 482 in cerebral white matter disorders, 482 clinical use of, 480-483 with antiepileptic medications, 482 in cerebral white matter disorders, 482 in cortical visual impairment, 481-482 in delayed visual maturation, 482 in intraventricular hemorrhage, 483 in malingering, 483 in nystagmus, 483 in optic nerve, chiasm, and tract disorders, 481 patient issues and, 480-481 in perinatal asphyxia, 482 in periventricular leukomalacia, 483 in phenylketonuria, 482-483 in posthemorrhagic hydrocephalus, 483 in prenatal substance exposure, 483 technical issues and, 481 in visual loss of unknown etiology, 483 in cortical visual impairment, 481-482 in delayed visual maturation, 482 flash, 474f, 474-475 in intraventricular hemorrhage, 483 in malingering, 483 normal maturation of, 475-480 acuity development and, 477-480, 479f amplitude and latency of flash visual evoked potentials and, 475-477, 476f, 477f amplitude and latency of pattern visual evoked potentials and, 477, 478f in nystagmus, 483 in optic nerve, chiasm, and tract disorders, 481 pattern onset!offset, 475 pattern-reversal, 475 in perinatal asphyxia, 482 in periventricular leukomalacia, 483 in phenylketonuria, 482-483 in posthemorrhagic hydrocephalus, 483 in prenatal substance exposure, 483 in visual loss of unknown etiology, 483
Index Peli/aeus-Merzbacher disease, brainstem auditory evoked potentials in, in infants, 540 Pelvic floor dysfunction with cauda equina lesions, electrodiagnostic testing and, 662-663 with conus medullaris lesions, electrodiagnostic testing and, 662-663 with pudendal nerve lesions, electrodiagnostic testing and, 663 with sacral plexus lesions, electrodiagnostic testing and, 663 Pelvic fractures, electrophysiologic testing in, in intensive care unit, 752 Pelvic reflex evaluation, as autonomic function test, 417 Penicillamine, neurotoxic disorders from, 807 mvositis as, EMG in, 246 Penicillin, EEG and, 796 Penile nerve(s) dorsal, electroneurography of, 660 stimulation of, pudendal somatosensory evoked potentials following, 658f, 658-659 Penile tumescence, polysomnographic studies of, 716--717, 717f Penis stimulation of, to elicit sacral reflexes, 656--657, 657f sympathetic skin response recording on, 661 Pentothal test, in epilepsy, 195 Perineal nerve, nerve conduction studies of, as autonomic function test, 417 Periodic complexes, 48, 52, 61, 65, 67, 69, 71, 76, 79, 738, 740t Periodic lateralized epileptiform discharges (PLEDs), 52[, 52-53, 65,69,70,75,79,737,738,741 in newborns, 100, 101 Periodic leg movement disorder, polysomnography in, 726--727, 727f Periodic paralysis, hypokalemic, EMG in, 245 Peripheral nerve(s). Seealso specific nerves. involuntary activity originating in, disorders associated with, nerve conduction studies in, 314-315 lesions of diffuse, nerve conduction studies in, 302-303, 304f EMG in, 252-253 localized, nerve conduction studies in, 302, 303f maturation of, somatosensory evoked potentials and, .')78 nerve conduction studies of, for intraoperative monitoring, 315, 3l6f stimulation of, for motor evoked potentials, 602-603 Peripheral nervous system disorders. Seealso Nerve conduction studies and specific disorders. autonomic function tests in, 418-421 F waves in, 365 neurotoxic, 800-808 clinical examination in, 800-801 electrodiagnostic evaluation of, 801-808 in impaired neuromuscular transmission, 807-808 in multifocal sensorimotor neuropathy, 806--807 in myopathy, 808 in predominantly motor axonal neuropathies, 802-803 in predominantly motor neuropathies characterized by conduction slowing, 803-804 in sensorimotor axonal polyneuropathy, 805-806 in sensory motor neuronopathies, 804-805 somatosensory evoked potentials in, 560-565 cervical spondylotic radiculopathy or myelopathy as, 562-563 plexus lesions as, 561-562, 584 radiculopathy as, 563-565, 563f-565f thoracic outlet syndrome as, 562 Peripheral neuropathy(ies) axonal, nerve conduction studies in, 304-305 clinical trials for, 782-787 autonomic function studies in, 786--787
847
Peripheral neuropathy(ies) (Continued) nerve conduction studies in, 782-784 neurophysiologic techniques in, 787 pathophysiologic considerations in, 782 quantitative sensory testing in, 784-786, 785f, 786f demyelinating, nerve conduction studies in, 305f, 305-306,306f mixed axonal and demyelinating, nerve conduction studies in, 306--307 nerve conduction studies in, 303-306, 305t in axonal neuropathies, 304-305 in mixed axonal and demyelinating neuropathies, 306--307 in segmental demyelinating neuropathies, 305f, 305-306, 306f polyradiculopathy distinguished from, by sensory nerve conduction studies, 298 sacral dysfunction caused by, nerve conduction studies in, 662 Peripheral transmission time, in brainstem auditory evoked potentials, 496 Peri stimulus time histogram, 591 Peritoneal dialysis, monitoring of, with brainstem auditory evoked potentials, 543, 544f Periventricular leukomalacia, visual evoked potentials in, in pediatric patients, 483 Peroneal nerve nerve conduction studies of of deep accessory branch, 299, 30lf motor, 286 in neuropathy, 310f, 310-311 repetitive nerve stimulation studies of, 344 Petit mal seizures, EEG in, 59-60, 60f, 66, 109-110 Pfaff, C. H., 9 Phalen's sign, microneurography in, 328-329 Phase, in digital electroencephalography, 187 Phenobarbital EEG effects of, 64 event-related potentials and, 616 Phenothiazines, event-related potentials and, 616 Phenylephrine, in autonomic function testing, 417 Phenylketonuria brainstern auditory evoked potentials in, in infants, 540 visual evoked potentials in, in children, 482-483 Phenytoin EEG effects of, 64 event-related potentials and, 616 Pheochromocytoma, EEG in, 75 Phi rhythm, in sleep, in children, 107 Phosphofructokinase deficiency, EMG in, 245 Phosphorylase deficiency (McArdle's disease), EMG in, 245 Photic stimulation, for EEG activation, 40, 56f, 56--57 in children, 107 Photoparoxysmal responses, in EEG, 55, 56f, 56--57 Photopic e1ectroretinograms, 431-433, 432t Photoreceptors (rods and cones) adaptation of, 438f, 438-439, 439f degeneration of, acquired, electroretinography in, 441-442 electroretinography and in cone degenerations, 440 in rod dysfunction without degeneration (stationary nyctalopias), 440-441 electroretinography of, 431 functional organization of, 433f, 433-435, 434f off-responses of, 435, 435f, 436f in primates, 435, 436f responses of, distinguishing, 430-431, 432f S-cone electroretinography and, 435-437, 436f, 437f spectral sensitivity of, 439f, 439-440
848
Index
Phrenic nerve conduction studies in critical illness myopathy, 750 in Cuillain-Barre syndrome, in intensive care unit, 745 motor, 286 Physiologic tremor, exaggerated, 391-392 Physostigmine, event-related potentials and, 616 Pick's disease, EEG in, 74 Plasticity, motor evoked potentials and, 604 Platysma muscle, in repetitive nerve stimulation studies, 343 PLEDs. See Periodic lateralized epileptiform discharges (PLEDs). Plethysmography, respiratory, inductive, 714 Plexopathy(ies) brachial idiopathic (neuralgic amyotrophy or Parsonage-Turner syndrome), EMG in, 252 nerve conduction studies in, 311, 311£ obstetric lesions causing, EMG in, 252 traumatic, EMG in, 252, 752 EMG ill, 250-252, 251£ lumbar, EMG in, 252, 752 lumbosacral, nerve conduction studies in, 311 radiation, EMG in, 252 sacral, EMG in, 252 somatosensory evoked potentials in, 561-562, 584 Pneumothorax, with EMG, 235 Poisson statistics, in statistical motor unit number estimation, 278-279, 279f Polioenccphalopathies, somatosensory evoked potentials in, 583 Poliomyelitis, EMG in, 248 Polymodal hyperalgesia, 330 Polymorphic delta activity, in EEG, 46f, 46-47, 47f, 70, 122 Polymyalgia rheumatica, EMG in, 245 Polymyositis, EMG in, 244-245 Polyneuropathy (ies) amyloid, of Portuguese type, autonomic function tests in, 420 blink reflex with, 380, 381£ critical illness, electrophysiologic testing in, in intensive care unit, 747-749, 751-752 demyelinating, inflammatory, acute. See Guillain-Barre syndrome. diabetic, blink reflex in, 379t, 380, 381£ F waves in, 365 somatosensory evoked potentials in, 561 Polyradiculoneuropathyfies) demyelinating, inflammatory, acute. See Guillain-Barre syndrome. dernyelinative, chronic inflammatory, blink reflex in, 379t, 380, 381f P,ilyradiculopathy (ies) peripheral neuropathy distinguished from, by sensory nerve conduction studies, 298 somatosensory evoked potentials in, 565 Polysomnography (PSG), 701, 709-727 indications for, 709-711 maintenance of wakefulness test in, 713 multiple sleep latency test in, 711-712, 712f portable monitoring in, 711 protocols for, 710-711, 714-718 for gastrointestinal secretion studies, 715-716, 716f for impotence, 716-717, 717f for long-term sleep disorder evaluation, 718 for monitoring cardiovascular variables, 715 for sleep apnea, 714-715 for sleep-related seizures, 717-718 sleep disorders identified by, 718-727 enuresis as, 724-725 idiopathic central nervous system hypersomnia as, 722 of initiating and maintaining sleep, 722-724 narcolepsy as, 720-721, 722f
Polysomnography (PSG) (Continued) parasomnias as, 724 sleep apnea as, 718-720, 719f-721£ sleep-related epilepsy as, 725-727 of sleep-wake schedule, 725 sleep recording in, 709-710, 710t videoelectroencephalography with, 713-714 vigilance performance tests and, 713 Pornpe's disease, EMG in, 245 Pontine tumors, brainstem auditory evoked potentials in, in infants, 537, 538f Popcorn discharges, intraoperative, 639, 640f Porphyria autonomic function tests in, 419 EEG in, 740t Portable monitoring, polysomnographic, 711 Positional testing, 679-680, 682f, 683f Positional vertigo, benign paroxysmal, vestibular testing in, 687 Positioning nystagmus, testing of, 680, 683f Positive occipital sharp transients (POSTs), in sleep, 57, 57f POST(s). See Positive occipital sharp transients (POSTs). Postactivation facilitation, in neuromuscular transmission, 336, 338f Posterior fossa tumors, brainstem auditory evoked potentials in, 516 in infants, 537 Posterior slow waves of youth, 46 Postganglionic lesions, somatosensory evoked potentials in, 562 Postural orthostatic tachycardia syndrome, autonomic function tests in, 420 Postural (static) tremor, 391 cerebellar, 393 Posture, change in, blood pressure variation with, 414 Posturography, dynamic, computerized, 685-686, 691£, 692f Potentiation, in repetitive nerve stimulation, 340, 340f Power, in digital electroencephalography, 187, 187f Pravdich-Neminsky, V. v, II Precentral cortex, localization of, by somatosensory evoked potentials, 642, 642f Preganglionic lesions, somatosensory evoked potentials in, 562 Premature infant(s) assessment of, somatosensory evoked potentials in, 582 brainstem auditory evoked potentials in, 527-528, 528f EEG in, serial, 94-95 Prenatal substance exposure, visual evoked potentials in, in pediatric patients, 483 Prevost, J. L., 7 Primidone, EEG effects of, 64 Progressive neurologic syndromes, in children, EEG in, 118t, 118-119 Progressive supranuclear palsy autonomic function tests in, 418 EEGin, 80 Propionic acidemia, brainstem auditory evoked potentials in, in infants, 542 Protocols, for polysomnography, 710-711, 714-718 for gastrointestinal secretion studies, 715-716, 716f for impotence, 716-717, 717f for long-term sleep disorder evaluation, 718 for monitoring cardiovascular variables, 715 for sleep apnea, 714-715 for sleep-related seizures, 717-718 Pseudobulbar palsy, blink reflex in, 385 Pseudodementia, event-related potentials in, 617 Pseudofacilitation, in repetitive nerve stimulation, 340, 340f Pseudoseizures, ambulatory electroencephalography in, 157 Pseudotumor cerebri, EEG in, 74 PSG. See Polysomnography (PSG).
Index Psychiatric disorders, See alsospecific disorders. ambulatory electroencephalography in, 1.',7 disorders of initiating and maintaining sleep associated with, 722-723 U:C in, 80 quantitative, 198t, 198-199 Psychogenic tremor, 394 Psychomotor variant discharge, 54, 108 Pudendal nerve(s) dorsal, electroneurography of, 660 lesions of, electrodiagnostic testing and, 663 nerve conduction studies of, as autonomic function test, 417 somatosensory evoked potentials in, 658f, 658-659 Pudendal nerve terminal motor latency, 659 Pudendal neuropathy, 659 Pulmonary failure, EEG in, 74 Pupil(s), constriction of, visual evoked potentials and, 456 Pupillary function, as autonomic function test, 417 Pupillometry, 713 Pyridoxine, neurotoxic disorders from, 804 Pyruvate decarboxylase deficiency, brainstern auditory evoked potentials in, in infants, 540
Q QEEG. See Quantitative electroencephalography (QEEG). QEMG. See Quantitative electromyography (QEMG). QSART. See Quantitative sudomotor axon reflex testing