Neurology and General Medicine, 4th Edition

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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 1 Breathing and the Nervous System ROGER P. SIMON •

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RESPIRATORY EFFECTS OF NERVOUS SYSTEM DYSFUNCTION Alteration of Gas Exchange Pulmonary Hydrostatic Pressure Capillary Permeability Central Effects on Ventilation Autonomic Dysfunction Extrapyramidal Disorders Forebrain Influences on Ventilation Apraxia of Ventilatory Movements Posthyperventilation Apnea Hindbrain Control of Ventilation Other Ventilatory Patterns Cheyne–Stokes Breathing Central Hyperventilation Alveolar Hypoventilation NERVOUS SYSTEM EFFECTS OF RESPIRATORY DYSFUNCTION Hypoxia Acute Hypoxia Hypercapnia Chronic Hypercapnia Acute Hypercapnia Hypocapnia Acute Hypocapnia Chronic Hypocapnia HICCUP SNEEZING YAWNING

The relationship between breathing and the nervous system can be considered from two perspectives, both of which are important to neurologists as well as to general physicians. First, neurological dysfunction can have effects on respiration that may be the most disturbing aspects of the underlying neurological disease. Second, primary respiratory dysfunction may affect the nervous system and lead to a request for neurological consultation. Both interactions are considered in this chapter. In revising this chapter for the current edition,

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many old but classic references were removed, but interested readers will find these cited in earlier editions, to which they are referred. RESPIRATORY EFFECTS OF NERVOUS SYSTEM DYSFUNCTION

Alteration of Gas Exchange One of the most dramatic and life-threatening effects of nervous system dysfunction on respiration is the impairment of alveolar gas exchange by a neurologically induced increase in pulmonary interstitial and alveolar fluid: the phenomenon of acute pulmonary edema. The fluid producing pulmonary edema originates in the pulmonary capillaries. Fluid movement from the pulmonary capillary bed into the alveolar air space is governed by the variables in the classic Starling equation. In its simplest form, the Starling equation expresses transcapillary fluid flux as a balance between intravascular pressures (tending to push fluid out of the vascular lumen) 1and plasma osmotic forces (which tend to retain fluid within the by which neurogenically induced vascular lumen) (Fig. 1-1). Although the mechanisms 2 pulmonary edema occurs remain uncertain, the major recognized factors are discussed in the following sections.

FIGURE 1-1 Relationships between microvascular hydrostatic pressure (PMV); perimicrovascular hydrostatic pressure, that is, within the interstitial space (PPMV); plasma colloid osmotic pressure (πMV); and perimicrovascular pericolloid osmotic pressure (πMv). Under normal conditions, the sum of forces is slightly positive, producing a small vascular fluid flux into the pericapillary interstitium of the lung, which is drained as lymph. (From Fein A, Grossman RF, Jones JG, et al: The value of edema fluid protein measurement in patients with pulmonary edema. Am J Med 67:32, 1979, with permission.)

Pulmonary Hydrostatic Pressure The main variable under the control of the nervous system affecting pulmonary capillary fluid flux is pulmonary intravascular pressure. A marked increase in this pressure can force fluid from the vascular compartment, flood the interstitial space (Fig. 1-1), produce pulmonary edema, and impair oxygenation. can unbalance the Starling equation and result in An elevation in intracranial pressure 2 neurogenic pulmonary edema. This early experimental observation in animals has been 3 confirmed in patients with traumatic head injury. Experimental studies have demonstrated that the effect of increased intracranial pressure on pulmonary vascular pressure and transcapillary fluid flux occurs as intracranial pressure approaches systemic pressure. An

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increase in systemic pressure (the Cushing response) then occurs to protect cerebral perfusion. In most studies, an increase in intracranial pressure alone, in the absence of the Cushing response, has no effect on transcapillary fluid flux in the lung. During the Cushing response, pulmonary vascular pressure increases in concert with systemic pressure, with a 4 resultant increase in pulmonary transcapillary fluid flux. Only one experimental study has shown an increase5in pulmonary transcapillary fluid flux in the absence of elevated pulmonary vascular pressure. Other classic models of induction of neurogenic pulmonary edema also appear to be those of centrally induced pulmonary vascular hypertension. These models include “sympathetic activation” induced by intracisternal veratrine and intracisternally 6–8 administered thrombin and fibrinogen with or without vagotomy in rabbits. Focal central nervous system (CNS) lesions can cause both an elevation of systemic vascular pressure and pulmonary edema. Although hemodynamic data in humans are lacking, there are many reports that the brainstem, particularly the medulla, is the site of focal 2,9–11 In unanesthetized small animals, brainstem CNS injuries that result in pulmonary edema. lesions in the region of the nucleus tractus solitarius produce marked systemic hypertension and fulminant pulmonary edema; pulmonary vascular pressure cannot be measured in these small animals. Following bilateral lesion placement in the ventral lateral nucleus tractus solitarius in sheep, however, pulmonary arterial pressures and transcapillary fluid flux in the lung can be measured and may increase significantly without a change in systemic or left 12 to a CNS injury is similar to that reported for atrial pressures. This pattern of response 2 neurogenic pulmonary edema in humans. Furthermore, a patient has been reported in whom a unilateral injury occurred to the tractus solitarius during a neurosurgical procedure and in whom the contralateral tractus solitarius was absent because of a congenital brainstem9 syrinx. The patient died of pulmonary edema and hypoxemia 34 hours postoperatively. The localization by magnetic resonance imaging (MRI) of a lesion at the obex (Fig. 1-2) in patients with recently diagnosed multiple sclerosis (MS) and acute pulmonary edema supports this 13,14 Recent corroborative data anatomical site as that inducing neurogenic pulmonary edema. come from a subset of patients with EV71 encephalitis in whom brainstem encephalitis and a polio-like acute flaccid paresis picture occur associated with neurogenic pulmonary edema. Brain MRI performed within hours of onset of pulmonary edema showed restricted diffusion in 15 the posterior medulla, anterior to the inferior aspect of the fourth ventricle (Fig. 1-3).

FIGURE 1-2 Rostral to caudal (A to C) schematic reconstruction of the medullary lesion in a patient with multiple sclerosis and pulmonary edema, based on magnetic resonance imaging, illustrating the major nuclear groups and tracts involved. AP, area postrema; 4th, fourth ventricle; LRN, lateral reticular nucleus; MLF, medial longitudinal fasciculus; MRN, medial reticular nucleus; NA, nucleus ambiguus; NTS, nucleus of the solitary tract; Ob, obex; ST, solitary tract; V, spinal trigeminal nucleus; X, dorsal motor nucleus of the vagus; XII, hypoglossal nucleus. (From Simon RP: Respiratory manifestations of neurologic diseases. p. 496. In Goetz CG, Tanner CM, Aminoff MJ [eds]: Handbook of Clinical Neurology. Vol 63. Elsevier, Amsterdam, 1993, with permission.)

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FIGURE 1-3 A, Diffusion magnetic resonance image at the level of the fourth ventricle, performed within hours of onset of neurogenic pulmonary edema, showing paired areas of restricted diffusion paracentrally in the region of the dorsal motor nucleus of the vagus, nucleus tractus solitarius, and medial reticular formation. Axial (B) and sagittal (C) T1-weighted images of same patient performed 4 weeks after onset of neurogenic pulmonary edema. Note the well-defined signal abnormality anterior to the inferior aspect of the fourth ventricle consistent with encephalomyelomalacia. (A kindly provided by Dr. P. Ian Andrews; B and C modified from Nolan MA, Craig ME, Lahra MM, et al: Survival after pulmonary edema due to enterovirus 71 encephalitis. Neurology 60:1651, 2003.)

Generalized seizures produce an abrupt, marked increase in sympathetic outflow from the 16 brain, and both systemic and pulmonary vascular pressures increase. The degree of systemic pressure elevation cor relates with the number of seizures and is maximal during status epilepticus. The magnitude of the pressure elevation in the pulmonary vasculature is independent of the number of seizures, however, although the duration of the elevation is maximal with status epilepticus (Fig. 1-4). The increase in transcapillary fluid flux resulting from this17transient pulmonary vascular hypertension persists for hours after the pressure transient and probably explains the phenomenon of pulmonary edema following seizures in humans.

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FIGURE 1-4 Vascular pressure changes that occur during seizures in sheep. Mean values have been plotted at 10-second intervals. Spinal cord refers to animals with cervical spinal cord transection prior to seizures. Single, 5, and 20 shocks refer to the number of electroconvulsive seizures induced; bicuculline refers to bicuculline-induced status epilepticus. LA, left atrial; PA, pulmonary arterial. (From Bayne LL, Simon RP: Systemic and pulmonary vascular pressures during generalized seizures in sheep. Ann Neurol 10:566, 1981, with permission.)

The development of postictal pulmonary edema requires an increase in pulmonary vascular pressures. If these pressure transients are aborted by a diversion of blood from the pulmonary artery and left atrium during experimental status epilepticus, pulmonary edema does not occur. As these peripheral vascular manipulations do not alter central sympathetic output during the seizure, the studies support a hydrodynamic mechanism for postictal pulmonary edema rather than the pulmonary edema being a manifestation of increased 18 activity of the sympathetic nervous system. Capillary Permeability Fulminant neurogenic pulmonary edema occurs in the setting of an alteration in pulmonary 5 19 capillary permeability, possibly independent of or in association with an imbalance of the forces in the Starling equation. The classic explanation for the pathogenesis of the altered permeability is that the rapid elevation of pulmonary vascular pressures and blood flow mechanically disrupts the pulmonary capillary bed, resulting in a pulmonary capillary leak 20 phenomenon and noncardiogenic pulmonary edema. Although this explanation is likely, some studies indicate the possibility that altered capillary permeability occurs in the absence 5 of altered intravascular pressure. Other studies in animals have demonstrated an inverse correlation between maximal pulmonary vascular pressures and altered capillary permeability, suggesting that a combination of “cardiogenic” and “noncardiogenic” factors 19 may be the most common cause of neurogenic pulmonary edema. A similar conclusion has been reached from the study of patients in whom the ratio of the protein concentration of edema fluid to plasma protein concentration has been used as an index of altered capillary 21 permeability.

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Central Effects on Ventilation Autonomic Dysfunction Neural pathways subserving volitional ventilation descend from cortex through the brainstem and spinal cord in the region of the corticospinal tract. The neuronal pools subserving rhythmic involuntary ventilation originate in the caudal medulla and give rise to descending pathways in the ventrolateral brainstem and spinal cord. Accordingly, appropriately placed focal lesions may interfere with voluntary or involuntary ventilation independently. Impairment of autonomic but not volitional ventilation produces the phenomenon of sleep apnea, or “Ondine's curse.” This term was taken from a 1956 play by Jean Giraudoux, who recreated a German mythical legend. The sea nymph Ondine cursed the unfaithful knight Hans with the necessity of voluntary control over all of his autonomic functions: “He died, they will say, because it was a nuisance to breathe.” In the brainstem, bilateral medullary 22 infarctions (Fig. 1-5A) have resulted in sleep apnea, as has unilateral medullary infarction (Fig. 1-5B). In the latter case, the lesion depicted in Figure 1-5B will have destroyed primary ventilatory nuclei in and about the nucleus retroambigualis and the nucleus tractus solitarius as well as fibers from these nuclear groups, which descend contralaterally. Transient 23 vertebrobasilar ischemia has also resulted in transient episodes of Ondine's curse. Congenital disorders of central alveolar hypoventilation may represent a primary defect in neural crest cell migration and function, resulting in altered central chemoreceptors. Accordingly neuroblastoma formation and Hirschsprung's disease sometimes occur in these 24 have lost patients. Patients with myotonic dystrophy and alveolar hypoventilation 25 catecholaminergic neurons in the medullary reticular formation. Incomplete and asymmetric involvement in the region of the dorsal and ventral ventilatory complex of the medulla at about the obex has been described in two patients with multiple sclerosis who died of sleep 26 apnea.

FIGURE 1-5 A, Location of bilateral brainstem infarcts in a patient with automatic respiratory failure. B, Brainstem section showing a unilateral lesion that resulted in failure of autonomic respiration. (A from Devereaux MW, Keane JR, Davis RL: Automatic respiratory failure associated with infarction of the medulla. Arch Neurol 29:46, 1973, with permission. B from Levin BE, Margolis G: Acute failure of automatic respirations secondary to a unilateral brain stem infarct. Ann Neurol 1:583, 1977, with permission.)

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Primary involvement of autonomic ventilatory nuclei was a common consequence of bulbar poliomyelitis (Fig. 1-6). As with lesions of the descending pathways from these nuclear groups, these lesions led to temporary or permanent sleep apnea. There are rare reports of 27,28 and pathological material from hypoventilation in patients with systems degeneration, such cases suggests that the causal abnormalities are located in the region of the solitary tracts in the caudal medulla. Vertebral artery dissection involving the dorsal medulla and 29 anterior spinal artery with resultant central ventilatory failure has been reported.

FIGURE 1-6 Medullary lesions found in 17 patients with bulbar poliomyelitis who died of respiratory failure. (From Baker AB, Matzke HA, Brown JR: Poliomyelitis. III: Bulbar poliomyelitis: a study of medullary function. Arch Neurol Psychiatry 63:257, 1950, with permission.)

Iatrogenic sleep apnea occurs in some patients following bilateral cervical tractotomy30 performed for intractable pain (6 of 112 patients reported by Tranmer and associates ). Figure 1-7 shows the most common site of the cordotomy lesion and the descending autonomic pathways in the reticulospinal tract. Descending pathways for voluntary ventilation are located in the corticospinal tract and thus are distant from the lesion site (Fig. 1-7).

FIGURE 1-7 Cervical spinal cord at the C1–C2 level showing the area commonly damaged in cervical cordotomies and the site of the descending autonomic pathway subserving ventilation. (From Tranmer BI, Tucker WS, Bilbao JM: Sleep apnea following percutaneous cervical cordotomy. Can J

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Neurol Sci 14:262, 1987, with permission.) Sleep apnea also occurs on an obstructive or mixed basis. Such patients are usually obese, hypertensive men older than 40 years. Excessive daytime sleepiness and sleep attacks are associated symptoms. Nocturnal breath cessation is associated with prominent snoring, snorting, and gasping sounds. Obstructive sleep apnea has been associated with neurodegenerative diseases, such as syringobulbia and olivopontocerebellar degeneration, 31 and miscellaneous unilateral lesions of the rostrolateral medulla, which may produce 32 oropharyngeal weakness. Nonobstructive ventilatory dysfunction may occur as well. 33 Treatment with continuous positive airway pressure (CPAP) during sleep is effective. Further discussion of this syndrome can be found in Chapter 32. Impairment of voluntary ventilatory efforts with preservation of autonomic ventilation may also occur. Cases have been reported from a demyelinating lesion in the high cervical cord and a bilateral pyramidal tract lesion in the medulla resulting from syphilitic arteritis. In another case, an infarct of the basal pons produced quadriplegia; autonomic ventilation was modulated normally by laughing, crying, and anxiety, supporting a nonpyramidal location of descending 27 pathways from limbic structures to medullary ventilatory nuclei. The most common cause, however, is a midpontine lesion that produces the “locked-in” syndrome. Patients may have a regular ventilatory pattern and a preserved response to CO2 stimulation, or a Cheyne–Stokes pattern that is volitionally unalterable. Extrapyramidal Disorders Symptomatic or asymptomatic ventilatory dysfunction is an infrequently recognized but relatively common manifestation of extrapyramidal syndromes34of multiple causes. Respiratory dysrhythmias were common in postencephalitic parkinsonism. Tachypnea, the most common abnormality, may be episodic or continuous during sleep or wakefulness; rates as high as 100 per minute are reported. Ventilatory dysrhythmias are less common and manifest as breath-holding spells, sighing, forced or noisy expiration, inversion of the inspiration/expiration ratio, or the Cheyne–Stokes pattern. Respiratory tics occur as well, manifesting as yawning, hiccupping, spasmodic coughing, and sniffing. In a study by Kim, all nine patients with postencephalitic parkinsonism had an increase in 35 respiratory rate, and the normal variation in respiratory amplitude did not occur. The most striking abnormality in these patients was their inability to alter the respiratory rhythm voluntarily so that, for instance, they were unable to hold their breath. Direct fiberoptic visualization of the upper airway in patients with extrapyramidal disease 36 (essential tremor, parkinsonian tremor, rigid parkinsonism, or dyskinesia) has disclosed rhythmic or irregular glottic and supraglottic involuntary movements. Symptomatic stridor and ventilatory failure that could be reversed by endotracheal intubation were described in a number of these patients and suggested upper airway obstruction. Abnormal flow-volume curves were commonly found. Such upper airway dysfunction may be a factor in the retention of secretions and respiratory infections that occur in many patients. Alternatively, a reduction in both maximal static inspiratory and expiratory pressures precluding the ability to rapidly 37 increase peak expiratory flow for maximally effective coughing may be an important factor. Respiratory distress and dyspnea are also described in patients with extrapyramidal dysfunction in whom no cardiopulmonary cause is found, but in whom respiratory rates are irregular owing to involuntary respiratory dyskinesias that are either levodopa induced or 38 related to a tardive dyskinesia. Respiratory dyskinesias, then, may be an accompaniment of choreiform movement disorders and may account for subjective complaints of dyspnea in 39 Parkinson's disease and dystonia. Forebrain Influences on Ventilation That the forebrain influences both ventilatory rate and rhythm is documented by the volitional acts of overbreathing and breath-holding as well as by the coordinated semivoluntary or involuntary rhythmic alterations in ventilatory pattern that occur as part of speaking, singing, laughing, and crying. Furthermore, during sleep, normal ventilatory patterns become more irregular, total ventilatory volume decreases, Paco2 is elevated, and the CO2 response curve shifts to the right. Cortical “readiness potentials” originating from supplementary motor and primary motor cortex can40be recorded from humans prior to volitional but not automatic inspiration or expiration. Using positron emission tomography of changes in regional cerebral blood-flow, areas of cortical activation during volitional inspiration and expiration 41 have been identified. Inspiration is associated with increased cerebral blood-flow in primary

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motor cortex bilaterally, the right supplementary motor cortex, and left ventrolateral thalamus. In expiration, the structures implicated are similar and overlapping but extend beyond those in inspiration and include the cerebellum. In the cortex, the identified regions activated during ventilation conform to the homuncular regions of thoracic and abdominal muscles. Diaphragmatic contraction induced from these cortical regions with magnetic stimulation does 42 not, however, affect automatic breathing. Hemispheric stroke results in attenuation of diaphragmatic excursion on the hemiplegic side but only during 43 volitional breathing; thus, the diaphragm lacks bilateral cortical 44 representation. The intercostal muscles are similarly affected by hemispheric stroke. Sleep-disordered breathing is common in acute supra- and infratentorial stroke but rarely has 45 localizing value. The cortical areas effective in inducing apnea in humans are similar to those in primates (Fig. 1-8) and include the anterior portion of the hippocampal gyrus, the ventral and medial surfaces of the temporal lobe, the anterior portion of the insula, and the anterior portion of the limbic gyrus. An episode of partial seizures with ictal apnea following encephalitis in humans has been studied with ictal-interictal subtraction single-photon emission computed tomography (SPECT), showing an abnormality in the left posterior lateral temporal region 46 consistent with the ictal electroencephalographic (EEG) findings. Respiratory changes have also been associated with paroxysmal abnormalities on the electroencephalogram. Such 47 episodes have been implicated in epileptic sudden death.

FIGURE 1-8 Points on the anterior lateral (top) and ventromedial (bottom)

cerebral cortex of Macaca mulatta where electrical stimulation elicited inhibition of respiration. C, cingulate gyrus; CC, corpus callosum; CF, central fissure; HG, hippocampal gyrus; IN, insula; LO, lateral orbital gyrus; OLF, olfactory tract; OT, optic tract; PO, posterior orbital gyrus; R, gyrus rectus; ST, superior temporal gyrus. (From Kaada BR: Somato-motor, autonomic, and electrocorticographic responses to electrical stimulation of “rhinencephalic”

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and other structures in primates, cat, and dog. Acta Physiol Scand 24:1, 1951, with permission.) Apraxia of Ventilatory Movements The inability to take or hold a deep breath despite normal motor and sensory function is termed respiratory apraxia. This phenomenon is noted most often in elderly patients with evidence of mild or moderate cerebrovascular disease. For example, in a patient with progressive supranuclear palsy, rhythmic breathing movements persisted during planned 48 volitional inspiration or breath-holding. As cortical magnetic stimulation of primary motor cortex produces diaphragmatic contraction but does not affect ongoing nonvolitional ventilation, cortical or subcortical regions other than primary motor cortex must be the site of respiratory apraxia in such patients. Posthyperventilation Apnea In 1867, Hering observed that brief periods of apnea followed hyperventilation in anesthetized 49,50 animals, and in 1908, Haldane reported apnea after voluntary hyperventilation in humans. Modern reanalysis of posthyperventilation apnea in awake normal human subjects shows that both hyperpnea and apnea of 10 to 30 seconds may occur in an individual subject; apneic pauses occur about 1 minute after cessation of hyperventilation; the apnea's length and occurrence, although variable among subjects, was reproducible in individual subjects; and 51 the occurrence of apnea was unrelated to the Pco2 during hyperventilation. In patients with brain injury, apnea occurred for more than 1052seconds with equal frequency in patients with unilateral (67%) and bilateral (70%) damage. No correlation was found between the decrease in end-tidal CO2 and the occurrence of apnea. A depressed level of consciousness in normal subjects, as during drowsiness, sleep, or anesthesia, also leads to posthyperventilation apnea. Posthyperventilation apnea has also been described in normal 53 patients engaged in an intellectual task. Hindbrain Control of Ventilation The concept that the hindbrain controls ventilatory function, rate, and rhythm has grown from the experiments of Lumsden (Fig. 1-9). These studies in anesthetized cats localized the brainstem ventilatory centers to regions below the inferior colliculus because transection at this level did not alter the ventilatory pattern when the vagi were intact. Transection at the medullary-cervical junction produced the cessation of all ventilatory functions. Accordingly, the neuronal centers responsible for ventilation are located between these levels. Transection at the pontomedullary junction resulted in rhythmic breathing with a gasping quality unchanged by vagal transection, demonstrating that the most primitive respiratory oscillator is located within the medulla. The higher brainstem “centers” play a modulatory role. A modern example of such experiments in anesthetized cats is found in Figure 1-10.

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FIGURE 1-9 A, The original illustration from Lumsden (1923) showing the level of “crucial sections” producing ventilatory alteration in cats. Ventilatory effects produced with lesions: 1, no alteration; 2, apneusis; between 3 and 4, uncoordinated inspiratory spasms and gasping; 4, gasping; between 5 and 6, cessation of all respiratory movements. B, Respiratory tracings from Lumsden (1923). a, normal animal; b, after vagotomy; c, apneusis (transection 2); d, gasping (transection 4). (From Lumsden T: Observation on the respiratory centres in the cat. J Physiol [Lond] 57:153, 1923, with permission.)

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FIGURE 1-10 Effects of brainstem and vagal transection on the ventilatory

pattern in an unanesthetized cat. APC, apneustic center; CP, cerebellar peduncle; DRG, dorsal ventilatory group; IC, inferior colliculus; PNC, pneumotaxic center; VRG, ventral ventilatory groups. Transections at different levels are indicated by roman numerals. Tracings on right represent the tidal volume with inspiration upward. (From Berger AJ, Mitchell RA, Severinghaus JW: Regulation of respiration. N Engl J Med 297:139, 1977, with permission.) Cerebellum

Classic studies of the role of the cerebellum in ventilation focused on the inhibitory effects of the anterior lobe induced by stimulation. Modern studies have extended these observations to the posterior lobe, showing stimulation-induced ventilatory inhibition from the fastigial nucleus and uvula. Stimulation of large regions of the cerebellum, however, produced no ventilatory alteration. Stimulation of the fastigial nucleus produced early termination of bursting in both 54 the inspiratory and the expiratory medullary neurons in the cat. Functional magnetic resonance imaging and positron emission tomography studies have also shown activation of the cerebellum along with other brainstem and basal forebrain structures during volitional 41,55,56 A breathing in humans. In some studies, expiration particularly involved the cerebellum. congenital syndrome associated with hypoplastic posterior cerebellar vermis (Joubert's syndrome) is characterized by prominent ventilatory abnormalities: episodic hyperpnea and 57 apnea. Pneumotaxic Center

Lumsden named the pneumotaxic center (pneumotaxy: normal rhythmic ventilation) and 58 localized it to the rostral pons in the parabrachial complex. Transection at this level results in regular breathing, and the rate of this breathing, but not the rhythm, is slowed by vagotomy. Destruction of this region or transection below it produces the phenomenon of apneusis (Fig. 1-9B), which is discussed in the next section. Modern electrophysiological and cytoarchitectural studies have localized respiratory-related neuronal activity to multiple nuclei 59 in the dorsal and ventral pons and its connections. Electrical stimulation within this region produces premature switching of respiratory phases. This off-switching is modified at least in 60 part by the classic Hering–Breuer (and possibly other) afferents carried within the vagus. 61 Glycinergic and GABAergic input is critical for off-switching. Neuroanatomical and neurophysiological studies in animals support the belief that the pneumotaxic center functions as a relay station, finely tuning the ventilatory pattern generator. Stimulation by glutamate injection of the parabrachial complex Kolliker–Fuse nucleus to include the margins of the sensory and motor trigeminal nuclei have identified functionally distinct cell populations producing specific but sometimes opposing ventilatory responses, which include both 62 respiratory facilitation and inhibition.

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Apneustic Center

The phenomenon of apneusis consists of prominent, prolonged end-inspiratory pauses that 58,63 Although the can be produced by pontine transection in vagotomized animals (Fig. 1-9). phenomenon of apneusis is well recognized, anatomical definition of a neuronal aggregate that can reasonably be called the apneustic center is still lacking. Apneusis is defined operationally as a failure of activation of normal inspiratory off-switching. The phenomenon of apneusis may result from one of a number of lesions (Fig. 1-11) or pharmacological manipulations. Systemic, but not local, administration of antagonists of the N-methyl-d-aspartate (NMDA) subset of the glutamate receptor, but not non-NMDA 64 antagonism induces apneusis, thus defining the neurotransmitter system involved and the 65 lack of a specific inducing site. However, altered membrane66potentials in neurons of the ventral respiratory group are produced by NMDA antagonists.

FIGURE 1-11 Areas of the brainstem infarction in two patients with apneustic

breathing. (From Plum F, Alvord EC: Apneustic breathing in man. Arch Neurol 10:101, 1964, with permission.) Apneustic respiration is rare in humans. Children with brainstem damage from hypoxic-ischemic injury or other brainstem lesions may have apneustic breathing, with cyanosis during inspiratory pauses. Tandospirone or buspirone, serotonin-1A agonists, 67,68 Five patients with cervicomedullary compression from normalize breathing. achondroplasia had apneustic breathing patterns that were “reduced in the majority” following decompressive surgery. The absence of a compressive effect at the level of the pneumotaxic 69 center and the integrity of the vagus nerves are notable in this clinical description. Medullary Center

Rhythmic ventilatory excursions persist with brainstem transection at the pontomedullary level, and all ventilatory movements are abolished by transection at the medullary-cervical junction. Accordingly, attention has been focused on the medulla as the generator of rhythmic ventilatory movements. Medullary centers responsible for inspiration and expiration were identified and were held to explain both ventilatory function and ventilatory rhythmicity. Two major neuronal pools are responsible for ventilation. Primary inspiratory cells located in the ventrolateral nucleus tractus solitarius constitute the dorsal respiratory group, which receives all primary pulmonary afferents from the vagus nerves. GABAB receptors are the major 70 modulators. Inspiratory and expiratory neurons are found in a separate grouping within the nucleus ambiguus and the nucleus retroambigualis, which together constitute the ventral respiratory group (Fig. 1-12). Excitatory amino acid neurotransmitter function is necessary to modulate ventral respiratory group function. NMDA receptors are the major mediators of ventral respiratory group ventilatory drive, with modulation by non-NMDA glutamate 71 systems. Thus, ventilatory rhythmicity is mediated by the dorsal respiratory group, and projection to spinal respiratory motor neurons and vagally mediated auxiliary muscles of respiration occurs via the ventral respiratory group. Although rhythmic ventilatory responses occur from the medulla following ponto-medullary transection, this respiratory pattern has a rather gasping quality and is not normal rhythmic ventilation.72A gasping center has been found just rostral and ventral to the dorsal respiratory group. The primary ventilatory rhythm generator appears to reside in a limited region of the ventral medulla (the pre-Bötzinger

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complex) just rostral to the rostral ventilatory group (Fig. 1-12). Rhythm generation is eliminated by removal of this region, and medullary slices containing this region generate 73 complex responds to hypoxia, and this respiratory-related oscillations. The pre-Bötzinger 74 membrane response is modified by glutamate receptors. The network and intrinsic 75,76 properties of this region are an intensive area of current investigation.

FIGURE 1-12 A, Dorsal view of brainstem and cervical spinal cord indicating regions involved in control of breathing and progression of labeling with a viral tracer injected into the phrenic nerve. The percentage of labeled third-order neurons (propiobulbar neurons) in the pre-Bötzinger complex and adjacent regions is plotted in the set at right. Note that the pre-Bötzinger complex contains almost entirely third-order neurons, whereas adjacent regions, rVRG and BötC, contain 0 to 20 percent. BötC, Bötzinger complex; cVRG, caudal ventral respiratory group; KF, Kölliker-Fuse nucleus; NTS, nucleus tractus solitarius; PB, parabrachial nuclei; PGi, paragigantocellular reticular nucleus; preBötC, pre-Bötzinger complex; RTN, retrotrapezoid nucleus; rVRG, rostral ventral respiratory group. B, Sagittal and transverse view of the location of the pre-Bötzinger complex. cNA, caudal nucleus ambiguus; LRN, lateral reticular nucleus; rNA, rostral nucleus ambiguus; VII, facial nucleus. (From Rekling JC, Feldman JL: PreBötzinger complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation. Annu Rev Physiol 60:385, 1998, with permission.)

Other Ventilatory Patterns

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Cheyne–Stokes Breathing Periodic, or 77 Cheyne–Stokes, breathing suggests left ventricular failure or nervous system dysfunction. Its original description by Cheyne was in a patient who died of heart failure, but both CNS and cardiac dysfunction (or a combination of the two) can produce this ventilatory 78 pattern. The Cheyne–Stokes pattern is that of escalating hyperventilation followed by decremental hypoventilation and finally apnea, which recurs in cycles. Cycle lengths of 40 to 100 seconds 79 have been reported in humans. Arterial blood gas assays during Cheyne–Stokes breathing indicate a rising pH and a falling Paco2, which become maximal at the apnea point and never 80 return to normal values (Fig. 1-13). Cheyne–Stokes patterns are seen in 30 to 40 percent of patients in congestive heart failure, and Cheyne–Stokes breathing is associated with an 81–83 This ventilatory pattern also occurs in normal premature infants, increased mortality. during normal sleep, in subjects at high80,84 altitude, and with equal frequency in association with 85 Associated changes in arousal, pupillary size, supratentorial and infratentorial stroke. 86 cardiac rhythm, heart rate, blood pressure, muscle tone, and consciousness may occur cyclically in patients with Cheyne–Stokes breathing. The alterations in Paco2 also affect the cerebral vasculature, producing changes in the intracerebral volume of the vascular compartment with associated alterations in cerebral blood-flow and intracranial pressure. The periodicity80 of ventilation can be eliminated by intravenous theophylline or by oxygen inhalation.

FIGURE 1-13 Periodicity of arterial oxygen saturation (Sao2; upper trace), chest

wall motion (middle trace), and CO2 concentration in the expired air (lower trace) in a stroke patient with Cheyne–Stokes respiration. The phase shift between the upper and middle traces is due to the sampling time of the pulse oximeter of approximately 40 seconds. The drops in CO2 concentration during hypopnea are due to dead space ventilation. (From Nachtmann MD, Siebler M, Rose G, et al: Cheyne-Stokes respiration in ischemic stroke. Neurology 45:820, 1995, with permission.) Based on studies in patients with heart failure, the ventilatory oscillations result from Pco2

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87

fluctuations about the apneic threshold. The reciprocal fall in Po2 results from attenuated ventilatory drive. Cheyne–Stokes breathing is abolished by inhalation of CO2 (increasing the 88 Pco2 over the apneic point) but not by inhalation of oxygen. A host of factors that might explain Cheyne–Stokes ventilatory oscillations has been addressed experimentally and clinically. The possibility that a prolonged circulation time may itself produce ventilatory oscillations by creating a feedback loop delay to central receptors was classically considered as the factor responsible for the Cheyne–Stokes ventilatory pattern. However, Hoffman and associates, studying patients with cardiogenic pulmonary edema, found no differences in left ventricular ejection fractions in patients with or without 89 delay did correlate Cheyne–Stokes breathing. Hall and colleagues found that circulatory 90 with Cheyne–Stokes cycle length, but not with apnea length. Lorenzi-Filho and co-workers showed that CO2 inhalation blocked Cheyne–Stokes breathing in patients with heart failure and argued that reduction in Paco2 sensed by peripheral chemoreceptors triggered central 88 apneas. The issue of an abnormal feedback to91the CNS in the genesis of respiratory oscillations was studied in animals by Cherniack who used the normal phrenic nerve stimulus to trigger a mechanical ventilator that had been modified so that the gain could be varied to amplify or retard the induced tidal volume triggered by the phrenic stimulus. This model produced periodic ventilations when the gain was increased. Supporting the concept of abnormal feedback loops generating Cheyne–Stokes breathing, ventilatory periodicity was eliminated by destruction of peripheral chemoreceptors but was unchanged by vagotomy. Furthermore, all animals had a persistent respiratory alkalosis. Duplicating observed clinical phenomena, the oscillations were enhanced by hypoxia and eliminated by increasing the oxygen or CO2 content of inspired air. Hypoxemia (during sleep) also induces 92 Cheyne–Stokes breathing in humans. Originally described as a variant of Cheyne–Stokes breathing, Biot breathing is characterized by clusters of breaths having equal and regular inspiratory and expiratory phases, rather than the spindle characteristics of Cheyne–Stokes breathing. The similarity to Cheyne–Stokes breathing is in the separation of the ventilatory periods by apnea, which in Biot breathing occurs in end-expiration. Although first described in patients with meningitis, a ganglioglioma 93 and bihemispheric involving the cerebellum and pons was responsible in one patient, 94 infarction in another. Central Hyperventilation Hyperventilation was thought, at one point, to be the 95 respiratory pattern characteristic of midbrain dysfunction during transtentorial herniation. The exhaustion resulting from such hyperventilation may be fatal; morphine or methadone will suppress the abnormal ventilatory 96 drive. A specific midbrain localization for lesions pro-ducing this ventilatory pattern cannot be supported any longer. Cases of isolated brainstem tumors and sustained tachypnea offered the possibility of an unambiguous anatomical localization of the source of this ventilatory pattern. In some instances the pons or medulla was involved. Extra-axial medullary 97 compression has also caused central hyperventilation. Central hyperventilation has been associated with CNS lymphoma,98,99 the infiltrating nature of which has been suggested as the Table 1-1 shows the incidence of various abnormal common feature in such cases. ventilatory patterns associated with lesions at different CNS sites. Click here to view this table.... The possibility of central stimulation of medullary chemoreceptors due to local lactate production from tumors or stroke has been suggested to explain the lack of correlation between anatomical lesion site and ventilatory pattern. However, a markedly alkaline cerebrospinal fluid (CSF) pH was reported in a patient with central hyperventilation and a 100 pontine tumor. Pulmonary congestion of neurogenic cause (neurogenic pulmonary edema) might induce this respiratory pattern via stimulation of pulmonary receptors in the pulmonary interstitial space. At the San Francisco General Hospital, the author saw three patients with sustained tachypnea following stroke. Their in vivo lung water content was measured with a double indicator dilution technique (by Dr. Frank Lewis), and no elevation was found.

Alveolar Hypoventilation Hypoventilation, hypoxia, and apnea are major risks in diseases of the anterior horn cells,

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peripheral nerves, myoneural junctions, and muscles. Motor neuron disease, polyneuropathy, myasthenia gravis, and the muscular dystrophies are, respectively, the most common 101 examples of such diseases that cause ventilatory disturbances. In part because of the decreased exercise demands induced by the disease processes, dyspnea is often absent and arterial blood gases may show little alteration immediately prior to fatal ventilatory compromise. Furthermore, the amount of muscle weakness in extremity and girdle muscles is often a poor predictor of ventilatory muscle function. Vincken and associates examined this point and documented that maximal inspiratory (diaphragmatic, intercostal, and accessory neck muscles) and expiratory (abdominal and intercostal muscles) pressure measurements were required to assess 102 the risk of respiratory compromise in patients with chronic neuromuscular disease. Unsuspected ventilatory dysfunction was found in one half of the 30 patients studied, and in one third of patients, it was severe. In no case was the ventilatory dysfunction clinically suspected. Traumatic myelopathies or myelopathies resulting from infiltrative tumors produce ventilatory insufficiency with lesions above the cervical roots innervating the phrenic nerve (C3, C4, C5). Such patients' ventilatory dysfunction has been successfully managed without mechanical ventilation by electrical pacing of the diaphragm. In patients with lesions between C3 and C5, this treatment is feasible if the C5 root is preserved below the level of the lesion. Each of eight patients with traumatic tetraplegia reported by Vanderlinden and co-workers were successfully weaned from ventilator support using this 103 have been used to assess diaphragm technique. Cervical and cortical magnetic stimulation 104 strength in patients proposed for phrenic pacing. Although ventilatory compromise is often the terminal event in advanced motor neuron disease, isolated respiratory insufficiency may be the presenting feature of the disease. In patients with primary bulbar disease, sleep apnea or nocturnal hypoventilation occurs, manifesting itself by both obstructive and central apnea. Orthopnea may be the presenting symptom of motor neuron disease. Such patients have predominantly diaphragmatic weakness, and this may be unilateral or bilateral. Paradoxical chest wall and abdominal movements are seen during inspiration, and vital capacity is reduced, especially when the patient is tested in the supine position. In this group of patients with diaphragmatic weakness in the absence of bulbar impairment), symptomatic relief is obtained with ventilatory support (CPAP or nocturnal105 intermittent positive pressure ventilation) without unwarranted positive airway pressure (BiPAP) is now an prolongation of life. Continuous bimodal 105,106 important alternative to tracheostomy. Ventilatory failure requiring mechanical assistance has been reported in 10 to 80 percent of were needed in 43 percent patients with Guillain–Barré syndrome. Intubation and ventilation 104 of the 111 patients from the French plasmapheresis study and in 47 percent of the 123 107 patients in the American study. The mean duration of the assisted ventilation was 31 days in the French study, and it was reduced to 18 days by plasmapheresis. Intubation is usually required when vital capacity falls below 18 ml/kg. Sunderrajan and Davenport analyzed the presenting and early stages of their patients' illness and were unable to identify any 108 characteristics or neurological features that would predict the need for assisted ventilation. While the mean hospital day on which intubation was required was 4.4, the range was broad (0 to 21 days). The hospital day on which the patient was extubated had an equally wide range: hospital days 5 to 90. Two unusual cases required ventilatory support for more than a year. This experience suggests that extubation will be successful when vital capacities exceed 1 liter. A detailed study of diaphragmatic performance in patients with Guillain–Barré syndrome suggested that improvement in the maximal transdiaphragmatic pressure was the best predictor of recovery, and this measure was correlated with maximal inspiratory force, 109 but not forced vital capacity. The duration of mechanical ventilatory support required in patients with the Guillain–Barré syndrome was nearly halved by treatment with plasma 110 exchange; treatment with intravenous gamma globulin is equivalent. An acute, primary axonal degeneration of motor and sensory fibers occurs in the setting of 111 prolonged sepsis (approximately 2 weeks) with multiple organ failure. This syndrome has been termed critical illness neuropathy and is described in detail in Chapter 52. The neuropathy is characterized clinically by distal weakness with reduced or absent tendon reflexes; when it is severe, there is paralysis with areflexia. The syndrome is frequently recognized only because of unexpected difficulty in weaning patients from assisted ventilation. Phrenic nerve conduction velocities have been abnormal, and autopsy studies have shown axonal degeneration of112 the phrenic nerve, with denervation atrophy in the intercostal muscles and diaphragm. Complete recovery over a period of 6 months is the rule in mild and moderate cases, but patients with severe polyneuropathy may fail to improve and have a fatal outcome. A similar syndrome of critical care myopathy is recognized, with a 113,114 Neuromuscular blockade and corticosteroid treatment may be risk similar prognosis. 113 factors, especially in transplant patients.

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Temporary ventilatory support may be required in myasthenia gravis. Indications include the post-thymectomy period and failure of outpatient pharmacological therapy. Of 22 such patients seen at the Mayo Clinic, the duration of ventilatory support116required was 1 to 32 115 exchange days, with 1 to 41 days reported by O'Donohue and colleagues. Both plasma 117 and intravenous immunoglobulin treatments may be useful in myasthenic crisis. In patients with myopathy, ventilatory dysfunction may occur and may be disproportionate to the severity of the muscle weakness. Although the poor prognosis in the muscular dystrophies usually commits patients to ventilatory support for the remainder of their lives, two patients with Duchenne muscular dystrophy were weaned from39continual positive pressure ventilation with intermittent negative pressure techniques. Recurrent episodes of ventilatory failure independent of muscle weakness have been reported in patients with 118 mitochondrial myopathies. Patients have depressed respiratory responses to hypoxia and often to hypercapnia as well. Life-threatening hypoventilation often occurs in the setting of surgery, sedation, or infection. Reported cases include typical Kearns-Sayre syndrome, MERRF (myoclonic epilepsy and ragged-red fibers) syndrome, and familial mitochondrial myopathy. No specific biochemical defect has been found, although a defect in cytochrome-c 118 oxidase has been suggested. The cause of the hypoventilation may be central rather than 119 muscular. NERVOUS SYSTEM EFFECTS OF RESPIRATORY DYSFUNCTION

Hypoxia Acute Hypoxia The terms hypoxic and anoxic encephalopathy are frequently used to describe neurological syndromes that occur following cardiac arrest. The encephalopathy, however, is due primarily to cerebral ischemia. Acute hypoxia results in transient alterations of cognitive function similar to those due to intoxication with alcohol. Hallucinations and alterations in judgment and behavior are well known in mountain climbers at high altitudes. Climbers to the Mt. Everest summit, at 8,854 meters (29,000 feet) have been studied to determine the potential acute and long-term neurological deficits from hypoxia at these altitudes. The results of simple tests of short-term memory (number recall) and simple motor tasks (finger tapping) are shown in immediately after Figure 1-14. Significant reductions in performance in both tests were found 120 the expedition, and significant impairments persisted 12 months later.

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FIGURE 1-14 Results of finger-tapping and short-term memory tests performed

before, immediately after, and 1 year following an expedition to Mt. Everest. (From West JB: Do climbs to extreme altitude cause brain damage? Lancet 2:387, 1986, with permission.) Neuropathological studies of the CNS in primates subjected to hypoxia have revealed lesions only in the watershed distribution between major arterial territories. Thus, the effects of acute 121 Structural abnormalities do not hypoxia on the brain are those of cerebral hypoperfusion. 122,123 However, polymerase occur in the brain in the setting of hypoxia without ischemia, chain reaction (PCR) techniques to simultaneously amplify long random segments of DNA have shown that pure hypoxia for 30 minutes in vivo124 produces both nuclear and mitochondrial DNA damage, which have dissimilar repair kinetics.

Hypercapnia Chronic Hypercapnia A reversible syndrome of headache, papilledema, and impaired consciousness with “tremor 125 of the extremities” has been described in patients with chronic pulmonary insufficiency. Tremulousness is most prominent with the fingers outstretched and has the characteristics of an action tremor or the features of asterixis; in some patients, it resembles myoclonus. The headaches are attributed to the increased intracranial pressure. Arterial oxygen saturations in 125 one study ranged from 81 to 94 percent (but may be as low as 40%), and the Paco2 levels ranged from 39 to 68 mmHg (but can be higher). The electroencephalogram shows slowing in the theta or delta range. The etiology of such CO2 narcosis is probably multifactorial, including hypercapnia, hypoxia, and elevated intracranial pressure. 126 The increased intracranial pressure may produce papilledema that can progress to blindness. Ventilatory support and discontinuation of sedative drugs constitute effective treatment. Acute Hypercapnia Nervous system abnormalities from hypercapnia are related in significant measure to the rate of increase of Paco2. The rapid diffusibility of carbon dioxide across the blood–brain barrier produces a prompt fall in CSF pH in respiratory acidosis, a decrease that does not occur in + metabolic acidosis. A potent inhibitory effect of H upon the postsynaptic receptor for glutamate, the brain's major excitatory neurotransmitter, has been described and may be 127 responsible for the acute encephalopathy of hypercapnia.

Hypocapnia Acute Hypocapnia Acute hypocapnia occurs during hyperventilation. The symptom complex of dizziness, lightheadedness, faintness, paresthesias, and impaired consciousness can be reproduced in normal subjects during hyperventilation, supporting a cause-and-effect relationship between acute hypocapnia and the symptoms of the hyperventilation syndrome (Table 1-2), although 128 some have found hyperventilation as a consequence, rather than a cause, of the attacks. 129 Asthma was significantly associated in one series. This syndrome has its maximal incidence during the third decade. Distal paresthesias are notable and may be asymmetric, prompting evaluation for a more sinister cause. Alteration or loss of consciousness is common (31% in the series of Perkin and Joseph; Table 1-2), leading to an inappropriate diagnosis of epilepsy. Symptoms can often be reproduced by voluntary hyperventilation, and the electroencephalographic findings while the patient is symptomatic can help to exclude a diagnosis of seizure disorder. The effects of hypocapnia include cerebral vasoconstriction, alteration in the ionic balance of calcium, and a shift in the oxyhemoglobin dissociation curve with reduced delivery of oxygen to peripheral tissues. A combination of these events is responsible for the clinical symptoms. Click here to view this table.... Chronic Hypocapnia Fixed respiratory alkalosis is a common or even diagnostic finding in a number of metabolic disorders, the most prominent being hepatic encephalopathy; sepsis and salicylate poisoning are additional examples. However, the role of the alkalosis itself in causing CNS dysfunction

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is uncertain. Potential mechanisms by which alkalosis may affect the brain include a shift in the oxyhemoglobin dissociation curve (which decreases oxygen availability to tissues), a decrease in cerebral blood-flow resulting from cerebral vasoconstriction, and alkalosis-induced hypophosphatemia. Posner and Plum also found that control of the alkalosis by mechanical ventilation did not alter the encephalopathic manifestations in 130 patients with hepatic failure. Accordingly, alkalosis per se appears to have a minimal effect on the CNS. HICCUP 131

Persistent or intractable hiccup is an abnormality resulting from many133 systemic, 132 134 pharmacological, and CNS causes, including brainstem neoplasm, multiple sclerosis, 135 136,137 and thoracic herpes zoster. It may also occur with cortical pathology. Cases of 138 intractable hiccup are much more common in men than women. Hiccup results from CNS-induced synchronous contraction of the diaphragm and the external (inspiratory) intercostal muscles, followed rapidly by inhibition of expiratory intercostal muscles and glottal 139 closure. The glottal closure minimizes air exchange. However, with tracheostomy, the induced ventilatory movements of hiccup cause air exchange, and a respiratory alkalosis is 139,140 produced. The frequency, but not amplitude, of hiccuping is modulated by arterial Paco2. Hiccup 139 frequency is reduced with elevated Paco2 levels and increased with a fall in arterial Paco2. This observation is in keeping with the traditional cure for hiccups—breath-holding. Another common lay remedy for hiccup is swallowing or pharyngeal stimulation, maneuvers that may increase vagal tone. Thus, hiccups are most common at maximal inspiration because vagal afferents are inhibited by maximal lung inflation. High-frequency diaphragmatic flutter, 137 responsive to carbamazepine, is responsible for hiccups in some patients. Chlorpromazine remains the most141–143 popular pharmacological treatment, although baclofen and gabapentin are 144 ; a host of other approaches has been suggested. now also popular SNEEZING The coordinated act of sneezing arises from a caudal brainstem center near the nucleus 145 mass lesion or lateral medullary syndrome can prevent sneezing ambiguus. A medullary146–148 despite the urge to do so. Cortical input to sneezing has149 long been recognized. The central mediation of sneezing was noted by Penfield and Jasper in a patient during temporal lobe stimulation when both sneezing and chewing movements were induced. A common reflex that induces sneezing is 150 that which occurs on sudden exposure to bright light. This reflex was found in 80 percent of the families of medical students in whom the phenomenon of light-induced sneezing was reported.151 It has been suggested that this reflex is inherited in an autosomal dominant manner. YAWNING 152

Yawning is coordinated from brainstem sites near the paraventricular nucleus via 153 extrapyramidal pathways using a number of neurotransmitters and neuropeptides. This reflex may occur in patients “locked in” from pontine transection who have nonvolitional 154 mouth opening with spontaneous yawns. Yawning in the setting of a pyramidal lesion (capsular infarction) may be associated155 with arm stretching in the paretic limb, supporting the input also occurs, as reflected by the involvement of extrapyramidal circuitry. Cortical 156 Yawning has been seen to initiate a yawning related to boredom and somnolence. 149 temporal lobe seizure. Previous

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Aminoff: Neurology and General Medicine: Neurological Complicatio...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 2 Neurological Complications of Aortic Disease and Surgery DOUGLAS S. GOODIN •

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CLINICAL NEUROLOGICAL SYNDROMES DUE TO AORTIC PATHOLOGY Spinal Cord Ischemia Anatomy Ischemic Cord Syndromes Cerebral Ischemia Anatomy Strokes and Transient Ischemic Attacks Peripheral Neuropathy Mononeuropathies Radiculopathies Polyneuropathies Autonomic Neuropathies AORTIC DISEASES AND SURGERY Aortitis Syphilitic Aortitis Takayasu's Arteritis Giant Cell Arteritis Aortic Aneurysms Nondissecting Aneurysms Dissecting Aortic Aneurysms Traumatic Aortic Aneurysm Coarctation of the Aorta Surgery and Other Procedures Aortic Surgery Aortography and Other Procedures on the Aorta Intraoperative Adjuncts to Avoid Spinal Cord Ischemia

The aorta is the main conduit through which the heart supplies blood to the body, including the brain, brainstem, and spinal cord. In addition, this vessel is situated close to important neural structures. In consequence, both disease of the aorta and operations on it may have profound but variable effects on nervous system function. Often the neurological syndrome produced by aortic disease or surgery depends more on the part of the aorta involved than on the nature of the pathological process itself. For example, either syphilis or atherosclerosis may produce symptoms of cerebral ischemia if the disease affects the aortic arch or of spinal

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cord ischemia if the pathological process is in the descending thoracic aorta. Even when the nature of the pathological process is important in determining the resultant neurological syndrome, several diseases may result in the same pathological process. Thus, atherosclerosis, infection, inflammation, and trauma may each result in the formation of aortic aneurysms; similarly, coarctation of the aorta may be congenital, a result of Takayasu's arteritis, or a sequela of radiation exposure during childhood. The initial focus of this chapter is on the three major areas of neurological dysfunction resulting from aortic disease and surgery: spinal cord ischemia, cerebral ischemia, and peripheral neuropathy. Specific conditions that merit special consideration are then discussed individually. The normal anatomical relationships are also considered in order to provide insight into the pathogenesis of the resulting neurological syndromes. CLINICAL NEUROLOGICAL SYNDROMES DUE TO AORTIC PATHOLOGY Aortic disease may produce a variety of neurological syndromes. The specific syndrome depends to a large extent on the site of involvement along the aorta.

Spinal Cord Ischemia Anatomy Embryological Development

During embryological development, primitive blood vessels arise along the spinal nerve roots bilaterally and at each segmental level. Each of these segmental vessels then divides into anterior and posterior branches, which ramify extensively on the surfaces of the developing spinal cord. As development proceeds, most of these vessels regress and a few enlarge, so that by birth, the blood supply to the spinal cord depends on a small but highly variable 1–11 (Fig. 2-1). In the thoracic region, where the aorta number of persisting segmental vessels is situated to the left of the midline, the persisting vessels entering the spinal canal are those 5,6,8 from the left in 70 to 80 percent of cases.

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FIGURE 2-1 Extraspinal contributions to the anterior spinal arteries showing the three arterial territories. In the cervical region, an average of three arteries (derived from the vertebral arteries and the costocervical trunk) supply the anterior spinal artery. The anterior spinal artery is narrowest in the midthoracic region, often being difficult to distinguish from other small arteries on the anterior surface of the cord; occasionally it is discontinuous with the anterior spinal artery above and below. In addition, this region is often supplied by only a single small radiculomedullary vessel. The lumbosacral territory is supplied by a single large artery, the great anterior medullary artery of Adamkiewicz, which turns abruptly caudal after joining the anterior spinal artery. If it gives off an ascending branch, that branch is usually a much smaller vessel. This artery is usually the most caudal of the anterior radiculomedullary arteries, but when it follows a relatively high thoracic root, there is often a small lumbar radiculomedullary artery below. In this and subsequent illustrations, a indicates artery; m, muscle; n, nerve. Anterior Spinal Artery

The anterior spinal artery is formed rostrally from paired branches of the intracranial vertebral arteries that descend from the level of the medulla (Fig. 2-1). These two arteries fuse to form1 a single anterior spinal artery that overlies the anterior longitudinal fissure of the spinal cord. This artery is joined at different levels by anterior radiculomedullary arteries, which are branches of certain segmental vessels (Fig. 2-2). The number of these vessels is variable among5,6individuals, ranging from 2 to 17, although 85 percent of individuals have between 4 and 7.

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FIGURE 2-2 Anatomy of the spinal cord circulation, showing the relationship of the segmental arteries and their branches to the spinal canal and cord. The left rib and the left pedicle of the vertebra have been cut away to show the underlying vascular and neural structures.

The anterior spinal artery in the region that includes the cervical enlargement (C1 to T3) is particularly well supplied, receiving contributions from an average of three segmental 6 vessels. One constant artery arises from the costocervical trunk and supplies the lower segments; the others arise from the extracranial vertebral arteries and supply the middle 6 cervical segments. In addition, branches of the vertebral arteries have rich anastomotic connections with other neck vessels, including the occipital artery, deep cervical artery, and 6 ascending cervical artery. The anterior spinal artery in the midthoracic portion of the cord (T4 to T8) often receives only 6,8 a single contribution from a small artery located at about T7, most often on the left. The anterior spinal artery has its smallest diameter in this region, and it is sometimes 5,6 discontinuous with the vessel in more rostral or caudal regions. The anterior spinal artery in the region of the lumbar enlargement (T9 to the conus medullaris) is, as at the cervical enlargement, richly supplied, deriving its blood supply predominantly from a single large (1.0 to 1.3 mm in diameter) artery, the great anterior medullary artery of Adamkiewicz. This artery almost always accompanies a nerve root between T9 and L2,5,6usually on the left, although rarely it may accompany a root above or below these levels. Identification of the actual location of this great vessel has become an important part of the planning and execution of operations on the aorta such as repair of thoracoabdominal aortic aneurysms. Although digital subtraction angiography has been used for this purpose, the use of contrast-enhanced magnetic resonance angiography has recently 11 medullaris, the been proposed to offer a noninvasive alternative. Caudally, at the conus 6 anterior spinal artery anastomoses with both posterior spinal arteries. Posterior Spinal Arteries

The paired posterior spinal arteries are formed rostrally from the intracranial portion of the vertebral arteries. They are distinct paired vessels only at their origin,5,6however, and thereafter become intermixed with an anastomotic posterior pial arterial plexus (Fig. 2-3). This plexus is joined at different levels by a variable number (10 to 23) of posterior radiculomedullary 5 vessels that accompany the posterior nerve roots.

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FIGURE 2-3 Vascular anatomy of the spinal cord. The anterior spinal artery gives off

both peripheral and sulcal branches. The sulcal branches pass posteriorly, penetrating the anterior longitudinal fissure. On reaching the anterior white commissure, they turn alternately to 5the right and to the left to supply the gray matter and deep white matter on each side. Occasionally two adjacent vessels pass to the same side, and on other occasions, a common stem vessel bifurcates to supply both sides. Terminal branches of these vessels overlap those from vessels above and below on the same side of the cord. The peripheral branches of the anterior spinal artery pass radially and form an anastomotic network of vessels, the anterior pial arterial plexus, which supplies the anterior and lateral white matter tracts by penetrating branches. The posterior pial arterial plexus is formed as a rich anastomotic network from the paired posterior spinal arteries. Penetrating branches from this plexus supply the posterior horns and posterior funiculi. Intrinsic Blood Supply of the Spinal Cord

In contrast to the extreme interindividual variability in the extraspinal arteries that supply the spinal cord, the intrinsic blood supply of the cord itself is more consistent. The anterior spinal artery gives off central (sulcal) arteries that pass posteriorly, penetrating the anterior longitudinal fissure and supplying most of the central gray matter and the deep portion of the anterior white matter (Fig. 2-4). The number of these sulcal vessels is variable, with 5 to 8 vessels per centimeter in the cervical region, 2 to 6 vessels per centimeter in the thoracic 5,6 region, and 5 to 12 vessels per centimeter in the lumbosacral region.

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FIGURE 2-4 Intrinsic blood supply of the spinal cord. The vascular territories are depicted on the right half of the cord. The hatched lines indicate the territory supplied by the posterior spinal arterial system. The remainder is supplied by the anterior circulation, with the dark stippling indicating the area supplied exclusively by the sulcal branches of the anterior spinal artery.

The anterior spinal artery also gives off peripheral arteries that pass radially on the anterior surface of the spinal cord to supply the white matter tracts anteriorly and laterally. These arteries form the anterior pial arterial plexus, which is often poorly anastomotic with its 5 posterior counterpart. The posterior horns and posterior funiculi are supplied by penetrating vessels from the posterior pial arterial plexus. Ischemic Cord Syndromes Ischemia of the spinal cord may be produced either by the interruption of blood flow through critical feeding vessels or by aortic hypotension. The resulting neurological syndrome depends on the location of ischemic lesions along and within the spinal cord, which depends, in turn, on the vascular anatomy discussed previously. A wide variety of pathological disturbances of the aorta result in 12–15 spinal cord ischemia. They include both iatrogenic causes, and intrinsic aortic diseases, such as dissecting and 20 such as surgery and aortography, 16,17 6,18,19 inflammatory aortitis, occlusive atherosclerotic disease, nondissecting aneurysms, 21,22 6,23 infective and noninfective emboli, and congenital coarctation. Spinal cord ischemia is a 24 possibly due to aortic compression, which can occur toward rare complication of pregnancy, 25 the end of gestation. Some authors have suggested that the midthoracic region (T4 to T8) is particularly vulnerable to ischemia because of the sparseness of vessels feeding the anterior spinal artery in this 6 region and its poor anastomotic connections. Others have stressed the vulnerability of the watershed areas between the three anterior spinal arterial territories. Although the concept is theoretically appealing, documentation of the selective vulnerability of these regions is not 16,26–29 with respect to the completely convincing. For example, a review of 61 case reports distribution of ischemic myelopathies resulting from surgery on the aorta does not especially suggest that either of these areas is more vulnerable than other cord segments (Table 2-1). Even when the operation was performed on the thoracic aorta (and thus the proximal clamp was placed above the midthoracic cord feeder), the lumbosacral cord segments were the site of the ischemic damage more often than the supposedly more vulnerable midthoracic segments (Table 2-1). Similarly, the watershed area between these two arterial territories (T8 to T9) does not seem particularly vulnerable. In fact, the most frequently affected cord segment within each vascular territory in these 61 cases was centrally placed—T6 in the midthoracic territory and T12 in the lumbosacral territory—rather than at the borders, as would be anticipated with watershed vulnerability (Fig. 2-5). Click here to view this table....

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FIGURE 2-5 Upper segmental level of spinal cord involvement in 61 cases of spinal cord ischemia after surgery on the aorta (based on previously published 16,26–29 reports ).

Moreover, of the 25 cases of spinal cord infarction in an unselected autopsy series of 300 6 cases, two thirds were in cervical cord segments ; the most commonly affected segment was C6. Such a distribution would be unexpected if either the midthoracic or the watershed area was particularly vulnerable. Perhaps relating to such observations, it was recently found that, contrary to earlier reports, the anterior 9spinal artery is continuous along its length without interruption in all 51 cadavers studied. If this observation can be generalized, it may be the case that the poorly vascularized thoracic cord, which has much less gray matter than the cervical and lumbar enlargements, actually matches its sparse blood supply with its reduced 3,6,30 metabolic requirements. The site of aortic disease also plays an important role in the location of the lesion along the spinal cord. For example, distal aortic occlusion often presents with lumbosacral 6,20 whereas dissecting6,17,31,32 aneurysm of the thoracic aorta commonly presents with involvement, Similarly, cord ischemia following surgery on the infarction in the midthoracic region. abdominal aorta is essentially confined to the lumbosacral territory, whereas surgery on the thoracic aorta not infrequently involves the midthoracic segments (Table 2-1). Regardless of the pathological process affecting the aorta, however, it generally involves the suprarenal 6,33 because the important radiculomedullary arteries usually portion if there is cord ischemia originate above the origin of the renal arteries. Anterior Spinal Artery Syndrome

Ischemic injury of the spinal cord at a particular segmental level may present with a complete 6 transverse myelopathy. Within the spinal cord, however, there are certain vascular territories that can be affected selectively. In particular, the territory of the anterior spinal artery, 3,6 especially its sulcal branch, is prone to ischemic injury. This increased vulnerability probably relates to two factors. First, the anterior1,3,4,6 circulation receives a much smaller number Second, the posterior circulation is a of feeding vessels than the posterior circulation. 1,3,6 and therefore probably provides better collateral flow network of anastomotic channels than the single anterior artery, which in some6,34,35 patients is discontinuous along its length. The presumably reflects the relative constancy relative constancy of the resulting syndrome of the intrinsic vascular anatomy of the cord. As mentioned earlier, the anterior spinal artery supplies blood to much of the spinal gray matter and to the tracts in the anterior and lateral white matter. Ischemia in this arterial territory therefore gives rise to a syndrome of diminished pain and temperature sensibility with preservation of vibratory and joint position sense. Weakness (either paraparesis or quadriparesis, depending on the segments involved) occurs below the level of the lesion and

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may be associated with other evidence of upper motor neuron involvement, such as Babinski signs, spasticity, and hyperreflexia. Bowel and bladder functions are affected, owing to interruption of suprasegmental pathways. Segmental gray matter involvement may also lead to lower motor neuron deficits and depressed tendon reflexes at the level of the lesion. Thus, a lesion in the cervical cord may produce flaccid areflexic paralysis with amyotrophy in the upper extremities, spastic paralysis in the lower extremities, and dissociated sensory loss in all limbs. In contrast, a lesion in the thoracic cord typically presents with only spastic paraplegia and dissociated sensory loss in the legs. The syndrome usually comes on 36 abruptly, although occasionally it is more insidious and progressive. Motor Neuron Disease

On occasion, diseases of the aorta (e.g., dissecting aneurysms or atherosclerosis) that interfere with the blood supply to the anterior spinal artery result in more restricted cord ischemia, perhaps because of better anastomotic connections between the anterior and the posterior pial arterial plexuses in some individuals or because of greater vulnerability of the 6,14,36 The ischemic injury in these anterior horn cells with their greater metabolic activity. circumstances is limited to the gray matter supplied by the sulcal branches (Fig. 2-6). Clinical impairment is then confined to the motor system and is associated with amyotrophy. When 6 the ischemic nature of the lesion usually is apparent, but when the onset the onset is abrupt, 6,36 and especially when pyramidal signs are also present, it may mimic other is more gradual, diseases, such as amyotrophic lateral sclerosis or spinal cord tumors.

FIGURE 2-6 Area of infarction within the spinal cord over four adjacent spinal segments in a patient reported by Herrick and Mills (Herrick MK, Mills PE: Infarction of spinal cord. Two cases of selective gray matter involvement secondary to asymptomatic aortic disease. Arch Neurol 24:228, 1971). The infarction was extensive but limited to the gray matter, particularly the anterior horns. Posterior Spinal Artery Syndrome

In contrast to the anterior spinal artery syndrome, selective ischemia of the posterior circulation, characterized by prominent loss of posterior column function with relative sparing 2,14 and only occasionally reported of other functions, is rarely recognized clinically 10,20,37 For example, in a review of 27 cases 10 of nonsurgical spinal cord pathologically. ischemia, only 2 (7%) had posterior spinal artery patterns. The relative infrequency of this syndrome presumably relates to the more abundant feeding vessels and better anastomotic connections in this arterial system compared to the anterior spinal artery. Unilateral Cord Syndromes

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In some cases, the area of ischemic damage can be confined to only a small portion of the 10 spinal cord. For example, in the review cited previously, eight (29%) of the patients with nonsurgical spinal cord ischemia had unilateral syndromes involving either the anterior or posterior aspects of the spinal cord. Intermittent Claudication

Intermittent claudication (limping) refers to a condition in which a patient experiences difficulty in walking that is brought about by use of the lower extremities. Charcot initially described this syndrome in381858 and related it to occlusive peripheral vascular disease in the lower extremities. In 1906, Dejerine distinguished claudication39caused by ischemia of the leg muscles from that caused by ischemia of the spinal cord. In the latter condition, the arterial pulses in the legs tend to be preserved, pain tends to be dysesthetic or paresthetic in quality and may not occur, and neurological signs are frequently present, especially after exercise. In 1961, Blau and Logue identified another form of neurogenic claudication caused by ischemia or compression of the cauda equina and resulting from a narrowed lumbosacral canal (either 40 congenital or due to degenerative disease). This condition is similar to that produced by ischemia of the spinal cord; however, the sensory complaints tend to have a more radicular distribution, and signs of cord involvement (e.g., Babinski signs) are not present. The clinical distinction between various types of claudication, particularly between the two neurogenic varieties, is sometimes 6,41 difficult. The cauda equina variety, however, is far more Intermittent spinal cord ischemia, when it occurs, is common than the spinal cord form. often associated with intrinsic diseases of the aorta, such as coarctation or atherosclerotic 6 occlusive disease. Bony erosion through vertebral bodies from an abdominal aortic aneurysm with direct compression of the spinal nerve roots has also been reported to produce intermittent 42 neurological symptoms. The clinical details of the single reported case, however, are not sufficient to determine whether the symptoms resemble those of intermittent claudication.

Cerebral Ischemia Anatomy The aortic arch gives rise to all the major vessels that provide blood to the brain, brainstem, and cervical spinal cord (Fig. 2-7). The first major branch is the innominate (brachiocephalic) artery, which subsequently divides into the right common carotid and right subclavian arteries. The latter artery subsequently gives rise to the right vertebral artery, which ascends through the foramina of the transverse processes of the upper six cervical vertebrae to join with its counterpart on the left and form the basilar artery. The basilar artery provides blood to the posterior fossa and posterior regions of the cerebral hemispheres. The second major branch of the aortic arch is the left common carotid artery, and the third is the left subclavian artery, which, in turn, gives rise to the left vertebral artery.

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FIGURE 2-7 Vascular anatomy of the aortic arch and its branches.

Strokes and Transient Ischemic Attacks Diseases of the aortic arch, such as atherosclerosis, aneurysms, and aortitis as well as surgery on this segment of the aorta, may give rise to symptoms of6,13,18,32,43–47 cerebrovascular A young insufficiency, such as strokes or transient ischemic attacks (TIAs). woman has even been reported with a stroke secondary to an occlusion of the48aorta that was associated with the use of birth control pills and recurrent venous thromboses. Cerebral ischemia is produced either by occlusion of a major vessel or by embolization of atheromatous or other material to more distal arteries. The resulting neurological syndromes are not specific for any disease process but depend on the location and duration of the vascular occlusion. Atherosclerosis

Atherosclerosis of the aortic arch and its branches, compared with atherosclerosis at the origin of the internal carotid artery, is an infrequent cause of stroke or TIAs, probably for two reasons. First, atherosclerosis is much less common in this location than at the carotid 49 Second, the anastomotic connections between the major vessels in bifurcation (Table 2-2). 6,50 and an occlusion at their origin from the aortic arch is therefore the neck are extensive, less likely to be associated with symptoms of ischemia than a more peripheral obstruction. Click here to view this table.... Transient Emboligenic Aortoarteritis

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Transient emboligenic aortoarteritis has51been reported by Wickremasinghe and colleagues to be a cause of stroke in young patients. They described 10 patients (aged 16 to 36 years), all of whom had presented with pathologically verified thromboembolic strokes, and 3 of whom had a history of TIAs preceding the event by as much as 4 years. All these patients had both active and healed inflammatory lesions of the central elastic arteries, such as the aorta, innominate, common carotid, and proximal subclavian arteries. Active lesions were small (200 to 300 μm in diameter) and associated with a mural thrombus on the intimal surface. Healed lesions usually were associated with fibrous plaques but not with a mural thrombus. More peripheral arteries supplying the brain were normal. This condition seems to be distinct from segmental aortitis of the Takayasu type. Clinically it is an acute, intermittent disorder with an approximately equal sex incidence, whereas Takayasu's disease is more chronic and has a strong female predominance. The systemic symptoms of Takayasu's disease are absent, and occlusion of the central arteries does not occur in this condition. Subclavian (Cerebral) Steal

Disease of the aortic arch may result in occlusion of either the innominate artery or the left subclavian artery proximal to the origin of the vertebral artery. This, in turn, may result in the reversal of the usual cephalad direction of blood flow in the ipsilateral vertebral artery (Fig. 2-8), depending on individual variations in the collateral circulation and may result in ischemia 52–56 In some patients, this is particularly evident when the in the posterior cerebral circulation. metabolic52demand (and therefore the blood flow) of the affected arm is increased during exercise. If the innominate artery is blocked proximally, it may also cause a reversal of blood flow in the right common carotid artery, resulting in anterior circulation ischemia (Fig. 2-8).

FIGURE 2-8 Mechanisms producing subclavian steal syndrome in diseases of the aortic arch and its branches. A, Obstruction of the left subclavian artery at its origin, resulting in reversal of blood flow in the left vertebral artery. B, Obstruction of the right subclavian artery distal to the takeoff of the right common carotid artery, resulting in reversal of blood flow in the right vertebral artery. C, Obstruction of the innominate artery at its origin, producing reversal of blood flow in the right common carotid artery.

Killen and colleagues reviewed the clinical features of a series of patients with demonstrated reversals of arterial blood-flow in52a vertebral artery (i.e., with flow from the vertebral artery into the ipsilateral subclavian artery). The left subclavian artery was affected more than twice as often as the right subclavian and innominate arteries combined, probably as a result of the more frequent involvement of this artery by atherosclerosis (Table 2-2). Men were affected three times as often as women, probably reflecting the greater prevalence of atherosclerosis in men. Of the 87 patients in this series with symptoms that were adequately described, 75 (86%) had symptoms referable to the central nervous system (CNS). These symptoms were usually transient, lasting seconds to a few minutes, although the deficits were sometimes permanent. The neurological manifestations of steal were varied but most frequently included motor difficulties, vertigo, visual deficits, or syncope. Ischemic symptoms in the arms occurred in only a few patients, and precipitation of CNS symptoms by exercise of the arm ipsilateral to the occlusion was uncommon. Although reconstructive surgery relieved

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52

symptoms in most patients in this series, it was the frequent failure of surgery to correct such nonspecific symptoms that led to a more recent reassessment of the importance of 56 cerebral steal. Thus, when noninvasive techniques such as Doppler ultrasonography have been used to define the direction of blood flow in the great vessels in a large spectrum of patients with vascular disease, the majority (50% to 75%) of patients with documented subclavian steal are 53–55 When symptoms do occur, found to be asymptomatic, even when the steal is bilateral. they are suggestive of transient vertebrobasilar insufficiency in only 7 to 37 percent of 54,55 For patients with steal; the occurrence of infarcts in this vascular territory is distinctly rare. this reason, a recent review of this topic concluded that subclavian steal is a actually a marker of generalized atherosclerotic disease and that it is rarely a cause for symptoms of 56 cerebral ischemia.

Peripheral Neuropathy The peripheral nervous system is sometimes affected by aortic disease or surgery. The syndromes produced may be the presenting manifestations of aortic disease and may mimic less life-threatening conditions. Mononeuropathies Left Recurrent Laryngeal Nerve

The left recurrent laryngeal nerve descends in the neck as part of the vagus nerve and wraps around the aortic arch just distal to the ligamentum arteriosum (Fig. 2-7) before reascending in the neck to innervate all the laryngeal muscles on the left side except the cricothyroideus. It may be compressed by disease of the aortic arch, such as dissecting and 56 nondissecting aneurysms or aneurysmal dilatation proximal to a coarctation of the aorta. The resulting hoarse, low-pitched voice may be one of the earliest presenting symptoms of these conditions, although it is often overshadowed by other symptoms or57signs, such as chest pain, shortness of breath, congestive heart failure, or hypertension. Femoral Nerve

The femoral nerve arises from the nerve roots of L2, L3, and L4. It forms within the belly of the psoas muscle and then exits on its lateral aspect to innervate the quadriceps femoris, iliacus, pectineus, and sartorius muscles and the skin of the anterior thigh and medial aspect of the leg. The nerve is located considerably lateral to the aorta (Fig. 2-9) and hence is rarely involved by direct compression. It may, however, be compressed by a hematoma from a ruptured aortic aneurysm into the psoas muscle and thereby signal a life-threatening 6,58–60 condition that requires an urgent operation.

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FIGURE 2-9 Anatomy of the abdominal aorta showing its relationship to the femoral and obturator nerves, which form within the psoas muscle from branches of the L2, L3, and L4 segmental nerves.

The femoral nerve may also be injured as a consequence of aortic surgery. Boontje and Haaxma reported this complication in 3.4 percent of 1,006 abdominal aortic operations for atherosclerotic or aneurysmal disease, the left femoral nerve being involved unilaterally in two 61 thirds of the cases and jointly with the right femoral nerve in another 6 percent. The mechanism of injury in these cases was presumed to be ischemic and related to poor collateral blood supply to the intrapelvic portions of the femoral nerves, especially on the left. Obturator Nerve

The obturator nerve also forms within the belly of the psoas muscle by the union of fibers from the L2, L3, and L4 segments, but, in contrast to the femoral nerve, exits medially from this muscle (Fig. 2-9). It innervates the adductors of the leg and the skin on the medial aspect of the thigh. It too is lateral to the aorta and not usually involved by direct compression. Like the femoral nerve (and often together with it), the obturator nerve may be compressed by a 6 hematoma in the psoas muscle. Radiculopathies Nerve roots, particularly L4, L5, S1, and S2, which lie almost directly underneath the terminal aorta and iliac arteries (Fig. 2-10), may be directly compressed by an aortic aneurysm in this region. The syndromes produced are typical of radicular disease, with unilateral radiating pain 6 and a radicular pattern to the sensory and motor findings.

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FIGURE 2-10 Anatomy of the terminal branches of the aorta in relationship to

the nerve roots that subsequently join to form the sciatic nerve. Aneurysmal dilatation of the abdominal aorta often includes dilatation of these branch vessels, which can compress the nerve roots, particularly the L4, L5, S1, and S2 nerve roots, which lie directly underneath. Radiculopathies may also be produced by erosion of one or more vertebral bodies by an aortic aneurysm, with consequent compression of the nerve roots in the cauda equina or at the root exit zones. The syndrome produced is not necessarily associated with back pain; it 62–64 may result in multisegmental involvement on one side or even in paraplegia. Polyneuropathies Ischemic Monomelic Neuropathy

Ischemic monomelic neuropathy was described in detail by Wilbourn and co-workers, who reported 3 patients (and alluded to another 11) who had a distal “polyneuropathy” in one limb 65 after sudden occlusion of a major vessel. One of their patients had a saddle embolus to the distal aorta that occluded the right common iliac artery, another had a superficial femoral artery occlusion after placement of an intra-aortic balloon pump, and the third had upper-extremity involvement. The syndrome consists of a predominantly sensory neuropathy with a distal gradient. It affects all sensory modalities and is associated with a constant, deep, causalgia-like pain. The symptoms persist for months, even after revascularization or without evidence of ongoing ischemia. The results of nerve conduction studies and needle electromyography suggest an axonal neuropathy. There is no evidence of ischemic muscle injury, such as induration, muscle tenderness, or elevated serum creatine kinase levels. This condition is rare, 66 although a similar syndrome has been reported in the setting of an acute aortic dissection, and it may be that it is more prevalent than currently appreciated. Autonomic Neuropathies Anatomy

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The autonomic nerves, particularly the lower thoracic and lumbar sympathetic fibers that lie close to the aorta and its branches, may be injured by disease of or surgery on the aorta. The preganglionic efferent sympathetic finerve fibers originate in the intermediolateral cell column 67 in the spinal cord (Fig. 2-4) and exit segmentally between T1 and L2 with the ventral roots. The sympathetic fibers part company with the segmental nerves through the white rami communicantes (Fig. 2-2), which enter the paravertebral sympathetic ganglia and trunks to form bilateral sympathetic chains; these chains are situated lateral to and parallel with the vertebral column (Fig. 2-11). Some of these fibers synapse on postganglionic neurons in the ganglia of their segmental origin, whereas others ascend or descend in the trunk to different segmental levels before making such synapses. In the lumbosacral and cervical segments, where there are no white rami (i.e., below L2 or above T1), the segmental ganglia receive preganglionic contributions only from cord segments either above them (lumbosacral ganglia) 67 or below them (cervical ganglia). The postganglionic fibers rejoin the segmental nerves through the gray rami communicantes (Fig. 2-2) to provide vasomotor, sudomotor, and pilomotor innervation throughout the body.

FIGURE 2-11 Anatomy of the terminal aorta and pelvis in the male in

relationship to the sympathetic and parasympathetic nerves in the region. Some of the preganglionic fibers, in contrast, do not synapse in the paravertebral ganglia but pass through them to form splanchnic nerves, which then unite in a series of prevertebral ganglia and plexuses (many of which overlie the thoracic and abdominal aorta). These structures, in turn, provide sympathetic innervation to the viscera. The plexus that overlies the aorta in the region of its bifurcation, the superior hypogastric plexus (Fig. 2-11), is responsible (via the inferior hypogastric and other pelvic plexuses) for sympathetic innervation of the pelvic organs, including the prostate, prostatic urethra, bladder, epididymis, vas deferens, seminal vesicles, and penis in men (Fig. 2-12) and the uterus, bladder, fallopian tubes,

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vagina, and clitoris in women. This plexus is formed by the union of the third and fourth lumbar splanchnic nerves with fibers from the more rostral inferior mesenteric plexus. Its segmental contribution usually derives from T11 to L2.

FIGURE 2-12 Distribution of sympathetic (left) and parasympathetic (right) nerves to the pelvic viscera and sexual organs in the male.

The visceral afferent fibers accompany the efferent autonomic fibers and pass uninterrupted back through the trunk, ganglia, and white rami to reach their nerve cells of origin in the dorsal root. Postsympathectomy Neuralgia

Operations on the distal aorta to treat symptomatic aortic disease from atherosclerosis or other causes frequently include intentional sympathectomy as part of the effort to improve blood flow to the legs. This is usually done by dividing the sympathetic chain below the last white ramus at L2, thereby depriving the lower lumbar and sacral ganglia of their preganglionic innervation. Such an operation is often followed by a distinctive pain 68 68,69 which Raskin and associates termed postsympathectomy neuralgia. In their syndrome, experience with 96 such operations, this syndrome occurred in 35 percent of the patients. In each case, the sympathetic chain was interrupted at L3 by removal of the segmental ganglion. The pain was characterized as deep, boring, nonrhythmic, and nonradiating; it had an abrupt but delayed onset. The mean delay from sympathectomy to onset of pain was 12 days. The pain was located predominantly in the thigh, either medially or laterally, and was associated with tenderness in the area of pain. The course was always self-limited, with an average duration of 3 weeks.

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Disorders of Sexual Function

Normal male sexual function has two distinct components. The first, erection, is a response mediated predominantly through the parasympathetic nervous system by the pelvic splanchnic nerves (nervi erigentes) arising from segments S2, S3, and S4 (Fig. 2-12). Activation of 6,70 these nerves causes vasodilatation and engorgement of the penile musculature The blood supply to the penis is provided by the internal pudendal artery via and sinuses. have at the internal iliac artery (Fig. 2-10). The sympathetic nervous system, however, must 6,70 The least a modifying influence on erection because sympathectomy may disturb it. second component, ejaculation, can be divided into two phases. The first phase, expulsion of seminal fluid into the prostatic urethra, is a response mediated predominantly by the 6,70 The second phase, sympathetic nervous system through the superior hypogastric plexus. emission, is produced by the clonic contraction of penile musculature (bulbocavernosus and ischiocavernosus) innervated by somatic (pudendal) nerves (Fig. 2-12). 6,71–76

Female sexual Male sexual function may be disturbed by aortic disease or surgery. function has not been as well studied in77these circumstances, although it seems to be affected to a similar degree as in men. Because the superior hypogastric plexus lies close to the aortic bifurcation (Fig. 2-11), most preoperative and postoperative sexual disturbances occur with disease of this portion of the aorta, and most involve ejaculation (Table 2-3). The pelvic splanchnic nerves are not situated near the aorta (Fig. 2-11) and usually are not affected by aortic disease or surgery. Disturbances in erection, however, do occur, possibly because of sympathetic dysfunction, a71–76 reduction in blood flow to the internal pudendal artery To determine whether blood flow or sympathetic and penis, or cavernovenous leakage. function was more important in this regard, Ohshiro and Kosaki examined the outcome of (1) terminal aortic operations either done traditionally or designed to spare the superior 74 hypogastric plexus and (2) operations that did or did not preserve internal iliac blood-flow. Their results indicated that preservation of the hypogastric plexus appeared to be more important for maintenance of normal erection and ejaculation than was preservation of internal iliac artery blood-flow (Table 2-4). Other authors have also found that modification of operative technique to spare the superior hypogastric plexus considerably improves 6,71,73 postoperative sexual function. Click here to view this table.... Click here to view this table.... Despite the importance of operative technique in preserving sexual function, preservation of blood flow is probably also important. Thus, Nevelsteen and colleagues reported a clear relationship between the occurrence of preoperative impotence and the adequacy of blood 75 flow through the internal iliac arteries. In this study, however, no special attempt was made to improve blood flow in the internal iliac artery during surgery, so that it is unclear whether a different operative approach might have been beneficial in restoring postoperative sexual function. AORTIC DISEASES AND SURGERY Certain conditions affecting the aorta merit special consideration because of the variety of nervous system syndromes that each can produce.

Aortitis Injury to the aorta by a variety of infectious, toxic, allergic, or idiopathic causes may produce 18 similar inflammatory pathological changes in the elastic media (Table 2-5). Such aortic damage may lead to neurological syndromes either primarily through direct involvement of important branch arteries by the pathological process or secondarily through the development of aneurysms, aortic stenosis, or atherosclerosis. The neurological syndromes produced either primarily or secondarily by aortitis depend on both the nature and the location of the resulting aortic lesion. Click here to view this table.... Syphilitic Aortitis 18,78

During the prepenicillin era, syphilis was a common cause of aortitis, although by the 78 1950s, its occurrence had markedly declined. A report in 1958 on the relative occurrence of atherosclerotic and syphilitic thoracic aortic aneurysms showed cases of syphilis 79 outnumbering atherosclerosis by a ratio of 1.3:1.0. A similar report published in 1982 gave

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79

this ratio as 0.13:1.0. The pathological process in syphilitic aortitis is almost always in the 19,78 in contrast to the distribution of atherosclerosis, which is more prevalent in thoracic aorta, the abdominal aorta (Table 2-2). The aortitis78is accompanied by aneurysmal dilatation of the aorta in approximately 40 percent of cases. 6 Rarely, it presents with multiple arterial occlusions and mimics Takayasu's arteritis, although patients are generally older than those with Takayasu's arteritis and are usually men. Takayasu's Arteritis Takayasu's arteritis is an idiopathic inflammatory condition affecting the large arteries, 6,45,80,81 The pathogenesis seems to involve particularly the aorta and its branches. cell-mediated autoimmunity, although the responsible antigen is unknown. The onset of disease is typically between the ages of 15 and 30 years, and the condition seems most 6 prevalent in Asian and Hispanic populations. More than 85 percent of affected individuals are women. In the early (prepulseless) phase, the disease may be characterized by systemic symptoms such as fever, night sweats, weight loss, myalgia, arthralgia, arthritis, and chest pain. In some patients, however, the systemic symptoms are either inconspicuous or absent. The later (pulseless) phase of the disease is characterized by occlusion of the major vessels of the aortic arch, producing symptoms such as Takayasu's retinopathy, hypertension (secondary to renal artery stenosis, coarctation, or both), aortic regurgitation, and aortic aneurysms. Symptoms of cerebral ischemia can occur; however, they are typically reported in 6,45,81 Nevertheless, a report from South Africa on 272 patients who were only a few patients. diagnosed with Takayasu's arteritis, based on the criteria of the American College of Rheumatology, found that 20 percent of the cohort had symptoms of cerebrovascular 81 of this cohort experienced disease, including TIAs and stroke. In addition, 32 percent 81 Seizures and headaches have also intermittent claudication of either upper or lower limbs. 6 been reported but are uncommon. Involvement along the aorta is typically diffuse, although some patients (perhaps as many as 20%) present with symptoms related to more restricted 18,81 The disorder is discussed further in Chapter 29. aortic involvement. Giant Cell Arteritis Giant cell arteritis (GCA) seems to be a particularly important cause of aortitis in the 6,18,19,82 ; although it typically affects medium-sized vessels, as many as one fourth or elderly 83 more of affected individuals have large-artery involvement. For example, in18one series of eight consecutive patients with aortitis, GCA seemed to be its basis in many. Thus, four had definite GCA diagnosed based on their age at onset, the new onset of headaches, and an elevation in erythrocyte sedimentation rate. However, all these patients were older than 57 years, each of the eight had an elevation of some serum inflammatory marker (e.g., increase in Creactive protein levels, erythrocyte6 sedimentation rate, or fibrinogen levels), and three had symptoms of polymyalgia rheumatica. In another series of 45 patients undergoing aortic resection and who had microscopic evidence of active noninfectious aortitis, the majority had either unclassifiable aortitis (47%) or GCA (31%), two entities that were histopathologically 82 indistinguishable. The presenting symptoms in patients with GCA or unclassified aortitis are generally nonspecific and include exhaustion, night sweats, weight loss, chest and back pain, 19,82 Typically, all segments headache, fevers of unknown origin, TIAs, and arm claudication. of the aorta (ascending aorta, arch, and descending aorta) are involved in the inflammatory 6,18,19 Between 10 and 20 percent of process, although involvement can be more restricted. patients with unclassified aortitis or GCA will82,83 subsequently develop either dissecting or, more commonly, nondissecting aortic aneurysms.

Aortic Aneurysms Nondissecting Aneurysms Nondissecting aortic aneurysms can be caused by any pathological process that weakens the 6,15,18,53,60,84,85 In the past, arterial wall, such as inflammation, infection, or atherosclerosis. 86 syphilis was an important cause, but at present, almost all these aneurysms are caused by atherosclerosis. As a result, the distribution of aortic aneurysms essentially parallels the distribution of atherosclerosis within the aorta, with most occurring in the abdominal aorta (Tables 2-2 and 2-6). In a study from Sweden, it was found that the incidence of ruptured abdominal aortic aneurysms in men (but not women) had increased by more than 100 87 percent between 1971 to 1986 and 2000 to 2004. The reason for this increased incidence is unclear, and it is unknown whether a similar increase has occurred in other parts of the world. The prognosis of untreated aneurysms is grave, with 80 percent of patients dying of rupture 84 within 12 months of the onset of symptoms. Disturbances of neurological function in aortic

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aneurysms are uncommon, but when they occur, they are variable and depend in part on the location and extent of the lesion. Abdominal aneurysms may result in sexual dysfunction, 6,58–62,71–77 or, rarely, spinal cord ischemic syndromes, including compressive neuropathies, 88 ; descending thoracic intermittent claudication, asymmetric paraparesis, and paraplegia 16 arch aneurysms may result in aneurysms may produce spinal cord ischemia, and aortic6,57 Most commonly, neurological cerebral ischemia or recurrent laryngeal nerve dysfunction. symptoms are produced by either rupture or direct compression. Even when aneurysms result in paraplegia, the neurological deficit is often caused by bony erosion through the vertebral bodies and direct compression of the spinal cord or cauda equina rather than by 64,89 ischemia. Click here to view this table.... Dissecting Aortic Aneurysms Dissecting aortic aneurysms, in contrast to nondissecting aortic aneurysms, predominantly involve the thoracic aorta, either at the beginning of the6,17,32,57,66,89,90 ascending segment (type A) or Their etiology has not immediately distal to the left subclavian artery (type B). been established. Atherosclerosis is probably not a major factor because atherosclerosis is seldom found in the region of the intimal tear because the distribution of these aneurysms along the aorta is unlike that of atherosclerosis and because atherosclerosis is only 90–92 Nevertheless, hypertension probably is a factor as it is present in infrequently present. 91,92 Moreover, the large majority of patients with either type A or type B dissections. dissecting aortic aneurysms have been associated with cystic medial necrosis, a degenerative condition focally affecting the arterial media, which may itself be related to hypertension. This condition is increased in patients with Marfan's syndrome, as are dissecting aneurysms. Most aneurysms, however, do not occur in patients with Marfan's syndrome89,91,92 or other identifiable collagen disorders, and the pathophysiology remains Neurological involvement from dissecting aneurysms (due to the cutoff of unknown. important arteries by the dissection or by embolization) is well described but uncommon. It 91,92 and it usually involves either occurs more frequently with type A than type B dissections, spinal or cerebral ischemia. Neurological involvement may also occur during surgery to repair 57 the aneurysm. Thus, in one large series of 527 patients, preoperative stroke occurred in 4 percent, and paraparesis occurred in another 2 percent. Patients with aortic dissection usually present with acute chest or back pain, which generally leads to the proper 57,91,92 On6,66 occasion, however, pain is absent, and the neurological syndrome is the diagnosis. Moreover, the neurological deficit produced by the dissecting presenting feature. aneurysm is sometimes only transient, lasting for several hours, and thereby mimicking other 6 transient disturbances of neurological function. Traumatic Aortic Aneurysm Brutal deceleration injuries to the chest, especially from motor vehicle accidents, may result in traumatic rupture of the thoracic aorta, often just distal to the left subclavian artery. Many of 93–96 Still others these patients die immediately, but some present with an acute paraplegia. have a chronic aortic aneurysm that may present years later with acute spinal cord 93 94 ischemia or other neurological symptoms.

Coarctation of the Aorta 97

Coarctation of the aorta, a relatively common congenital condition, typically results in constriction of the thoracic aorta just distal to the origin of the left subclavian artery. Less commonly, it occurs as part of Takayasu's arteritis, and this condition should be suspected if 6,81 It may also follow radiation exposure during the location of the coarctation is atypical. 6,98 infancy ; in these cases, the pathological process is focal and limited to the segment of aorta that was in the field of irradiation. Coarctation can result in a variety of neurological 6,23,97,98 Cerebral infarcts probably result from embolization of symptoms (Table 2-7). 6 thrombotic material in the dilated aorta proximal to the obstruction. Click here to view this table.... Subarachnoid hemorrhage from ruptured saccular aneurysms can occur with coarctation. In the general population, aneurysmal hemorrhage has an annual incidence of approximately 8 6,99 6,99 and rarely occurs before the age of 20 years. Accordingly, the reported97 per 100,000 occurrence of ruptured aneurysms in 2.5 percent of patients with coarctation of the aorta suggests an association of these two disorders,6 although the coincidental occurrence of the two conditions cannot be completely excluded.

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Headache is a common accompaniment of coarctation, perhaps as a result of secondary hypertension, but, again, the incidental occurrence of two unrelated conditions cannot be excluded. Episodic loss of consciousness may also occur in patients with coarctation of the aorta. It6,97 may result either from syncope due to associated cardiac abnormalities or from seizures. It is unclear, however, whether seizures unrelated to cerebrovascular disease are more 97 prevalent in these patients than in the general population. Neurogenic intermittent claudication can result from aortic coarctation. In patients with coarctation of the aorta, blood flow to the legs is often provided by collateral connections between the spinal arteries and the distal aorta. In these situations, the blood 6,52 flow through the and the radiculomedullary and intercostal arteries distal to the obstruction is reversed, exercise-related spinal ischemia may be related to “steal” by the increased metabolic 6 demands (and thus increased blood flow) of the legs rather than aortic hypotension distal to the coarctation (Fig. 2-13). These collaterals are sometimes so extensive that they cause spinal cord compression and mimic (clinically and radiologically) vascular malformations of 6,14,98 the spinal cord.

FIGURE 2-13 Mechanism of steal in coarctation of the aorta. Obstruction of the

aorta at the isthmus causes dilatation of the anterior spinal artery and reversal of blood flow in anterior radiculomedullary arteries distal to the obstruction. In this circumstance, the blood flow to the lower extremities is provided by these (and other) collaterals, and use of the lower extremities may cause shunting of blood from the spinal circulation to the legs, which, in turn, sometimes results in spinal cord ischemia.

Surgery and Other Procedures Aortic Surgery

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As with diseases of the aorta, the risks of aortic surgery depend in part on the site of operation. Thus, operations on the aortic arch may produce cerebral ischemia either by intraoperative occlusion of major6,13,46,47 vessels or by embolization of material such as calcified Operations on the suprarenal aorta may result in plaque loosened13during surgery. on the distal aorta may result in sexual dysfunction or spinal ischemia, whereas operations 6,58–62,71–77 ischemia of the femoral nerve. The major complication of all aortic operations, however, is intraoperative spinal cord ischemia with resultant paraplegia or paraparesis. The occurrence of this complication varies with the location of the surgery and the nature of the pathological process affecting the aorta (Table 2-8). Thus, operations on dissecting or nondissecting aortic aneurysms that are entirely abdominal are associated with a lower incidence of this complication than operations 6,26,100–104 Surgery on aneurysms involving 100 the on aneurysms confined to the thoracic aorta. entire abdominal and thoracic aorta carries the highest risk of producing cord ischemia. Operations on the distal aorta for occlusive disease only rarely result in spinal ischemia, 26,33 This variability presumably occurs especially when confined to the infrarenal portion. because important feeding arteries to the spinal circulation are more likely to be ligated during surgery, included within the segment of the aorta that is cross-clamped, or subjected to distal hypotension when the aortic lesion is above the level of origin of the renal arteries. Click here to view this table.... Operations on the thoracic aorta for coarctation are much less frequently complicated by 23 spinal ischemia than thoracic operations done for other reasons. There are probably at least two reasons for this difference. First, the former patients are younger, and the extent of overall arterial disease is therefore less. Second, as mentioned earlier, 6,105 the flow in the so obstruction of radiculomedullary vessels below the coarctation is frequently reversed, blood flow in them (either by ligation or cross-clamping the aorta above and below their origin) may actually result in an increased blood supply to the spinal cord. Aortography and Other Procedures on the Aorta 16

6,106

Aortography may be associated with either spinal or cerebral ischemia, depending on the portion of the aorta visualized. This complication, however, is distinctly rare (Table 2-8). Paraplegia may also occur during intra-aortic balloon assistance after myocardial 6,107 revascularization. Intraoperative Adjuncts to Avoid Spinal Cord Ischemia Several adjuncts are commonly used during surgery in an attempt to avoid spinal cord injury. They include the use of deep hypothermia and circulatory arrest in addition to thiopental anesthesia and intraoperative corticosteroids, all of which are thought 57 to reduce the metabolic requirements of the cord or otherwise enhance tolerance to ischemia. In addition, many authors have reported that minimization of cross-clamp time results in a lower incidence of spinal ischemia. Other adjunctive methods such as the reattachment of intercostal arteries, the use of shunts to maintain distal perfusion pressure, and the use of cerebrospinal fluid drainage have not 7,46,49,108–114 although the more proved consistently effective at preventing cord ischemia, 7,49,113,114 Part of recent experience with such adjunctive techniques has been quite favorable. the difficulty with these procedures may relate to the extreme variability of the blood supply to the spinal cord. For example, if a crucial spinal artery leaves the aorta within the cross-clamped section, the preservation of distal blood-flow is irrelevant. Furthermore, because the important intercostal arteries are few and unpredictably situated, the random reattachment of a few intercostal arteries may be fruitless. There has been considerable interest in the use of somatosensory evoked potentials (SEPs) and motor94,115–125 evoked potentials (MEPs) for assessing spinal cord function during operations on The combined use of SEPs and MEPs may ultimately prove better than the aorta. 124 and, indeed, the most recent reports with both techniques have either technique alone, 7,46,123–125 An approach that seems particularly valuable is the use of been encouraging. intraoperative MEPs or SEPs to identify those vessels that perfuse the spinal cord and therefore need reattachment, should not be sacrificed, or should not be included within the 7,121,124 Another approach that has been reported to be useful is the use of aortic cross-clamp. intraoperative MEPs to monitor patients and to quickly increase both the123 distal aortic pressure and the mean arterial pressure in response to a drop in MEP amplitude. Nevertheless, although these reports are quite encouraging, the best method of monitoring intraoperative

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spinal cord function and how best to use the information to alter the operative technique so that postoperative spinal cord function is maintained are still being determined. Previous

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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 3 Neurological Complications of Cardiac Surgery JOHN R. HOTSON •

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EXTRACORPOREAL CIRCULATION Technique Consequences During “Normal” Convalescence NEUROLOGICAL SEQUELAE OF CARDIAC SURGERY Brain Disorders Peripheral Nerve Disorders Neuro-ophthalmological Disorders NEUROCOGNITIVE DECLINE RISK FACTORS FOR STROKE PREVENTION OF NEUROLOGICAL COMPLICATIONS CARDIAC TRANSPLANTATION

Neurological complications are a potential consequence of cardiac surgery that can nullify or 1–8 limit any benefits of such surgery. The probability of these complications increases as coronary artery bypass graft surgery is used for treating ischemic heart disease in older patients,9 in patients with multiple comorbid conditions, and as heart transplantation programs expand. In spite of the increased use of catheter-based coronary revascularization, more than 400,000 people per year have coronary artery bypass graft surgery in the United 10 adverse cerebral outcome States. A substantial number of patients have a postoperative 6,11 Many more patients may develop such as stroke or hypoxic-ischemic encephalopathy. 8,12 Prevention of perioperative neurological loss of cognitive performance after heart surgery. complications remains an important medical problem. EXTRACORPOREAL CIRCULATION Cardiopulmonary bypass was first used successfully in cardiac surgery in 1953 and was the 13 pivotal development that led to modern cardiac surgery. Its early use in humans resulted in frequent complications, which restricted its employment to seriously ill patients with progressive heart failure. Although the safety of extracorporeal circulation has increased, it remains a potential cause of neurological complications independent of other heart surgery procedures.

Technique

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Open heart surgery with cardiopulmonary bypass begins with exposure of the heart, usually by a median13sternotomy, followed by cannulation of the ascending aorta and vena cava or material in a right atrium. Insertion of the aortic cannula can dislodge atheromatous 14 severely diseased aorta, thereby leading to cerebral embolization. In addition, this procedure can produce rotational torsion or compression of the brachial plexus, with 15,16 subsequent injury. Extracorporeal circulation is used in association with systemic heparinization, hypothermia, 13 and hemodilution. Anticoagulation is used to prevent clot formation when blood is exposed to the nonendothelial surfaces of the bypass pump oxygenator and microaggregation filtration system. Core hypothermia is often used in combination with selective cooling of the heart, or cold cardioplegia, in order to protect the heart, brain, and other vital organs from ischemic damage. Infusion of ice slush solutions into the pericardium is one technique for inducing 17–19 Normothermic cold cardioplegia, but it occasionally produces focal phrenic nerve injuries. cardiopulmonary bypass may also be used in patients with few risk factors for stroke because 20,21 it provides better hemodynamic function and decreases cardiopulmonary bypass time. Normovolemic hemodilution is used in part to conserve blood loss. It also compensates for the progressive hemoconcentration,13decrease in plasma vol ume, and reduced blood flow that is associated with hypothermia. During cardiac surgery with extracorporeal circulation, the ascending aorta is routinely cross-clamped; during valve-replacement surgery, congenital heart disease repair, or left ventricular aneurysm resection, the cardiac chambers are entered. These procedures may disrupt diseased tissue and produce emboli. Arterial systolic, diastolic, and mean pressure, pump pressure and flow rate, and central venous pressure are monitored during cardiopulmonary bypass. Mean arterial pressure13is usually maintained above 40 to 50 mmHg by vasodilators, pressors, or volume expanders.

Consequences During “Normal” Convalescence Extracorporeal circulation has predictable effects that result in a postperfusion syndrome and 13,22 This syndrome includes systemic inflammatory response during “normal” convalescence. the following conditions. Reduced Clotting Factors. Exposure of blood to an abnormal environment during cardiopulmonary bypass leads to consumption of platelets and coagulation factors. Platelets adhere to the unphysiological surface of the oxygenators and filtration system of the bypass pump. This clumping of platelets not only predisposes to platelet emboli but also can reduce the number of circulating platelets. The exposure to foreign surfaces also causes release and depletion of granule-stored aggregating proteins in 13,22 surviving platelets. Therefore, the remaining platelets have decreased adhesiveness. Coagulation factors are also consumed during cardiopulmonary bypass. A variety of carrier proteins and lipoproteins are denatured when blood passes through the bypass pump oxygenator. Even with adequate heparin levels, these damaged proteins can initiate a 22,23 The clinical significance of cascade in several coagulation and inflammatory systems. these hematological changes is usually minor. They may contribute, however, to the 24 intracranial hemorrhages that are occasionally observed after open heart surgery. Cardiovascular Response. During the early postoperative period, the degree of peripheral 13 vasoconstriction provides a clinical estimate of cardiac output. Transient atrial fibrillation, 25,26 A which carries a risk of cardiac emboli, is common during the convalescent period. metabolic acidosis is also common during the 2 hours immediately after operation and reflects a washout of lactic acid from regions of poor perfusion during extracorporeal circulation. Persistence of a metabolic acidosis may indicate inadequate tissue perfusion 13 secondary to low cardiac output. Red Blood Cell Fragmentation. Exposure of blood to nonendothelial surfaces during bypass surgery causes a breakdown of13red blood cells, with subsequent anemia, hemoglobinemia, and hemoglobinuria. Mild Mental Confusion. Transient mild disturbances of orientation, memory, and level of alertness that resolve13within the first few days after open heart surgery with cardiopulmonary bypass are frequent. Whether the changes in mentation are totally reversible events that accompany most major operations or whether they indicate long-term sequelae is an area of 8,11 sustained interest.

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Brain Swelling. Brain swelling is present when magnetic resonance imaging (MRI) is obtained immediately following coronary artery bypass surgery. When brain imaging studies are repeated 2 to 3 weeks after the surgery, the brain swelling has remitted. There are no 27 clinical findings associated with the brain swelling, and its cause is unknown. These expected consequences of cardiopulmonary bypass are functionally reversible and compensated for during convalescence. Firm evidence that extracorporeal circulation itself permanently harms the brain is lacking. Cardiopulmonary bypass, however, does create numerous potential hazards that, if augmented by procedural mishap, may lead to permanent injury of the central nervous system (CNS). Cardiac operations using extracorporeal circulation carry the risks of embolus formation (from platelets, fibrin, tissue or surgical 13,22 For these reasons, debris, air, or fat), cerebral hypoperfusion, and even hemorrhage. there is 28 interest in performing coronary artery surgery without the use of cardiopulmonary bypass. This off-pump technique can produce excellent cardiac outcomes. It is associated with fewer cerebral microemboli and29,30 less short-term neurocognitive decline when compared The short-term difference in cognitive performance, to on-pump coronary artery surgery. however, is limited, has not been consistently found across studies, and is not statistically 28,30,31 The off-pump technique does not lower the overall stroke rate, but significant at 1 year. may decrease stroke in a high-risk subgroup of patients with a severely atheromatous 32 aorta. Comparisons of performing coronary artery bypass grafting off-pump and28with cardiopulmonary bypass have not proven the overall superiority of either method. NEUROLOGICAL SEQUELAE OF CARDIAC SURGERY Diffuse or multifocal anoxic-ischemic damage, focal cerebral infarction, and brachial plexus injuries remain the main causes of permanent, disabling neurological complications after 1,6,15,33 Therefore, the common, obvious postoperative symptoms include cardiac surgery. diffuse impairment of cognition and level of consciousness, focal deficits from stroke, and isolated peripheral weakness and sensory loss in one arm and hand.

Brain Disorders Stroke, encephalopathy, coma, and seizures are the major brain disorders complicating 6,34 Stroke is reported in prospective studies to occur in 1 percent to more cardiac surgery. than 5 percent of patients following coronary artery bypass surgery, and the incidence 6,21,35–37 Stroke after cardiac increases in association with preoperative stroke risk factors. surgery increases hospital mortality approximately five- to sixfold, prolongs intensive care, 38,39 and typically requires inpatient rehabilitation or nursing home placement. 39The majority of stroke patients who survive to hospital discharge are substantially disabled. Most strokes occur in the first 2 to 3 days after coronary artery bypass surgery, but they may continue with 8,39,40 Stroke occurs more increased frequency during the first 2 postoperative weeks. frequently when valvular heart surgery is combined with coronary artery bypass graft 41,42 This increase is due to the additional risk of cerebral macroemboli with operations. operations that require opening a heart chamber and removal or repair of diseased mitral or aortic valves. Imaging and clinical studies, including cerebral arteriograms, suggest that the main cause of cerebral infarction with either coronary artery bypass surgery or valvular heart 40,43 Diffusion-weighted brain MRI is more surgery is embolization and not hypoperfusion. sensitive that computed tomography (CT) for detecting acute stroke after heart surgery and, when combined with measurements of the apparent diffusion coefficient, distinguishes acute 44 from chronic ischemic lesions. Intra-arterial thrombolysis for stroke occurring 1 to 14 days after heart surgery has been reported as a potential treatment option that merits further 45–47 study. Intracranial hemorrhage is an infrequent cause of stroke, but its rapid 40,48,49 identification is Hematomas may important so that surgical evacuation can be undertaken if necessary. be located in the brain parenchyma or in subdural or epidural spaces. Intracranial hemorrhage may be related to reduced platelet adhesion and coagulation factors during cardiopulmonary bypass. The global encephalopathy that can follow heart surgery varies from coma to confusion or delirium with impaired cognition. Stupor or coma after uncomplicated surgery is infrequent, 34 occurring in less than 1 percent of patients. It may be due to global anoxia-ischemia, massive stroke, or multiple brain infarctions. Postoperative hyponatremic encephalopathy is important to recognize and reverse because it can lead to brain damage and death, 50 Additional, rarely reported causes of encephalopathy or particularly in younger women. 51 52 a hypernatremic hyperosmolar state, and acute obstructive coma include hypoglycemia, 53 hydrocephalus.

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When anoxia-ischemia is the cause of coma, myoclonus, at times accompanied by seizures, may be prominent. Recurrent postanoxic myoclonus and seizures are often poorly responsive to anticonvulsant therapy. The outcome in these comatose patients is usually extremely poor, 54 with only a rare patient making a meaningful recovery. Clinical assessment55,56 identifies confusion or delirium after cardiac surgery in greater than 8 Its prevalence is even greater in patients57older than 65 to 70 years percent of patients. and in patients with known preexisting cerebrovascular disease. Confusion and delirium after cardiac surgery increase postoperative morbidity and prolong postoperative hospitalization. These encephalopathic patients may be slow to emerge from anesthesia, are often agitated, and have fluctuating moderate to severe impairment of cognitive function. Hallucinations may be present, and occasionally there are bilateral Babinski signs. Improvement often occurs during the first postoperative week. In comparison, patients who are matched for age and clinical condition but who have major surgery for peripheral vascular disease without 3 cardiopulmonary bypass rarely develop such transient impairment of intellectual function. Some confused patients have multiple, acute, small44ischemic brain lesions detected with diffusion-weighted MRI, suggesting multiple emboli. However, in many patients, the cause of confusion or delirium cannot be clinically defined. Coronary artery bypass grafting without the use of cardiopulmonary bypass results in less55frequent postoperative delirium, whereas prolonged operating time increases its frequency. Therefore, exposure to cardiopulmonary bypass appears to be a contributing factor to a transient encephalopathic state in otherwise uncomplicated cardiac surgery. Acute psychosis after open heart surgery has been attributed to a situational psychiatric 58 reaction if the level of alertness and memory remain intact. When the latter processes are also impaired, the psychotic behavior has been called an organic delirium. In patients undergoing cardiac surgery, this differentiation may be incorrect. When the psychotic response has cleared and neuropsychological testing is performed, both groups have similar, 59 multiple cognitive impairments compared to patients without neurobehavioral complications. The diagnosis of an intensive care unit psychosis is usually restricted to reactions that begin 2 to 5 days after surgery, are associated with preserved memory and alertness, and rapidly resolve after treatment with neuroleptic agents or discharge from the intensive care unit. Psychotic reactions that occur during the first 48 postoperative hours in a previously stable patient probably represent a behavioral response to an anoxic-ischemic insult associated with 58,60 cardiac surgery and cardiopulmonary bypass. Seizures may accompany coma, encephalopathy, or delirium, or they may occur 6,34 They occur in fewer than 1 percent of patients, usually independently after cardiac surgery. early in the postoperative period and often within the first 24 hours. Tonic-clonic or partial motor seizures are clinically apparent, but partial complex seizures in an encephalopathic patient may be difficult to recognize clinically. Choreoathetosis after heart surgery, a complication that occurs mainly in children, sometimes raises the question of a seizure 61 disorder. Nonconvulsive status epilepticus may occur with stroke complicating cardiac surgery and will then contribute to a prolonged confusional state that is treatable with 62 anticonvulsant drugs. Therefore, the electroencephalographic evaluation of patients with a persistent encephalopathy may be valuable.

Peripheral Nerve Disorders The brachial plexus and phrenic nerves are the most frequent peripheral nerves injured during cardiac surgery. A polyneuropathy may also occur under certain circumstances. A persistent brachial plexopathy after median sternotomy has been reported to occur in more 1,15,16 Transient and minor brachial plexus injuries may be even than 5 percent of patients. 63 more common. Most frequently, the lower trunk of the brachial plexus is injured. Therefore, the intrinsic hand muscles are often most severely impaired, and the triceps reflex may be decreased in the affected arm. Sensory loss is sometimes present in the affected hand. Pain is prominent in some patients, and a minority have Horner's syndrome. Injuries of the upper brachial plexus can also occur but are less frequent. Although not life-threatening and usually reversible in 1 to 3 months, a brachial plexus injury may produce permanent disability, particularly if it affects the dominant hand or produces intractable causalgia. The plexus injuries may be due to torsional traction or compression during the open heart 16,63 Intraoperative electrophysiological monitoring of upper extremity sensory nerve surgery. conduction reveals significant disturbances during sternal retraction in the majority of patients. This intraoperative monitoring technique can detect functional disorders of the

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brachial plexus during surgery, predict postoperative nerve injury, and identify intraoperative 64,65 Brachial plexus injuries may be reduced factors that predispose to brachial plexus injury. by minimizing the opening of the sternal retractor, placing the retractor in the most caudal 16 location, and avoiding asymmetric traction. Unilateral phrenic nerve injuries with hemidiaphragmatic paralysis occur in at least 10 percent 18,66,67 The location of the phrenic nerve adjacent to the of patients during open heart surgery. pericardium makes it particularly vulnerable to injury from hypothermia associated with topical cold cardioplegia, as well as injury from manipulation and ischemia. Unilateral phrenic nerve injury causes atelectasis and inspiratory muscle weakness, predisposing to postoperative respiratory complications. Phrenic nerve injury in patients with preoperative chronic obstructive pulmonary disease adds particularly to postoperative morbidity. In most patients, however, morbidity is low. Some recovery is usually evident by about 6 months after injury, but there may be a more protracted course consistent with axonal injury and regeneration. Severe, bilateral phrenic nerve injury is a rare complication of heart surgery and leads to 68 prolonged mechanical respiration. Mononeuropathies resulting from compression or trauma during surgery may involve the accessory, facial, lateral femoral15,69–72 cutaneous, peroneal, radial, recurrent laryngeal, saphenous, A recurrent laryngeal nerve injury with vocal cord long thoracic, and ulnar nerves. 15 Ischemia to the paralysis and a persistent peroneal neuropathy can be disabling. 73 cochlea-auditory nerve can result in severe hearing loss. Most compressive mononeuropathies, however, are transient. This reversibility, usually within 4 to 8 weeks, may reflect the focal selective injury to myelin, with relative sparing of nerve axons, which occurs 74 with compression neuropathies. Awareness of possible intraoperative compression sites helps to prevent these complications. Diffuse paralysis as a result of the Guillain–Barré syndrome may follow otherwise 75 uncomplicated cardiac surgery as well as other surgical procedures. Persistent paralysis also occurs after cardiac surgery in critically ill patients 76 who have renal failure and require days of vecuronium to facilitate mechanical respiration. If heart surgery is complicated by sepsis and multiorgan failure lasting for more than a week, a “critical illness” polyneuropathy and myopathy may develop, with difficulty in weaning from a respirator, distal weakness, and 77 reduced tendon reflexes.

Neuro-ophthalmological Disorders Visual disorders from cardiac surgery are frequent but usually asymptomatic and reversible. Retinal disorders include multifocal areas of retinal nonperfusion in almost all patients, cotton wool spots consistent with retinal infarctions in 10 to 25 percent of patients, and visualization of retinal emboli in fewer individuals. These retinal disorders are infrequently associated with 5,78 reduced visual acuity. An anterior ischemic optic neuropathy is an uncommon, disabling complication of heart surgery. It produces infarction of the optic nerve head, optic disc swelling with a painless and usually permanent decrease in visual acuity. An anterior ischemic optic neuropathy may 78 produce a monocular altitudinal, arcuate, or central scotoma. A retrobulbar or posterior 79 ischemic optic neuropathy due to infarct of the intraorbital nerve is even less common. It produces 80 acute blindness without optic disc swelling accompanied by impaired pupillary posterior ischemic optic neuropathies may produce reactions. Both the anterior and 79 unilateral or bilateral blindness. Homonymous visual field defects occur with focal ischemic injury of the visual cortex or retrochiasmal visual pathways. An occasional patient is found to be cortically blind after heart surgery, usually from bilateral ischemia of the occipital cortex. Retinal and pupillary examination are both normal in patients with cortical blindness. Some of these patients deny 5,78 any visual impairment. At least partial recovery from cortical blindness is possible. Horner's syndrome occurs in association with injuries to the lower brachial plexus and may result from concomitant injury to the preganglionic sympathetic fibers that travel through the 5 eighth cervical and first thoracic ventral roots. It also develops in the postoperative period in81 hypertensive and diabetic patients, presumably due to ischemic injury to sympathetic fibers. Gaze deviations, gaze paralysis, and dysconjugate gaze may occur in postoperative patients who have a brainstem or large hemispheric stroke involving eye movement systems. Intermittent gaze deviation with nystagmoid movements raises concerns about postoperative 82 focal seizures.

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Pituitary apoplexy resulting from acute hemorrhage or infarction of a pituitary adenoma is a 83 rare complication of cardiopulmonary bypass. The pituitary tumor is usually not recognized prior to surgery and is particularly susceptible to the ischemic and hemorrhagic risks associated with cardiopulmonary bypass. After heart surgery, patients awake with headache, ptosis, ophthalmoplegia, and visual impairment from compression of the adjacent cranial nerves and the anterior visual pathways. Transsphenoidal surgical decompression has been used safely in some patients. Infarction of a normal pituitary during coronary84artery bypass surgery also occurs, may initially be silent, and leads to panhypopituitarism. Visual hallucinations solely on eye closure have been reported following cardiovascular 85,86 Patients are otherwise fully alert and lucid and can stop the hallucinations simply surgery. by opening their eyes. Atropine or lidocaine toxicity and complex partial seizures have been associated with such hallucinations. NEUROCOGNITIVE DECLINE Neuropsychological studies of cognitive function before and after cardiac surgery have identified both a transient early and a subsequent late decline in cognitive function occurring 7,87–91 The early postoperative changes in cognition have been shown by after heart surgery. comparing repetitive neuropsychological test results in patients undergoing coronary artery surgery with extracorporeal circulation to nonsurgical control subjects. Performance declines on tests of attention, visuospatial ability, and memory 3 days after coronary artery bypass surgery compared to preoperative testing. A similar decline does not occur in age- and gender-matched nonsurgical control subjects. The impaired neurocognitive performance, 87,89–92 Although numerous however, typically returns to the preoperative level within weeks. factors may contribute to this transient postoperative cognitive impairment, direct evidence of 7 a specific etiology in individual patients is often lacking. A late decline in cognitive function occurs in the interval from 1 to 5 years after coronary 88,90,93 The cause of this late92decline is unproven, in part because few artery bypass surgery. of the longitudinal studies included control groups. One postulated etiology is that diffuse brain microemboli associated with extracorporeal circulation injure a neuronal reserve that is 94,95 Transcranial Doppler needed to compensate for brain aging and to prevent dementia. ultrasonography of the middle cerebral artery and carotid artery can detect microemboli during heart surgery. During cardiopulmonary bypass, there is a continuous dissemination of 78,94,96–98 The brain microemboli producing microvascular occlusions followed by reperfusion. washout of brain emboli 99 and reperfusion may be impaired if there is concurrent systemic or localized hypoperfusion. Patients with a high total microemboli count during heart surgery have a significantly higher frequency of neuropsychological test deficits than patients with low microemboli counts. Patients with long cardiopulmonary bypass durations also have a higher total microemboli 100–102 If extracorporeal circulation count and higher frequency of neuropsychological decline. does lead to a late decline in cognitive performance, then patients with off-pump coronary surgery on the beating heart should have less of a late decline. This comparative study is 103 pending. Evidence exists against the belief that disseminated brain microemboli from the extracorporeal circulation account for the late cognitive decline. Cognitive function 5 years after patients are randomly assigned to undergo either coronary surgery or angioplasty is 104 similar. Cognitive performance at 3 years is also similar in patients receiving on-pump coronary103 artery bypass surgery and a nonsurgical control group with coronary artery disease. One study with a small number of patients in which individuals with preexisting neurological or psychiatric diseases or impaired cognition were excluded showed no late decline in cognitive performance after 3 to 5 years. These patients also had very good 105 vascular risk factor control over the interval of neuropsychological testing. A case-control study found a similar incidence of coronary artery bypass surgery in control subjects and patients with dementia, including a subgroup with a diagnosis of Alzheimer's disease. 106 Coronary artery bypass surgery does not appear to be a major risk factor for dementia. A slow accumulation of microvascular brain ischemia due to vascular risk factors is an alternative explanation for the late decline in neurocognitive performance after cardiac surgery. Elderly subjects with asymptomatic ischemic lesions on brain imaging who have not had heart surgery have a greater decline 107–109 in cognitive function over a period of 3 to 4 years Similarly, subjects with symptomatic than individuals without ischemic lesions. cerebrovascular disease have increased progressive cognitive decline compared to control 110,111 Patients undergoing coronary artery bypass grafts typically have vascular risk subjects. factors for asymptomatic and symptomatic brain lesions that are associated with cognitive

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112

decline. It would be valuable to know whether very good control of vascular 7,105 risk factors eliminates the late decline in cognitive performance that follows heart surgery. RISK FACTORS FOR STROKE Several preoperative factors have been identified as placing a patient at a higher risk of a neurological complication (Table 3-1). Increasing older age is associated with increasing frequency of neurological and cognitive disorders following coronary artery bypass 6,113,114 A multicenter, prospective study of 5,000 patients found that the occurrence surgery. of stroke was 1 percent in patients younger than 50 years of age, almost 2 percent in patients aged 50 to 59 years, approaching 4 percent in patients aged 60 to 69 years, and greater than 115 5 percent in patients older than 70 years. With a growing elderly population, the number of patients older than 80 years who are evaluated for coronary artery bypass grafts may 116 increase. Click here to view this table.... Dislodgment of prothrombotic atheroma during instrumentation of the aorta is a risk factor for 14,32,117–120 Atheromatous aortic disease can be identified with intraoperative stroke. ultrasonographic scanning and transesophageal echocardiography. Approximately 25 to 50 percent of patients receiving a coronary artery bypass graft have atherosclerotic plaques in their ascending aorta identified by these techniques. The frequency of such aortic disease increases with age and is particularly prominent in patients older than 70 years. Identification 118,121 of a moderately to severely atheromatous aorta may alter surgical management. A preoperative history of hypertension, diabetes mellitus, stroke, severe stenosis of the carotid artery (>70%), and other markers 6,8,38,114,115,122 of vascular disease are also risk factors for stroke Cardiac surgery123 within 3 months of a following coronary artery bypass surgery. stroke may carry a risk of worsening preoperative neurological deficits. The greater the number of preoperative risk factors, the higher is the probability of a perioperative stroke. For example, a 65- to 75-year-old patient with a history of a stroke and hypertension has a risk of postoperative stroke that is three times greater than that of a patient of the same age without a history of stroke or hypertension. A patient older than 75 years with a history of stroke and hypertension has a probability for postoperative stroke that is 13 times greater than a patient younger than 65 years with no previous stroke or history of hypertension. Stroke risk indexes may identify patients124,125 prior to coronary artery bypass surgery who are at high risk of a perioperative stroke. Intraoperative factors also influence the frequency of stroke (Table 3-1). As noted previously, individuals who require coronary artery bypass surgery combined with a left-sided 38,126 Patients who require intracardiac procedure have a relatively high rate of stroke. cardiopulmonary bypass lasting more than 2 hours have a higher number of intraoperative cerebral microemboli detected by transcranial Doppler ultrasound monitoring and a higher 38,115,127,128 A large fluctuation in hemodynamic parameters during frequency of stroke. surgery, such as129 mean arterial pressure, has been associated with postoperative stroke and encephalopathy. The risk from sustained intraoperative hypotension with a mean arterial pressure below 40 to 50 mmHg during cardiopulmonary bypass remains unclear. Atrial fibrillation occurs in approximately one third of continuously monitored patients following cardiac surgery and is a risk factor for stroke. Its initial occurrence is most common during the first 3 postoperative days, and 20 percent of patients have more than one episode. Advancing age is a risk factor for atrial fibrillation, and patients older than 70 years are at high risk of arrhythmia. Withdrawal from β-adrenergic receptor–blocking agents or angiotensin-converting enzyme inhibitors is also associated with recurrent atrial fibrillation. Use of β-blocking drugs or angiotensin-converting enzyme inhibitors preoperatively and postoperatively and β-blockers postoperatively is associated with a reduced risk of atrial 25,115,122,130,131 fibrillation. PREVENTION OF NEUROLOGICAL COMPLICATIONS Attempts to prevent neurological sequelae after cardiac surgery have focused on improved 8,132,133 surgical and cardiopulmonary bypass techniques and neuroprotective drugs. Identification of surgical and technical factors that carry particular risks of neurological 8,13,132 An complications after cardiac surgery has led to the adoption of preventive measures. arterial line microfilter system has been incorporated into the extracorporeal circulation with the aim of reducing cerebral embolization. Improved surgical techniques reduce the bypass time and the total number of cerebral microemboli. Maintenance of the mean arterial blood pressure above 50 mmHg provides a safety margin against periods of relative hypoperfusion.

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The use of a membrane oxygenator decreases the magnitude of air emboli. Preoperative or early postoperative administration of β-blocking agents decreases the incidence of postoperative atrial fibrillation. Early postoperative use of aspirin decreases ischemic 134 complications of multiple organs including132,135 the brain. Perioperative monitoring and control Delaying heart surgery for 4 or more weeks of hyperglycemia may influence outcome. 132 after a recent stroke has been recommended if the cardiac condition allows such a delay. The benefit of combined carotid revascularization and coronary artery bypass surgery in patients with asymptomatic carotid stenosis awaits confirmation in a prospective clinical 114,136–139 Carotid endarterectomy for patients with severe (70% to 99%) internal carotid trial. stenosis that has been neurologically symptomatic in the past 6 months is of established 140 benefit independent of cardiac surgery. Performing a carotid endarterectomy before or simultaneous with coronary artery bypass surgery in such patients is an accepted 132,141,142 Carotid stenting has evolved as an alternative procedure for such practice.8,138,139,143,144 patients. An increased concern that an atheromatous aorta is a primary source of embolic stroke has led to intraoperative identification with transesophageal echocardiography and epiaortic 14 scanning. The presence of prominent aortic atheroma alters surgical techniques including the site of aortic cannulation, the aorta clamping technique, the use of intra-aortic filtration, and using off-pump coronary artery surgery to avoid manipulation of a severely diseased 28,32,118,132,145,146 aorta. The magnitude of cerebral microemboli and the frequent neuropsychological and anoxic-ischemic findings associated with cardiac surgery suggest a need and opportunity to study brain protective agents. Proposed mechanisms of pharmacological neuroprotection include decreasing cerebral oxygen consumption; decreasing cerebral blood-flow and, with it, the total number of microemboli; interrupting the cascade of cerebral ischemic events that are mediated via excitotoxins such as glutamate; and decreasing the inflammatory response 133,147–151 Clinical trials, and coagulation cascade associated with cardiopulmonary bypass. however, have yet to identify an effective pharmacological neuroprotective agent that has wide clinical application during coronary artery bypass surgery. CARDIAC TRANSPLANTATION Cardiac transplantation is an established treatment for selected patients with progressive, preterminal heart failure. Cardiac transplantation centers now report survival rates at 1 year of greater than 80 to 85 percent, at 5 years of 60152,153 to 80 percent, at 10 years of approximately The annual153 number of heart 50 percent, and at 15 years of 30 to 40 percent. transplantations worldwide is estimated to be greater than 4,000. Neurological sequelae occurring either in the perioperative period or as a late complication may negate an otherwise successful heart transplantation. The early identification of treatable complications offers the best opportunity to prevent severe disability. The perioperative neurological sequelae from cardiac transplantation are similar to the complications associated with valvular or bypass graft surgery, dis cussed previously, except 41 that neurological complications occur more frequently in transplant recipients. Postoperative encephalopathy, stroke, headaches, psychosis, seizures, and peripheral nerve disorders are 154–160 the most common problems. Vascular headaches accompanied by nausea and vomiting may occur in the first week after 156 transplantation. The headaches are associated with a rapid shift from low preoperative to high postoperative mean arterial pressures. Similar headaches may rarely precede an intraparenchymal hemorrhage. These vascular headaches respond to β-adrenergic receptor–blocking agents. 157

Seizures have been reported in as many as 15 percent of patients with cardiac transplants. They commonly occur during the perioperative period. They also occur as a side effect of cyclosporine or as a late complication of a brain infection or tumor. Seizures in the perioperative period are usually due to stroke and may not require long-term anticonvulsant therapy. When anticonvulsant drugs are indicated, phenytoin, phenobarbital, and carbamazepine are often avoided because they induce the hepatic metabolism of cyclosporine, tacrolimus, and sirolimus. When these antiepileptic agents are used, immunosuppression may be reduced. Levatiracetam and gabapentin have negligible hepatic 161 enzyme–inducing effects and few drug interactions and may be preferred anticonvulsants. Pregabalin, a newer antiepileptic drug, has similar characteristics. Psychotic behavior with hallucinations, delusional thought processes, and disorganized behavior can occur during the first 2 weeks after transplantation or as a late complication.

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When it occurs during the postoperative period, multiple causal factors may be present, but with time, the psychotic behavior usually resolves. When psychotic behavior occurs as a late complication, it is often a manifestation of an intracranial infection, most commonly viral. A thorough neurological evaluation is therefore indicated when a cardiac transplant recipient 154,155 develops an acute late psychosis. Immunosuppression remains a cause of late neurological complications after cardiac transplantation. Opportunistic infections can occur as early as 2 weeks after surgery and immunosuppression, but usually there is an interval of at least 1 month. Focal meningoencephalitis or brain abscess, meningitis, and diffuse encephalitis are three common 154,155,162 Aspergillus fumigatus, presentations of infections in cardiac transplant recipients. Toxoplasma gondii, Cryptococcus neoformans, Listeria monocytogenes, and herpesvirus infections are the more common causes of CNS infections in heart transplant 162,163 recipients. Aspergillosis is the most frequent fungal infection that produces a necrotizing 162 meningoencephalitis and single or multiple brain abscesses. Cerebral aspergillosis is almost always disseminated from a preceding pulmonary infection.164 The abscesses may have MRI ring, irregular, or no contrast enhancement on MRI and CT scans. Diffusion-weighted 165 may demonstrate restricted diffusion of water in the center of the abscess. Aspergillosis also causes an invasive necrosis of intracranial vessels that may lead to hemorrhagic infarction. Therefore, focal hemorrhage on brain imaging is suggestive of Aspergillus infection. The diagnosis is confirmed by direct needle aspiration or biopsy; cerebrospinal fluid studies and cultures usually are not helpful. If the diagnosis is made late, the disease is fatal; early diagnosis and treatment in an immunosuppressed patient, however, improve 166,167 survival. T. gondii is the second most common cause of focal162,168 or multifocal meningoencephalitis and abscess formation following cardiac transplantation. It can produce multiple ring-enhancing lesions, seen with contrast CT scans. MRI may demonstrate additional lesions not apparent on CT and may also show a rapid response to antibiotic therapy. Serological evidence of T. gondii is supportive evidence, particularly if there is seroconversion 168 after transplantation or an increase in titer compared to the preoperative baseline serology. While tissue diagnosis with material aspirated from a brain abscess is diagnostic, a presumptive diagnosis based on imaging and serological testing may lead to a therapeutic trial. Consideration of the diagnosis is mandatory because of the excellent therapeutic 169 cause an inflammatory response to antitoxoplasmic antibiotics. Toxoplasmosis may also170,171 myopathy in association with intracranial and multisystem infection. Other less frequent opportunistic infections that produce focal meningoencephalitis or brain abscess include the rhinocerebral phycomycotic organisms, Candida albicans in the setting of disseminated candidiasis, Nocardia infections, Klebsiella (abscess), and Rhodococcus 155,162,172–175 equi. Meningitis after cardiac transplantation is most commonly due to C. neoformans when the symptoms are subacute or chronic and the white blood count in the cerebrospinal fluid is mildly to moderately elevated with predominantly mononuclear cells. L. monocytogenes is the most common organism when the symptoms are acute and there is a prominent cerebrospinal fluid pleocytosis consisting of polymorphonuclear and mononuclear cells. Coccidioides immitis and Pseudoallescheria boydii, as well as previously mentioned fungi, 154,157,176,177 are less frequent causes of meningitis. Cytomegalovirus, herpes simplex, and herpes zoster encephalitis also occur, in association 157,163,178 with a disseminated viremia, in patients who have undergone cardiac transplantation. Immunosuppression, however, transforms the acute necrotizing focal herpes simplex encephalitis into a more diffuse and slowly progressive process. Progressive multifocal leukoencephalopathy after heart transplantation is thought to be due to reactivation of a JC 179 virus infection that is initially acquired during childhood. Pathogens can also be transferred from donor to transplant recipients, typically causing neurological deterioration during the first post-transplantation month. West Nile virus has been transferred from a donor heart to a 180 heart recipient causing an encephalitis shortly after transplantation. Rabies virus, lymphocytic chorimeningitis virus, and Trypanosoma cruzi are also reported donor-derived 181–183 infections. Immunosuppression for cardiac transplantation combined with Epstein–Barr virus infection can cause a post-transplantation lymphoproliferative disorder that leads to systemic 184 malignant lymphoproliferation including involvement of the brain. Post-transplantation lymphoproliferative disorders may regress with reduction of immunosuppressive therapy or

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185,186

they may require radiotherapy. The CNS can be the only site of malignant lymphoproliferation in association with Epstein–Barr virus in brain tissue. The response of this 184,187 post-transplantation primary CNS lymphoma to multimodal therapies is often poor. Glioma is another isolated brain tumor that can188occur after heart transplantation, although the relationship to immunosuppression is unclear. Immunosuppressive agents can also cause neurological side effects more directly. Prior to the use of cyclosporine, high-dose prednisone in combination with azathioprine was commonly used. The main side effect of the prednisone was weakness of the proximal lower extremities, osteoporosis 176 with lower thoracic and lumbosacral compression fractures, or psychiatric complications. With the use of calcineurin inhibitors, cyclosporine, and 189,190 tacrolimus, the dose of prednisone has been lowered, thereby reducing its side effects. Cyclosporine and tacrolimus themselves, however, may have neurotoxic side effects, including prominent tremor, headache, a lowered seizure threshold, paresthesias, mental confusion, acute mania, weakness, ataxia, dysarthria, visual hallucinations, and cortical blindness. Brain imaging may reveal a posterior leukoencephalopathy. Diffusion-weighted MRI studies suggest that the onset of neurotoxicity is due to vasogenic brain edema. Vasogenic edema is reversible, which is consistent with the typical remission of adverse effects and MRI findings following reduction of the cyclosporine or tacrolimus dose. Prolonged drug exposure at neurotoxic levels, however, may cause residual neurological 191–193 The newer immunosuppressive agent sirolimus has few reported impairment. neurotoxic effects and may be used as an alternative to cyclosporine or tacrolimus when 194 neurotoxicity occurs. 190

Cyclosporine also induces gout and produces chronic nephrotoxicity. When gout is treated with colchicines, the impaired renal function may lead to colchicine toxicity and a peripheral 195 neuromuscular disorder that improves when the colchicine is stopped. The monoclonal anti-CD3 antibody (OKT3) is used to prevent and treat graft rejection following cardiac transplantation. Aseptic meningitis with fever, headache, seizures, and a variable encephalopathy is reported to occur in 5 percent of patients as a reaction to it. This aseptic meningitis may occur during the course of OKT3 therapy or in the weeks immediately subsequent to it. The aseptic meningitis and encephalopathy resolve within days of 176,196,197 onset. As noted previously, most of the neurological complications of cardiac transplantation with immunosuppression may present with a confusional state in which headache and focal neurological findings may be present or absent. It is not uncommon, however, for more than one complication of 155 immunosuppression to cause symptoms in an individual cardiac transplant recipient. Previous

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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 4 Neurological Complications of Congenital Heart Disease and Cardiac Surgery in Children CATHERINE LIMPEROPOULOS • ADRÉ J. DU PLESSIS •

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NEUROLOGICAL DYSFUNCTION BEFORE CARDIAC SURGERY Chromosomal Disorders Cerebral Dysgenesis Acquired Preoperative Cerebrovascular Injury MECHANISMS OF NEUROLOGICAL INJURY DURING CARDIAC SURGERY Intraoperative Brain Injury Focal or Multifocal Hypoxic-Ischemic Injury Global Hypoxic-Ischemic Injury Mechanisms of Postoperative Injury MANIFESTATIONS OF NEUROLOGICAL DYSFUNCTION IN THE POSTOPERATIVE PERIOD Delayed Recovery of Consciousness Postoperative Seizures Periventricular White Matter Injury Stroke Movement Disorders Spinal Cord Injury Brachial Plexus and Peripheral Nerve Injury NEUROLOGICAL COMPLICATIONS OF CARDIAC TRANSPLANTATION

Pediatric neurologists have become increasingly challenged by diagnostic and management decisions in children with congenital or acquired heart disease experiencing neurological dysfunction. Of the 30,000 infants born with heart defects in the United States each year, 1,2 approximately half require some form of surgical intervention within the first year of life. Since the late 1960s, there have been major changes in the clinical profile of neurological injury in children with congenital heart disease. In earlier years, the neurological complications of congenital heart disease were mediated for the most part by chronic hypoxia and polycythemia in cyanotic children, uncorrected right-to-left shunts, and the effects of 3,4 repeated palliative heart operations. Advances in surgical technique and intensive care management have allowed the anatomical correction of many heart lesions in early infancy. These early-life corrective procedures have resulted in major decreases in the mortality rate of congenital heart disease. Consequently, neurological sequelae are now increasingly seen

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in adult survivors of congenital heart disease. Heart defects considered inoperable in the mid-1980s are now successfully repaired with a very low mortality rate. More infants with critical congenital heart disease and profound hemodynamic disturbances in the newborn period are now rescued, only to manifest later the neurological consequences of this early-life morbidity. Furthermore, the same surgical support techniques responsible for advancing survival have, paradoxically, been associated5 with an incidence of neurological complications that approaches 25 percent in some centers. Consequently, mechanisms of brain injury during cardiac surgery have been the focus of intense investigation over the past two decades. Understanding of these intraoperative mechanisms has been advanced through 6,7 7–12 as well as by intraoperative animal experimental models and several large clinical trials, cerebral monitoring and perioperative magnetic resonance imaging (MRI). More recently, there has been increased recognition that both acquired and developmental brain disturbances in infants with congenital heart disease may have their origin prior to 13–22 It is expected that these surgical intervention, in many cases during the fetal period. mechanisms will receive particular attention over the next few years as the role of fetal 23,24 imaging expands and the potential for fetal interventions is explored. NEUROLOGICAL DYSFUNCTION BEFORE CARDIAC SURGERY Recent studies have demonstrated a high prevalence of neurological abnormalities prior to infant cardiac surgery, in some studies exceeding 50 percent. These abnormalities include 8,13,15,25 as well as microcephaly, hypotonia, behavioral dysregulation, and feeding difficulties 14,16 These preoperative neurological and abnormal electrophysiological studies. electrophysiological abnormalities are increasingly recognized as significant predictors of 14,16,25–28 The presence of these preoperative longer term neurodevelopmental sequelae. abnormalities in the early neonatal period strongly suggests a fetal onset of neurological impairment.

Chromosomal Disorders A number of chromosomal disorders have a phenotype that includes both cardiac and neurological malformations, including trisomies 11, 18, and 21. The most common neurological manifestation in children with trisomy 21, or Down syndrome, is cognitive dysfunction. Epilepsy develops in approximately 5 percent of children with trisomy 21. Congenital heart defects, most commonly endocardial cushion defects, are present in 40 percent of children with Down syndrome. Gross structural brain alterations in Down syndrome include a narrow superior temporal gyrus and a disproportionately small cerebellum and 29 brainstem. Trisomy 13 is associated with ventricular septal defects and patent ductus arteriosus; the associated cerebral dysgenesis in this syndrome is often severe, with holoprosencephaly and agenesis of the corpus callosum being the most common lesions. The most common cardiac lesions in infants with trisomy 18 are ventricular septal defects and patent ductus arteriosus, with neuronal migration defects the usual form of brain 30 dysgenesis. The phenotypic spectrum of specific chromosome 22 deletions, particularly in31the 22q11 region, includes a variety of cardiac malformations and neurological features. Recent population-based data suggest that at least 700 infants with chromosome 22 deletion 32 syndromes are born annually in the United States. The acronym CATCH 22 (cardiac defect, abnormal facies, thymic hypoplasia, cleft palate, hypocalcemia, chromosome 22q11 deletions) has been used to designate this group of apparently related syndromes. The two most common syndromes, DiGeorge and velocardiofacial (or Shprintzen) syndromes, have 33 neurological and cognitive manifestations in association with structural cardiac defects. The fundamental problem in DiGeorge syndrome is a developmental defect of the third and fourth pharyngeal pouches, manifesting with thymic and parathyroid hypoplasia and conotruncal cardiac malformations, which include interrupted aortic arch (type B), truncus arteriosus, and tetralogy of Fallot. A common neurological presentation in both DiGeorge and the velocardiofacial syndrome is hypocalcemic seizures due to hypoparathyroidism. In addition to the usual cardiac lesions (i.e., ventricular septal defect or tetralogy of Fallot), the velocardiofacial syndrome is associated with cleft palate or velopharyngeal insufficiency and a typical facial appearance, including a broad, prominent nose and retrognathia, and microcephaly in up to 40 percent. Neuroimaging and autopsy studies may show a small posterior fossa and vermis, small cystic lesions adjacent to the frontal horns of the lateral ventricles, dysgenesis of the corpus 34–42 Delayed opercular development callosum, and abnormal cortical gyrification patterns. and disproportionately enlarged sylvian fissures as well as white43matter abnormalities might underlie some of the developmental problems in these children, including nearly universal

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learning difficulties. The mean intelligence quotient (IQ) in this syndrome is around 70, with mild to moderate mental retardation in up to 50 percent of patients.

In recent years, a high rate of autism spectrum disorders and attention deficit/hyperactivity 45,46 disorder has been described in this group. 34,36Psychiatric disorders occur in up to 22 percent A peculiar and inappropriately blunt affect of patients with 22q11 deletion syndromes. 47 often evolving to frank psychosis during adolescence and may be evident during childhood, 48 adulthood. Altered prefrontal cortex-amygdala circuitry, reduced cerebellar and thalamic volumes, and increased basal ganglia and corpus callosal volumes, as shown by quantitative neuroimaging studies, may underlie the disrupted emotional processing and form the 38,39,44,49–51 neurobiological substrate for the psychiatric disturbances in these children.

Cerebral Dysgenesis The prevalence of brain dysgenesis in children with congenital heart disease approaches 30 29,52,53 The risk of cerebral dysgenesis appears related to percent in some autopsy studies. the underlying cardiac lesion. For example, infants with hypoplastic left heart syndrome may be at particular risk of associated developmental brain lesions, which range in severity from 52 microdysgenesis to gross malformations, including agenesis of the corpus callosum, holoprosencephaly, and immature cortical mantle. With advances in neuroimaging, the relationship between cardiac and brain dysgenesis is becoming more clearly defined. Clinically, these dysgenetic lesions may present in the newborn period with seizures, alterations in level of consciousness, and abnormalities in motor tone. Conversely, these lesions may remain clinically occult until later infancy and childhood, when they present with developmental delay, epilepsy, and cerebral palsy. For these reasons, it is important to consider cerebral dysgenesis in any child with congenital heart disease and neurological manifestations.

Acquired Preoperative Cerebrovascular Injury Infants with congenital heart disease are at increased risk of acquired antenatal or perinatal brain injury. During fetal life, congenital heart lesions may be associated with changes in cerebrovascular blood-flow distribution and resistance. Fetuses with hypoplastic left heart syndrome, whose cerebral perfusion is supplied retrograde through the ductus arteriosus, 19,20 Preoperative MRI studies have demonstrated that brain injury is may be at particular risk. common in infants with critical congenital heart disease and during invasive diagnostic 54,55 Preoperative findings detected by MRI procedures (e.g., balloon-atrial septostomy). include intracranial hemorrhage, cerebral venous thromboses, thromboembolic infarctions, dilation of the ventricles and subarachnoid spaces (suggestive of cerebral atrophy), 17,18,20,56,57 Elevated preoperative brain periventricular leukomalacia, and gray matter injury. lactate levels have been found by magnetic resonance spectroscopy in over half of 17,24,56 newborns. Complex corrective operations are performed in ever smaller and less mature newborn 58 infants. Consequently, the vascular lesions associated with less mature infants are now seen. Intraventricular/periventricular hemorrhage (IVH-PVH) is a common neurological 59 complication in the newborn. The risk of IVH-PVH is related to the severity of the vascular insult and inversely to the infant's gestational age. Prematurity predisposes to IVH-PVH because of the structural and physiological vulnerability of the immature periventricular germinal matrix. The hemodynamic instability commonly seen in more severe forms of congenital heart disease predisposes to the systemic hypotension or fluctuations in blood 59 pressure that trigger IVH-PVH. Compared with the incidence of 3.5 percent for IVH-PVH in term infants overall, the incidence in term infants with congenital heart disease is as high as 22 16 percent in some studies. At autopsy,6025 percent of infants with hypoplastic left heart syndrome have intracranial hemorrhage. Infants with coarctation of the aorta are also at increased risk of intracranial hemorrhage because of the intracranial vascular malformations 59,61 and hypertension associated with this condition. The detection of intraventricular hemorrhage in infants with congenital heart disease in the preoperative period creates a major management dilemma because the risk of extending such hemorrhage is increased by cardiopulmonary bypass and cardiac surgery. Specifically, cardiopulmonary bypass requires anti-coagulation to prevent clot formation in the bypass 62 circuit; in addition, it has been associated with enhanced systemic fibrinolytic activity. The more complex operations require periods of decreased perfusion to approach the cardiac defect. The requirement for anticoagulation and the potentially severe intraoperative perfusion changes increase the risk of extending any preoperative intracranial hemorrhage. The dilemma is further complicated by the fact that intracranial hemorrhage occurs most

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commonly in infants with the most critical cardiac lesions, that is, those in greatest need of early surgical repair. There are no prospectively tested protocols for managing the dilemma of preoperative intracranial hemorrhage in infants requiring cardiac surgery. At our center, we use the following guidelines. We perform preoperative cranial ultrasonography to exclude IVH-PVH in all premature infants with a birth weight less than 1,500 g and newborn infants with preoperative neurological dysfunction, coagulation disturbances, or hemodynamic instability causing significant metabolic acidosis. In those infants with IVH-PVH, surgical planning is based on the severity of the cardiac illness (which may directly affect the risk of hemorrhage extension), the likely complexity of surgery, and the severity of preoperative IVH-PVH. Minor 63,64 and should not delay cardiac subependymal hemorrhage carries a low risk of extension surgery. In infants with hemorrhage into the ventricles or the parenchyma, we delay cardiopulmonary bypass for at least 7 days if the cardiac condition permits. MECHANISMS OF NEUROLOGICAL INJURY DURING CARDIAC SURGERY Neurological dysfunction presenting during the early postoperative period is likely due in most cases to intraoperative hypoxic-ischemic/reperfusion injury. However, the risk of cerebrovascular injury extends into the postoperative period, when cardiorespiratory instability, together with cerebral autoregulatory dysfunction, predisposes to cerebral hypoxic-ischemic injury. Despite the remarkable advances facilitated by deep hypothermia and pharmacological agents, the persistent neurological morbidity in the postoperative period 65,66 attests to the incomplete neuroprotection offered by these strategies. The precise onset and evolution of hypoxic-ischemic/reperfusion injury may be difficult to establish. First, the mechanisms of both parenchymal and vascular hypoxic-ischemic/reperfusion injury are known to evolve over time. Second, during the early posthypoxic-ischemic period, cells that have sustained an insult may be at particular risk of irreversible injury from subsequent disturbances in oxygen supply. Consequently, it is difficult to ascribe with any certainty hypoxic-ischemic/re-perfusion injury to one of the preoperative, intraoperative, or postoperative periods. Rather, it is likely that in many cases the injury is multifactorial and cumulative.

Intraoperative Brain Injury There are multiple interrelated mechanisms by which brain injury may occur during cardiac surgery. However, hypoxic-ischemic/reperfusion injury is likely60,67 the principal mechanism, a that is, laminar cortical notion supported by the topography of injury seen at autopsy, 68,69 Animal models of deep hypothermic necrosis and periventricular white matter injury. circulatory arrest have also demonstrated selective neuronal necrosis in a distribution that70 corresponds closely to that seen after normothermic hypoxic-ischemic/reperfusion injury. Neuropathological studies of infants after deep hypothermic cardiac surgery suggest that cerebral white matter lesions tend to be the most prevalent and severe, followed by a 67 spectrum of gray matter lesions. The changes in cerebral perfusion and metabolism during cardiac surgery are complex, interrelated, and often extreme. When these changes exceed the brain's ability to maintain a balance between cerebral oxygen/substrate supply and utilization, a hypoxic-ischemic/reperfusion insult is triggered. The multiple factors determining intraoperative cerebral oxygen availability may be categorized as extrinsic, that is, related to the extracorporeal circulation (e.g., loss of pulsatility, low or no pump flow, hypothermia, emboli) or intrinsic (e.g., disturbances in cerebral blood-flow autoregulation). During deep hypothermic cardiac surgery, cerebral oxygen delivery may be impaired by focal or multifocal vaso-occlusive phenomena generated by 65,66 the bypass circuit or global hypoperfusion due to excessive attenuation of bypass flow rate. Focal or Multifocal Hypoxic-Ischemic Injury The relatively small intravascular volume of the young infant compared with the large blood volume required to “prime” the cardiopulmonary bypass circuit results in increased exposure 65,66 71 These may be either 72 embolic or inflammatory due to the to insults related to the bypass. extensive interface between blood and artificial surfaces. The replacement of bubble oxygenators with membrane devices has decreased but not eradicated the embolic “load” of bypass circuits. Both gaseous and particulate emboli may enter the circulation directly from the surgical field. Because the bypass circuit delivers oxygenated blood directly to the aorta, circulating emboli circumvent the normal pulmonary filtration bed and enter the systemic (and

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cerebral) arterial circulation directly. Earlier autopsy studies described cerebral embolic brain injury after cardiac surgery, and subsequent studies following cardiopulmonary bypass have 71 described a significant prevalence of cerebral capillary-bed aneurysmal dilatations. Cardiopulmonary bypass activates a host of inflammatory cascades that cause diffuse vascular injury, resulting in a postperfusion syndrome that in severe cases is associated with 73 and multiple organ failure. Pathways triggered include the eicosanoid, complement, 74 cause antioxidant kallikrein pathways. These pathways activate free radical generation, 75 depletion, and upregulate adhesion molecules on neutrophils and endothelial cells. These activated neutrophils appear to be potent mediators of reperfusion injury in the brain. Hypothermia delays and modifies the effect of these processes but does not completely 76 prevent them. Global Hypoxic-Ischemic Injury Several techniques used during neonatal cardiac surgery jeopardize cerebral oxygen delivery by altering cerebral perfusion, arterial oxygen content, and tissue oxygen delivery. Under deep hypothermic conditions, cerebral oxygen availability may be limited by cold-induced 77,78 impairment of cerebral pressure-flow increases in cerebral vascular resistance, 79,80 81 and increased oxygen-hemoglobin affinity. Normally, during periods of autoregulation, decreased perfusion pressure, cerebral oxygen delivery is maintained by an initial 82 However, both these vasodilatory response followed by an increase in oxygen extraction. 83 compensatory responses are compromised at deep hypothermia. To approach the often tiny cardiac defects, the bypass flow rate is decreased and often arrested for periods depending on the complexity of the lesion. Although there are general guidelines for “safe periods” of deep hypothermic circulatory arrest at different temperatures, these remain controversial and unpredictable in the individual infant. In addition, the safety of low-flow bypass compared with hypothermic circulatory arrest has been debated. Low-flow bypass prolongs exposure to bypass-related phenomena, as well as increasing the risk of incomplete ischemia. Conversely, deep hypothermic circulatory arrest (DHCA) allows more rapid completion of the intracardiac phases of the repair and reduces the exposure to bypass 65,66 Over the past perfusion; however, it exposes the infant to periods of complete ischemia. 15 years, a number of studies have focused on the relationship between DHCA and84–87 In the neurological outcome; most studies have reported a deleterious effect on outcome. first major clinical trial randomizing infants to a strategy of predominant hypothermic circulatory arrest or low-flow8 bypass, infants exposed to the former were at significantly 9 greater risk of perioperative and 1-year neurological sequelae. At age104 years, the DHCA group had significantly worse behavior, speech, and language function, but no difference in mean intelligence score. Furthermore, at 8-year follow-up, those assigned to DHCA scored worse on motor and speech domains, whereas those assigned to low-flow bypass had worse 11 scores for impulsivity and behavior. Therefore, the long-term follow-up of this large cohort has provided important insights into the evolution of neurodevelopmental outcome in this 88 complex population over time. Although it is now generally accepted that prolonged periods of uninterrupted DHCA may have adverse neurological effects, certain studies have shown 89–91 that shorter durations of DHCA are not consistently associated with adverse outcomes. In fact, available data suggest that the relationship between DHCA duration and neurodevelopmental sequelae is not linear and that the risk of brain injury increases 84,92 These studies have again emphasized that significantly after about 40 minutes of DHCA. the neurological dysfunction in this population is undoubtedly mediated by numerous interrelated preoperative and postoperative risk factors in addition to DHCA. In addition to the bypass flow rate, a number of other factors associated with cardiopulmonary bypass may affect cerebral perfusion and predispose to hypoxic-ischemic/reperfusion injury. Most centers in the United States use nonpulsatile bypass devices as well as hemodilution to reduce the magnitude of blood cell trauma. Deep hypothermia is widely used to suppress oxygen consumption during infant cardiac surgery. In addition to their intended beneficial effects, these techniques all have potential adverse effects on cerebral oxygen delivery. The nonpulsatile perfusion of cardiopulmonary93bypass, particularly at low-flow rates, may fail to maintain perfusion in distal capillary beds. Furthermore, nonpulsatile blood-flow may disrupt pressure-flow and metabolism-flow 77,80,94 Hemodilution is used during bypass to reduce rheologic injury to autoregulation. circulating red cells during deep hypothermia. However, because the concentration of oxygenated hemoglobin is the major determinant of oxygen-carrying capacity, hemodilution may limit cerebral oxygen delivery. In animal studies, extreme hemodilution (to hematocrit levels less than 10%) was associated with neurological injury, whereas hematocrit levels 6 above 30 percent improved cerebral recovery after DHCA. These experimental results were

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confirmed by a randomized clinical trial in which infants randomized to a hematocrit of 20 percent during cardiac surgery had significantly worse developmental scores at 1 year than 7 those randomized to a hematocrit of around 30 percent. Another important intraoperative factor is the management of acid-base status during cardiopulmonary bypass. In a randomized, single-center trial, infants undergoing cardiac operations were assigned12to the alpha-stat versus pH-stat strategy during deep hypothermic pH-stat management was associated with lower cardiopulmonary bypass. The use of 12 had no effect on overall early postoperative morbidity. Treatment assignment 95 neurodevelopmental outcome at 1, 2, and 4 years of age. Despite these equivocal findings, many centers are currently using pH-stat management during core cooling. After repair of the cardiac defect, bypass flow rates are increased using rewarmed and highly oxygenated blood. Rewarming aims to reactivate cellular enzyme function and oxygen utilization. During this period of reperfusion, a number of factors may predispose to free 65,66 Several studies have suggested a delay in recovery of mitochondrial 97 radical injury. 96 function, possibly by nitric oxide, which is generated in abundance during the bypass. The combination of a highly oxygenated reperfusion and98persistent mitochondrial dysfunction may after deep be a major source of injurious oxygen free radicals. Excessively rapid rewarming 100 99 hypothermia may be deleterious. Hyperthermia is a trigger for glutamate release, predisposing to excitotoxicity as well as further stressing the recovering cerebral metabolism.

Mechanisms of Postoperative Injury During the postoperative period of intensive care, a number of factors may predispose to brain injury. Cerebral perfusion pressure may be compromised by a combination of decreased cardiac output and elevated central venous pressure resulting from postoperative cardiac dysfunction. In addition to these systemic circulatory factors, there may be intrinsic cerebrovascular disturbances in the postoperative period. Specifically, elevated cerebral 3,66,79,101,102 and impaired vasoregulation vascular resistance, decreased cerebral blood-flow, have been described after deep hypothermic circulatory arrest. Together, these factors may render the brain vulnerable to injury in the postoperative period. MANIFESTATIONS OF NEUROLOGICAL DYSFUNCTION IN THE POSTOPERATIVE PERIOD 103

Recent studies suggest a decrease in acute neurological morbidity following surgery. However, intraoperative and postoperative insults may injure the neuraxis at any level. Because a detailed discussion of the entire spectrum of neurological manifestations is not possible in the current context, this review focuses on the more common clinical issues confronting the child neurologist.

Delayed Recovery of Consciousness Prolonged impairment of mental status after cardiac surgery, anesthesia, and postoperative sedation is a common reason for neurological consultation. The evaluation104should follow the well-established clinical guidelines for assessing impaired consciousness. Certain specific etiologies should be excluded, including postoperative hepatic or renal impairment, which may impair the metabolism or excretion of sedating drugs. Prolonged use of neuromuscular blocking agents in the preoperative or postoperative period may delay the recovery of motor 105 function (discussed later) and, if severe, may suggest impaired consciousness. This condition should be excluded at the bedside with a peripheral nerve stimulator or formal nerve conduction studies. Postoperative seizures are a common complication of cardiac surgery (as discussed in the next section), and not infrequently these seizures are clinically 8 silent. Such “occult” seizures or a prolonged postictal state should be considered in the evaluation of a depressed postoperative mental state. In spite of this approach, the precise cause of an impaired postoperative mental status is not established in most cases. Many of these children ultimately demonstrate features suggestive of hypoxic-ischemic/reperfusion injury.

Postoperative Seizures Seizures early in the postoperative period are among the most common neurological complications after open heart surgery. Postoperative clinical seizures have been reported to 106 occur in up to 19 percent of survivors of neonatal cardiac surgery, and in certain subgroups this risk may reach 50 percent. Clinical seizures are reported8,107 less frequently than those since postoperative seizures detected by continuous electroencephalographic monitoring

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may occur without typical motor correlates.

Postoperative seizures may be divided into two broad groups. First are those seizures with a readily identifiable cause, such as hypoglycemia, hypocalcemia, and cerebral dysgenesis. Postoperative seizures may also result from hypoxic-ischemic/reperfusion injury due to either generalized cerebral hypoperfusion (e.g., cardiac arrest) or focal vaso-occlusive insults. The second and more common category of postoperative seizures is that in which the etiology remains unknown. Although these cryptogenic seizures, commonly referred to as postpump seizures, are often assumed to relate to hypoxic-ischemic/reperfusion injury, their etiology is likely multifactorial8,108 with risk factors that include the use and duration of deep hypothermic circulatory arrest, younger age at106 surgery, the type of heart defect (e.g., aortic arch obstruction), and genetic conditions. Furthermore, postpump seizures differ in several respects from other forms of posthypoxic seizures. First, these seizures typically develop later than, for instance, those occurring after perinatal asphyxia. Second, although less 9 benign than previously believed, the prognosis of postpump seizures is significantly better than that 109 of asphyxial seizures, in which up to 50 percent of survivors are neurologically disabled. Both the delayed onset and more favorable outcome of postpump seizures may be due to the partial protective effect110of hypothermia at the time of intraoperative hypoxic-ischemic/reperfusion insult. The clinical course of postpump seizures is fairly typical. These seizures appear confined to a relatively narrow time-window, with onset between 24 and 48 hours after surgery. This is followed by several days during which serial seizures occur, often evolving to status epilepticus; thereafter, the tendency toward further seizures wanes rapidly. The clinical manifestations of these electrographic seizures are often subtle even in the absence of sedating and paralyzing drugs and may be confined to paroxysmal autonomic changes. When evident, convulsive activity is usually focal or multifocal. The therapeutic approach to postpump seizures should be based on their typical clinical course. After excluding reversible etiologies such as hypoglycemia, hypomagnesemia, and 111,112 the tendency toward repeated seizures and status epilepticus should be hypocalcemia, countered by rapid achievement of therapeutic anticonvulsant levels by an intravenous route. Most postpump seizures are controlled by lorazepam, followed by phenobarbital or phenytoin. Potential cardiotoxicity due to these agents in children recovering from cardiac surgery should be monitored carefully, particularly during the initiation of treatment. The apparently circumscribed window of susceptibility to postpump seizures often allows early withdrawal of anticonvulsants. Prospective studies have demonstrated a significant correlation between postoperative 8 9 seizures and9,106,113 risk of perioperative and 1-year neurological sequelae, as well as abnormal The longer term impact of postpump seizures may be less than MRI studies. 11,88,107 The development of subsequent epilepsy is rare; however, West previously thought. 114 syndrome (infantile spasms, mental retardation, and epilepsy) has been described after more intractable postpump seizures. When postoperative seizures have an identified cause, the long-term outcome is related to etiology. For instance, cerebral dysgenesis, which is increased in congenital heart disease, may present with seizures in the early postoperative period, and here the long-term outcome 106 to is usually poor, with epilepsy a common sequela. Infants with seizures due 115 postoperative stroke have a 20 to 30 percent risk of subsequent epilepsy.

Periventricular White Matter Injury Brain MRI of neonates following cardiac surgery has shown a prevalence of periventricular 116 leukomalacia in excess of 50 percent in some studies ; this is a rare finding in older infants. The precise onset of these lesions remains unclear, but the MRI features appear to be 56 transient in many cases. Reported risk factors for these MRI lesions include prolonged exposure to cardiopulmonary bypass (with or without DHCA), possibly related to inflammatory mechanisms activated by cardiopulmonary bypass. In addition, early postoperative hypotension (especially diastolic) and hypoxemia appear to increase the risk of periventricular 116,117 Magnetic resonance spectroscopy studies are leukomalacia in these MRI studies. beginning to provide insights into disturbed brain metabolism in the postoperative 17,118,119 Although significant decreases in brain N-acetyl-aspartate, a neuronal-axonal period. 118,119 marker, have been described, more recent data have shown an apparently improved cerebral oxidative metabolism postoperatively as evidenced by improved lactate/choline 17 ratios. The long-term significance of these acute structural and metabolic disturbances in children who survive cardiac surgery remains to be determined.

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Stroke The incidence of cerebrovascular accidents (strokes) in children ranges from 2.5 to 8 per 120 leading known association of childhood stroke 100,000. Congenital heart disease is the 120–122 In earlier autopsy studies, almost 20 and is present in 25 to 30 percent of cases. percent of children with congenital heart disease demonstrated features of cerebrovascular injury. Stroke associated with heart disease (cardiogenic stroke) may be classified on the basis of the likely embolic or thrombotic source as (1) cardioembolic (i.e., a probable intracardiac embolic source); (2) paradoxical (i.e., a cardiac anatomy that permits an embolus of systemic venous origin access to the cerebral circulation); or (3) venous (i.e., cerebral vein thrombosis due to central venous hypertension and venous stasis). Risk factors for cardiogenic stroke include the elements of Virchow's triad—altered vascular surface, stasis, and hypercoagulability—as well as the presence of “paradoxical” embolic pathways. Risk factors for cardiogenic stroke have changed over the years. In earlier studies, the risk of stroke was related to the effects of long-standing heart defects, such as chronic hypoxia and polycythemia, and uncorrected paradoxical pathways (e.g., right-to-left shunts). 1 The trend in recent decades toward earlier corrective surgery has reduced exposure to such stroke risk factors, shifting the focus to intraoperative and postoperative mechanisms for stroke. A number of intraoperative mechanisms related to cardiopulmonary bypass may predispose 71 to cerebral vascular occlusion. Embolic material (particulate/gaseous) generated during bypass avoids filtration by the pulmonary bed, gaining direct entry to the systemic arterial circulation. Earlier autopsy data demonstrated a substantial incidence of cerebral embolic infarction after surgery for congenital heart disease. Advances in bypass technique, including refinements in membrane oxygenators, in-line arterial filters, and anticoagulation, have 123 reduced the incidence of macroembolization and large-vessel occlusion. The impact of these advances on the incidence of microembolization and small-vessel disease is difficult to evaluate. The extensive interface between circulating blood and the artificial surface of the bypass circuit may trigger an inflammatory response, which in turn activates complex physiological 72 cascades, including endothelium–leukocyte interactions. This process further enhances the risk of ischemic injury during the intra-operative and postoperative periods. In the postoperative period, factors predisposing to stroke include stasis (intracardiac and extracardiac), altered vascular surfaces (native or prosthetic), and, in some situations, a 124 Intracardiac stasis may result potential procoagulant shift in the humoral clotting systems. 125 from localized areas of low flow or global ventricular dysfunction. Transient or sustained elevations of right heart and, hence, central venous pressure in the 126 early postoperative period predispose to local thrombosis in the right atrium and central veins. Prosthetic material in such areas of disturbed flow increases the likelihood of thrombus formation, and the presence of a right-to-left shunt (native or iatrogenic) compounds the risk of paradoxical embolization. Elevated right atrial pressure transmitted to the cerebral venous circulation predisposes to venous thrombosis, particularly in the dural venous sinuses. Elevated 127 impairment, and systemic venous pressure may cause a protein-losing enteropathy, liver124 pleural effusions, factors that may disturb the humoral coagulant systems. A number of the aforementioned stroke risk factors may be present after the Fontan operation, as highlighted 125,128 In one study, a 2.6 percent incidence of stroke was found in a in several reports. retrospective review of 645125patients after the Fontan operation; the risk extended over 3 a 20 percent incidence of years after the procedure. Rosenthal and co-workers found 128 thromboembolic complications after the Fontan procedure. Strokes originating during or immediately after cardiac surgery may escape clinical recognition for several days because of the effects of postoperative sedating and paralyzing 129 agents. In the young infant, stroke often presents with focal seizures or changes in mental status; focal motor deficits may be subtle. In older infancy and childhood, stroke usually presents with acute focal motor deficits, language disturbance, or visual dysfunction. The therapeutic approach to stroke in the child with heart disease includes (1) preventive and (2) “rescue” strategies. Experience with rescue therapies remains confined to adult and experimental stroke. These rescue therapies aim to salvage potentially viable brain using techniques designed to revascularize ischemic brain regions (thrombolytic therapy) or to 130 curtail injurious biochemical cascades. This discussion focuses on the principles of stroke prophylaxis using antithrombotic agents. Preventive stroke therapy may be categorized as

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131

primary or secondary. Primary stroke prevention aims to identify and treat high-risk patients before a stroke, whereas secondary prevention aims at minimizing the risk of stroke recurrence. Consistent and universally accepted guidelines for both primary and secondary stroke prophylaxis in children are lacking. Current guidelines are largely empirical, anecdotal, and derived from experience in adults. Established indications for primary stroke prophylaxis in children include prosthetic heart valves, dilated cardiomyopathy, or intracardiac thrombus on echocardiogram. The decision regarding whether and when to initiate secondary stroke prophylaxis with antithrombotic agents should aim to balance the risk of (1) recurrent cerebral embolization and (2) potentiating secondary hemorrhage into an area of cerebral infarction. Embolus recurrence risks after cardioembolic stroke are unknown in children. In adults (after myocardial infarction), this risk is highest in the early 132 poststroke period, at approximately 1 percent per day (10% to 20% over the first 2 weeks). Cardioembolic strokes are 133 particularly prone to hemorrhagic transformation, especially in the early poststroke period. Hemorrhagic transformation occurs (often silently) in 20 to 40 percent of adult cardioembolic 133 strokes. The risk of significant clinical deterioration after hemorrhagic transformation is greater in the anticoagulated patient. Although it is difficult to predict which infarcts will undergo hemorrhagic transformation, certain guidelines have been formulated. Among infarcts destined to83undergo hemorrhagic transformation, 75 percent do so within 48 hours after stroke onset. Large infarcts, particularly those larger than 30 percent, or one lobe, of a cerebral hemisphere, are at greater 134 risk of hemorrhagic transformation. Uncontrolled systemic hypertension and stroke due to septic emboli and cerebral venous thrombosis are additional risk factors for hemorrhagic infarction. The details of antithrombotic management are discussed elsewhere. The cerebrovascular disease associated with infective endocarditis warrants brief mention. The protean neurological manifestations of infective endocarditis include meningitis, brain abscess, and seizures. However, cerebrovascular injury, specifically septic embolism and hemorrhage, is the most common complication. Even with advanced antibiotic agents, neurological complications occur in one third of infective endocarditis cases in children; in 135 one half of such cases, the complications are embolic in origin. Cerebrovascular complications carry the highest mortality rate (up to 80% to 90%), primarily due to intracranial hemorrhage. The risk of and mortality rate of cerebral hemorrhage in this population contraindicates anticoagulant therapy. In all cases of cardiogenic stroke, the possibility of septic embolism should be considered before initiating anticoagulant therapy.

Movement Disorders 136

Reports of serious postoperative movement disorders go back to the early 1960s and the 137,138 Choreoathetosis is the most frequent early days of deep hypothermic cardiac surgery. form of dyskinesia complicating cardiac surgery; other rarer postoperative movement disorders include oculogyric crises and parkinsonism. The reported 139 incidence of 88 postoperative choreoathetosis reached 19 percent in earlier years ; fortunately, this complication has become rare in recent years. Despite their relative rarity, these movement disorders are often dramatic, frequently intractable, and, in severe cases, associated with a substantial mortality rate. Postoperative movement disorders have a fairly typical clinical course. The involuntary movements are preceded in most cases by a 2- to 7-day latent period during which postoperative neurological recovery appears to be uncomplicated. Thereafter, a subacute delirium (marked irritability, insomnia, confusion, and disorientation) develops, followed closely by the emergence of involuntary movements. Typically, these movements start in the distal extremities and orofacial muscles, progressing proximally to involve the girdle muscles and trunk. In severe cases, violent ballismic thrashing may develop. The abnormal movements are present during wakefulness, peak with distress, and resolve during brief periods of sleep. Oculomotor and oromotor apraxia are common, with loss of voluntary gaze as well as feeding and expressive language skills. The involuntary movements often intensify over a 1-week period, followed by a 1- to 2-week period during which movements remain relatively constant. The period of recovery is highly variable in duration. The long-term outcome of postoperative movement disorders depends largely on their initial severity. Mild cases tend to resolve within weeks to months, whereas severe cases have a mortality rate approaching 40 percent and a high incidence of associated, significant, long-term neurodevelopmental deficits, including diffuse hypotonia, persistent dyskinesia (47%), and 137,139 pervasive deficits in memory, attention, language, and motor abilities. The diagnosis of postoperative hyperkinetic syndromes is essentially clinical. Currently

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available neurodiagnostic studies are useful only for excluding other disorders. Cerebral changes by computed tomography (CT), MRI, and single-photon emission CT are137 nonspecific, seldom focal, and most commonly consist of diffuse cerebral atrophy and a high incidence of both cortical and subcortical perfusion defects. The electroencephalogram is usually normal or diffusely slow, with no ictal changes associated with the involuntary 140 movements. Descriptions of the neuropathological findings at autopsy are limited and inconsistent. Findings have ranged from normal to extensive neuronal loss and gliosis, 140 particularly in the external globus pallidus. Typical features of infarction are characteristically absent. Certain risk factors have been suggested, including (1) cyanotic congenital heart disease, particularly with systemic-to-pulmonary collaterals from the head and neck; (2) age at surgery older than 9 months; (3) excessively short cooling periods before attenuation of intraoperative blood-flow; (4) alpha-stat pH management strategy; 141–143 (5) deep hypothermia and extracorporeal Postoperative dyskinesias, usually circulation; and (6) preexisting developmental delay. 144,145 mild and transient, have been reported after prolonged use of fentanyl and midazolam. Once manifest, the involuntary movements are very refractory to treatment and generally respond poorly to a wide variety of conventional antidyskinetic medications, including dopamine receptor blockers (phenothiazines and butyrophenones), dopamine-depleting agents (reserpine, tetrabenazine), dopamine agonists (levodopa), GABAergic agents (benzodiazepines, barbiturates, baclofen), and other agents such as valproic acid, carbamazepine, phenytoin, diphenhydramine, and chloral hydrate. In general, successful movement control has been achieved only at the expense of excessive sedation. Given these limitations, the management of postoperative movement disorders should focus on the often severe agitation and insomnia. General measures, such as a decrease in the level of external (e.g., noise, light) and internal (e.g., pain) stimuli, are useful in decreasing the intensity of involuntary movements. Judicious use of sedation should aim to restore the fragmented sleep-wakefulness cycle. Oromotor dyskinesia is often severe enough to impair feeding and predispose to aspiration. Nasogastric or even gastrostomy tube feedings may be necessary to meet the high caloric demands of the constant involuntary movements.

Spinal Cord Injury 146,147

Spinal cord injury is a relatively rare complication of pediatric cardiac surgery and usually occurs after aortic coarctation repair, in which 0.4 to 1.5 percent of cases may be affected. Intraoperative spinal cord injury is mediated by hypoxic-ischemic/reperfusion injury to watershed territories in the cord, most commonly in the lower thoracic cord, where transverse infarction results in postoperative paraplegia. An additional watershed zone runs between the supply territories of the anterior and posterior spinal arteries; ischemia in this region results in predominant or selective anterior horn cell loss.

Brachial Plexus and Peripheral Nerve Injury Prolonged immobility during and after cardiac catheterization and surgery predisposes peripheral nerves to pressure and traction injury. Pressure palsies may occur at any dependent site, but most commonly involve the peroneal and ulnar nerves. Brachial plexus 148,149 Injury to the lower plexus results injury is not uncommon after cardiac catheterization. from prolonged traction during the extreme and sustained arm abduction required in some procedures. This neuropraxic lesion resolves gradually but usually completely. During cardiac catheterization, the insertion of indwelling central venous catheters through the internal jugular vein may injure the upper brachial plexus by direct physical trauma or extravasation of blood into the plexus. Phrenic nerve injury results from150 hypothermic injury by ice packed around the heart or from phrenic nerve injury has also been direct intraoperative transection. Postoperative 151,152 Intraoperative phrenic nerve injury presents described after malposition of chest tubes. with diaphragmatic palsy and prolonged postoperative ventilator dependence. The lesion may 153 be confirmed at the bedside by nerve conduction studies and electromyography. Most phrenic nerve injuries resolve spontaneously, but154 occasionally diaphragmatic plication or, in Younger infants are more likely than rare instances, diaphragmatic pacing is required. 151,152 older children to require diaphragm plication. Postoperative ventilation is commonly facilitated by the use of neuromuscular blocking agents. Prolonged use of nondepolarizing agents, especially vecuronium and pancuronium, 105,155–157 The concomitant use of has been associated with neuromuscular dysfunction. 157 steroids may increase the risk. The neuropathological spectrum in these conditions is

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highly variable, ranging from necrotizing myopathy to axonal motor neuropathy with variable 156 sensory involvement. These conditions may be difficult to distinguish from “critical illness polyneuropathy.” NEUROLOGICAL COMPLICATIONS OF CARDIAC TRANSPLANTATION Cardiac transplantation has become a rescue treatment for children with either primary (myocarditis/cardiomyopathy)158 or secondary (to associated congenital heart disease) 10-year survival rates from various pediatric end-stage myocardial failure. Reported 159 institutions range from 42 to 73 percent. More effective immunosuppression has advanced the survival of transplant recipients; however, long-term immunosuppression remains a major challenge and has well-recognized neurological complications. The passage to heart transplantation is itself fraught with risk of neurological injury, particularly hypoxic-ischemic, as is the transplantation procedure, which may be complex and involve long periods of bypass support. Adult autopsy studies have described brain injury in more than 80 percent of transplant recipients, consisting of vascular (up to 60%), infectious (20%), and lymphoproliferative disorders (13%). In a recent pediatric 160 autopsy study, brain injury was described in 87 percent of transplant recipients. In the first 2 weeks after transplantation, the most common complications are stroke, drug neurotoxicity, hypoxic-ischemic encephalopathy, and acute psychosis. In a recent report, 161 seizures occurred in 21 percent of children post-transplantation. Later, the complications of chronic immunosuppression, such as opportunistic 162 infections, lymphoma, drug neurotoxicity, and metabolic encephalopathy, are more common. Further discussion of these complications is provided in Chapters 3 and 46.

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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 5 Neurological Manifestations of Acquired Cardiac Disease, Arrhythmias, and Interventional Cardiology COLIN D. LAMBERT • DAVID J. GLADSTONE •

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CARDIOGENIC EMBOLISM Clinical Features Investigations Causes Atrial Fibrillation and Flutter Cardioversion in Atrial Fibrillation or Flutter Chronic Sinoatrial Disorder Cardiomyopathies Myocardial Infarction and Left Ventricular Dysfunction Rheumatic Heart Disease Atrial Myxoma Marantic (Nonbacterial Thrombotic) Endocarditis Other Echocardiographic Abnormalities Linked to Stroke Acute Medical Treatment of Cardiogenic Embolism SYNCOPE INTERVENTIONAL PROCEDURES Coronary Catheterization Percutaneous Transluminal Coronary Angioplasty and Stenting Thrombolytic Therapy for Acute Myocardial Infarction

The neurological manifestations of acquired cardiac disease fall into several categories: 1. The sudden onset of a focal neurological deficit due to occlusion of a cerebral or retinal artery by an embolus that has developed within the heart (cardiogenic embolism) 2. Transient, self-limited episodes of generalized cerebral ischemia that occur as a consequence of brief failures of cardiac output, due to either rhythm disturbances or outflow obstruction, resulting in presyncope or syncope 3. The complications of invasive techniques for the investigation or management of cardiac disease

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The major exceptions to these generalizations occur with atrial fibrillation (AF), which is associated with embolus formation rather than syncope, and with chronic sinoatrial disorder, which predisposes to both syncopal and embolic disturbances. Topics that are the focus of other chapters are not considered here. In this chapter, the term stroke is used to mean the sudden onset of a focal neurological deficit of ischemic origin. Cerebral embolus is used where the deficit is thought to be of embolic origin. The term cardiogenic embolism is reserved for events in which the embolic occlusion is considered to be the result of a cardiac source of emboli. This chapter addresses three major situations: (1) cardiogenic embolism, (2) arrhythmias and their manifestations (syncope), and (3) interventional procedures. CARDIOGENIC EMBOLISM

Clinical Features Ischemic stroke or transient ischemic attack (TIA) may be classified into six major etiological 1 categories, which have implications for treatment and prognosis. This is the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) classification, the standard now for clinical studies. These categories are cardioembolism, large-artery atherosclerosis, small-artery (lacunar) occlusion, stroke of other determined etiology, stroke of undetermined etiology, and events of multiple possible etiologies. The first four categories are also subdivided into probable or possible. Strokes in the undetermined group are classed as either completely or incompletely evaluated. The last category accommodates those in whom more than one established cause is present. Cardiogenic brain embolism accounts for about 20 percent of acute ischemic strokes overall. Coexistent pathology (i.e., arterial and heart disease in the same patient) may be present in 2 up to one third of patients with a potential cardiac source of embolism. The most common 3 cardiac cause of ischemic stroke is AF, which accounts for about one sixth of all strokes. Other cardiac causes of stroke are listed in Table 5-1. Click here to view this table.... In the young stroke population (generally regarded as patients who have their first stroke 4 around the age of 15 to 45 years), 60 or so causes had to be considered in one study. In that study of 329 patients, cardioembolism was thought to be responsible in 64 (just under 20 percent). There were 13 diagnoses in these 64 patients, with the top three being paradoxical embolism and prosthetic or rheumatic valve disease. No patients had AF, a feature also 5 noted in a Swedish study. Strokes attributable to a cardiac source show striking differences in various studies. In a Persian study of 124 patients, 54 percent were thought to be of 6 cardiac origin. Rheumatic heart disease was the major culprit.7 In contrast, a French study of 296 patients attributed less than 9 percent to a cardiac cause. In Italy, the figure was 34 8 percent. This was a hospital-based study of 394 consecutive young adults with ischemic stroke submitted to a comprehensive diagnostic protocol. Of the 133 considered to be of cardiac origin, these were subdivided into two groups according to TOAST criteria. The smaller group (23) had a probable cause including recent myocardial infarction, AF, valvulopathy, patent foramen ovale (PFO) with deep vein thrombosis (DVT) and atrial myxoma. The much larger group (110 patients) had various possible causes: PFO with right to left shunt (60), atrial septal aneurysm (ASA) (22), and PFO plus ASA (16). Looked at another way, 23 of 394 patients (6%) had an established cardiac cause. Attribution was less certain in 28 percent. In Korea and Taiwan, around 18 percent of cases were attributed to a 9,10 Comparison of etiological factors in the occurrence of TIAs in younger, as cardiac cause. opposed to older, patients disclosed that only two cardiac sources were encountered 11 more frequently in the younger age group: valvular heart disease and mitral valve prolapse. Features suggesting cardioembolism are usually derived from analysis of the clinical presentation and neuroimaging features of acute ischemic strokes that occur in12–19 patients with Emboli cardiac abnormalities thought to predispose to thrombus formation (Table 5-2). may lodge in either the anterior (carotid) or the posterior (vertebrobasilar) circulation. The anterior circulation is affected four times more commonly than the posterior. Least likely to be affected are the20entire internal carotid artery, deep branches of the middle cerebral artery, and brainstem. Although the posterior circulation is less commonly affected, studies of the mechanism of infarction in specific territories (e.g., those of the posterior inferior cerebellar artery and superior cerebellar artery) implicate cardiogenic embolism in 50 percent of 21 with isolated cerebellar cases. A cardioembolic mechanism occurred in 67 percent of cases 22 infarcts (i.e., without concomitant brainstem or occipital infarcts). Embolism is also a

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http://www.merckmedicus.com/pp/us/hcp/printpage.jsp 23

common mechanism of infarction within the territory of the posterior cerebral artery. Click here to view this table....

Stroke recurrence rate and prognosis have been estimated in several studies. A meta-analysis showed that the 3-month risk of recurrent stroke was 12 percent if the etiology was cardioembolism, compared to 19 percent for large-vessel atherosclerosis, 3 percent for 24 small-vessel disease, and 9 percent for unknown cause. In a population-based study of first stroke in Bavaria, patients with cardioembolic stroke had the lowest 2-year survival rate (55%) and were three times more likely to be dead at 2 years compared to those with 25 small-artery occlusion.

Investigations The first neurological investigation for suspected stroke is usually a computed tomography (CT) scan of the head to exclude intracranial hemorrhage or other nonischemic pathological processes and to identify signs of acute infarction or vessel occlusion. In patients at high-risk of cardioembolism, cranial CT disclosed infarcts that were more likely to involve one half of a 12 lobe or more, or the infarcts involved both superficial and deep structures. Deep small infarcts were underrepresented and were considered to have a predictive value of 90 percent 12 for the absence of a major cardiac source. Similar conclusions were drawn in an earlier study, namely, that the mechanism underlying lacunes is infrequently embolic and that infarctions in26the pial (superficial) artery territory are usually indicative of an embolic mechanism. The potential for embolic infarcts to develop hemorrhagic transformation remains a concern, especially when anticoagulant therapy has to be considered. A hemorrhagic infarct was seen on the initial CT scan of 612percent of patients in a series of 244 cases, none of whom were In a series of scans performed within 48 hours of onset, the figure receiving anticoagulants. 27 rose to2824 percent ; on prospective follow-up scanning, a total of 40 percent was found at 1 month. With the more sophisticated technology of magnetic resonance imaging (MRI), the figure rose to nearly 70 percent at 3 weeks. Both of the latter studies showed that larger infarcts were more liable to demonstrate hemorrhagic3 transformation, with a figure of 90 29 percent for infarcts with a volume greater than 10 cm . Thus, the key factors that determine whether hemorrhagic transformation occurs appear to be the time of the study, size of the infarct, and technology applied. The age of the patient may also be a factor in that patients 28 older than 70 years may be more liable to hemorrhagic transformation. Because of concerns for the complications of acute stroke treatment by thrombolysis or anticoagulation, early pointers to hemorrhagic transformation have been sought. The only independent predictor identified in a study of 150 consecutive patients was focal hypodensity found by CT scanning within the first 5 hours after stroke onset. Mortality was twice as high in the hemorrhagic-transformation group owing to the larger size of infarcts in that group. Evolution29of the transformation process was similar in anticoagulated and nonanticoagulated patients. MRI is the most sensitive test for detecting 30 early infarction. Diffusion-weighted images are superior to T2-weighted images and to CT. The pattern of diffusion-weighted imaging abnormalities can help to determine the most likely etiological diagnosis. For example, a pattern of multiple acute lesions in more than one vascular territory (bilateral lesions or lesions in the anterior and posterior circulations) suggests a shower of cardiogenic emboli. Single cortical-subcortical lesions are also associated with a cardiac source of emboli. Conventional catheter angiography remains the definitive method for assessing structural abnormalities of the extra- and intracranial circulation. Use of this invasive procedure requires recognition of the associated risks. A review of 15 studies (8 prospective) concluded that the mortality rate was very low (less than 0.1%) but that the risk of a neurological complication (TIA or stroke) was approximately 4 percent and that of a permanent neurological deficit was 31 1 percent. The characteristic angiographic appearance of an embolic occlusion is of a proximal, meniscus-like filling defect in an artery that is otherwise normal and lacks evidence of atherosclerotic change. Emboli tend to fragment. In a study of 142 patients who underwent angiography, the initial procedure, performed at a median of 1.5 days after the precipitating event, revealed an occlusion in 82 percent. Follow-up angiography, at a median of 20 days, 28 showed reopening of the vessels in 95 percent. Distal branch occlusions are often also considered to be embolic manifestations. Conventional catheter angiography has now been largely replaced by noninvasive contrast-enhanced CT angiography or magnetic resonance angiography in many countries because of increased availability and lower complication rates.

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Echocardiography has come to occupy a preeminent place in the structural evaluation of the heart. Transthoracic echocardiography (TTE) is noninvasive but has limitations that can be overcome by using the transesophageal (transesophageal echocardiography [TEE]) route. For the latter procedure, the patient is usually mildly sedated and topical anesthetic is applied to the posterior pharynx. In experienced hands, the procedure was successfully 32 accomplished in 98 percent of instances. The complication rate was less than 1 percent. The technique employed (TEE or TTE) depends on the area to be visualized. The two procedures can be considered complementary; TTE images the left ventricle well, but TEE is required for adequate assessment of the left atrium and its appendage. TEE is also better for visualizing a PFO. TEE is the most sensitive and specific test for detecting a cardiac source of embolism. For patients with AF, TEE may assist in risk stratification and guide 3 cardioversion. A review of papers published between 1966 and 1998 evaluated the yield of TTE or TEE, or both, in various subgroups of patients with stroke. The figures reached were, for TTE, an overall yield of less than 1 percent in patients without clinical evidence of cardiac disease, rising to 13 percent in those with cardiac disease. The corresponding figures for TEE were 33 less than 2 percent and 19 percent. The recommendations reached highlight some uncertainties. It was concluded that there was fair evidence to recommend echocardiography in patients with stroke and clinical evidence of heart disease (grade B recommendation). Because the yield from TEE is higher than that for TTE, controversy arises as to whether this should be the first intervention. Some have preferred a sequential approach with TTE 34 but others have suggested that it is more cost-effective to followed by TEE, if indicated, 35 proceed directly to TEE. Clearly, the area to be visualized is a major consideration. Cardiac MRI is emerging as a new technology for noninvasive structural imaging of the heart. MRI is more sensitive than TTE and comparable to TEE for the detection of cardiac thrombi. Transcranial Doppler ultrasonography is a noninvasive tool that can be of value in the acute stroke setting for detecting acute intracranial vascular obstruction (e.g., due to an occlusive embolus in the middle cerebral artery) and can monitor recanalization following treatment with thrombolysis. It can also be used to detect right-to-left cardiac shunts due to PFO. By identifying microbubbles reaching the middle cerebral arteries, especially following the Valsalva maneuver, contrast-enhanced transcranial Doppler ultrasonography has shown near-perfect 36,37 correlation with contrast-enhanced TEE for the detection and quantification of such shunts. It remains necessary for the clinician to balance extensive investigation against its impact on patient management, usually the justification for lifelong anticoagulant therapy and its consequent risks. In several situations, there are no established guidelines for management. The onus remains on the clinician to determine the significance of potential sources of emboli and their implications for management.

Causes Atrial Fibrillation and Flutter Atrial fibrillation, the most common arrhythmia in medical practice, is a major risk factor for stroke and death. This arrhythmia accounts3 for nearly half of all cardiac causes of stroke and about one quarter of strokes in the38elderly. Strokes associated with AF are generally severe, and 1-year39,40 mortality is 50 percent. AF is also a risk factor for silent strokes and vascular dementia. The prevalence of AF is strongly age dependent, ranging from 0.1 percent among adults 38 older than 55 years to 9 percent in those 80 years38or older. Over 2 million individuals have AF in the United States, and prevalence is rising. AF typically occurs in patients with underlying cardiac disease (i.e., valvular heart disease, heart failure, coronary disease, hypertension, cardiomyopathy, mitral valve prolapse, mitral annular calcification, and cardiac tumors), but may also occur as “lone AF” in young patients who have no cardiac disease. It may be paroxysmal (self-terminating episode, lasting less than 7 days), recurrent (2 or more episodes), persistent (more than 7 days), or permanent (cardioversion failed or not attempted). Reversible or temporary causes include alcohol, surgery, hyperthyroidism, acute 3 myocardial infarction, pulmonary embolism, and pericarditis, among others. The average annual risk of stroke in individuals with AF is 5 percent and is heavily dependent on age and the presence of additional risk factors (Table 5-3). In the Framingham Study, stroke risk41was 1.5 percent in the age group 50 to 59 years and 23.5 percent in those 80 to 89 years.

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Click here to view this table.... It is well established that the risk of stroke in AF is related to the presence or absence of associated structural cardiac disease and other risk factors. For example, in the absence of rheumatic heart disease, there is a fivefold increase in stroke42incidence, but this increases to 17-fold when associated with rheumatic mitral valve disease. Only in lone AF (i.e., fibrillation in the absence of overt cardiovascular disease or precipitating illness) developing in middle age is the prognosis relatively benign. Follow-up at 1543years disclosed a rate of thromboembolic events of 0.55 per 100 person-years. This was equivalent to 1.3 percent of the patients experiencing a stroke on a cumulative actuarial basis. The most important predictor of stroke risk in patients with AF is a history of thromboembolism (i.e., previous TIA, stroke, or systemic arterial embolism). Other independent risk factors for stroke in AF are hypertension, heart failure, increasing age, and diabetes mellitus. Other factors that have been associated with increased stroke risk in some 3 studies include female sex, systolic hypertension, and left ventricular dysfunction. Echocardiographic features that have been used for risk stratification in patients with AF include left ventricular systolic dysfunction, atrial thrombus, dense spontaneous echo contrast or reduced blood flow velocity within the left atrium or left atrial appendage on 44 TEE, and aortic atheroma. Left atrial size does not appear to predict risk of thromboembolism. TEE is the method of choice for evaluating the left atrial appendage, the site at which most thrombi form, and the left atrium. In a prospective study of patients with AF considered on clinical grounds to be at high risk of stroke, risk was 18 percent per year in those with dense spontaneous echo contrast who were treated with low-dose warfarin (international normalized ratio [INR] 1.2 to 1.5) plus aspirin compared to 4.5 percent for those on dose-adjusted warfarin. Prevalence of thrombus in the left atrial appendage was similar initially in the two treatment groups (10% to 12%) when TEE was performed more than 2 weeks after study entry, but atrial thrombus was present in 6 percent of those on warfarin compared to 18 percent of those on combination therapy, and stroke rate was 13 percent per year in the latter group. Absence of thrombus predicted a low rate of ischemic events (2.3% per year); the presence 45 of thrombus predicted a high rate (18% per year). That the risk of stroke in AF can be significantly reduced by anticoagulation was clearly 46–49 A fifth, Canadian, study was terminated prior to established by four independent studies. 50 completion because the other studies51had shown clear evidence of benefit. A meta-analysis published in 1999 evaluated 16 trials. Six were of dose-adjusted warfarin versus placebo. The conclusions drawn from the original four studies were upheld. Warfarin reduced stroke risk by 62 percent overall. Absolute risk reductions were higher for secondary prevention (8.4% per year) than primary prevention (2.7%). These percentages translate into the numbers needed to treat (NNT) of 12 and 37, respectively. Although more intracranial hemorrhages (ICHs) occurred in the warfarin group (0.3% per year) compared to those on placebo (0.1%), this was not statistically significant. Major extracranial hemorrhage occurred in 0.6 percent per year of patients on placebo, with a relative risk of those on warfarin of 2.4 (absolute risk increase, 0.3% per year). The total number of patients in the six trials was 2,900, with an average follow-up of 1.7 years. The aforementioned risk reduction with warfarin was based on intention-to-treat analysis; the on-treatment analysis reveals more than 80 percent relative risk reduction in stroke. This meta-analysis also evaluated adjusted-dose warfarin compared to aspirin. There were five trials, all unblinded, totaling 2,837 individuals. Excluding one study because the range of the INR was wide (2.0 to 4.5), the relative risk reduction for warfarin compared to aspirin was 46 percent. 51

The issue of aspirin as an alternative to warfarin has also been addressed in several trials. Aspirin dose ranged from 25 to 1,200 mg daily. More than 3,000 patients were studied, with an average follow-up of 1.5 years. In patients receiving placebo, the stroke rate was 5.2 percent per year for primary prevention and 12.9 percent for secondary prevention. Aspirin reduced stroke risk by 22 percent, resulting in numbers needed to treat of 67 and 40, respectively. The trials showed only a trend toward reduced stroke in aspirin-treated patients. All-cause mortality was not reduced. The authors suggested that the benefit of aspirin is to prevent nondisabling stroke that is not of cardioembolic origin. Therefore, published guidelines strongly recommend warfarin52rather than aspirin for stroke prevention in individuals with AF who are at high risk. In practice, despite the clear benefit of warfarin in stroke prevention in patients with AF, this therapeutic intervention is frequently underused. Many studies from different countries have 53–55 demonstrated suboptimal rates of appropriate antithrombotic therapy for patients with AF.

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Several potential reasons account for underuse of warfarin, including physician factors, patient factors, and geographic practice variations. Warfarin is a difficult medication for patients because of the inconvenience of INR monitoring, drug and food interactions, and bleeding risks. However, physicians frequently overestimate the bleeding risks 56 but underestimate the benefits of warfarin and overestimate the benefits of aspirin. Although major adverse bleeding events associated with warfarin occur with a relatively low 57 58 incidence, they may profoundly bias physician prescribing behavior. There is often a bias against prescribing warfarin to patients of advanced age, especially elderly women, despite 59 the fact that safety in patients 80 years and older has been established. Individual patient preferences, knowledge, and attitudes affect compliance with long-term anticoagulation therapy. Among AF patients taking warfarin in one study, about one half did not know that AF was a risk factor for stroke and could not state why they were taking warfarin; ethnic differences in knowledge about their diagnosis and treatment were also 60 identified. Methods to encourage compliance with appropriate antithrombotic prophylaxis include use of a patient decision aid. One such tool is available for download at www.canadianstrokenetwork.ca/research.clinicians.php and is highly recommended for use by primary care physicians and specialists who are counseling AF patients about the benefits and risks of warfarin compared to those of aspirin for stroke prevention. A home INR finger-stick device for self-monitoring may increase the duration patients spend in the 61 therapeutic INR range. Bleeding is the major concern with anticoagulant therapy. The average risk of major bleeding in the clinical trials was 1.3 percent per year with warfarin compared to 1 percent with aspirin 62 rate of major or placebo. The Stroke Prevention in Atrial Fibrillation study had a higher 62 bleeding at 2.3 percent on warfarin and 1.1 percent per year on aspirin. Rates of ICH were 0.9 percent per year and 0.3 percent per year, respectively. Age older than 75 years increased the risk of major hemorrhage to 4.2 percent per year (relative risk = 2.6) compared to 1.7 percent per year in the younger population. Of patients on warfarin, 16 were in the therapeutic range, 4 were below, and 13 were above at the time of their bleed. All had had therapeutic levels on their last routine prothrombin time ratios. Intensity of anticoagulation was a risk factor for bleeding only in those older than 75 years. The other identified risk factor 62 was the use of more than three prescription drugs. Interestingly, in another study, patients with cerebral ischemia of presumed arterial origin had a substantially higher risk of ICH than 63 those anticoagulated for AF. Leukoariosis is a newly identified risk factor. Analysis of a cohort of patients attending five anticoagulation clinics documented the cumulative risk of bleeding over an 8-year period. Serious bleeds occurred at a rate of 7.5 events per 100 patient-years. Points that emerged were that the incidence of bleeding and thromboembolic complications remained approximately constant, with a prothrombin time ratio of 1.3 to 2.0, but it increased sharply above or below those limits (i.e., thromboembolism was much more likely with a prothrombin time ratio of less than 1.3). No increase in bleeding complication was found related to any specific indication for therapy, including cerebrovascular disease. Older patients did not have a greater risk of bleeding. The highest risk of bleeding was seen during the first 3 months of therapy, and then it tended to plateau somewhat. Of particular note was the high risk of recurrence (32%) in patients who experienced one serious bleed. It was also noted that patients who had more than four dose 64 adjustments per year bled 25 percent more often than those who had fewer adjustments. With the exception of some patients with lone AF, all patients with AF (regardless of whether this is paroxysmal, persistent, or permanent) require some form of antithrombotic therapy unless contraindicated. It remains necessary to individualize management strategies for specific patients, taking into account compliance, risk of bleeding complications, and other medical conditions. Risk stratification is essential to determine the optimal treatment, i.e., warfarin or aspirin. Many different schemes have been devised for identifying patients with AF unassociated with valvular heart disease that are at high, moderate, or low risk of stroke. According to the 2006 American Heart Association guidelines, high risk factors 3are previous stroke, TIA, or systemic embolism, mitral stenosis, and prosthetic heart valves. Moderate risk factors include age 75 years or older; hypertension; heart failure; left ventricular ejection fraction 35 percent or lower; and diabetes. Warfarin is recommended for patients with any high risk factor or more than one moderate risk factor. This means that all patients with a previous ischemic stroke or TIA are considered at high risk and require warfarin anticoagulation for secondary stroke prevention, unless contraindicated. Warfarin or aspirin (81 to 325 mg) is recommended for those with only one moderate risk factor. Aspirin alone (81 to 325 mg) is considered sufficient for patients without any of these risk factors. For patients receiving warfarin, the target INR should be 2.5 (range 2.0 to 3.0). The INR should be monitored closely: usually weekly initially and then monthly once stable. A

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minimum INR of 2.0 is recommended for stroke prevention; stroke risk increases 65 exponentially as the intensity of anticoagulation declines. In addition to protecting against stroke, antithrombotics attenuate stroke severity: patients taking warfarin at the time of stroke have less-disabling strokes compared to individuals taking aspirin or no antithrombotic therapy, and stroke severity is negatively correlated with 66,67 Table 5-4 gives a summary of the indications for warfarin in INR at stroke onset. secondary stroke prevention for patients with selected cardiac conditions. Click here to view this table.... For patients with a mechanical heart valve, the INR should be maintained above 2.5, and for 52 secondary stroke prevention, the target INR should be 3.0 (range 2.5 to 3.5) Dual antiplatelet therapy (aspirin plus clopidogrel) was investigated in a randomized trial and found to be inferior to warfarin for stroke prevention in AF and associated with a higher rate of 68 adverse bleeding events than warfarin. If warfarin therapy needs to be interrupted for surgical procedures, temporary discontinuation for up to 1 week is usually considered reasonable for patients without mechanical heart valves. However, this practice can be associated with increased stroke risk. Heparin may be substituted in high-risk patients. In addition to medical therapy for stroke prevention in AF, interventional techniques are being investigated. These include percutaneously implanted left atrial appendage occlusive devices and surgical resection of the left atrial appendage, given that 91 percent of thrombi are 69 localized at that site. Carotid artery endovascular devices to filter emboli are also under investigation. Cardioversion of AF to sinus rhythm (either pharmacological or electrical) does not reduce the risk of stroke and therefore does not obviate the need for continued anticoagulation 70,71 therapy for stroke prevention. AF occurring in the postoperative setting following cardiac surgery is fairly common and usually self-limited. Anticoagulation is reasonable if AF persists for more than 48 hours, but it may not need to be continued long-term if sinus rhythm is restored. Similarly, other conditions associated with transient AF (e.g., alcohol, thyrotoxicosis) usually do not need long-term 3 antithrombotic prophylaxis. In patients with atrial flutter, the risk of thromboembolism is thought to be less than that for AF but higher than for patients in sinus rhythm. These patients frequently go on to develop AF. For practical purposes, the antithrombotic treatment recommendations are similar to 3 those for AF. Cardioversion in Atrial Fibrillation or Flutter Cardioversion (electrical or pharmacological) undertaken to convert AF back to sinus rhythm is associated with an increased risk of thromboembolism. Review of7222 series published over a 30-year period showed an overall risk of embolism of 1.5 percent. Figures have changed 73 It appears that up to 3 weeks may be little in recent years, with an incidence of 1.3 percent. 74 required for atrial mechanical activity to recover. It is therefore recommended that warfarin (INR 2.0 to 3.0) be given for at least 3 weeks before elective cardioversion of patients who have been in AF for 2 days or more or when the duration of AF is unknown and that it be 3 continued until normal sinus rhythm has been maintained for 4 weeks. For patients requiring immediate cardioversion, intravenous heparin is recommended 3 concurrently followed by warfarin for at least 4 weeks. Alternatively, TEE prior to cardioversion can be performed; if no thrombus is detected, then cardioversion can occur as soon as the patient is anticoagulated and continue for at least 4 weeks. If a thrombus is detected on TEE, warfarin is recommended for at least 3 weeks before and may need to be continued for a longer duration afterward. 3

The recommendations for cardioversion in atrial flutter are the same as for AF. Atrial flutter has been studied less extensively than AF, but embolism can occur in relation to cardioversion or during subsequent months. The total incidence of acute and chronic events was found to be 7 percent over a period of 26 75 ± 18 months in a consecutive series of 191 unselected patients undergoing cardioversion. The same percentage was found in a smaller study of 86 patients who were followed for a longer period (mean,764.5 years). Annual risk was estimated at 1.6 percent, one third of the rate for those with AF. Prior

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transesophageal echocardiography is not an adequate predictor of those at risk. A total of 3 of 41 patients who had no left atrial77clot developed ischemic neurological syndromes within echo contrast was a more 48 hours of elective cardioversion. In another study, spontaneous 78 common finding than atrial thrombosis (34% versus 11%). Chronic Sinoatrial Disorder As with atrioventricular block, chronic sinoatrial disease (sick sinus syndrome) presents usually with syncope and dizziness but differs in predisposing to systemic embolism. In a study comparing age- and sex-matched control subjects with atrioventricular heart block to those having chronic sinoatrial disorder, prevalence of systemic embolism was found in 16 percent of those with 79 sick-sinus syndrome compared to 1.3 percent of those with patients with the atrioventricular block. Other studies have disclosed similar figures; 80,81 Insertion of a “brady-tachy” form of the disorder appear to be particularly at risk. pacemaker does not protect against embolic phenomena. In one series, 6 of 10 strokes developed after pacemaker insertion. Only one of these patients was anticoagulated at the 82 time. Concern was raised that, although ventricular pacing provides symptomatic relief, this modality may worsen the underlying disease process by increasing the rate at which AF, 83 congestive heart failure, and thromboembolism occur. Many studies relating to various pacemaker types have followed. A Cochrane review noted poor quality of reporting but concluded that physiological (primarily dual-chamber) pacing had a statistically significant 84 benefit in preventing the development of AF compared to ventricular pacing. A nonsignificant preference for stroke prevention was found. A large subsequent study, also comparing ventricular with dual-chamber pacing, concluded that clinical features were the 85 key predictors of stroke. In the same year, a Danish study showed single-chamber atrial pacing to be superior to dual-chamber pacing in the prevention of AF and 86 thromboembolism. Patients in the brady-tachy group were noted to be more at risk of developing AF and stroke. It was concluded that warfarin treatment should be considered for these patients. Cardiomyopathies This continues to be a rapidly changing field. A new definition and classification were 87 proposed in 2006. Cardiomyopathies are defined as “a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually ‘but not invariably’ exhibit inappropriate ventricular hypertrophy or dilatation and are due to a variety of 87 causes that frequently are genetic.” Specifically excluded are those diseases of the myocardium secondary to congenital or valvular heart disease, systemic hypertension, or atherosclerotic coronary disease. The cardiomyopathies are then divided into two major groups based on predominant organ involvement. The primary cardiomyopathies are those solely or predominantly confined to heart muscle. Genetic, mixed, and acquired forms are recognized. Both hypertrophic and dilated cardiomyopathies are considered primary diseases. Also now included are the ion channel disorders, in which there is a primary electrical disturbance without structural cardiac pathology. These are further considered in the section devoted to syncope. The list of secondary cardiomyopathies is extensive. Neuromuscular or neurological causes listed are Friedreich's ataxia, Duchenne or Becker muscular dystrophy, Emery–Dreifuss muscular dystrophy, neurofibromatosis, and tuberous sclerosis. Surprisingly, the mitochondrial cytopathies, quintessentially multisystem disorders, are listed as primary cardiomyopathies. The secondary cardiomyopathy table classification does not include infective processes, such as Chagas' disease or infection with human immunodeficiency virus, although these are briefly mentioned in the text. In North America, the most common cardiomyopathy is hypertrophic cardiomyopathy, which 88 is an autosomal-dominant disease affecting 1:500 of the general population. The disorder is notorious as 89 a major cause of sudden cardiac death in athletes but is compatible with survival until old age. Mortality rates overall have been estimated at 1.0 to 1.5 percent for ages 16 to 65, 3.9 percent over the next decade, and 4.7 percent for ages older than 75 years. Risk was 90 risk in hypertrophic generally similar in Western and Asian populations. Stroke 91 cardiomyopathy has been studied in a group of 900 patients. Stroke occurred in 44 patients over a period of 7 ± 7 years. A small number (7) of other vascular events were noted. Age at first event ranged from 29 to 86 years, with a mean of 61 ± 14 years. Stroke was particularly associated with advanced age, congestive symptoms, and AF. The cumulative incidence of events was significantly higher in nonanticoagulated patients with AF compared to those receiving warfarin. Other studies confirm increased risk of stroke when AF develops in

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hypertrophic cardiomyopathy, but surprisingly also identified a subgroup in which the course 92 92,93 also increased the risk of stroke. The odds was largely benign. Outflow tract obstruction 92 ratio for stroke in patients with AF was 17.7. There are considerable geographic variations in the causes of cardiomyopathy. In Latin America, American trypanosomiasis (Chagas' disease) is a major cause. Stroke has been increasingly well documented as a complication. A study of 94 consecutive stroke patients with the cardiomyopathy of Chagas' disease compared these with 150 consecutive stroke 94 patients without Chagas' disease. A cardioembolic basis for stroke was considered present in 56 percent of the former compared to 9 percent of the controls. Most strokes in the group with Chagas' disease were in the anterior circulation (85%); the posterior circulation was rarely affected (5%) and less than 10 percent of the patients presented with lacunar syndromes. In Chagasic cardiomyopathy, the apical region of the left ventricle is the typical site for formation of thrombosis or aneurysm. Echocardiography in this study revealed an apical aneurysm in 37 percent and mural thrombosis in 12 percent, but the most common finding was left ventricular diastolic dysfunction (49%). The ECG was abnormal in 67 percent. The most common abnormality was a right bundle branch block pattern (35%), followed by left His fascicular block (17%), and AF (15%). A pacemaker had been inserted in 10. Oral anticoagulation has been recommended for all94individuals with Chagasic stroke who demonstrated risk factors for cardioembolism. In Africa, the major cardiomyopathy is the dilated type, but peripartum cardiomyopathy is 95 ubiquitous with an incidence ranging from 1:100 to 1:1,000. There are regional variations: endomyocardial fibrosis is restricted to the tropical regions of East, Central, and West 95 Africa. The incidence of human immunodeficiency virus (HIV)–associated cardiac disease, including cardiomyopathy, is increasing in contrast to developing countries where the availability of96highly active antiretroviral therapy has significantly reduced the incidence of myocarditis. In Japan, hypertrophic cardiomyopathy is the most97common cause of cardiomyopathy, followed closely by dilated cardiomyopathy (DCM). Cardiomyopathy associated with the prolonged QT interval syndrome came in a distant third, followed by mitochondrial disease, 97 arrhythmogenic right ventricular dysplasia, and Fabry's disease of the heart. In young adults arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is 98 another rare hereditary disorder causing sudden death. In a natural history study of 130 patients, 100 male, age at onset of symptoms was 32 ± 14 years. The annual 99 mortality rate Diagnosis was 2.3 percent; all patients who died had a history of ventricular tachycardia. 87 requires a high index of suspicion. In the dilated cardiomyopathies, a necropsy study showed a high incidence of embolic events (systemic or pulmonary) at 60 percent of 152 cases. In the living, once52a TIA or stroke has occurred, either warfarin or antiplatelet therapy should be considered. There is insufficient evidence to recommend warfarin or antiplatelet therapy for primary prevention, in the 100 absence of other indications. Myocardial Infarction and Left Ventricular Dysfunction 101

Patients with a history of coronary artery disease have a threefold increase in stroke risk. 102 This risk is particularly high within the first month after myocardial infarction (MI). Mechanisms include embolism from left ventricular 103 mural thrombosis and the development of AF (which occurs in up to 20% of patients after MI). A community-based study of 2,160 patients hospitalized between 1979 and 1998 found stroke risk during the 30 days after a first MI to be increased 44-fold, and it remained two to 102 three times higher than expected during the subsequent 3 years. Of note, the 20-year duration of the study enabled the conclusion to be drawn that acute MI treatment by 102 following MI is approximately 1 thrombolysis did not reduce stroke risk. Overall, stroke risk104,105 For a non-ST elevation percent during the first month and about 2 percent at 1 year. 106 acute coronary syndrome, the early stroke risk was found to be 0.7 percent at 3 months. In large randomized trials of aspirin versus the combination of aspirin and clopidogrel in patients 103 with MI or acute coronary syndrome, the stroke rate ranged between 0.9 and 1.7 percent. In a meta-analysis, predictors of stroke following MI included advanced age, diabetes,104 hypertension, previous stroke or MI, anterior MI, AF, heart failure, and nonwhite race. 107 Anterior wall MI has been a predictor of stroke in some, but not all, studies. Left ventricular

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thrombus develops in about one third of individuals in the first 2 weeks following an anterior 108 MI. A meta-analysis of 11 studies concluded that mural thrombus formation after an MI109 poses a significantly increased risk of embolization, which is reduced by anticoagulation. The current recommendation, in the absence of thrombolytic therapy, is that, after acute MI, heparin should be initiated and followed by warfarin for 3 months in patients considered to be at increased risk of embolism, either pulmonary or systemic. High-risk patients are those with severe left ventricular dysfunction, congestive heart failure, a history of pulmonary or systemic embolism, echocardiographic evidence of mural thrombosis, or the presence of AF. Because of the increased frequency of mural thrombosis in anterior as opposed to inferior myocardial infarcts, it is also recommended that patients with an anterior Q-wave infarction 110 receive heparin followed by warfarin. In patients with TIA/ischemic stroke related to an acute MI in which LV mural thrombus is identified, oral anticoagulation is recommended for at least 3 months and52up to 1 year (INR 2 to 3) in addition to aspirin for coronary artery disease (up to 162 mg/day). Stroke risk is inversely proportional to left ventricular ejection fraction (LVEF). In a study of 2,231 patients with LV dysfunction after an acute MI, those with LVEF less than 29 percent had a stroke risk nearly double that of patients with LVEF exceeding 35 percent: the annual stroke rate was 1.5111 percent overall. Thus, reduced LVEF is an independent risk factor for in risk of embolic events for subsequent stroke. Another study found a 58 percent increase 112 every 10 percent decrease in LVEF in women, but not men. Congestive heart failure carries a two- to threefold increase in the relative risk of stroke. Among patients enrolled into heart failure trials, the overall annual stroke 113 risk has ranged between 1.3 to 3.5 percent; most patients were taking aspirin or warfarin. In the absence of clinically overt heart failure or MI, the presence of asymptomatic left ventricular systolic 114 dysfunction, even of mild degree, is an independent risk factor for stroke. The optimal antithrombotic prophylaxis for patients with poor LV function remains uncertain; 115 the efficacy of warfarin versus aspirin is the subject of ongoing trials. Rheumatic Heart Disease Extensive experience has accumulated over several decades concerning the association of systemic embolism with rheumatic heart disease. A 1973 review concisely summarized 116 relevant features. A minimum of 20 percent of patients with rheumatic heart disease experience a thromboembolic complication at some time, and 40 percent of these arterial emboli involve the brain. Embolic events are the cause of death in 16 to 35 percent of adults dying of rheumatic heart disease, and subgroups of patients having a much greater frequency of embolic complication can be identified. The risk of embolism is substantially increased when atrial thrombus is present (risk increases from 16% to 41%) or AF develops (risk increases from 7% to 30%). The proportion of patients developing left atrial thrombus increases from 9 to 41 percent when AF is present; conversely, 80 percent of patients with atrial thrombus are in AF. Embolism is most likely to occur when the dominant valvular lesion is that of mitral stenosis, either alone or in combination with aortic valve disease or mitral insufficiency. Isolated aortic valve disease is rarely associated with embolic events. Older patients more frequently have AF, atrial thrombus, and embolic events. Studies of atrial thrombosis initially involved TTE, an insensitive method. Of 293 patients in one study who were to undergo open heart surgery, TTE disclosed thrombi in the left atrium in 33. At surgery, this was confirmed in 30 of the cases, but the study had missed 21 additional patients, including all 11 in whom thrombus was located in the left atrial 117 appendage. 118

Once embolization has occurred, recurrence rate is high, approaching 60 percent. Current recommendations are therefore strongly in favor of the use of long-term warfarin (to prolong the INR to 2.0 to 3.0) in patients with rheumatic mitral valve disease who have a history of systemic embolism or who develop AF, either chronic or paroxysmal. It is also recommended that the same treatment be given to patients in normal sinus rhythm if the left atrial diameter is in excess of 5.5 cm. Furthermore, if recurrent systemic embolism occurs despite adequate 119 warfarin therapy, addition of aspirin should be considered. The beneficial effect of adding aspirin,120 100 mg daily, to warfarin has been demonstrated in the context of prosthetic heart valves.

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Atrial Myxoma Atrial myxomas have long been recognized as a cause of cerebral embolism. They are uncommon. A French hospital reviewed experience with 112 cases collected over 40 121 years. Women outnumbered men 72 to 40; ages ranged from 5 to 84 years. The presenting symptoms were cardiac, constitutional, and embolic in 67, 34, and 29 percent, respectively. Younger and male patients were more liable to have embolic events.122 Neurological manifestations, in 113 patients, were evaluated in a literature review. Ischemic stroke was the most common at 83 percent, often at multiple sites. Syncope (28%), psychiatric presentations (23%), headache (15%), and seizures (12%) were all encountered. In a Spanish study of 28 patients, it was noted that in the 9 with stroke, TIA had preceded the 123 A rare delayed complication is that of distal multiple stroke in 7. Treatment is surgical. 124 cerebral aneurysm formation. Transient ischemic attacks led to this diagnosis 5 years after successful surgery in one person. Symptoms were controlled with clopidogrel. Marantic (Nonbacterial Thrombotic) Endocarditis Although there are several causes of nonbacterial thrombotic endocarditis, a review of 14 series, predating the era of echocardiography, found an underlying malignancy in half. The most common tumor was lung cancer. Cancers of gastrointestinal origin accounted for a similar number of cases. Breast cancer appeared underrepresented. The mitral valve was most commonly affected (43%), followed by the aortic valve (36%). Overall, embolism 125 cancers of the occurred in 42 percent of patients. An autopsy series (171 cases) found126 ovaries, biliary system, pancreas, stomach, and lung to be most common. The widespread availability of echocardiography has facilitated recognition of vegetations. A prospective study of 200 unselected ambulatory patients with solid tumors found vegetations in 19 percent compared to 2 percent in controls. Vegetations were seen in 50 percent of pancreatic cancers, 28 percent of lung cancers, and 19 percent of lymphomas. Only two 127 patients had cerebral events. On MRI, numerous lesions of various sizes may be found in multiple arterial territories. At one cancer center, 96 stroke patients were assessed. Echocardiography (TTE) was performed in 61; none had TEE. An embolic mechanism was thought to be causative in 52. The heart was implicated in 14, but nonbacterial thrombotic endocarditis in only 3. Stroke of embolic origin carried a dismal prognosis. Life expectancy was just over 2 months, and 128 treatment had no apparent influence. Other Echocardiographic Abnormalities Linked to Stroke Patent Foramen Ovale and Atrial Septal Aneurysm

A PFO is present in about one quarter of adults and represents a potential mechanism for 129 cardiogenic embolism. Case-control studies of young adults (younger than 55 years) with cryptogenic stroke found130a fivefold increase in prevalence of PFO compared to control subjects without stroke. In a French prospective study of individuals with stroke and an isolated PFO, the 4-year stroke recurrence risk was 2.3 percent. For those with both PFO and ASA, the rate was 15.2 percent compared to 0 percent for those with ASA alone. In the “control group” with neither 131 PFO nor ASA, the rate was 4.2 percent. All patients in this study were taking aspirin. In another study, the presence of a PFO (with or without ASA) did not confer a significant increase in stroke recurrence rate over a 2-year follow-up; furthermore, recurrence rate did 132 not differ between patients on aspirin or warfarin or in those with large or small PFO. 133

ASA was found in 2 percent of persons in a population-based study. In elderly patients undergoing cardiac surgery, the incidence was nearly 5 percent. No patient had a cerebrovascular event over a follow-up period of 70 months; most were receiving aspirin. It 134 was concluded that the risk of embolic stroke was low. The optimal management of patients with PFO is not currently known. Treatment options include (1) antiplatelet therapy, (2) anticoagulation, (3) percutaneous device closure, and (4) surgical closure. Opinions differ between specialists: neurologists are more likely to recommend medical management, whereas cardiologists are more likely to suggest device 135 closure. Randomized trials are currently under way to compare the efficacy and safety of medical therapy with percutaneous closure. For patients with cryptogenic stroke and isolated 136 PFO, antiplatelet therapy is usually recommended. For patients with PFO and ASA,

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anticoagulation or device closure may be considered, although evidence to support these treatments is lacking. Left Atrial Spontaneous Echo Contrast

Left atrial spontaneous echo contrast (smoke) may be detected by TEE and is thought to represent stasis of blood within the atrium. The finding may thus indicate a predisposition to thrombus formation. It is most commonly encountered in patients with either AF or mitral stenosis and has been found to be highly associated with previous stroke or peripheral 137 embolism in this context. Mitral Annular Calcification

Mitral annular calcification (MAC) has been suggested as a potential source of calcific or thrombotic emboli to the cerebral and retinal circulations, but the evidence has been conflicting on whether it is an independent risk factor for stroke. A Framingham study documented a doubled stroke risk in those with MAC compared to those without, but it was unclear whether this relationship is causal or a marker for other risk factors; for example, in 138,139 Although one study found MAC to MAC, the risk of developing AF is increased 12-fold. 140 141,142 did not. One of these involved be an independent predictor of stroke, two others 142 nearly 6,000 patients followed over 6 to 7 years. MAC appears to be a marker of generalized atherosclerotic disease including carotid stenosis, calcified aortic plaque, and 143,144 coronary disease. Mitral Valve Prolapse

Mitral valve prolapse (MVP) is the most frequent valve disease in adults, with146a prevalence of 145 a cause of stroke/TIA in the young, this has not about 2 percent. Initially postulated as 147,148 Stroke risk is increased with older age and the been confirmed in more recent studies. development of cardiac conditions: AF, mitral valve thickening, left atrial enlargement, and 149 diagnosis of MVP alone, confirmed by mitral regurgitation. In those with an auscultatory 150 significant echocardiography, no increase in risk was found. In the Framingham cohort, no151 difference was found in the prevalence of stroke/TIA in those with or without MVP. Treatment guidelines are therefore (1) no antithrombotic therapy151for primary prevention in individuals with MVP who have not experienced embolic events and (2) long-term antiplatelet therapy for secondary prevention in MVP patients who have had ischemic stroke 52 or TIA. If other cardiac abnormalities develop, these are treated according to their own merits. Aortic Valve Sclerosis and Stenosis

Systemic embolism in patients with aortic valve disease is uncommon in the absence of AF or other risk factors. Aortic sclerosis (valve thickening without outflow obstruction) is a common finding in the elderly and is associated 152 with generalized atherosclerotic vascular disease and increased cardiovascular mortality. A prospective study of patients with echocardiographically documented aortic valve calcification showed no statistically significant difference in stroke risk in patients with calcification without stenosis (8%) compared to those with stenosis (5%) or control subjects 153 (5%). Additionally, aortic valve disease was not associated with the presence of silent brain infarcts in this study. A larger study compared stroke risk in those with stenosis to those with sclerosis. Over a mean follow-up of 5 years, stroke risk was 12 percent in those with stenosis and 8 percent in those with sclerosis compared to 6 percent in those with a normal aortic valve. After adjusting for other variables,152 there was no statistically significant increase in stroke153 risk in those with aortic sclerosis. A similar conclusion was found in another cohort only if severe was it an independent predictor of study. With regard to aortic stenosis, 154 stroke in addition to age and AF.

Acute Medical Treatment of Cardiogenic Embolism The landmark study comparing thrombolysis of acute ischemic stroke with intravenous tissue plasminogen activator 155 (t-PA) against placebo showed improved clinical outcome at 3 months for all stroke subtypes. Cardioembolism accounted for 28 percent of the patients. Therefore, this acute intervention should be considered for stroke of cardioembolic origin. The two fundamental eligibility criteria are (1) treatment initiated within 3 hours of stroke

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onset (therefore the time of stroke onset must be clearly defined) and (2) absence of hemorrhage on CT brain scan. Prompt assessment and treatment are required because the odds of a favorable outcome with t-PA decline rapidly the longer the interval to t-PA injection time. 156

A series of inclusion and exclusion criteria exist. The purpose is to minimize the risk of intracerebral hemorrhage, the major complication of intravenous t-PA, and to avoid treating minor or rapidly resolving processes such as TIAs, or nonischemic events. The dose of t-PA for stroke thrombolysis (0.9 mg/kg) is lower than that for acute MI. The risk of intracerebral hemorrhage in the treated group (6.4%) was 10 times higher than that of the placebo group in 155 one report. This risk appears increased if the treatment window is extended beyond 3 hours. Patients treated with t-PA cannot receive heparin, warfarin, or aspirin for the first 24 hours after infusion. Subsequently, long-term anticoagulation for secondary stroke prevention must be considered. Other interventional approaches to achieve recanalization include direct intraclot lysis via a microcatheter and mechanical clot disruption, but availability of such procedures is limited. Mechanical clot removal devices may especially have a role in the acute treatment of patients 157 with severe stroke in whom thrombolysis is contraindicated (e.g., recent cardiac surgery). Some embolic infarcts undergo secondary hemorrhagic transformation, which may lead to clinical deterioration. Factors found to increase this possibility in one study were large infarct 158 size and initiation of early anticoagulation (less than 12 hours from presentation). The optimal timing of initiation of anticoagulation after cardioembolic stroke is not known. One recommendation is that nonhypertensive patients without evidence of hemorrhage on CT scan performed 24 to 48 hours after stroke can start anticoagulation. Anticoagulation is usually delayed for about 7 days in those with large infarcts. The American Stroke Association states that initiation of warfarin is generally recommended within 2 weeks after a stroke, but longer delays may be appropriate in patients with large infarcts or uncontrolled 52 hypertension. Decisions must be individualized. SYNCOPE Transient self-limited interruptions of cardiac output result in generalized cerebral ischemia, a 159 condition that is termed syncope when it results in a loss of consciousness. Syncope is discussed in Chapter 8 but is considered further here with particular regard to its occurrence in patients with acquired cardiac disease and arrhythmias. A study of syncope induced in 14 patients with pacemakers noted that consciousness was lost 9 or more160seconds after induction of a ventricular arrhythmia (fibrillation or tachycardia). Patients felt distant, dazed, or as if they were “fading out” before loss of consciousness. Motor activity was noted in 10 of 15 episodes, with generalized tonic contraction of axial muscles followed or accompanied by irregular jerking of the extremities, generalized rigidity without clonic activity, or irregular facial movement or eyelid flutter without tonic activity. None of the patients bit their tongue or was incontinent. During the recovery phase, tonic flexion of the trunk was seen in three patients. Patients remained dazed or confused for up to 30 seconds or more after restoration of the circulation. This study confirmed that motor phenomena occur in association with syncope without corresponding electroencephalographic (EEG) evidence of epileptic discharges. The authors noted 160 variability in EEG findings and poor correlation of these changes with the clinical ones. Videometric analysis of syncope lasting on average 12 seconds induced in 42 healthy volunteers showed that myoclonic activity occurred in 90 percent. Head turns, oral automatisms, and writhing movements were common. Upward eye deviation was also common, and eyes remained open in three quarters of the subjects. Visual hallucinations occurred in 60 percent and were associated with auditory hallucinations in 36 percent, 161 although never with intelligible speech. Focal neurological symptoms are rare with cardiac arrhythmia. Evaluation of 290 patients who required pacemaker insertion disclosed that only 4 had focal neurological symptoms or signs; among these,162 only 2 had focal symptoms that could be related to a specific episode of cardiac dysfunction. Rarely, features suggestive of complex partial seizures are seen. The clinical spectrum of abnormalities that occur with generalized cerebral hypoperfusion is thus an extended one, ranging from nonspecific “dizziness” through a variety of sensory disturbances, including paresthesias and alterations of vision to loss of consciousness, sometimes with convulsive features. This has long been recognized in the context of blood donation, where 12 percent of syncopal reactions were shown to have some convulsive

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features. Confusion may occur upon recovery. These observations highlight potential difficulties in distinguishing syncope from seizure. A collaborative study between cardiologists and neurologists identified historical criteria to identify seizure patients among those presenting with presumed syncope: waking with a lacerated tongue, loss of consciousness with emotional stress, head turning 164 to one side during loss of consciousness, and postictal confusion or abnormal behavior. Of note, syncopal events indistinguishable from seizures have been observed in the context of cardiac arrhythmias. Additionally, seizures may cause arrhythmias. 165

Syncope is common, especially in the elderly, who show a high recurrence rate. Of the many causes, it is important to identify those of cardiac origin because mortality is significantly increased in this group of patients. A cardiac basis, in different studies, ranged 159 from 1 to 8 percent for organic heart disease and 4 to 38 percent for arrhythmias. In addition to common structural causes, aortic tract outflow stenosis or intermittent obstruction to outflow may occur, for example, by a mobile thrombus or tumor in the left atrium. Echocardiography is the test of choice. In the case of arrhythmias, the prime objective is to document a relevant abnormality during an episode. In the past, no cause for syncope was found in about one third of patients, but diagnostic yields as high as 76 percent have been achieved,166 for example, in a Swiss study of 788 patients presenting to an emergency department. Evaluations were completed in 650 of those patients. History and clinical examination led to a diagnosis in 38 percent. In 10 percent, a possible cause for syncope was identified, and in about 3 percent this was refuted. In 21 percent, the cause of syncope was not initially determined, and the majority of this group underwent an extensive work-up. A probable cause of syncope was found in only 30 of the 122 patients in this group. Among the 650 patients, 69 (11%) were considered to have a cardiac cause, and arrhythmias were most prominent (44 patients). A sinus bradycardia or pause was seen in 15, as was atrial ventricular block, whereas 4 showed a supraventricular tachycardia and 1 had a pacemaker malfunction. Acute coronary syndromes were found in 9, aortic stenosis in 8, and pulmonary embolism in 8. The 18-month mortality in the cardiac group, noncardiac group, and group with unidentified cause was 26, 6, and 7 percent, respectively. A relatively common disorder predisposing to paroxysmal supraventricular tachycardia is the Wolff–Parkinson–White syndrome, usually a sporadic disorder, with a prevalence of up to 1 167 in 1,000 persons. AF may develop. Dizziness, syncope, and, rarely, sudden death may occur. The characteristic electrocardiographic (ECG) hallmarks are a short PR interval and a slowly rising prolonged QRS complex. It is those patients with an apparently normal heart that present a special challenge and raise 168 the possibility of disorders of the conducting tissues. The long QT syndrome is seen throughout the world. A recessive form is associated with deafness, whereas the more common form, without deafness, has autosomal-dominant inheritance. Acquired forms, often drug related, are more common. Exertion or emotion may trigger events. The characteristic feature, as the name implies, is a prolonged QT interval (corrected for heart rate) on a standard ECG. The disorder predisposes to87polymorphic ventricular tachycardia, which in turn predisposes to syncope and sudden death. 169

Recently, a short QT interval syndrome has been identified. Especially affected are the young, including infants. It is rare and predisposes to paroxysmal AF and episodes of ventricular fibrillation, which may lead to syncope and sudden death. It has been suggested 170 that the disorder may be responsible for some cases of sudden infant death. Sudden death in males from Southeastern Asia attributable to ventricular fibrillation has been recognized for more than 20 years. Episodes indistinguishable from generalized seizures 171 may occur in sleep, and the sudden death is presumed due to ventricular fibrillation. It is now known as SUNDS (sudden unexplained nocturnal death syndrome) and has been linked to the 172 Brugada syndrome, which is said to be phenotypically, genetically, and functionally the same. However, the Brugada syndrome has been described in Europe and in females. The Brugada syndrome is also characterized by sudden death due to malignant arrhythmias. The baseline ECG may be abnormal in showing ST elevation in leads V1, 2, and 3, together with the presence of a right bundle branch block pattern. However, this pattern may be concealed and require unmasking by the use of sodium channel blockers. Another disorder, but one in which the resting ECG is unremarkable, although it may show a sinus bradycardia and prominent U waves in some patients, is catecholamine-induced 173 polymorphic ventricular tachycardia. This is a disorder of childhood with an average age at symptom onset of 8 years. Syncope or events indistinguishable from seizures are triggered

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by exercise or emotional stress. Evaluation of syncope therefore requires attention to family history, age at onset, unexplained sudden deaths, note of apparent epileptic disorders, relation of events to exertion and distress, and effects of postural change. In the presence of an apparently normal heart, evaluation of the standard ECG may suggest a cause, as indicated previously. In the context of a normal ECG or with intermittent events, prolonged recordings may be required in order to capture an episode. With daily events, a Holter monitor may suffice. More prolonged recording techniques are available, as are sophisticated electrophysiological studies. Details are beyond the scope of this chapter;174 a useful modern overview of an approach to the investigation of syncope is available. Cardiac arrhythmias may also result from175 epileptic events. Tachycardia is the most atrioventricular commonly observed rhythm disturbance. Sinus bradycardia, complete176–178 Asystole block, and cardiac arrest all have been documented as epileptic effects. secondary to179 an epileptic event, often a partial seizure, has been documented to last for up to It should be noted that carbamazepine can cause heart block, especially in 60 seconds. 180 elderly women. INTERVENTIONAL PROCEDURES

Coronary Catheterization Coronary angiography carries a small (0.2%) risk of central nervous system (CNS) complications. An unexplained observation is the preponderance of embolic events within the 181 posterior circulation, regardless of the route of catheterization. The corresponding clinical features are visual disturbances that may be migrainous, transient, or persistent; confusion 182,183 For patients experiencing an iatrogenic ischemic stroke in the context may also occur. of coronary 184 catheterization, thrombolytic therapy is a potential treatment option that should be considered.

Percutaneous Transluminal Coronary Angioplasty and Stenting Percutaneous transluminal coronary angioplasty had an overall mortality of 0.1 percent in a large series of more than 12,000 patients. Of the 121 who died, low-output failure was the 185 most common cause (66% of deaths); stroke was responsible for 4 percent. Another study showed that in the presence of peripheral vascular186 disease the risk of any major complication (stroke included) was higher: 12 versus 8 percent. Angioplasty has187 also been compared to coronary stenting. Stroke rate (0.2%) was equal in the two groups. To prevent stent thrombosis, an antithrombotic regimen is required. The addition of clopidogrel188 to aspirin reduces stroke incidence both before and after percutaneous coronary intervention. In a study of more than 18,000 patients with a non–ST-segment elevation acute coronary syndrome, the 6-month stroke risk was 1.3 percent (1.1% for those not undergoing coronary189 artery bypass graft surgery) and the 6-month mortality in these patients was 27 percent. Independent predictors of stroke risk were coronary bypass surgery (especially when performed early), previous stroke, diabetes, and older age, among others. Percutaneous coronary intervention was not associated with an increased risk of stroke in this group. In a study of 12,407 percutaneous coronary interventions (1990190to 1999), the periprocedural risk of stroke and TIA was 0.38 and 0.12 percent, respectively. More than 90 percent of patients in this study underwent balloon angioplasty, and nearly half also underwent coronary stenting. Independent predictors of stroke were advanced age, use of an intra-aortic balloon 190 pump, and need for saphenous vein graft intervention. Primary angioplasty, compared to thrombolysis, has been noted to decrease significantly the 191 192 risk of stroke, but when used as a rescue therapy, stroke risk was marginally increased. In a review of 23 randomized trials involving more than 7,000 patients with acute MI and ST-segment elevation who were randomly assigned to either primary percutaneous transluminal coronary angioplasty or thrombolysis, the overall stroke rate was 1 percent with angioplasty compared to 2 percent with thrombolysis (a statistically significant reduction in 193 favor of angioplasty).

Thrombolytic Therapy for Acute Myocardial Infarction Concern that the introduction of thrombolytic therapy for MI would result in an increase in

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stroke was not substantiated by the results of the initial large Italian trial of nearly 12,000 patients. Stroke rate was 0.77 percent in the streptokinase group compared to 0.92 percent in the control group. An excess of stroke was evident only during the first day after randomization to streptokinase. After this time, patients in194 the control group had more stroke or TIA events. The study did not include CT scan results. Extended experience from this group, specifically stressing stroke risk, found that stroke occurred in 236 (1.14%) of 20,768 patients. Autopsy or CT scanning enabled the cause of stroke to be identified in 74 percent. Perhaps surprisingly, infarction was more common (42%) than hemorrhage 195 (31%). Patients receiving recombinant t-PA showed a small but significant excess of stroke. Comparison of four thrombolytic strategies confirmed a slight excess of hemorrhagic stroke in those receiving t-PA and in those receiving196 combined thrombolytic agents. This excess risk was on the order of 2 to 3 per 1,000 treated. In the four groups, stroke risk rate ranged from a low of 1.22 percent in those treated with streptokinase and subcutaneous heparin to 1.64 percent in those treated with intravenous heparin and both t-PA and streptokinase. These percentages are equal to or less than those documented in recent large prethrombolytic studies of acute MI. The risk of ICH following thrombolytic therapy has been linked to the intensity of heparin anticoagulation and timing of partial thromboplastin time (PTT) monitoring. Recent trials that have used reduced-dose heparin regimens and 3-hour PTT monitoring have reduced ICH 197 rates. When ICH does occur, it is likely to be large in size, supratentorial in site, and more often lobar than deep. Mass effect is common, and blood may extend into the ventricles or subarachnoid space. Of the 244 cases in the study referred to earlier, symptoms emerged within 8 hours of treatment in 55, after 30 hours in 58, and between these times in the 194 remainder. A small percentage (3%) of hemorrhages were subdural. Syncope within 48 hours of treatment, or facial or head trauma within 2 weeks of treatment were 198 disproportionately noted, but numbers were small (7). Review of risk factors in 150 patients with documented ICH identified four factors as independent predictors: age older than 65 years, body weight less than 70 kg, hypertension on hospital admission, and administration of alteplase. The same risk factors for ICH were identified in the GUSTO-I trial; additional predictors included a history of cerebrovascular 199 disease or hypertension, and elevated systolic and diastolic blood pressure on admission. If ICH is suspected, immediate brain CT scan and discontinuation or reversal of thrombolytic or antithrombotic therapy are recommended. Neurosurgical consultation should be 200 considered.

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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 6 Neurological Manifestations of Infective Endocarditis LINDA S. WILLIAMS • BRADLEY L. ALLEN •

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HISTORICAL OVERVIEW EPIDEMIOLOGY OF NEUROLOGICAL COMPLICATIONS PATHOPHYSIOLOGY OF NEUROLOGICAL COMPLICATIONS RISK FACTORS FOR NEUROLOGICAL COMPLICATIONS Site of Infection Infecting Organism Acuteness of Infection Valvular Vegetations Hematological Risk Factors ISCHEMIC STROKE Clinical Presentation Seizures Evaluation of Patients Treatment of Ischemic Stroke Anticoagulation in Native Valve Endocarditis Anticoagulation in Prosthetic Valve Endocarditis Surgical Treatment HEMORRHAGIC STROKE Clinical Presentation Evaluation Treatment of Hemorrhagic Stroke Intraparenchymal Hemorrhage Mycotic Aneurysms CEREBRAL INFECTION Clinical Presentation Evaluation Treatment of Cerebral Infection OTHER NEUROLOGICAL COMPLICATIONS SUGGESTED MANAGEMENT ALGORITHM PROGNOSIS CONCLUDING COMMENTS

HISTORICAL OVERVIEW

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The relationship between infection of the heart valves and arterial embolization was first 1 recognized by Rudolf Virchow in the mid-1800s and the classic clinical triad of fever, heart murmur, and hemiplegia was described 30 years later by Osler in his Gulstonian Lectures of 2 1885. The understanding of infective endocarditis has evolved since these early descriptions to a concept of the disease having different predisposing conditions, different propensity for sites of valve infection, different infecting organisms, and different treatments, but the proportion of patients with neurological manifestations has remained relatively constant. It is important to recognize any neurological complications not only because they are frequent but also because they may require alterations in treatment and are often associated with increased morbidity and mortality in infective endocarditis. Although the key to treating neurological complications is appropriate antibiotic therapy, the presence of neurological manifestations often alters concomitant medical or surgical treatment of infective endocarditis. This chapter reviews the most common neurological manifestations of infective endocarditis, detailing their epidemiology and clinical presentations, suggesting appropriate diagnostic evaluations, and discussing treatment options. EPIDEMIOLOGY OF NEUROLOGICAL COMPLICATIONS Neurological events have long been recognized as frequent and severe complications of infective endocarditis. In series of patients from the 1950s onward, the overall frequency of neurological complications has remained relatively constant at approximately 20 to 40 3–15 One reason for the similarity of these reports is that cerebral emboli percent (Table 6-1). are almost always symptomatic; the only study to date that has systematically performed cerebral and abdominal imaging in patients with infective endocarditis regardless of symptoms showed that the overall proportion of cases with cerebral embolization was 34 9 percent and that more than 90 percent of these cerebral emboli were symptomatic. Nevertheless, because of the high overall incidence of stroke in the general population, infective endocarditis is an unusual cause of stroke. Neurological complications of infective endocarditis can be divided into three major types: ischemic stroke, hemorrhagic stroke, and cerebral infection (Table 6-1). Ischemic stroke is by far the most common, occurring in 20 to 30 percent of patients and accounting for 50 to 75 percent of all neurological complications. Primary cerebral hemorrhage, usually intraparenchymal or subarachnoid, is less common, reported in 2 to 17 percent of patients. Secondary hemorrhagic transformation of an ischemic stroke, however, is not uncommon and is estimated to occur in 20 to 40 percent of ischemic strokes. Cerebral infections may manifest without previous clinical evidence of ischemic or hemorrhagic stroke in less than 10 percent of cases; typical infections include cerebritis, meningitis, and microabscesses or macroabscesses. Other neurological symptoms, including seizures, headache, mental status changes, and neuropsychological abnormalities, sometimes occur but are usually secondary to one of the three major complications. Rarely, endocarditis has been associated with spinal cord infarction or abscess, discitis, retinal ischemia, and ischemic cranial and peripheral neuropathies. Click here to view this table.... PATHOPHYSIOLOGY OF NEUROLOGICAL COMPLICATIONS Almost all the neurological complications of infective endocarditis have embolization as their primary9cause. Although cerebral emboli are probably not more common than extracerebral emboli, they are more often symptomatic and thus more frequently reported, and they are associated with an increased morbidity and mortality compared to other systemic emboli. Cerebral emboli most often affect the middle cerebral artery (MCA) territory and may be septic or nonseptic; either type can cause ischemic stroke. Septic emboli may also lead to hemorrhagic stroke through the development of arteritis or mycotic aneurysm, to cerebral microabscess or macroabscess, usually by seeding of ischemic tissue, and to cerebritis or the term bacterial intracranial meningitis by seeding of the meninges (Fig. 6-1). Although 16 aneurysm has been suggested as more appropriate, the term mycotic aneurysm continues to be widely used and is therefore used here.

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FIGURE 6-1 Embolization to various cerebral structures is responsible for most of the neurological complications of infective endocarditis. Emboli that lodge in the lumen of cerebral vessels may lead to ischemic stroke and can lead to arteritis or mycotic aneurysm formation with resultant vessel rupture and cerebral hemorrhage. Emboli to the meninges may produce meningitis, and emboli to the brain parenchyma, especially when associated with cerebral ischemia, may result in meningoencephalitis or abscess. (Reprinted with permission from Solenski NJ, Haley EC Jr: Neurological complications of infective endocarditis. p. 331. In Roos KL [ed]: Central Nervous System Infectious Diseases and Therapy. Marcel Dekker, New York, 1997.)

Most primary intracerebral hemorrhages in infective endocarditis result from septic embolism, followed by septic necrosis and5,17,18,19 rupture of the vessel wall; less commonly, they result from Masuda and colleagues found that 10 of 16 patients rupture of mycotic aneurysms. with infective endocarditis and intracerebral bleeding had pyogenic arteritis, in 5 of whom rupture occurred without evidence of concomitant mycotic aneurysm; 13 of the 16 had either 18 septic emboli or arteritis, or both. Intracerebral hemorrhage may also occur owing to a secondary hemorrhage into an ischemic infarct. In one histopathological series of 17 patients, it was due to secondary transformation of ischemic infarction in 24 percent of cases, necrotic arteritis in 24 percent, mycotic aneurysm in 12 percent, and other causes in 11 percent; in 29 17 percent it was of unknown etiology. Mycotic aneurysm formation has been related to (1) septic embolization20to the arterial lumen, producing intraluminal wall necrosis and outward extension of infection, and (2) septic embolization to the adventitial layer of the artery, resulting in destruction of the adventitia and 21,22 Mycotic aneurysms are usually muscularis layers and subsequent aneurysmal dilation. small, located at distal arterial bifurcations, rather than on the circle of Willis, and can be single or multiple. Branches of the MCA are the most common location for mycotic aneurysms; in one series, almost 40 percent of all mycotic aneurysms involved distal MCA 23 vessels. Rarely, mycotic aneurysms involve extracranial vessels, including the internal carotid artery (Fig. 6-2).

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FIGURE 6-2 This patient with fungal endocarditis developed headache, confusion, and decreased level of consciousness without focal deficits. A, Head computed tomography (CT) showed subarachnoid hemorrhage (increased density) in the perimesencephalic cistern, left more than right, and dilatation of the temporal horns of the lateral ventricles. B, Digital subtraction angiography showed a large aneurysm of the cavernous portion of the left internal carotid artery. The aneurysm was treated with endovascular coils to occlude the carotid artery.

Brain macroabscesses account for less than 1 percent of all neurological complications of infective endocarditis and may occur secondary to ischemic infarction from a septic embolus or to extension of infection from adjacent arteritis or mycotic aneurysm. Brain microabscesses are more common than macroabscesses and usually occur in cases with multiple ischemic infarctions as a result of distal migration of septic embolic fragments. Microabscesses have been associated most commonly with Staphylococcus aureus infections. Meningoencephalitis is usually a result of embolization to meningeal vessels, with subsequent parenchymal or cerebrospinal fluid (CSF) invasion of the infecting organism. Aseptic meningitis may also occur with subarachnoid hemorrhage due to a necrotic arteritis or ruptured mycotic aneurysm. RISK FACTORS FOR NEUROLOGICAL COMPLICATIONS A variety of clinical and laboratory variables have been associated with an increased risk of neurological complications (Table 6-2), including site and type of valve infection, virulence of the infecting organism, acuteness of infection, presence of valvular vegetations, increased size and mobility of vegetations, and certain hematological factors. Click here to view this table....

Site of Infection Neurological 11,24,25 complications are more common with left-sided than with right-sided valve although some series have found increased embolism in patients with involvement, 26,27 Cerebral embolization in right-sided endocarditis may right-sided infective endocarditis. occur via embolization through a patent foramen ovale or a pulmonary arteriovenous 28,29 Mitral valve infection has been associated most commonly with neurological fistula. complications; in one series, mitral valve infection was found in 76 percent of cases with 30 < 0.005), and this neurological complications compared to 37 percent of other cases (P 3,10,31–33 association has also been reported by others. However, Wong and colleagues reported associations between aortic valve infection and stroke, with 44 percent of those with stroke having large aortic valve vegetations compared with a 9 percent prevalence in those 34 relationship between the site of infection and without stroke. Some authors have found no4,13,26,35 36,37 Although disagreement exists, most the occurrence of neurological complications. reports comparing native valve and prosthetic valve endocarditis indicate no significant difference in the proportion of patients with neurological complications. Among patients with prosthetic valve endocarditis, however, mechanical 38 valves may be associated with complications more often than bioprosthetic valves.

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Infecting Organism Several important changes in the type and characteristics of the infecting organism in infective endocarditis have become evident in the past few years. Although streptococci, staphylococci, and enterococci remain the three most prevalent infecting organisms, some recent studies report that staphylococcal is now more common than viridans group 12,39 More problematic than a shift in type of infecting streptococcal infective endocardi tis. organism is the growing prevalence of antibiotic resistance among these organisms, especially resistant viridans group streptococci and methacillin- and van-comycin-resistant S. 40,41 aureus. This changing resistance pattern is reflected in updated guidelines from the American Heart Association on diagnosis, antimicrobial treatment, and management of 42 complications in patients with infective endocarditis. It is unclear whether antibiotic susceptibility changes have an impact on the risk of embolic complications, although an infection with a resistant organism that takes longer to control might well be associated with an increased risk of embolization. Previous studies have linked 3,4,30,33,35,43 S. aureus, an increased3 risk of cerebral embolization to endocarditis due to 3 44 3 enterococci, Escherichia coli, Streptococcus bovis, various fungi, enterobacteriaceae, 3,45 and anaerobic bacteria. Several14studies have shown that, even after adjusting for other 14,15 and S. bovis were independently associated with embolism. In factors, S. aureus prosthetic valve endocarditis, specifically, Staphylococcus epidermidis has been associated 46 with more neurological complications than S. aureus. Endocarditis due to Streptococcus pneumoniae has been associated with an increased risk of meningitis (50% to 90% of 47,48 49 cases), and S. aureus endocarditis has been associated with brain abscess. The current summation of these varied reports is that the virulence of the organism, the availability of effective antimicrobial therapy, and the potential development of large, friable vegetations all contribute to the propensity for embolization.

Acuteness of Infection There is a higher risk of neurological complications with acute endocarditis than with subacute endocarditis. This probably relates to the typical etiological agents noted in acute disease (S. aureus and beta-hemolytic streptococci), the potential for large vegetations or valve damage, and the subsequent increased risk of cerebral embolization. Many authors have observed that the risk of cerebral embolization is highest in the first 1 to 2 weeks of infection, with most patients either presenting with a neurological3,5,10,13,14,33,50 complication or Similarly, the experiencing an acute event in the first 48 hours after diagnosis. risk of embolization decreases as the duration of effective antibiotic treatment increases, with 14,33,50 most events occurring in the first 2 weeks of therapy.

Valvular Vegetations Valvular vegetations are detected by two-dimensional echocardiography in 50 to 80 percent of patients with infective endocarditis and by transesophageal echocardiography (TEE) in 32,36,51–53 Because of its increased sensitivity and ability to more than 90 percent of cases. evaluate the more posteriorly located aortic valve, transesophageal echocardiography appears to be cost-effective as the initial study if clinical suspicion of infective endocarditis is 54,55 Although some older clinical series revealed no significant difference in the high. development4,8,50,56–58 of neurological complications between patients with and without most recent studies have linked either the presence of vegetations, vegetations, increased vegetation size, or vegetation mobility to an increased risk of 13,26,27,32,59–63 The emergence of this relationship may be related to greater embolization. access and improved technical capabilities of echocardiography in the more recent series. A prospective study of 384 patients with infective endocarditis, all of whom had transesophageal echocardiography, found that vegetation length greater than 10 mm and vegetation mobility increased the risk of embolism and that vegetation length greater than 15 14 mm independently increased 1-year mortality. The significance of changes in vegetations on serial echocardiography remains unclear: some investigators report that morphological 64 changes in vegetation size or consistency are not associated with complications, whereas others find that an increase in vegetation size during antibiotic treatment is associated with 33,65,66 A final echocardiographic variable that may be related to increased complications. complications is the presence of spontaneous echo contrast imaging. In a multivariate analysis, Rohmann and colleagues found that spontaneous echo contrast on transesophageal echocardiography was an independent predictor for embolization and 67 hypothesized that this finding signified increased spontaneous platelet aggregation. Current recommendations suggest that repeat echocardiography may be useful if clinical changes

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that suggest treatment failure occur during antibiotic therapy and that it should be performed urgently for unexplained42progression of heart failure, new heart murmurs, or the development of atrioventricular block.

Hematological Risk Factors In addition to spontaneous echo contrast, some reports also present evidence of an 13,68–71 In a series of association between coagulation system activation and embolic events. 91 patients with infective endocarditis, antiphospholipid antibodies were present in 62 percent of patients with embolic events compared to 23 percent of those without such events (P = 0.008) and were also positively correlated with69other markers of endothelial cell activation, have also been thrombin generation, and impaired fibrinolysis. Antiphospholipid antibodies 70 reported to decrease after successful treatment of infective endocarditis. Whether antiphospholipid antibodies independently increase the risk of embolism or this risk results from the association of these antibodies with increased numbers and size of vegetations remains to be determined. Similarly, soluble adhesion molecules have also been reported to 13,71 At present, however, these hematological independently increase the risk of embolism. studies do not clearly aid in risk prediction for patients with infective endocarditis. ISCHEMIC STROKE Ischemic stroke secondary to embolization of friable valvular material is the most common neurological complication of infective endocarditis. Most cerebral emboli are symptomatic, 9 stroke is the but they can be asymptomatic in as many as 35 percent of patients. Ischemic 3,30 and is most presenting symptom of infective endocarditis in up to 20 percent of cases common in the acute stage of the infection, that is, before antibiotic treatment is begun or 4,5,10 Because of this during the first several days of treatment (median time, 4 to 10 days). clustering of symptoms in the acute phase, transient focal neurological symptoms in a febrile patient, especially in the presence of a regurgitant murmur, should always raise suspicion for infective endocarditis.

Clinical Presentation In accordance with their embolic etiology, the majority of ischemic strokes involve the cortex, rather than being confined to subcortical brain tissue. One series found that 62 percent of strokes affected the cerebral or cerebellar cortex (with or without additional subcortical 5 Brainstem strokes account involvement), and only 16 percent were exclusively subcortical. 3 for 10 percent or less of all strokes in infective endocarditis. Because of their cortical involvement, ischemic strokes often present with aphasia, if the dominant hemisphere is involved, or visual or spatial neglect, if the nondominant hemisphere is affected. If the embolus lodges in the posterior cerebral artery, homonymous hemianopia can result. In addition to the more typical focal cerebral hemispheric or brainstem syndromes, 3 in more multiple microemboli are clinically manifest in as many as 11 percent of cases and 72 than 50 percent of cases systematically evaluated with neuroradiological studies. Patients with microemboli can present with nonlocalizing symptoms, including diminished level of consciousness, encephalopathy, or psychosis. Clinical worsening of ischemic stroke may result from a variety of mechanisms, including development of cerebral edema, recurrent embolization and stroke, secondary hemorrhage into the ischemic area, and development of cerebral abscess. Cerebral edema may occur regardless of ischemic stroke mechanism, is more likely to be symptomatic in larger strokes and younger patients, and is typically maximal between 72 to 96 hours after stroke. Recurrent embolization should be suspected if new focal deficits develop; this complication is most likely to occur early in the course of treatment or if infection is uncontrolled. Hemorrhagic transformation of an ischemic stroke occurs in 18 to 42 percent of all patients73with ischemic stroke and has been reported to be more common in cardioembolic strokes. An autopsy series of patients with neurological complications of infective endocarditis found hemorrhagic 18 transformation of an ischemic infarct in 9 of 16 patients. Hemorrhagic transformation of an ischemic stroke is often asymptomatic, although development of intrainfarct hematoma is 73 more likely to be symptomatic than is the development of petechial hemorrhage. The term septic infarction has been used when, several days to72weeks after an ischemic stroke, a cerebral abscess develops within the infarcted tissue (Fig. 6-3). The frequency with which this occurs is not known.

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FIGURE 6-3 This patient presented with left hemiparesis and mitral valve endocarditis. A, Noncontrast head CT showed a focal low-density lesion in the right internal capsule and lentiform nucleus with a central area of hemorrhage (increased density) and cortical hemorrhage in the insula. B, With contrast, large confluent areas of enhancement representing leaky blood–brain barrier can be seen in the right caudate and lentiform nuclei, the insula, and the temporal cortex. C, Fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). MRI 2 days after the head CT showed diffuse increased signal in the regions of CT enhancement and the right thalamus. D, After gadolinium, ring-like enhancement in the area of a previous infarct can be seen, representing possible secondary infection. This pattern is sometimes referred to as a “septic infarction.” This enhancement pattern resolved with antibiotic treatment and without development of a macroabscess.

Seizures Although seizures can occur in patients with infective endocarditis as a result of toxic or metabolic disturbances (e.g., hypoxia, antibiotic toxicity), most often seizures are secondary to ischemic or hemorrhagic stroke. The proportion of patients with seizure as the presenting symptom of infective endocarditis was 2 percent in one large series; 11 percent of patients 3 had seizures during the course of their illness. Seizures that are secondary to focal brain injury are usually focal in nature, with or without secondary generalization, whereas seizures due to metabolic or toxic factors are more often primarily generalized. The development of seizures during antibiotic treatment often signifies clinical worsening from either recurrent stroke, hemorrhagic transformation, or abscess formation. Thus, new onset of seizures

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should always prompt an urgent neuroimaging study. Rarely, seizures are secondary to antibiotic therapy, with imipenem the antibiotic having the greatest seizure proclivity.

Evaluation of Patients All patients with acute focal neurological deficits should have a noncontrast head computed tomography (CT) scan or brain magnetic resonance imaging (MRI). Noncontrast CT allows for the most accurate distinction between hemorrhagic and ischemic events and can be done more quickly than MRI in most settings. If infective endocarditis is known or suspected, head CT with and without contrast may be useful; areas of increased contrast enhancement, representing possible cerebral abscess may then be distinguished from areas of ischemia (Fig. 6-3). Although published radiological series are few, brain MRI appears to be more sensitive than CT in detecting the multiplicity of neurological lesions seen in infective endocarditis. In one series, multiple lesions were found in 10 of the 12 patients studied, with embolic branch infarction (8), multiple emboli and microabscesses (7), and hemorrhagic 72 stroke (4) being the most common findings. MRI findings have been categorized into four patterns: (1) embolic infarction, (2) multiple patchy infarctions (nonenhancing), (3) small nodular or ring-enhancing white matter lesions (probably microabscesses), and (4) 74 hemorrhagic infarctions (intraparenchymal or subarachnoid). Microabscesses usually develop several days75after the ischemic stroke and can be asymptomatic or associated with clinical deterioration. Multiple microabscesses are often responsible for nonfocal encephalopathy. MRI is superior to CT for symptoms referable to the brainstem or cerebellar regions. Once cerebral embolism has occurred, serial neuroimaging studies or subsequent angiography can be performed to assess the presence of secondary complications such as microabscess or macroabscess formation, hemorrhagic transformation of ischemic stroke, or development of a mycotic aneurysm. Most authors agree that patients without neurological symptoms do not require cerebral angiography and that those with intracerebral hemorrhage 76 do require angiography, but whether to perform cerebral angiography after ischemic stroke in patients with infective endocarditis is especially controversial. The 2005 AHA statement on diagnosis and treatment of infective endocarditis suggests that diagnostic pursuit of mycotic aneurysms should be considered in patients with severe headache, erythrocytes or 42 xanthochromia in CSF, or focal neurological signs. Based on the evidence that subarachnoid hemorrhage can occur without previous symptoms in more than 50 percent of patients with mycotic aneurysm, some authors recommend that all patients with cerebral embolism have arterial imaging performed at some time beyond 48 77 hours after the initial event. The basis for the timing of this recommendation is that mycotic aneurysm formation after septic embolization takes at least 48 hours to develop, and angiography immediately after embolization may therefore be negative. Although some studies suggest a more rapid angiographic evaluation based on78early mycotic aneurysmal rupture within 24 hours of the onset of neurological symptoms, others argue that a mycotic aneurysm develops in so few patients that angiographic complications present a greater risk. Using the published literature, van der Meulen and colleagues estimated the probability of 12-week survival in patients with infective endocarditis and ischemic stroke and found no added survival benefit for patients who had angiography, largely owing to the low prevalence of mycotic aneurysms and the low risk of their rupture in patients with adequate antibiotic 76 therapy. Since so few patients with infective endocarditis harbor mycotic aneurysms, the need to perform initial or serial angiography depends on the clinical presentation and proposed treatment. Patients with hemorrhagic stroke or hemorrhagic transformation of an ischemic stroke should have angiography to delineate mycotic aneurysm from arteritis because this distinction often influences subsequent evaluation and treatment. Patients with ischemic or hemorrhagic stroke who require long-term anticoagulation for mechanical valves or treatment of systemic thromboembolism, for example, may also benefit from angiography to exclude a mycotic aneurysm. Patients with ischemic stroke without hemorrhagic transformation or any indication for long-term anticoagulation probably do not benefit from repeated neuroimaging studies or conventional angiography. The diagnosis of infective endocarditis depends on the documentation of an infecting organism on serial42blood cultures and, in part, on the presence of valve abnormalities on echocardiography. Echocardiography is also important in assessing valve function and excluding conditions such as valve thrombosis or abscess formation that would change clinical management. Transesophageal echocardiography is more sensitive to mitral and aortic valve pathology and has been reported to change patient management in as many as 79 one third of cases. Whether serial echocardiography provides data that reliably predict risk of subsequent thromboembolism or otherwise influence management is not known.

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CSF examination is regarded by some authors as part of the standard evaluation of patients with infective endocarditis and neurological symptoms. The manner in which the CSF results will influence therapy, however, is not clear. The interpretation of CSF findings as a diagnostic tool for infective endocarditis in patients with acute stroke is complicated by the tendency for patients with cerebral embolism unrelated to endocarditis also to have mild to moderate increases in either white blood cells, red blood cells, or protein concentration in the 80,81 In one large series,3 CSF was abnormal in 48 of 69 patients with CSF shortly after stroke. infective endocarditis in whom it was examined. Of these, 28 percent had a purulent profile, 25 percent were aseptic, 13 percent were hemorrhagic, and 30 percent were normal. With the exception of purulent CSF in patients with meningismus, the type of neurological event in these patients did not correlate with the CSF pattern. For these reasons, CSF examination does not usually aid in the diagnosis or management of patients with neurological symptoms and infective endocarditis.

Treatment of Ischemic Stroke The cornerstone of treatment of infective endocarditis is appropriate antibiotic therapy directed at the infecting organism. Numerous studies have shown that the risk of either initial or recurrent thromboembolism decreases sharply after the first few days of adequate 4–7,33,51 Although this association may result in part from an ascertainment antibiotic therapy. bias, it is critical to ensure that antibiotics are begun empirically, immediately after drawing initial blood for cultures (preferably three sets from separate sites) in febrile patients with stroke in whom infective endocarditis is among the differential diagnoses. Since effective long-term antimicrobial therapy will be required to treat infective endocarditis, the isolation and susceptibility testing of the pathogen are of critical importance. Involvement of an infectious diseases consultant is recommended. Thorough discussion of a current approach to diagnosis and antimicrobial treatment in various clinical scenarios can be found in the 2005 42 AHA guideline statement. Recent studies have addressed the question of whether acute antiplatelet therapy is beneficial in reducing the risk of thromboembolism in infective endocarditis. In animal models of the disease, aspirin or aspirin plus ticlopidine has been found to reduce vegetation weight, echocardiographic evidence of vegetation growth, bacterial85titer of vegetations, or systemic 82–84 Although one pilot study confirmed this finding, a larger randomized controlled emboli. trial found no reduction of embolic events in patients treated with 325 mg aspirin compared to those given placebo, and there was a nonsignificant trend toward increased bleeding in the 86 aspirin-treated group. Based on this study, routine use of antiplatelet therapy for the purpose of decreasing embolic risk in patients with acute infective endocarditis is not 42 recommended. Anticoagulation in patients with infective endocarditis remains a controversial and complicated topic. Hemorrhagic complications are clearly more common in anticoagulated patients, with one retrospective study finding that 50 87 percent of the hemorrhages occurred in the 13 percent of subjects receiving anticoagulation. However, patients with mechanical prosthetic valves may be receiving long-term anticoagulation, and the decision as to whether and for how long to withhold anticoagulants in this setting is especially difficult. Given the divergent management strategies required, it is useful to consider anticoagulation in native and prosthetic valve endocarditis separately. Anticoagulation in Native Valve Endocarditis Many authors have documented an increased risk of hemorrhagic complications in anticoagulated patients with native valve endocarditis and ischemic stroke, and the risk of recurrent embolism is low in patients receiving appropriate antibiotic therapy. Accordingly, there appears to be little benefit to anticoagulating patients with native valve endocarditis. Whether lower-level anticoagulation (e.g., for prevention of deep venous thrombosis) is safe in patients with stroke and infective endocarditis is unknown. Because other strategies, such as using sequential compression devices, have been shown to be equally efficacious, a conservative approach is to use these nonpharmacological methods of prevention of venous thrombosis. Anticoagulation in Prosthetic Valve Endocarditis Patients with bioprosthetic valves are typically not on long-term anticoagulation and have a 38,46 ; thus, lower risk of stroke in infective endocarditis than patients with mechanical valves the same rationale applies to them as for patients with native valve endocarditis. Patients with

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mechanical prostheses who have endocarditis and stroke, however, present especially difficult management dilemmas. Most studies indicate that the proportions of patients with 4,5 native and prosthetic valves having endocarditis and cerebral embolism are similar ; initiating anticoagulation in a previously nonanticoagulated patient with infective endocarditis and a mechanical valve thus appears unwarranted. If a patient with a mechanical valve is receiving long-term anticoagulation and develops a cerebral embolus as a complication of infective endocarditis, the decision as to whether to continue anticoagulation or temporarily withhold it depends on several factors, including the size of the stroke and type of mechanical valve. Some authors have suggested that anticoagulation decreases the risk of cerebral embolism and87,88 should be instituted in all Because larger strokes, patients with newly diagnosed prosthetic valve endocarditis. especially those secondary to emboli, may be more likely to develop secondary hemorrhagic 76 complications, other authors favor withholding anticoagulation for several days in patients with acute cerebral embolism and mechanical valve endocarditis, especially when S. aureus 89,90 is the infecting organism. Regardless of the timing of anticoagulation, it is safer to convert the patient from oral anticoagulation to the more controlled intravenous route of therapy during the acute phase of infective endocarditis. Some authors have not found a decrease in cerebral emboli in patients 46 a with acute prosthetic valve endocarditis anticoagulated with warfarin or have documented 88 rate of hemorrhagic complications as high as 36 percent in this subgroup of patients, thus leading to the position that anticoagulants should not be initiated and perhaps should be temporarily discontinued in previously anticoagulated patients with prosthetic valve 5,91 If temporary discontinuation of anticoagulation is considered, determination endocarditis. of the patient's type of mechanical valve and consultation with a cardiologist or a cardiothoracic surgeon concerning the risk of valve thrombosis with that valve type will help guide the decision about how long the patient can safely remain off anticoagulation. Although the use of anticoagulants remains controversial, converting to the most controllable (i.e., intravenous) form of therapy and frequent monitoring of anticoagulation parameters (activated partial thromboplastin time or international normalized ratio [INR]) are recommended. Solenski and Haley recommend that large cerebral infarctions, hemorrhage on CT scan, presence of mycotic aneurysm, uncontrolled infection or infection with S. aureus, history of bleeding diathesis, and possibly advanced patient age are factors arguing against the use of anticoagulation in patients with neurological complications of mechanical valve 92 endocarditis.

Surgical Treatment Valve replacement is not usually recommended as a therapy for preventing initial or recurrent stroke, although multiple emboli, infection with a “virulent”26,61 organism, and the presence of Typically, surgery is reserved for large vegetations may be relative indications for surgery. patients with acute or refractory congestive heart failure, perivalvular abscess, unstable valve prosthesis, continued embolism, infection with a pathogen resistant to effective antimicrobial agents, or inability to clear the infection. If surgery is required, the timing of the procedure in a patient with ischemic or hemorrhagic stroke is controversial. If surgery is contemplated to prevent embolization, early surgery is associated with greatest benefit since the risk of embolization is greatest in the first 2 weeks of the infection. If stroke has occurred, the first 72 to 120 hours after stroke are the period of maximal risk of cerebral edema and disruption of cerebral autoregulation; thus, most authors recommend delaying cardiac surgery for at least 1 week after stroke if possible. One retrospective assessment of 247 patients operated on for left-sided native valve endocarditis found that operation at approximately 3 weeks after the neurological deficit appeared was as safe for patients with previous neurological 93 complications as for those without neurological manifestations of endocarditis. HEMORRHAGIC STROKE Intracerebral hemorrhage in infective endocarditis may be primary or secondary to ischemic stroke or other pharmacological or hematological conditions (Table 6-3; Fig. 6-4). Of the primary hemorrhages, intraparenchymal and subarachnoid hemorrhage are most common. Secondary transformation of an ischemic stroke is the most common form of intracerebral hemorrhage in17,18 infectious endocarditis, accounting for 24 to 56 percent of all hemorrhages in Intracerebral hemorrhage is a much less common complication than this condition. ischemic stroke, accounting for 2 to 17 percent of all neurological complications. In one recent series, only 8 cases of subarachnoid hemorrhage occurred among 489 patients with infective endocarditis; in 6 of these, no cause for the hemorrhage was identified by autopsy or 94 aneurysms in patients with infective angiography. The prevalence of asymptomatic mycotic 17 endocarditis is not known, but seems to be small.

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FIGURE 6-4 This patient had tricuspid valve endocarditis secondary to intravenous drug abuse. Initially, the patient had no neurological symptoms but left the hospital against medical advice after completing 6 days of antibiotic therapy. He returned 2 days later with a decreased level of consciousness and a right gaze preference. A toxicology screen was positive for cocaine. Noncontrast axial head CT at that time showed an approximately 3 × 4-cm hemorrhage in the right frontal lobe with intraventricular extension and subfalcial herniation. Cerebral angiography did not show a mycotic aneurysm. Echocardiography showed a large patent foramen ovale with right-to-left shunting and vegetations on the tricuspid valve. This case underscores several clinical points: (1) neurological complications of endocarditis are more common during uncontrolled infection; (2) neurologically asymptomatic patients may have silent cerebral emboli, particularly in the nondominant hemisphere; and (3) patients with right-sided endocarditis may develop cerebral embolization via a right-to-left shunt.

As described previously, in at least 40 percent of patients, septic embolization is the first 3,17,77 Depending on the location of the embolus, event leading to intracerebral hemorrhage. arteritis with secondary vessel rupture or development of a mycotic aneurysm may occur. Several series have documented that hemorrhagic complications are more common in anticoagulated patients, with one third of patients with endocarditis and subsequent 17 intracerebral hemorrhage either anticoagulated or having an underlying bleeding diathesis. In one series, 23 percent of all intracerebral hemorrhages occurred in the 3 percent of 3 50 percent of all such bleeds occurred in the 13 percent anticoagulated patients ; in another, 87 of patients who were anticoagulated. These observations have led to the consensus to avoid anticoagulation in native valve endocarditis and to a judicious approach to its use in

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prosthetic valve endocarditis. Other conditions that sometimes accompany infective endocarditis may also predispose to bleeding complications, including disseminated intravascular coagulation, thrombocytopenia, and vitamin K deficiency. Although mycotic aneurysms are most commonly found in the intracranial vessels, rarely these aneurysms may involve the extracranial carotid (Fig. 6-1), thoracic, or abdominal 95–97 Management in these cases should be individualized but may include surgical or vessels. endovascular interventions or vessel ligation.

Clinical Presentation Intracerebral hemorrhage usually presents with focal neurological symptoms as in ischemic stroke, but nonlocalizing symptoms, such as headache and decreased level of consciousness, may also predominate. Seizures may occur at the onset of the hemorrhage or later in its course. If subarachnoid hemorrhage occurs, either from rupture of an arteritic vessel or from a mycotic aneurysm, meningismus may be a prominent feature. Headaches 94 may be more diffuse and subacute than is typical with saccular aneurysm rupture. A transient ischemic attack (TIA) may precede intracerebral hemorrhage in as many as 25 98 percent of patients or may be the presenting symptom.

Evaluation As in ischemic stroke, noncontrast head CT is the best initial neuroimaging procedure. The hematoma appears as an increased-density signal on CT (Fig. 6-4) and can be localized to the intraparenchymal, subarachnoid, subdural, or intraventricular space. Hemorrhagic transformation of an ischemic infarct is most often patchy and may follow the contour of the gyri (Fig. 6-3A), but may appear as a homogeneous hematoma within an infarct. MRI is also useful and can better delineate stroke in the posterior fossa, although the signal change of blood products over time may make MRI more difficult to interpret in hemorrhagic stroke. A clue to the presence of an underlying mycotic aneurysm may be a focal area of cortical 99 enhancement adjacent to an area of hemorrhage. All patients with intracerebral hemorrhage complicating infective endocarditis should have imaging of the cerebral vasculature to visualize any underlying mycotic aneurysm. Since mycotic aneurysms tend to be small and to occur distally, rather than at the more proximal arterial branch-points as do saccular aneurysms, conventional cerebral angiography is preferred over magnetic resonance angiography (MRA) or CT angiography (CTA) for aneurysm detection. Although the resolution of these techniques continues to improve, at present they are adequate for screening in patients with infective endocarditis and ischemic stroke but should not be the primary diagnostic tool for evaluating patients with infective endocarditis and hemorrhagic stroke. They may be useful, however, for serial monitoring of aneurysm size following conventional angiography. One study reported the utility of monitoring mycotic aneurysms with serial thin-slice CT or MRI and found that all of six aneurysms identified with conventional angiography could be successfully followed for 6 to 8 100 weeks. Repeat angiography at the end of antibiotic treatment confirmed the resolution (in 2) or persistence (3 enlarged, 1 unchanged) of the aneurysms.

Treatment of Hemorrhagic Stroke Intraparenchymal Hemorrhage The mainstay of treatment for either primary or secondary intracerebral hemorrhage in patients with infective endocarditis is the same as that for cerebral emboli: effective treatment of the underlying infectious organism. This is especially true for patients with pyogenic arteritis but is also critical for the treatment of mycotic aneurysms. Some patients with intracerebral hemorrhage and progressive neurological deterioration, either from expanding hematoma or edema, may benefit from surgical evacuation of the clot, but no firm guidelines exist for assisting with management in these cases. Similarly, although recombinant factor VIIa has been used successfully to reduce hematoma growth and improve outcomes in 101 patients with intracerebral hemorrhage, no data are available for its use in patients with infective endocarditis and cerebral hemorrhage. The increased risk of thrombosis and stroke associated with its use would be of concern in this population. As discussed previously, patients with mechanical valves and receiving anticoagulation therapy may have their anticoagulant discontinued temporarily or converted to an intravenous form. All patients should have close neurological monitoring in an intensive care setting because deterioration from recurrent hemorrhage or edema is not uncommon.

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Mycotic Aneurysms The natural history of mycotic aneurysms is that approximately one third resolve with 6 to 8 weeks of antibiotic treatment, one third remain unchanged in size, and the remaining one third 17,78,100,102,103 are equally divided among those that increase and those that decrease in Because of their propensity to resolve with antibiotic therapy, the evaluation size. and treatment of mycotic aneurysms are controversial. Aspects of care that remain unclear are whether serial angiography is needed in patients with mycotic aneurysms and the indications for surgical therapy. Because more than one third of mycotic aneurysms either are unchanged in size or enlarge during antibiotic therapy, some authors recommend serial angiography every 2 weeks during 77,104,105 antibiotic treatment.104–106 If an aneurysm enlarges, surgical treatment to prevent rupture Late hemorrhage from a ruptured mycotic aneurysm in patients who may be advocated. have completed adequate 77 antibiotic therapy is rare, occurring in none of 122 patients with a 17,107 As discussed previously, the need mean 40-month follow-up, but it has been reported. for ongoing or subsequent long-term anticoagulation is another factor that may favor angiographic surveillance and surgical treatment, especially in patients with known cerebral embolization. Once an aneurysm is discovered, controversy also exists about its treatment. Asymptomatic aneurysms are often treated medically, with surgical intervention reserved for those that 105,106 Although either enlarge or do not resolve after antibiotic therapy is completed. symptomatic aneurysms may also resolve with antibiotic treatment and the risk of rebleeding is low, some authors105,106 favor surgical treatment of symptomatic mycotic aneurysms in addition This recommendation is usually based on the fear of recurrent to antibiotic therapy. bleeding, the associated increased morbidity and mortality, and the potential development of new aneurysms. Aneurysm accessibility and number are other features that influence the decision for surgical treatment; single aneurysms in a peripheral location are more likely to be treated surgically. Inaccessible aneurysms may be successfully treated endovascularly, 108–111 although the management and outcomes in these cases are highly individualized. Whether to undertake surgery at presentation or to wait until the completion of antibiotic therapy is debatable. For unruptured mycotic aneurysms, some authors have suggested 77,104,105 although the proportion of serial angiography every 2 weeks during antibiotic therapy, aneurysms that enlarge and thus may require urgent surgery is small. Since at least half of mycotic aneurysms persist after adequate antibiotic treatment and since new aneurysms can appear, it seems reasonable to repeat angiography, either conventional or MRA, at the conclusion of antibiotic therapy (usually 4 to 6 weeks) or to undertake serial imaging with a noninvasive procedure, such as MRA. Accessible aneurysms that persist after adequate antibiotic therapy or that enlarge during therapy are usually treated surgically. Because mycotic aneurysms often lack a defined neck amenable to clipping, other surgical techniques, including wrapping, excision, or endovascular obliteration, may be necessary. Because mycotic aneurysms are often difficult to locate at the time of surgery, new techniques, including stereoscopic brain-surface imaging 112 113 with MRA and stereotactic angiographic localization, are sometimes used to aid in aneurysm localization. CEREBRAL INFECTION Cerebral infection, most commonly abscess or meningitis, has been reported as a primary complication in 6 to 31 percent of cases, although these cases typically represent less than 10 percent of the entire population of patients with endocarditis and neurological complications (Table 6-1). These infections most typically occur after cerebral embolism; infection arising without clinical evidence of prior cerebral embolization is unusual. Encephalitis has also been reported, although the usual pathology in these cases is multiple emboli with microabscess formation. Meningitis accounts for 4 to 7 percent of all neurological manifestations of infective endocarditis and is reported to be more common with either S. aureus or S. pneumoniae 3,114,115 infections. When meningitis is associated with involvement of the cerebral cortex, evidenced by gyral enhancement on MRI, the terms cerebritis and meningoencephalitis are used. Rarely, cerebritis can lead to the development of a parameningeal abscess in the cortex. Meningitis typically results from septic emboli to the meningeal vessels with subsequent CSF colonization. Less commonly, meningitis is nonseptic, resulting from sterile inflammation of the meninges due to blood products or circulating immune complexes in the CSF.

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Cerebral abscesses are rare, accounting for approximately 2 percent of all neurological 116 Small “microabscesses,” often defined as complications in infective endocarditis. 3 abscesses smaller than 1 cm , are more common than “macroabscesses” but still account for less than 4 percent of all neurological complications. Cerebral abscess usually develops as the result of septic embolus and is not necessarily preceded by clinical symptoms. Radiographically, infarction-related abscesses are usually small and multiple and 72,74 demonstrate areas of nodular or ringlike enhancement in an area of prior ischemic stroke (Fig. 6-3D). Abscess has also been reported as a consequence of mycotic aneurysm or 117 septic arteritis.

Clinical Presentation Although the clinical diagnosis of meningitis is infrequent in infective endocarditis, symptoms of meningitis are not. In one series, meningeal symptoms or signs occurred in more than 40 31 percent of 84 patients with endocarditis. In addition to meningismus, headache, encephalopathy, cranial neuropathies, seizures, and increased intracranial pressure may occur. These symptoms may be subtle, especially in the elderly, and, when associated with fever, elevated white blood cell count, and regurgitant murmur should prompt an urgent evaluation for infective endocarditis.

Evaluation All patients with known or suspected infective endocarditis and neurological symptoms, whether focal or nonfocal, should have imaging with noncontrast head CT prior to lumbar puncture. This is critical because multiple embolic strokes, intracerebral hemorrhage, and abscess may all present with nonfocal symptoms and can also cause significant compartmental increases in intracranial pressure, thus increasing the risk of cerebral herniation. Lumbar puncture should not be done in any patient with a focal lesion and evidence of mass effect on neuroimaging studies. Because patients with endocarditis have a propensity toward hematological abnormalities, coagulation tests, including a platelet count and INR, are especially important before one performs a spinal tap.

Treatment of Cerebral Infection As for any type of meningitis, the goal of treatment is adequate antibiotic therapy to which the infecting organism is sensitive and that has good CSF penetration and activity in brain abscesses. Both microabscesses and macroabscesses usually respond to antibiotic treatment, although macroabscesses may occasionally produce significant mass effect and thus require stereotactic aspiration or surgical drainage. OTHER NEUROLOGICAL COMPLICATIONS Other extracerebral neurological complications may rarely occur. Although cerebral and 9 systemic emboli appear to occur with similar frequency, cerebral neurological complications predominate over extracerebral complications, probably because the brain receives more blood flow than peripheral neurological tissues and because cerebral complications are more likely to be symptomatic. Mononeuropathy simplex or multiplex has been reported in as many as 1 percent of patients 118 with infective endocarditis. Both peripheral and cranial nerves may be involved, and viridans streptococci appear to be an especially prominent infectious organism in these cases. Discitis, occasionally with associated abscess or osteomyelitis, has also been reported and is more common with S. aureus infection. Other rare sites of embolization include the spinal cord and the retina. SUGGESTED MANAGEMENT ALGORITHM The management of neurological complications of infective endocarditis is not standardized and substantial variations in care may be necessary based on the individual patient's characteristics. Nonetheless, it is helpful to consider a treatment algorithm that includes pathways for the major neurological manifestations of the disease (Fig. 6-5). This algorithm differs from some proposed previously in that cerebral angiography is not suggested for all patients with ischemic stroke, lumbar puncture is not recommended for all patients with 92,105 As many neurological complications, and serial angiography every 2 weeks is optional. other authors have suggested, the two keys to managing patients, regardless of any neurological complications, are (1) a high level of suspicion for the possibility of infective endocarditis and (2) prompt initiation of appropriate antibiotic therapy after obtaining multiple

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sets of blood cultures.

FIGURE 6-5 Suggested management algorithm for patients with focal neurological deficits and known or suspected infective endocarditis. Factors favoring either surgical or medical treatment of mycotic aneurysms are presented; management of these cases is highly individualized. Repeat angiography at the conclusion of medical therapy is suggested for all patients with known mycotic aneurysms and may be considered either for patients with intracerebral hemorrhage and a negative initial angiogram or for patients with ischemic stroke who require long-term anticoagulation. LP, lumbar puncture, MRA, magnetic resonance angiography.

PROGNOSIS Among patients with infective endocarditis, mortality is increased in those with neurological 3,4,9,10 Estimates of in-hospital mortality in various complications compared to those without. clinical series range from 16 to 58 percent compared with 14 to 20 percent for patients with and without neurological complications, respectively, although a population-based study from 12 France reported 16 percent in-hospital mortality in 1999. Mortality is higher in infections with more virulent organisms,14,15,39,119 with several large cohort studies showing an association between S. aureus and mortality. Intracerebral hemorrhage appears to confer added risk, as 17,30,119 mortality in these patients is reported to be 40 to 90 percent. Although rare, mycotic 106 aneurysm rupture is associated with even higher mortality. Mortality in patients with unruptured mycotic aneurysms appears no different from16the aggregate mortality rate in all patients with neurological manifestations of endocarditis. A multicenter, prospective study of 384 patients with infective endocarditis found that increasing age, female gender, serum creatinine greater than 2.0 mg/L, moderate to severe congestive heart failure, infection with S. aureus, increased medical comorbidity, and 14 vegetation length greater than 15 mm were all independently associated with 1-year mortality. Another study of factors related to in-hospital death also found an association with S. aureus infection and comorbidity as well 119 as embolic events and diabetes.

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http://www.merckmedicus.com/pp/us/hcp/printpage.jsp 3,5,6,77

The risk of recurrent neurological events, either embolic or hemorrhagic, is quite low.5 Recurrent ischemia has been documented in less than 0.5 percent of cases per day and 77 recurrent hemorrhage in less than 1 percent of all cases. Elimination of recurrent events 33,46,50 appears to depend more on effective antibiotic treatment than on other specific therapy. CONCLUDING COMMENTS Although infective endocarditis has evolved over the past several decades with regard to frequency of involvement of different valves and prevalence and susceptibility of infecting organisms, the proportion of patients with neurological manifestations and the type of neurological complications remain remarkably consistent. Most neurological complications are caused by embolization of friable valvular material resulting in either ischemic or hemorrhagic stroke. A high index of suspicion for infective endocarditis as the cause of stroke is critical because common treatments for acute stroke, such as thrombolysis or anticoagulation, are contraindicated in patients with native valve endocarditis and ischemic stroke. Management of patients with endocarditis and mechanical prosthetic valves is complicated, and decisions about continued anticoagulation in these patients must be individualized. Similarly, decisions about medical or medical plus surgical treatment of mycotic aneurysms must also be individualized because a number of clinical factors may influence treatment. Although many clinical decisions in patients with neurological manifestations of infective endocarditis must be individualized, it is clear that the cornerstone of prevention and treatment of all neurological complications is rapid delivery of appropriate antibiotic therapy. ACKNOWLEDGMENTS Dr. Williams is supported by grants from the Department of Veterans Affairs and the National Institutes of Health. Previous

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Keyword Index

Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 7 Neurological Complications of Hypertension S. CLAIBORNE JOHNSTON • JACOB S. ELKINS •

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EPIDEMIOLOGY PATHOPHYSIOLOGY EVALUATION AND TREATMENT STROKE CEREBRAL ANEURYSMS Unruptured Cerebral Aneurysms Subarachnoid Hemorrhage INTRACEREBRAL HEMORRHAGE LACUNAR INFARCT PERIVENTRICULAR WHITE MATTER DISEASE BINSWANGER'S DISEASE CADASIL CAROTID ARTERY STENOSIS INTRACRANIAL ATHEROSCLEROSIS AORTIC ARCH ATHEROSCLEROSIS CARDIAC EMBOLUS DEMENTIA PERIPHERAL NEUROPATHY HYPERTENSIVE ENCEPHALOPATHY ECLAMPSIA IMMUNOSUPPRESSION

Blood pressure was first measured in 1707 by an English divinity student, Stephan Hales, 1 using a glass tube attached directly into the arteries of animals. Methods of measurement improved slowly over the next 200 years, with Nikolai Korotkoff describing the modern cuff-and-stethoscope technique in 1905. Hypertension was recognized as an indicator of poor prognosis by Theodore Janeway, who published a case series of 7,872 hypertensive patients gathered from 1903 to 1912, in which hypertension was defined as a systolic blood pressure greater than 160 mmHg. He found a mean survival of 4 to 5 years after the development of symptoms of hypertension, with stroke being an important cause of death. Hypertension was initially considered a compensatory phenomenon rather than a disease in itself. Even into the 1940s, physicians were concerned that lowering blood pressure would exacerbate end-organ damage, particularly in the kidneys. Treatment options were not

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available until 1925, when surgical sympathectomy was shown to reduce blood pressure without impairment in renal function. The first antihypertensive medication, tetraethylammonium, was used in a patient in 1946, but the agent was poorly tolerated because of severe anticholinergic side effects. A tolerable oral agent was not available until 1957, when chlorothiazide was shown to reduce blood pressure in patients with essential hypertension and rapidly became the most commonly prescribed medication. Both acute hypertension and chronic hypertension produce neurological disease. Acute hypertension is associated with hypertensive encephalopathy, an uncommon presentation since the widespread identification and treatment of hypertension. Chronic hypertension is associated with stroke, which is its most important neurological complication. All stroke subtypes are linked to hypertension, including ischemic infarction, intraparenchymal hemorrhage, and aneurysmal subarachnoid hemorrhage. Chronic hypertension is also associated with dementia and with peripheral neuropathy in those with diabetes. EPIDEMIOLOGY Both systolic and diastolic blood pressures are distributed approximately normally in the population. For convenience, physicians have defined pathological states such as hypertension based on specific blood pressure thresholds, typically a systolic blood pressure of 140 mmHg or greater or a diastolic blood pressure of 90 mmHg or greater, or both. Thus defined, hypertension is common, affecting2 approximately 50 million individuals in the United States and as many as 1 billion worldwide. In the Framingham study, individuals who were normotensive3at age 55 had an approximately 90 percent lifetime risk of developing hypertension. Despite the frequent division of blood pressure into diagnostic categories such as hypertension and normotension, there is no obvious threshold at which higher blood pressure begins affecting the risk of complications, and even patients with diastolic blood pressures of 80 to 90 mmHg are at increased risk of stroke compared with those with blood 4 pressures of 70 to 80 mmHg (Fig. 7-1). Reflecting a growing awareness of the continuous risk associated with blood pressure, blood pressures in the range of 120–140/80–90 mmHg, 2 once considered to be “normal,” are now labeled as “prehypertensive.” Throughout much of the twentieth century, blood pressure risk was assessed according to the diastolic blood pressure, and it was not until 1993 that systolic blood pressure was formally incorporated into 5 the definition of hypertension in U.S. guidelines. Since that time, however, it has been increasingly recognized that systolic blood pressure is somewhat more informative than 6 diastolic blood pressure at predicting future cardiovascular events.

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FIGURE 7-1 Relative risks of stroke. Estimates of the usual diastolic blood pressure (DBP) in each baseline DBP category are taken from mean DBP values 4 years after baseline in the Framingham study. Solid squares represent disease risks in each category relative to risk in the whole study population; sizes of squares are proportional to the number of events in each DBP category; and 95 percent confidence intervals for estimates of relative risk are denoted by vertical lines. (From MacMahon S, Peto R, Cutler J, et al: Blood pressure, stroke, and coronary heart disease. Lancet 335:764, 1990, with permission.)

PATHOPHYSIOLOGY In the brain, the primary pathophysiologic process of hypertension is related to increases in vasomotor tone and peripheral arterial resistance. Acute elevation in blood pressure results in constriction of small arteries in the brain in a compensatory response termed autoregulation. Brain blood-flow is maintained at a relatively constant level over a range of pressures. At high pressures, vasoconstriction is thought to be protective by reducing pressure at smaller, more distal vessels. Acute severe hypertension overwhelms normal autoregulation at a mean arterial pressure of approximately 150 mmHg, with increased cerebral blood-flow occurring above this pressure threshold. Vasoconstriction in acute hypertension is patchy, and some small vessels are exposed to high pressures, which may lead to endothelial injury and focal 7 breakdown of the blood–brain barrier. Acute hypertensive encephalopathy is a fulminant presentation of this process. Fibrinoid necrosis of small vessels may also occur, lowering the threshold for future ischemic and hemorrhagic events. Chronic hypertension results in8 cerebral vascular remodeling. The media hypertrophies, and the lumen becomes narrowed. These changes are protective, with reduction in wall tension 9 and shifting of the autoregulation curve to allow compensation at higher blood pressures. However, vascular remodeling is accompanied by endothelial dysfunction, with impaired relaxation and poor compensation for hypoperfusion. The result is greater susceptibility to 7 ischemic injury due to reduced collateral flow. Hypertension also predisposes to atherosclerosis. Hypertension is proinflammatory and is 10 accompanied by increased plasma oxygen free radicals. Free radicals induce vascular

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smooth muscle cell proliferation and may oxidize low-density lipoproteins, which in turn promotes macrophage activation and monocyte extravasation. Angiotensin II is elevated in many hypertensives and may play a direct role in atherogenesis independent of its effects on 11 blood pressure. It directly stimulates smooth muscle cell growth, hypertrophy, and 10 lipoxygenase activity, with resultant inflammation and low-density lipoprotein oxidation, thus accelerating atherosclerosis. Angiotensin II also stimulates the production of transforming growth factor β (TGF-β), a cytokine that is linked to fibrosis in a number of disease states. In animal models, transforming growth factor β appears12to play a causal role in the development of hypertension and pathological vessel remodeling. EVALUATION AND TREATMENT The gold standard of blood pressure measurement is auscultation using a mercury sphygmomanometer. Newer devices can provide accurate readings but require calibration. Blood pressure should be measured in the seated position after a 5-minute rest with the patient's feet resting on the floor and the arm supported at heart level during the measurement. Accurate readings depend on the use of an appropriate-sized cuff with the bladder covering at least 80 percent of the arm. The classification of blood pressure into specific diagnostic categories is based on the average of two or more readings on each of 13 two or more office visits. A complete history and physical examination with basic laboratory measurements are essential to evaluate for identifiable causes of hypertension and assess risk. Several patient characteristics may suggest an identifiable cause of hypertension including young age, severe hypertension, hypertension that is refractory to multiple interventions, and physical or laboratory findings suggestive of endocrinological disorders, such as truncal obesity or hypokalemia. Abdominal bruits or decreased 14 femoral pulses may also be an indicator of renovascular disease or coarctation of the aorta. Lifestyle modification is recommended as an initial therapy for patients with blood pressure of 2 120/80 mmHg or higher. Effective lifestyle interventions include weight loss, limited alcohol intake, aerobic physical activity, adequate potassium intake (approximately 90 mmol/day), reduction in sodium intake, and dietary regimens such as the Dietary Approaches to Stop 15 Hypertension (DASH) eating plan. Antihypertensive medications are recommended in addition to lifestyle measures for patients with blood pressure of 140/90 mmHg or higher, and when the blood pressure is 130/80 mmHg or higher in those with diabetes and chronic kidney disease. For subjects without a history of cardiovascular disease or other compelling indication, initiating therapy with a thiazide diuretic such as chlorthalidone, is generally recommended. In the Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT), involving more than 33,000 participants, therapy with chlorthalidone was either equivalent or superior to lisinopril and amlodipine for the primary prevention of cardiovascular endpoints, with a 16 particular benefit for African American subjects both in terms of safety and efficacy. When the blood pressure is 160/100 mmHg or higher, initiating therapy with two-drug combinations 2 is generally recommended. There are many benefits to treating hypertension, especially reductions in myocardial infarctions, congestive heart failure, retinopathy, renal failure, and overall mortality. The focus of the remainder of this chapter is on specific neurological complications of hypertension and the unique aspects of treatment that they necessitate. STROKE Of all the identified modifiable risk factors for stroke, hypertension appears to be the most important, owing to its high prevalence and its associated three- to fivefold increase in stroke 17 percent of strokes could be risk. Based on epidemiological data, approximately 50 18 prevented if hypertension were eliminated (Table 7-1). Even small reductions in blood pressure result in large reductions in stroke risk. For example, in a meta-analysis of 37,000 hypertensive subjects from 14 studies, a reduction of 5 to 6 mmHg in diastolic blood pressure 19 with active treatment was associated with a 42 percent reduction in stroke risk. The benefits of blood pressure reduction on stroke risk extend similarly to the elderly with isolated elevations in systolic blood pressure. In the Systolic Hypertension in the Elderly Program (SHEP) trial of 4,736 subjects 60 years and older, a 36 percent reduction in stroke was seen with a20,21 12-mmHg decline in systolic pressure, a finding confirmed in other large randomized Although there is still some uncertainty surrounding the treatment of blood pressure trials. in the oldest old (>85 years), the best available data suggest that benefits will be comparable 22 with those seen in younger individuals. Stroke rates have generally declined worldwide, especially throughout the 1970s and 1980s, although more recently they appear to have 23 plateaued (Figs. 7-2 and 7-3). Although these historic trends are not entirely explained by

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better control of blood pressure, the rates of decline have roughly paralleled increased use of antihypertensive medications, suggesting that benefits of blood pressure therapy observed in 24 randomized trials have been at least partially realized in community practice.

FIGURE 7-2 Percent change in stroke mortality, men aged 35 to 74, 1972 to 1982. (From Thom TJ: Stroke mortality trends: an international perspective. Ann Epidemiol 3:509, 1993. Copyright 1993, with permission from Elsevier Science.)

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FIGURE 7-3 Age-adjusted death rates for stroke among men and women in the United States, 1900 through 1990. (From Higgins M, Thom T: Trends in stroke risk factors in the United States. Ann Epidemiol 3:550, 1993. Copyright 1993, with permission from Elsevier Science.)

Click here to view this table.... Hypertension contributes to each of the major intermediate causes of both ischemic and hemorrhagic stroke including carotid stenosis, intracranial atherosclerosis, small-vessel arteriosclerosis, and both macroscopic and microscopic aneurysms. Each of these conditions is considered separately in this chapter. In part because of the heterogeneity of its manifestations in the brain, there continues to be some uncertainty about the optimal management of blood pressure in both the acute and chronic phases after stroke. In the acute phase of cerebral ischemia, hypertension may play a compensatory role in 25 maintaining cerebral perfusion to viable but threatened areas of the brain. Loss of normal cerebral autoregulation has been demonstrated in areas of ischemic brain. When autoregulation is lost, blood flow to the brain becomes directly proportional to mean arterial pressure, and therefore, in theory, pharmacological increases in blood pressure could have 26 salutatory effects in preserving hypoperfused regions of the brain. In some small studies, rapid pharmacological reductions in blood pressure have predicted worse outcomes, and there are numerous anecdotal reports of the recrudescence of stroke symptoms after a 27,28 Therefore, most stroke guidelines recommend withholding decrease in blood pressure. pharmacological treatments of blood pressure in acute stroke in the absence of acute end-organ injury29or administration of thrombolytics, unless the blood pressure exceeds 220/120 mmHg. It is also possible, however, to make physiological arguments that would be supportive of acute blood pressure reduction, such as stabilization of an intra-arterial 30 thrombus or to reduce edema formation. Ongoing trials in this area will provide key data to help resolve this debate. Although historically there has been concern about lowering blood pressure even in the chronic phases after stroke, there is now overwhelming evidence to support the use of pharmacological interventions to lower blood pressure for secondary stroke prevention. In 6,105 subjects with a history of stroke, the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) demonstrated a 43 percent relative risk reduction for secondary stroke prevention when subjects were randomized to the combination of the angiotensin-converting 31 enzyme (ACE) inhibitor perindopril and the thiazide diuretic indapamide. Combination therapy with the ACE inhibitor and thiazide, which resulted in a mean blood pressure reduction of 12.3/5 mmHg, demonstrated a substantially more robust benefit for stroke prevention than monotherapy with ramipril (relative risk reduction 5%), which produced only a 4.9/2.8-mmHg average reduction in blood pressure (P for heterogeneity between treatments 40 GPL or MPL, or >99th percentile), on two or more occasions, at least 12 weeks apart, measured by a standardized enzyme-linked immunosorbent assay (ELISA); and (3) Aβ2A of IgG or IgM isotype in serum or plasma (in titer >99th percentile), present on two or more occasions, at least 12 weeks apart, measured by a standardized ELISA, according to recommended procedures. Depression, cognitive dysfunction, psychosis, seizures, chorea, and transverse myelitis have been associated with the presence of antiphospholipid antibodies, although there is evidence that not all arise from ischemia. An interaction between antibodies and CNS cellular elements may account for some of these manifestations. Sneddon's syndrome of cerebral thrombosis in association with livedo reticularis is strongly associated with the presence of antiphospholipid antibodies. In systemic lupus erythematosus, the risk of168thrombosis is increased two- to fivefold in subjects who have the lupus anticoagulant. Venous thrombosis is seen most commonly, 169,170 but arterial thrombosis may also occur in the absence of other recognized risk factors. A study of epilepsy in patients with the antiphospholipid syndrome reveals a prevalence of 8.6 percent. Multivariate logistic regression analysis found CNS thromboembolic events as the most significant factor associated with epilepsy, with an odds ratio of 4.05 (95% confidence interval, 2.05 to 8), followed by systemic lupus erythematosus (OR 1.4, 95% CI 1.2 to 4.7), 171 and valvular vegetations (OR 2.87, 95% CI 1 to 8.27). The cumulative clinical features during the evolution of the disease have been described in 157 1,000 patients with antiphospholipid syndrome. Neurological manifestations included migraine (20.2%), stroke (19.8%), transient ischemic attack (11.1%), epilepsy (7.0%), amaurosis fugax (5.4%), multi-infarct dementia (2.5%), retinal artery thrombosis (1.5%), chorea (1.3%), acute encephalopathy (1.1%), optic neuropathy (1.0%), retinal vein thrombosis (0.9%), transient amnesia (0.7%), cerebral venous thrombosis (0.7%), cerebellar ataxia (0.7%), transverse myelopathy (0.4%), and hemiballismus (0.3%). Many studies have examined the association between antiphospholipid antibodies and stroke, but with inconsistent conclusions as a result of the use of differing patient groups and a selective range of test methods. A study of unselected adults presenting with stroke suggested that the 172,173 but does presence of anticardiolipin antibodies is an independent risk factor for stroke not predispose to subsequent thrombotic events, although other studies failed to confirm 174 this. Another study showed that presence of an antiphospholipid antibody (either lupus anticoagulant or anticardiolipin) among patients with ischemic stroke did not predict either increased risk of subsequent vascular occlusive events over 2 years or a differential response to aspirin or warfarin therapy. Routine screening for antiphospholipid175 antibodies in unselected adults with ischemic stroke has therefore not been recommended. With the introduction of assays for antibodies directed specifically against β2-glycoprotein I, however, a 176 relative risk of stroke of 2 to 3 has been suggested. Studies of a wider range of antiphospholipid antibodies in the pathogenesis of cerebral ischemia suggest a relevant role for a combination of antiphosphatidylserine IgG and anti–β2-glycoprotein I IgA in stroke 177 etiology. A consensus is forming that one or a number of the antiphospholipid antibodies have an association with stroke in adults. Whether this is a risk factor for recurrent vascular events is uncertain, and whether specific treatment is required is quite unclear. Among younger patients, the association appears stronger, with antiphospholipid antibodies present in 46 percent of subjects younger than 50 years who present with stroke or a transient ischemic attack (TIA) compared with 8 percent in matched control subjects with 178 nonthrombotic neurological disease. In young adults, the presence of antiphospholipid antibodies, particularly lupus anticoagulant, has been identified as an independent risk factor 179 for first and possibly also for recurrent ischemic stroke, although a prospective study of young patients with recent TIAs or ischemic stroke suggested that antiphospholipid 180 antibodies are not a strong risk factor for recurrent stroke or TIA. Prothrombotic abnormalities181have been identified in 20 to 50 percent of children presenting with acute ischemic stroke.

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Hereditary Thrombophilia The inherited thrombophilias are a group of disorders in which a defect or deficiency in the natural anticoagulant mechanisms predisposes to the development of venous thrombosis. Within the cerebral venous system, the superior sagittal and transverse sinuses are frequently involved, whereas cavernous sinus thrombosis is much less common. Antithrombin, protein C, and protein S deficiencies, factor V Leiden, the G20210A prothrombin gene mutation and MTHFR C677T mutation resulting in hyperhomocysteinemia predispose to thrombosis, although it is uncertain whether other inherited disorders, such as deficiency of heparin cofactor 2, plasminogen, tissue plasminogen activator, factor XII, or prekallikrein, also result in thrombosis. In homocystinuria, homozygotes are susceptible to arterial and venous thromboses. Genetic or acquired predisposing factors can be identified in 182 as many as 80 percent of patients who develop cerebral venous sinus thrombosis. A genetic risk factor is now identifiable in up to 50 percent of unselected patients with venous 183 thromboembolism, although a lower incidence of inherited thrombophilia of 15 to 19 percent is reported in patients with cerebral venous sinus thrombosis in studies undertaken 184,185 Investigation in before the identification of the 20210A prothrombin gene mutation. potentially inherited disorders must include assessment of family members. Antithrombin Deficiency Antithrombin is a plasma glycoprotein that inhibits thrombin and other activated serine proteases, including factors IXa, Xa, XIa, XIIa, and kallikrein. Heterozygous antithrombin 186,187 and may arise as a new deficiency affects 1 in 2,000 to 5,000 of the population mutation. Deficiency of antithrombin is associated with sagittal sinus and cerebral venous 188 189 thrombosis, and is an under-recognized cause of neonatal seizures. A rarer disorder is recognized in which a nonsense mutation results in a dysfunctional variant of antithrombin 190 causing recurrent venous thrombosis. Acquired antithrombin deficiency associated with cerebral thrombosis may also arise from reduced antithrombin synthesis in liver disease or 191 increased loss in nephrotic syndrome, oral contraceptive use, DIC, protein malnutrition, and heparin therapy. A retrospective cohort family study that assessed the risk of venous thromboembolism in individuals with thrombophilia suggested that individuals with antithrombin deficiency might have a higher risk of thrombosis than that with the other genetic 192 defects. Protein C Deficiency Protein C is a vitamin K–dependent protein that binds to thrombomodulin, an endothelial cell surface protein, and is converted to an active protease by the action of thrombin. In conjunction with protein S, protein C proteolyses factors Va and VIIIa, thereby reducing thrombin formation as well as promoting fibrinolysis. Inheritance of protein C deficiency is usually autosomal dominant, although in some families, heterozygotes with plasma concentrations of less than 50 percent of normal remain asymptomatic, giving an autosomal recessive–like pattern of inheritance. Dysfunctional molecules present in normal levels have been described. Sagittal sinus and cerebral venous thromboses are recognized in 193 association with deficiency of protein C. Population studies suggest that 1 in 200 to 300 subjects have levels of protein C consistent with congenital deficiency, although the incidence of protein C deficiency and venous thromboembolism suggests a prevalence of 1 in 194 30,000. This represents 4 percent of subjects with venous thromboembolism presenting before the age of 45 and demonstrates that other inherited and acquired risk factors are frequently required for thrombosis to occur. Protein S Deficiency Protein S is a vitamin K–dependent glycoprotein that acts as a cofactor for activated protein C. Approximately 60 percent of it is protein bound, so that total and free protein S must be measured. Only the unbound protein is biologically active, and since its level may fall in acute disease, repeat measurement and the demonstration of a persistently reduced level is required to prove association with disease. In the presence of factor V Leiden, functional assays of protein S may give a falsely low reading. Sagittal sinus and cerebral venous 195 thromboses are reported in association with deficiency of protein S. Factor V Leiden (RQ506Q) Factor V Leiden is a point mutation in factor V at Arg 506, where protein C cleaves and

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inactivates the Va procoagulant. This results in a poor response to the anticoagulant activity of activated protein C, a key enzyme in the downregulation of blood coagulation, resulting in a predisposition for a hypercoagulable state. It is the most common inherited prothrombotic 196 accounting for at least 90 percent of the cases with resistance to activated protein state, 197 C. The mutation is inherited as an autosomal-dominant trait and has a prevalence of 2 to 10 percent in the general white population. A number of clinical studies, using different inclusion criteria, show a prevalence of activated protein C resistance of 20 to 60 percent among patients with venous thromboembolism at any site, and 20 to 25 percent for cerebral venous thrombosis. The actual thrombotic risk is moderate, with an odds ratio of 5:7, but its high prevalence makes it by far the most important inherited risk factor known today, exceeding184,197–199 the sum of contributions from inherited deficiencies of antithrombin, protein C, and protein S. Activated protein C resistance, which is not due to factor V Leiden and which appears to be acquired, is also a risk factor for venous thrombosis. A decreased response to activated protein C is common during pregnancy and during the use of oral contraceptives, although the clinical relevance of these findings remains unclear. Thrombotic events often occur in the presence of inherited and circumstantial risk factors. Noninherited factors predisposing to cerebral venous thrombosis (e.g., oral contraceptive intake, pregnancy, puerperium, trauma, or prolonged immobilization) were reported in 72 percent of cases of cerebral venous 199 thrombosis with factor V Leiden. Prothrombin G:A 20210 Mutation Prothrombin is a precursor of the serine protease thrombin, a key enzyme in the production of fibrin from fibrinogen. A single nucleotide substitution (G to A) at position 20210 in the 3′-untranslated region of the gene encoding prothrombin is associated with elevated plasma prothrombin200,201 and an increased risk of deep venous thrombosis and cerebral venous The mutation is found in 18 percent of selected patients with a family thrombosis. history of venous thrombosis, 6 to 7 percent of unselected patients with deep vein thrombosis, and 1 to 2 percent of control subjects, making it the second most common cause 201–203 The prevalence of the prothrombin of hereditary thrombophilia after factor V Leiden. gene mutation is 20 percent in patients with cerebral vein thrombosis in comparison with 3 199 percent in healthy control subjects.

Hyperhomocysteinemia Hyperhomocysteinemia is a risk factor for venous thrombosis. A C-to-T mutation at position 677 in the methylene tetrahydrofolate reductase gene (MTHFR) gives rise to a thermolabile variant with reduced activity and to elevated plasma homocysteine. Homozygosity for the thermolabile form is found in 5 to 15 percent of the general population, who have significantly elevated plasma homocysteine levels. Some studies suggest that being a homozygote for 204,205 Others have found that although MTHFR-T is a risk factor for venous thrombosis. homozygotes have consistently elevated plasma homocysteine concentrations, this is not a 206–208 Moderate risk factor for deep-vein thrombosis, regardless of factor V Leiden genotype. hyperhomocysteinemia209is now recognized as a risk factor for arterial disease, including 210 carotid artery stenosis and stroke. This mutation has not yet been systematically investigated in cerebral venous sinus thrombosis. Further discussion of hyperhomocysteinemia is provided in Chapter 61.

Factor VIII Levels of factor VIII are associated with the risk of venous thrombosis, and factor VIII gene 211 variations do contribute to both levels of factor VIII and the risk of thrombosis. Elevated levels of factor VIII coagulant activity within families is associated with an increased risk of 212 both arterial and venous thromboses. Cerebral venous sinus thrombosis has been 213 described in hyperthyroidism, which may be associated with elevated factor VIII levels.

Interactions Between Inherited Thrombophilias The multifactorial nature of thrombophilia, both circumstantially and at a genetic level, is increasingly well recognized. Among 162 patients and 336 control subjects investigated for thrombophilia after documented venous thromboembolism, two or more polymorphisms were detected in 16.7 percent of patients and 0.9 percent of control subjects; the odds ratios for joint occurrence of factor V and prothrombin G20210A was 58.6, compared with 35.0 for

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factor V and MTHFR polymorphisms, and 7.7 for prothrombin G20210A and MTHFR 205 protein S polymorphisms. Coexistence of additional antithrombin III, protein C, or 214 deficiency is reported in 14.5 percent of patients with the Leiden mutation. A combination of prothrombin gene G20201A variant and factor V Leiden is associated with an increase in the prevalence of more unusual sites of venous thrombosis, such as the cerebral venous 215 system. A case has been reported of massive thrombosis of cerebral venous sinuses in a 2-year-old 216 boy with a combined inherited deficiency of antithrombin III and protein C. Concomitant inferior vena cava, iliac, femoral, and cerebral venous thromboses were reported in a woman with combined protein C deficiency and protein C–activated resistance commencing 10 days 217 after she had started using an oral contraceptive.

Interactions Between Inherited and Acquired Risk Factors The incidence of inherited thrombophilia exceeds the incidence of venous thrombosis, suggesting that additional factors are required for thrombosis to occur. The use of oral contraceptives is strongly and independently associated with cerebral vein thrombosis. The presence of both the prothrombin gene mutation and oral contraceptive use further raises the 199 risk of cerebral vein thrombosis. In women who use oral contraceptives and also carry factor V Leiden mutation, protein C, protein S, or antithrombin deficiency, the odds ratio for cerebral sinus thrombosis is about 30 relative to women who had neither risk factor. A combination of these factors appears to interact in a multiplicative way in the development of 185 cerebral sinus thrombosis. In a study of the interaction between various risk factors for cerebral venous thrombosis in children, 56.4 percent had at least one prothrombotic risk factor compared with 20.8 percent of controls. An underlying predisposing condition was found in 70.5 percent of 149 patients. On univariate analysis, factor V, protein C, protein S, and elevated lipoprotein(a) were found to be significantly associated with cerebral venous thrombosis. However, in multivariate analysis, only the combination of a prothrombotic risk factor with an underlying condition (OR 3.9, 95% CI 1.8to 8.6), increased lipoprotein(a) (OR 4.1, 95% CI 2.0 to 8.7), and protein C deficiency (OR 11.1, 95% CI 1.2 to 104.4) had 218 independent associations with cerebral venous thrombosis.

Thrombophilic Disorders and Arterial Thrombosis Although there are numerous220reports of cerebral arterial thrombosis and infarction occurring 219 221,222 223 deficiencies, and 224 factor V Leiden, the in antithrombin, protein C, and protein S risk is extremely small compared with the risk of venous thrombosis. A stroke in the presence of a strong risk factor for venous thrombosis should therefore always raise the suspicion of paradoxical venous embolism. Only rarely has familial thrombophilia been conclusively diagnosed following arterial thrombosis, by demonstrating that the deficiency persists after the acute event is over. This is particularly important in the case of protein S, since it binds to an acute-phase reactant (C4bBP), resulting in an acquired reduction in free or functional protein S. Low protein S levels are also found in acute nonvascular illness and during pregnancy, and protein C levels may fall in liver disease, postoperatively, and in association with DIC. Mayer and colleagues, in a case-controlled study, concluded that acquired deficiency of protein S is not a major risk 225 factor for226 stroke. The degree of reduction in protein C levels correlates with the severity of demonstrate that it may take 3 months for levels a stroke. Serial protein C measurements 227 studies have failed to identify an to return to normal following a stroke. Case-control 228,229 association between factor V Leiden and stroke. A number of reports suggest that hereditary thrombophilia may be associated with stroke in childhood, 230 but reference ranges are lower than for adults, so the association may be erroneous. Ethnic differences have also been noted in the levels of markers of 231 thrombophilia in stroke, emphasizing the need for care in interpreting these investigations. In a comparative study of 191 patients with arterial disease and 296 unmatched control subjects, 19 percent of those with arterial disease were homozygous for the mutated MTHFR-T allele compared with 4 percent of controls (odds ratio, 5.52). These data support the hypothesis that204,232 being a homozygote for the MTHFR-T is a risk factor for the development of arterial disease. A possible relationship has been described between the presence of prothrombin gene variant and233atrial fibrillation although not with thromboembolism in the context of atrial fibrillation.

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Patent Foramen Ovale Inherited prothrombotic states, such as the factor V Leiden and prothrombin gene G20210A mutations, elevated levels of factor VIII, and decreased activity of protein C, protein S, and antithrombin are linked to an increased risk of venous thromboembolism. There is still a lack of evidence supporting an association between these states and brain infarction in general. In patients 55 years or younger with cryptogenic brain infarction, patent foramen ovale has been shown to be a more common finding (56%) than in controls (18%) and in patients with brain infarction of undetermined cause (17%), suggesting paradoxical embolism as the mechanism 234,235 A strong association has been shown between the presence of coagulation for stroke. abnormalities, especially factor V Leiden and prothrombin G20210A mutations, and a history of Valsalva maneuver–like activity at stroke onset. Such activity was more common at stroke onset in patients with than without patent foramen ovale. Coagulation abnormalities have been found in 30 percent of patients with cryptogenic infarction who also had patent foramen 236 ovale. In another study in young adults, the PTG20210A variant and, to a lesser extent, the FVG1691A mutation, appeared to represent risk factors for cerebral infarcts related to patent foramen ovale. No significant association was found in the distribution of the MTHFR 237 genotype. Previous

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Aminoff: Neurology and General Medicine: Hepatic Encephalopathy: ...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 14 Hepatic Encephalopathy ALAN H. LOCKWOOD •

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HISTORY TERMINOLOGY FULMINANT HEPATIC FAILURE PORTAL SYSTEMIC ENCEPHALOPATHY Neuropathology Pathophysiology Cerebral Blood-Flow and Glucose Metabolism Ammonia Abnormalities of Neurotransmission GABA-Benzodiazepine Complex Mercaptans and Short-Chain Fatty Acids Summary Therapy General Measures and Diet Lactulose Neomycin Lactitol Transjugular Intrahepatic Portosystemic Shunts Outcome

The liver occupies a complex central position in the gastrointestinal system. The central nervous system (CNS) is absolutely dependent on the liver for (1) maintaining normal blood glucose levels; (2) the intermediate metabolism of a variety of other nutrients, vitamins, and trace elements, required for normal brain function; and (3) removal of toxic metabolic wastes. Hepatic encephalopathy is a common manifestation of liver disease in adults and is due primarily to a failure of this third function of the liver. Liver disease is an important contributor to morbidity and mortality in the United States. Data from the National Institute of Diabetes and Digestive and Kidney Diseases indicate that each year about 25,000 Americans die of cirrhosis of the liver, making cirrhosis a leading cause of death by disease. As cirrhosis reaches its terminal phases, neurological impairment becomes a problem of increasing importance. Other diseases of the liver may express themselves via secondary CNS dysfunction. Fulminant hepatic failure, Wilson's disease, and other metabolic disorders may have an important secondary impact on the neurological symptoms.

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HISTORY Descriptions of what was probably hepatic encephalopathy appear in the writings of early authors, including Galen, Hippocrates, and perhaps even Shakespeare. However, clear, 1 contemporary descriptions follow Frerichs's treatise on liver disease. Frerichs wrote (as translated by Murchison): In most cases we can distinguish two stages, that of excitement and depression…characterized by delirium and convulsions and…progressively increasing coma.…In most cases, the nervous system derangements appeared simultaneously with jaundice; and they usually attracted the attention of the observer sooner than the slight jaundiced tint of the conjunctivae. Frerichs noted that it is common for hepatic encephalopathy to be recognized first by someone other than the patient or physician—that is, the “observer,” who may be a family member or other associate. He further noted: Toward the termination of the disease the delirium and convulsions, as a general rule, gave place to stupor, which in a short time has merged into the deepest coma, from which no shaking could rouse the patient. Frerichs was undoubtedly describing what we would now call fulminant hepatic failure. This condition was invariably fatal at that time and is still associated with a high mortality rate in the absence of transplantation. As Frerichs did not describe remissions or recoveries, he was probably not describing portal systemic encephalopathy. This latter condition, now the most common form of hepatic encephalopathy, undoubtedly existed at that time, as suggested by this quote from Shakespeare's “Twelfth Night.” Sir Andrew Aguecheek: But I am a great eater of beef and believe that does some harm to my wit. The failure to differentiate portal systemic encephalopathy from acute hepatic failure may have been due to high mortality rates associated with both conditions. Frerichs also had excellent insight into the pathophysiological mechanisms causing encephalopathy: Abnormal nervous symptoms… must be referred to changes in the blood. I attribute the cause of the blood-intoxication to the complete arrest of the hepatic functions…[and] also [to] the cessation of the powerful influence which the liver exerts over the processes of metamorphosis of matter. Most of the progress in defining the pathophysiology of hepatic encephalopathy consists of nothing more than refinement of this broad but accurate statement. TERMINOLOGY Some of the current confusion in the literature is the result of terminology that is poorly defined and used. The term hepatic encephalopathy, which is often used synonymously with portal systemic encephalopathy, refers to a syndrome of reversible cerebral dysfunction associated with chronic liver disease (usually cirrhosis) that is often associated with portal hypertension and shunts that divert hepatic portal blood into the systemic circulation; chronic portal systemic encephalopathy implies a sustained condition with a potential for reversibility. This term should not be used synonymously with hepatocerebral degeneration. Other misused terms include subclinical hepatic encephalopathy, abbreviated as SHE, and latent hepatic encephalopathy. These terms refer to a condition of apparent clinical normality with impaired function detected by specialized testing. These tests include neuropsychological evaluations, the most reliable method, but may include electrophysiological tests, such as the electroencephalogram (EEG) or event related potentials. Minimal hepatic encephalopathy is the term advocated by a World 2 Gastroenterology consensus panel to describe these patients. FULMINANT HEPATIC FAILURE Fulminant hepatic failure is a condition in which patients with a previously normal liver develop encephalopathy within 8 weeks of the onset of their liver disease. Viral hepatitis and toxin exposure are frequent causes. Ingestion of excessive quantities of acetaminophen, a drug that is particularly hepatotoxic, is common as a suicide attempt or gesture or as an accident by children. A recent review indicates that there were nearly 400,000 reports to poison control centers of ingestions of analgesics, cough remedies, or cold preparations, i.e.,

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3

compounds that are likely to contain acetaminophen. This condition is associated with a mortality rate of about 85 percent. Death is often due to cerebral edema and may occur within days of the onset of the disorder. The features that differentiate fulminant hepatic failure from portal systemic encephalopathy are shown in Table 14-1. Click here to view this table.... Because the initial signs and symptoms of fulminant hepatic failure are frequently referable to the brain, neurologists may be among the first to be involved in the care of these patients. Nausea, vomiting, and abdominal pain associated with delirium or mania are common in the initial stages. These symptoms evolve rapidly to a comatose state associated with generalized seizures. The goal of therapy is to support patients so that they recover or remain candidates for orthotopic liver transplantation. This requires specialized care, preferably in a transplant center, and admission to an intensive care unit. Depending on the signs and symptoms and the tempo of evolution, computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain should be done to evaluate the size of the cerebral ventricles, an indicator of the presence of cerebral edema and an increase in intracranial pressure. The edema is due to an increase in brain water that is the result of an increase in astrocytic glutamine 4 content. The decision about whether to place an intracranial-pressure monitoring device must be made. These devices are not without risk, and their use is somewhat controversial. 5 Among 324 patients in a recent series, 28 percent had intracranial pressure monitored. In a subset of these, 10.3 percent had radiographic evidence of an intracranial hemorrhage. Of these hemorrhages, half were incidental findings. However, any cerebral hemorrhage, particularly in a patient who is likely to have clotting factor abnormalities, is a cause for concern. The authors concluded that patients who did not undergo intracranial-pressure monitoring were treated less aggressively, even though they were placed on transplant lists. Neurological treatments involve the use of hyperventilation, to reduce cerebral blood volume, and osmotic diuretics, to control increased intracranial pressure that is due to the combined effects of edema and changes in blood flow and volume. In a study of cerebral blood-flow in patients with fulminant hepatic failure, Strauss and co-workers. found that hyperventilation 6 appears to have no effect on the pattern of blood flow. In these patients, who had grade 4 hepatic encephalopathy, the relative reduction in blood flow in frontal and basal ganglionic regions that was found before the initiation of hyperventilation persisted and was not aggravated by hyperventilation. Among survivors, the pattern of flow returned to normal, suggesting that this therapy does not predispose to the development of hypoxic-ischemic damage. In addition to these measures, exchange transfusions may be performed to reverse clotting abnormalities and preserve neurological function. In some centers, experimentation with 7 hepatotrophic agents and artificial livers may serve as a bridge to transplantation. Since there are more candidates for transplantation than organs available, it is important to screen patients properly so that patients who do not require transplantation are not subjected to this therapy (i.e., those who do not have severe and worsening encephalopathy) and to avoid transplantation when the prognosis for neurological recovery is hopeless. Among children, the development of radiographic evidence of cerebral edema is an indicator of a very poor 8 prognosis. A better understanding of the pathophysiology of fulminant hepatic failure may lead to the development of better medical 9treatment that will reduce or obviate the need for orthotopic 10 transplantation. Studies by Blei and Norenberg and their associates have been particularly important in this regard. Blei and his colleagues have studied rats with portacaval shunts 11 during ammonia infusions. They found that the infusion led to an increase in glutamine, as might be expected, and an increase in blood flow. This led to a significant increase in brain water, i.e., brain edema. Treatment with the glutamine synthetase inhibitor, methionine sulfoximine, reduced the brain glutamine concentration and blood flow while increasing blood ammonia levels. Along with the decrease in glutamine, there was a decrease in edema, leading to the speculation that ammonia-induced glutamine formation plus the cerebral hyperemia that attends the increase in blood flow are important mechanisms for the production of brain edema. They suspect that nitric oxide synthase may mediate the blood flow increase and could be a target for future therapy. The work of Norenberg and co-workers is discussed later. PORTAL SYSTEMIC ENCEPHALOPATHY Alterations in the level and the content of consciousness are the hallmarks of hepatic encephalopathy. Most clinical grading systems are based on the level of consciousness, as

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shown in Table 14-2. There is a substantial amount of variation in the severity of these abnormalities, which may be so subtle that they are unrecognized. The onset may be slow and insidious, making early diagnosis and treatment difficult, or rapid, with progression to death within days. This early stage is a classic delirium, defined as a disturbance of consciousness with a reduced ability to focus, sustain, or shift attention. Delirious hypervigilant states are less common. As this is a disorder that affects the entire brain to varying degrees, all systems may be affected as the clinical condition worsens. Wernicke's encephalopathy should be suspected in patients with delirium, particularly if they have alcoholism. This disorder is more common than generally believed and usually presents without the full triad of delirium, disordered ocular motility, and ataxia. In some autopsy series, pathological evidence of unsuspected evidence of Wernicke's encephalopathy has been found in more than 2 percent of cases. Click here to view this table.... For over 20 years, some clinicians have recognized that many patients with cirrhosis will score in the impaired range on neuropsychological tests in spite of the fact that they do not have any overt evidence of encephalopathy. This association was first recognized by Rikkers 12 and colleagues in their evaluation of patients with portacaval shunts. They found impairment in 60 percent of their 30 patients. They attributed this impairment to hyperammonemia, and they reported that treatment led to improvement. They coined the unfortunate term subclinical hepatic encephalopathy, abbreviated as SHE by some, to describe this association. Since then, numerous studies, conducted under a variety of circumstances, have expanded on this finding. In a study of alcohol-induced cirrhosis that used alcoholics without liver disease as a control, Gilberstadt and 13 associates concluded that it was the liver disease itself that caused the cerebral dysfunction. Tarter and his colleagues performed one of the earliest, highly detailed neuropsychological investigations of patients with cirrhosis of several etiologies unrelated to alcohol consumption and found that measures of visuopractic 14 capacity, visual scanning, and perceptual-motor speed were impaired. The impairment was not global, in that intellectual, language, memory, attentional, motor, and learning abilities were intact. In that same study, an impact on daily life was found by use of the Sickness Impact Profile (SIP). The findings and the use of patients with Crohn's disease as a control for chronic disease suggested strongly that it was cirrhosis itself that caused these abnormalities. Other and larger studies have extended these findings. In a large, multicenter study performed in Germany, almost 300 different physicians administered a number connection15 and line drawing test to 783 patients: of the 771 valid results, 71.5 percent were abnormal. In a Dutch study of 179 patients, encephalopathy was defined as an abnormal result on the 16 Trailmaking A test, digit symbol test, or slowing of the EEG using automated analysis. The 48 encephalopathic patients whom they identified had significantly more impairment on the basis of the total SIP score as well as on all 12 scales of the SIP, the psychosocial subscore, and the physical subscore. Should patients with minimal hepatic encephalopathy drive an automobile? Recognizing that human error is the leading cause of automobile accidents, this question has been addressed by several groups. Schomerus and co-workers suggested that cirrhosis impacts daily life in a 17 was study that reported a large proportion of cirrhotics were unfit to drive. This finding 18 disputed by Srivastava and associates, who observed actual on-the-road driving. Wein and collaborators studied 14 cirrhotics with minimal encephalopathy, defined by neuropsychological testing, and compared their driving ability to 34 cirrhotics without encephalopathy and 49 patients with stable gastroenterological disease not affecting the 19 liver. They employed a blinded driving instructor who rated performance on a 22-mile 90-minute road test. The performance of encephalopathic patients was significantly worse in terms of handling, adaptation to road conditions, and cautiousness. Accident prevention required active intervention by the instructor in 5 of the 14 encephalopathic patients. These and other data show clearly that there are groups of cirrhotic patients whose lives are impacted by their condition. Several caveats are important. As with all forms of delirium, attentional mechanisms and the level of consciousness are likely to vary substantially over relatively brief periods of time. In employing neuropsychological tests, it is important to use age-defined normals, since performance on some tests changes as a function of aging. The use of young normal control values when testing an older patient is likely to generate a false-positive outcome. This problem is most likely to occur when poorly trained individuals administer the tests. A test battery consisting of Trailmaking tests A and B, serial dotting, line tracing, and the digit-symbol subtest of the Wechsler Adult Intelligence Scale (Revised) has

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been recommended for evaluation of patients who may have hepatic encephalopathy because it is sensitive and relatively specific for the disorder compared to other metabolic 2 encephalopathies. Taking these caveats into account, patients with cirrhosis should be evaluated in an attempt to determine whether their functional status is impaired, based on the best estimates of the premorbid state. If impairment is found, or even suspected, it is reasonable to treat these patients, preferably in a prospective manner, and re-evaluate their status at appropriate intervals. If improvement is found, treatment should continue. Since these patients are impaired by many measures, and because many improve, it is not appropriate to use the term subclinical hepatic encephalopathy, or SHE, to describe them. The problem is of clinical importance. The use of the term SHE and the related misnomer latent encephalopathy risks trivializing the importance of diagnosis and treatment for a condition that has a measurable and significant impact on the quality of life. The function of the cranial nerves in patients with hepatic encephalopathy is almost invariably intact unless the patient is near death, as may be the case for patients with cerebral edema complicating fulminant hepatic failure. Reliable assessment of the visual fields may be impossible (but visual evoked potentials usually indicate intact pathways). Frequently the pupils are smaller than normal, and pupillary constriction in response to light may be slower than normal. Oculovestibular and caloric responses are usually intact, and passive head moving typically produces eye movements that indicate functional integrity of the third and sixth cranial nerves. If a disorder of ocular motility is found, Wernicke's encephalopathy should be suspected, and the patient should be treated with thiamine. The corneal reflex is usually preserved. Motor responses may be varied, but the characteristic flapping tremor, or asterixis, is frequently encountered in patients well enough to be tested. Asterixis was originally thought to be pathognomonic for hepatic encephalopathy. However, experience has shown that this physical sign may be associated with other metabolic encephalopathies, such as uremia, and structural brain lesions. Electrophysiological studies have shown that the postural lapses are associated with sudden and unexplained periods of complete electrical silence in muscles. The sign may be elicited from a variety of voluntary muscles, including arm and hand extensors, flexors of the leg, and protruders of the tongue. Increased muscle tone, hyperreflexia, and extensor plantar responses are common and may be the source of some confusion when excluding a structural lesion of the brain, such as an occult chronic subdural hematoma. Abnormal involuntary movements may be observed transiently. The sensory examination may not be helpful and is probably best used to evaluate the depth of coma. Patients with liver disease may have peripheral neuropathies that can result in reflex loss or altered sensation. Although in many cases the ultimate decision concerning the diagnosis is clinical, laboratory tests are frequently helpful. Liver function tests are usually abnormal, but derangements may not be as drastic as expected on the basis of the clinical examination. Chronic, severe liver disease may be associated with relatively normal serum enzymes and a modest level of hyperbilirubinemia. In these cases, however, hypo-albuminemia and clotting factor deficiency may be substantial and a more reliable guide to the severity of the liver disease. The arterial blood ammonia level, when measured properly in the fasting state, is a useful test and provides an excellent correlation with the clinical state and the rate of ammonia uptake and metabolism by the brain. Several precautions must be taken to ensure that the results of the test are valid. The blood must be arterial. Venous blood is unacceptable because of the release of ammonia by muscle made partly ischemic by a tourniquet and the unpredictable ammonia uptake by muscle itself. Because of the phenomenon of toxin hypersensitivity, discussed later, a so-called normal or slightly elevated arterial ammonia level may still be compatible with encephalopathy that is severe. Electrophysiological studies, especially the EEG and perhaps visual evoked potentials, may be helpful in establishing the diagnosis and evaluating the response to therapy. Three phases in the evolution of the EEG abnormalities can be recognized: a theta stage with diffuse 4- to 7-Hz waves, a triphasic stage with surface-positive maximum deflections, and a delta stage with random, nonrhythmic slowing without much bilateral synchrony. Brenner in his review described bursts of moderate- to high-amplitude waveforms (100 to 300 20 μV) with low frequencies (1.5 to 2.5 Hz) as being the most characteristic abnormality. Weissenborn and colleagues have reported that the auditory oddball P300 event-related potential is abnormal in a fraction of patients with cirrhosis similar to the frequency of abnormal Trailmaking test 21 results. These tests are somewhat cumbersome to administer and require equipment and expertise not found in typical gastroenterology clinics. They may be helpful in the evaluation

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of some patients. Neuroimaging studies 22 have limited usefulness in the diagnosis of hepatic encephalopathy (as is reviewed elsewhere ). They are most useful in excluding structural lesions of the brain, such as a subdural hematoma. MRI has demonstrated abnormalities in the pallidum on 23–25 The abnormality was correlated with the T1-weighted images as shown in Figure 14-1. 26 blood ammonia level and may regress or disappear after successful liver transplantation. Although the increases in the pallidal T1 signal intensity are the most typical and easily observed abnormality, the T2 signal intensity is also abnormal. This shortening is more difficult to detect visually because of the already short T2 values seen in typical image sets. In addition to the pallidal abnormalities, T1 signals are increased in other brain regions including the pyramidal and extrapyramidal systems and limbic regions of the brain. The MRI 27–29 Similar abnormalities appear to be due to increased manganese levels in the brain. abnormalities have been observed in patients with increased manganese loads due to parenteral hyperalimentation, 30–32 after manganese exposure, and in monkeys after the administration of manganese.

FIGURE 14-1 T1-weighted transaxial plane magnetic resonance imaging (MRI)

of a patient with cirrhosis, showing an increase in signal intensity in the pallidum. Arrowheads define the abnormality on the right side of the image. This abnormality is thought to be the result of an increase in manganese content. The abnormality may regress or disappear after successful liver transplantation. (Courtesy of the Department of Radiology, Cleveland Clinic Foundation.) Proton MRI spectroscopic studies of cirrhotics have revealed a relatively consistent pattern of increases in the glutamate–glutamine 22,33–35 complex, reductions in choline and myoinositol, and With magnets of very high field strength, it is preservation of N-acetyl-aspartic acid. possible to separate the glutamate and glutamine signals. Although these spectroscopic findings are relatively specific, MR spectroscopy has no advantages over other testing methods, particularly neuropsychological testing, at the present time and is cumbersome and expensive.

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Neuropathology The Alzheimer type II astrocyte is the neuropathological hallmark of patients with hepatic encephalopathy. Adams and Foley provided a translation of the original description in their 36–38 These abnormal astrocytes are found in many locations, including the classic paper. cortex and the lenticular, lateral thalamic, dentate, and red nuclei. Adams and Foley speculated that the duration of coma might correlate with the severity of the abnormality. 39 Ammonia was shown to produce the Alzheimer II transformation by Cole and associates. In rats with portacaval shunt–induced hyperammonemia, Alzheimer II cells become evident after 5 weeks, a time course that parallels the development of the low blood flow and low oxygen metabolism in response to chronic hyperammonemia. Ultrastructurally, these astrocytes appear to be metabolically hyperactive, and immunohistochemical staining techniques have shown increases in the activity of glutamic acid dehydrogenase and glutamine synthetase, leading Norenberg to speculate that hepatic encephalopathy is a 10 syndrome due to astrocyte dysfunction.

Pathophysiology Improvements in the care of patients with hepatic 1encephalopathy have been substantial since the rather dismal account given by Frerichs. These improvements have been linked closely to improvement in our understanding of the pathophysiology of the disorder. Because of the complexity of the metamorphosis of matter that attends normal hepatic function, to use Frerichs's analysis, it is no surprise that a number of hypotheses have been advanced to explain the development of hepatic encephalopathy. Suspected factors include hyperammonemia and the effects of ammonia on neural function, altered amino acid and neurotransmitter function, elevated mercaptan concentrations, high levels of short-chain fatty acids, and altered function of the GABA-benzodiazepine complex. These abnormalities may then have further effects on cerebral metabolism. Cerebral Blood-Flow and Glucose Metabolism Cerebral blood-flow and metabolism studies in patients with hepatic coma have shown the reductions that would be expected in patients with reduced levels of consciousness. 40–42 Successful treatment normalizes flow and metabolism. Animal studies of flow and metabolism have been helpful in elucidating possible mechanisms related to ammonia intoxication. Gjedde and colleagues measured blood flow and oxygen metabolism in normal rats and in rats 4 and 8 weeks after portacaval shunting; measurements were made under baseline conditions and serially after an ammonia 43 challenge. The ammonia challenge had little effect on the control animals and in the rats at 4 weeks after shunting. However, after 8 weeks, the ammonia challenge caused a significant reduction in flow and metabolism. This increase in toxin sensitivity emerges during the same time interval that the Alzheimer II astrocyte transformation becomes apparent. These experimental data support the clinical observations and the hypothesis that toxin 44 hypersensitivity develops as liver disease advances. Studies of cerebral blood-flow and glucose metabolism in patients with minimal levels of 45 encephalopathy have shown a characteristic pattern. In patients with chronic liver disease and grade 0 to 1 encephalopathy, the pattern of blood flow and glucose metabolism, as shown by positron emission tomography (PET), is abnormal even though global rates are unaffected. In a study of patients with cirrhosis and minimal encephalopathy that used more sophisticated statistical methods to evaluate glucose metabolism, reductions were found in the cingulate46gyrus, a part of the anterior attentional center, the frontoparietal cortex, and the cerebellum. These regions may be functionally impaired and contribute to the expression of clinical symptoms. More recent PET studies have shown significant correlations between low glucose metabolic rates in distinct frontal and parietal 47 brain regions and impaired performance on a variety of neuropsychological tests. Additional studies are likely to clarify the relationships between cerebral metabolism and neuropsychological test performance and clarify the pathophysiology of minimal encephalopathy. Ammonia Ammonia is the most completely studied of the neurotoxins implicated in the pathogenesis of hepatic encephalopathy. Early investigators thought that ammonia in the blood was an artifact, produced by the breakdown of proteins as the blood stood at room temperature. However, after the perfection of suitable methodology, it was realized that ammonia is indeed

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present in normal blood. The beginnings of the link between ammonia and encephalopathy are best dated to the studies of Gabuzda and associates, who reported the development of encephalopathy in patients treated with resins that exchanged serum sodium ions for 48 resin-bound ammonium ions. Further studies correlated the changes in mental status with the development of hyperammonemia and led to recommendations that ammonia-containing compounds be avoided in patients with liver disease. Later, Sherlock correlated the fasting 38 a number of publications arterial ammonia level with the severity of coma. Subsequently, 37,49 The evidence that supports the and reviews supported and strengthened this correlation. ammonia hypothesis can be summarized briefly. First, there is a good correlation between the degree of hyperammonemia and the depth of coma. The metabolites of ammonia, notably glutamine and its transamination product, α-ketoglutaramate, are elevated in the brain and cerebrospinal fluid (CSF) of patients with hepatic encephalopathy. Second, patients with encephalopathy have higher rates of ammonia uptake and metabolic trapping by the brain than do nonencephalopathic controls. Third, ammonia reproducibly precipitates episodes of coma, along with compounds that form ammonia in the gastrointestinal tract, such as blood from a hemorrhage or protein meals. Fourth and finally, the most effective treatments for hepatic encephalopathy act to reduce blood ammonia levels. Ammonia is a gas that is highly soluble in water, where it forms a weakly basic solution. At physiological pH values, 1 to 2 percent of the ammonia is present as the gas, with the remainder present as the ammonium ion. Ammonia is normally produced in the gastrointestinal tract and carried to the liver by the hepatic portal vein (Fig. 14-2). In the liver, ammonia is converted to urea by the enzymes of the urea cycle, and the urea is excreted by the kidneys. A portion of the urea enters the gastrointestinal tract and is hydrolyzed to form ammonia in an enterohepatic circulation of nitrogen. In the rest of the body, ammonia is taken up by skeletal muscle to form glutamine, which is then transported to the liver, where the amide nitrogen is used in urea synthesis. Ammonia is released by skeletal muscle and the kidney. About 7 percent of the ammonia in the systemic circulation is trapped by the brain. Liver disease leads to the shunting of ammonia-rich blood from the portal into the systemic circulation.

FIGURE 14-2 Human ammonia metabolism. Most ammonia is formed in the colon,

although other organs make a contribution as well. Ammonia in the hepatic portal vein is normally detoxified by the enzymes of the urea cycle in the liver. Portal-systemic shunts cause excessive amounts of ammonia and probably other toxins to enter the systemic circulation and reach the brain. About 7 percent of the ammonia in the

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systemic circulation is taken up and metabolized by the brain. Skeletal muscle also is an important organ for ammonia homeostasis, taking up ammonia and converting it to glutamine, which is subsequently converted to urea in the liver. Data suggest a complex interaction between hyperammonemia, its effects on cerebral satiety centers, and the development of cachexia. (From Lockwood AH, McDonald JM, Reiman RE, et al: The dynamics of ammonia metabolism in man: effects of liver disease and hyperammonemia. J Clin Invest 63:449, 1979, with permission.) Cerebral ammonia metabolism studies 13 have been facilitated by the use13of the cyclotron-produced radioactive isotope N, which is easily made into [ N]ammonia. The first of these quantitative studies of ammonia metabolism was performed by Lockwood and associates. Their initial studies showed that about 1 mol of37ammonia is removed from the systemic circulation each day by the various body organs. Somewhat surprisingly, skeletal muscle was shown to be a major organ in ammonia homeostasis. In patients with end-to-side portacaval shunts, skeletal muscle becomes the single most important organ for maintaining 13 ammonia homeostasis. Subsequent studies using [ N]ammonia have shown that the blood–brain barrier is highly permeable to ammonia, despite the fact that it is highly ionized at physiological pH values and that the permeability of the barrier to ammonia is such that, at normal blood flow and pH values, about half the ammonia presented to the brain is extracted by the brain and trapped metabolically as glutamine. Two studies of cerebral ammonia metabolism have shown that the rate of ammonia uptake and metabolic trapping is disproportionately high in patients with hyperammonemia and 37,50 This may be due to51an increase of the permeability–surface area product of the cirrhosis. blood–brain barrier to ammonia. This observation was challenged in a more recent paper in which the blood–brain barrier to ammonia was reported to be less permeable to ammonia in 52 patients with hepatic encephalopathy. In correspondence that followed the publication of this paper, the authors indicated that an arithmetic error had occurred, and there was no difference between the controls and the patients with hepatic encephalopathy. Although this issue is unresolved, an increase in the ease with which ammonia in the arterial blood gains access to the brain would explain why some patients with minimal hyperammonemia become symptomatic and develop toxin hypersensitivity with the passage of time. The mechanisms by which ammonia affects brain function are still a matter of substantial interest. Virtually every aspect of neuronal function appears to be affected by ammonia. In addition to affecting glucose metabolism, ammonia affects brain energy metabolism, disrupts amino acids profiles in the brain (particularly that of glutamate), and alters the physiology of neural membranes by affecting the chloride pump, producing a reversible depolarizing shift in the inhibitory postsynaptic potential toward the resting potential. The subject is reviewed in 49 detail elsewhere. The studies of Norenberg and his collaborators suggest strongly that at least part of the effect 10 of ammonia is due to astrocytic dysfunction. These studies show that ammonia reduces the ability of astrocytes to remove glutamate from the extracellular space. This excess of glutamate may cause excitotoxic cellular injury. In addition, ammonia causes an increase in the peripheral type of benzodiazepine receptor and an associated increased production of neurosteroids that, in turn, modulate neuronal GABAA receptors. The increase in glutamine has osmotic effects on astrocytes and may contribute to the development of edema. 53

The response of the hypothalamic satiety center is of special interest. This center, like other hypothalamic regions, is sensitive to exogenous ammonia and is stimulated by relatively small amounts of ammonia delivered to the brain. Electrical stimulation of this brain region causes satiety. Thus ammonia-induced satiety may explain appetite loss and the development of cachexia in susceptible patients. Loss of muscle bulk, particularly in patients with portacaval shunts, may then facilitate the development of hyperammonemia. It has been hypothesized that the effects of ammonia on the hypothalamus, the loss of skeletal muscle bulk, and the development of toxin sensitivity may be important in the emergence and 53 perpetuation of terminal symptoms in patients with liver disease. Abnormalities of Neurotransmission Neurotransmitters and their role in normal brain function are among the most important characteristics that differentiate the brain from other organs, and abnormalities of neurotransmitter function are proved or implied in a variety of diseases ranging from parkinsonism to schizophrenia. It is therefore not surprising that neurotransmitter abnormalities have been proposed as being of potential importance in the pathogenesis of hepatic encephalopathy.

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Glutamate was the first of the amino acid transmitters to be implicated, and this led to unsuccessful attempts to treat patients with glutamic acid infusions. Hindfelt and associates 54 observed small reductions in brain glutamate levels in animals challenged with ammonia. The anatomical locus of the depleted glutamate could not be determined from that study. Glutaminase inhibition and reduced hippocampal glutamate release have also been suggested. As indicated earlier, Norenberg has suggested that disruptions of the glutamate–glutamine relationship take place at the astrocytic level and that this may have secondary effects on glutamate neurotransmission. Biogenic amines and false neurotransmitters, notably octopamine, were the source of considerable interest after Fischer and Baldessarini proposed the false neurotransmitter 55 hypothesis in 1971. Their observations and similar ones by others were buttressed by uncontrolled trials suggesting that some patients awoke in a near-miraculous fashion after the administration of levodopa. These observations were combined with new and existing data on the plasma amino acid profile associated with liver disease to produce a new hypothesis. This hypothesis stated that the ratio of the sum of the concentrations of valine, leucine, and isoleucine divided by the sum of the phenylalanine and tyrosine concentration is a useful predictor and index of the severity of encephalopathy, and that normalization of the ratio by the infusion of amino acid mixtures rich in the branched-chain amino acids of the numerator is therapeutic. A subsequent refinement of the hypothesis suggested that the high level of glutamine in the brain acts as the driving force behind the uptake of the deleterious 56,57 aromatic amino acids. The amino acid hypothesis was supported by uncontrolled clinical trials of branched-chain amino acids. Controlled trials were disappointing. Two of the controlled studies of 58,59 60 branched-chain amino acids showed no effect, 61 one showed worsening, and a fourth showed improved survival and cerebral function. In all these studies it was reported that the amino acid ratio was improved, but there was no correlation with electroencephalographic or clinical improvement. Thus, the potential benefit of this therapy for the treatment of encephalopathy is not defined. However, amino acid infusions may be useful as a safe way to maintain positive nitrogen balance in cirrhotics. 62

Michel and associates found levodopa to be ineffective. The dopaminergic agonist bromocriptine has been63evaluated and found to be no better than standard treatment with enemas and neomycin. In addition to the disappointing results of the branched-chain amino acid trials, the false neurotransmitter hypothesis has been weakened on other grounds. Zieve and Olsen injected octopamine directly into the brains of animals at concentrations 20,000 times those 64 encountered in life, with no effect on behavior. Similarly, monoamine oxidase inhibition and imipramine therapy both led to increases in brain octopamine without the induction of 65 encephalopathy. GABA-Benzodiazepine Complex The hypothesis that excessive GABAergic tone causes hepatic encephalopathy generated a great deal of attention. Normally, the brain is protected from numerous compounds in the blood, including GABA, by the impermeable blood–brain barrier. According to this hypothesis, excess GABA is produced in the gastrointestinal tract and enters the brain through a damaged, or permeable, blood–brain barrier. The GABA then binds to GABA receptors, which are present in excess numbers, and the increased inhibitory tone is expressed as coma. Experimental evaluation of the GABA hypothesis has made it less credible. Improved analytical methods have shown that early reports of elevated blood GABA levels were erroneous, GABA probably does not cross the blood–brain barrier to any appreciable 66 extent, 67GABA levels in the brains of patients who have died in hepatic encephalopathy are normal, and inhibition68of GABA transaminase (which increases brain GABA levels) does not cause encephalopathy. As interest in GABA waned, more attention was directed at benzodiazepines. Patients with cirrhosis have a heightened sensitivity to this class of drugs, suggesting to some that they, or an endogenous ligand with benzodiazepine activity, may cause hepatic encephalopathy. Reports of rapid recovery after the administration of the benzodiazepine antagonist flumazenil (RO 15-1788, or Anexate) led to increased interest in the benzodiazepines. Although there is no reason to doubt the validity of these anecdotal reports and open trials, the evidence that these responders had not taken benzodiazepines is often incomplete. Despite reports of elevated levels of endogenous benzodiazepines in some

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comatose patients, the levels are lower than those associated with anxiolytic activity in normal subjects. Benzodiazepine receptors are present in normal numbers69and exhibit normal kinetics in the brains of patients with fatal hepatic encephalopathy. Controlled trials of flumazenil have shown that more patients responded in the flumazenil group than in the 70,71 However, there was evidence of the presence of exogenous control group. benzodiazepines in some the responders and a history of benzodiazepine administration. The action of this drug may relate, in part, to its general ability to activate the brain rather than simply to the displacement of a benzodiazepine. Among patients who improve after flumazenil, complete recovery is unusual, suggesting that any benzodiazepine effect is probably augmented by other pathophysiological mechanisms. Albrecht and Jones presented a synthesis of data concerning deranged neurotransmitters in 72 hepatic encephalopathy. Their analysis suggests that an excess of extracellular glutamate, caused by hyperammonemia, leads to downregulation of glutamate receptors and a reduction in excitatory tone. This is associated with an increase in GABAergic inhibitory tone due to multiple factors including an increase in the release of GABA and stimulation of GABAA receptors, increased levels of a natural benzodiazepine, a direct effect of ammonia on the GABAA-benzodiazepine receptor, and an ammonia-induced increase in peripheral benzodiazepine receptors in astrocytes. The hypothesis that abnormalities of neurotransmission cause all or part of the hepatic encephalopathy syndrome is likely to be modified as new data emerge and as investigators gain a better understanding of this complex area of research. Mercaptans and Short-Chain Fatty Acids Mercaptans are thio alcohols containing–SH groups, in contrast to the–OH groups in conventional alcohols. Because of the–SH group, these compounds are malodorous and are responsible for the fetor hepaticus that is occasionally encountered in patients with hepatic encephalopathy. Methanethiol is the principal mercaptan in humans and is formed by the catabolism of methionine in the gastrointestinal system. Methanethiol levels are elevated in the blood and end-tidal air samples of patients with hepatic encephalopathy, and levels have been 73 correlated with the severity of the encephalopathy. Mercaptans also appear to act in a synergistic fashion with other toxins, notably ammonia and fatty acids, 75 to produce coma in 74 animals. Clinically, mercaptan levels correlate poorly with symptoms. Abnormalities in short-chain fatty acid concentrations affect a variety of metabolic reactions or processes directly or indirectly in a fashion that may cause or contribute to the development of encephalopathy. Coma can be produced in animals by the intraperitoneal injection of shortand medium-chain fatty acids. Deficiency of medium-chain acyl-coenzyme A (CoA) dehydrogenase appears to be a common condition that may present as coma and often 76 mimics other conditions, such as Reye's syndrome or sudden infant death syndrome. Summary A variety of compounds have been implicated in the pathogenesis of the encephalopathy associated with portal-systemic shunting of blood and fulminant hepatic failure. A similarly large number of experimental models have been used to study these conditions. It is not presently possible to create a unifying hypothesis that explains all aspects of this encephalopathy, but certain general comments can be made. First, ammonia is probably of central importance in the pathogenesis of portal systemic encephalopathy. Second, the actions of ammonia appear to be affected by the development of toxin hypersensitivity and synergism with other toxins. Third, endogenous benzodiazepine ligands may contribute to the development of the disorder. Fourth, many models of liver disease are most appropriately considered as models of fulminant hepatic failure, and the mechanisms causing brain dysfunction in this disorder are poorly understood, as is witnessed by the poor therapies available to treat this condition.

Therapy The management of liver failure accompanied by neurological disturbances may be a difficult task. Many patients have a variety of complicating problems, including severe infections, abnormalities of renal function, cardiovascular collapse, hemorrhagic disorders due to clotting factor deficiencies and hypersplenism, or other medical-surgical problems. Thus, it is unusual to encounter patients with relatively uncomplicated hepatic encephalopathy.

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In planning therapy, it is critical to differentiate patients with fulminant hepatic failure from patients with portal systemic encephalopathy. For the former, supportive care and evaluation for potential transplantation are urgent issues. For patients with portal systemic encephalopathy, supportive measures should be supplemented by specific treatment strategies including the elimination of precipitating factors, cleansing enemas, and the use of lactulose or neomycin (or both). In evaluating the results of the many reported therapies for encephalopathy associated with liver disease, it is critical to remember that mere inclusion in a therapeutic trial is likely to be beneficial because investigators are then better able to control diet, alcohol consumption, and other precipitating factors that are critical to the success of treatment. Because of this, open trials and placebo-controlled trials of almost any therapy for portal systemic encephalopathy are likely to be associated with improvement in clinical and laboratory measures designed to evaluate a response to therapy. Although lactulose and neomycin are mainstays of therapy, the clinical trials supporting their use would have difficulty meeting current standards for drug approval required by the U.S. Food and Drug Administration. However, clinical experience with these compounds is extensive, and they remain a mainstay in the therapy of hepatic encephalopathy. Most of the therapies that are clearly effective in the treatment of portal systemic encephalopathy are believed to work by influencing ammonia metabolism. These therapies are considered in some detail. General Measures and Diet Much of the body burden of ammonia is due to the action of urease and amino acid oxidases in the colon, and so a variety of successful measures designed to reduce colonic ammonia production have been evaluated. Much of the ammonia formed in the colon is derived from protein, and control of protein is therefore critical. This control can be achieved by several means, each of which should be considered. During acute exacerbations, complete elimination of dietary protein may be required. During this phase, the altered level of consciousness increases the risk of aspiration associated with any attempts at oral feeding. Prolonged protein restriction is unwarranted and contributes to acceleration of catabolic reactions that may interfere with hepatic regeneration and impair ammonia detoxification by nonhepatic tissues. Bleeding in the gastrointestinal tract must be stopped as quickly as possible, and elimination of blood must be facilitated by the judicious use of purgatives and enemas. These measures should be considered in every patient, especially when a history of constipation is obtained. Constipation maximizes the dwell-time for nitrogenous compounds in the colon and thereby the potential for conversion to ammonia. More aggressive measures such as surgery to remove or bypass the colon have been evaluated, but the morbidity and mortality of the surgery are high and obscure any possible therapeutic benefit. In patients with chronic liver disease, it is important to maintain adequate nutrition to optimize hepatic regeneration and prevent the development of cachexia. This may be an indication for the use of the branched-chain amino acid mixtures that have been developed for both intravenous and oral use, but further evaluation of this approach is required. Uribe and associates compared various diets, including 40 g of meat protein plus neomycin, 4077g of vegetable protein without neomycin, and 80 g of vegetable protein without neomycin. Both vegetable protein diets were found to be superior to the diet containing meat protein plus neomycin. However, two patients receiving the vegetable protein diet had episodes of hypoglycemia, and most patients found it difficult to eat the large volumes of food required to ingest 80 g of vegetable protein. These forms of therapy may work by reducing dietary methionine and its subsequent conversion to methanethiol and ammonia and by the cathartic effect of the fiber in diets that are high in vegetable protein. Dietary issues related to the treatment of patients with cirrhosis have been reviewed by 78 Kondrup and Müller. They point out that most patients with cirrhosis are malnourished. Energy and protein balance can be maintained in most patients by a diet providing 30 to 40 kcal/kg per day containing 0.8 to 1.3 g protein/kg. This may require frequent feedings, including nocturnal feedings. A recent randomized trial compared a progressive low protein diet (0 g on days 1 to 3, with progressive increases every 3 days to a target of 1.2 g/kg daily) 79 with a diet containing 1.2 g/kg daily. The two groups fared equally well, in terms of their encephalopathy, but the higher protein diet group suffered less protein breakdown. Micronutrients and vitamins should be supplied, as 10 to 50 percent of cirrhotics are deficient in these compounds. Lactulose Lactulose, a synthetic disaccharide, is currently the mainstay in the treatment of portal

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systemic encephalopathy and has largely replaced neomycin, since it is not associated with renal toxicity or ototoxicity. Effective lactulose therapy is associated with reductions in the arterial ammonia concentration that are paralleled by normalization of the EEG and improvements in mental status. Its therapeutic efficacy is therefore thought to be related to its effect on ammonia. The history of lactulose is of considerable interest. It was first given to patients with the expectation that it would acidify the colon, leading to repopulation of the colon with bacteria that did not contain urease and trapping ammonia as the less diffusible ammonium ion. Subsequent studies demonstrated that this hypothesis, although attractive from a theoretical perspective, was not correct. Lactulose appears to exert its effect by favoring nitrogen fixation 80 in several clinical in the gastrointestinal tract. The efficacy of lactulose has been established 81 trials and is a mainstay in the therapy of hepatic encephalopathy. The dose of lactulose varies from patient to patient, but 20 to 30 g four times daily is a typical effective regimen. The dose should be adjusted until two to three bowel movements per day are produced without unacceptable side effects. Patients with coma require more aggressive initial therapy, with hourly doses of 20 to 30 g of lactulose until a catharsis is produced, after which the dose is reduced. Adverse reactions most commonly include abdominal bloating and diarrhea. These symptoms are dose-related, and adjustments in the therapeutic regimen usually allow continuation of therapy. Care must be taken to prevent diarrhea and secondary electrolyte abnormalities. Patients with liver disease may be particularly susceptible to the development of central pontine myelinolysis. This condition may occur when hyponatremia is corrected too rapidly. This complication must be avoided. Neomycin Although the efficacy of neomycin was widely accepted, proof of 81 its utility did not come until the same cooperative study that proved the efficacy of lactulose. Neomycin is also effective in the management of acute encephalopathy. For this condition, the usual daily dose ranges between 4 and 12 g taken in divided doses, whereas chronic therapy is usually accomplished with 2 to 3 g daily. When chronic neomycin therapy is required, monitoring of drug levels and otological and renal function is mandatory to detect early toxicity. Lactitol 82

Another synthetic disaccharide, lactitol, has been reported to be as effective as lactulose. It remains to be seen whether this drug will find widespread acceptance. It is used as a sugar substitute in low-energy and low-fat foods, but it is not currently available for the treatment of hepatic encephalopathy in the United States. Transjugular Intrahepatic Portosystemic Shunts Transjugular intrahepatic portosystemic shunts (TIPS) may be created to control ascites. A meta-analysis of this procedure has shown that it controls ascites more effectively than large-volume paracentesis but carries the penalty of inducing encephalopathy without 83 the degree of shunting, increasing survival. Endovascular techniques, designed to reduce 84 may be effective in controlling encephalopathy in selected cases.

Outcome Patients with fulminant hepatic failure have an 80 to 85 percent expected mortality rate, and treatment has been of little help. The ultimate prognosis depends on the severity of the liver disease, the presence of complications, and in some cases the availability of livers for transplantation. Patients with portal systemic encephalopathy fare much better than patients with fulminant hepatic failure. Most patients with relatively uncomplicated encephalopathy can be expected to make a full recovery, at least after the initial episode. Again, complications and the nature of the precipitating factor have an impact on survival. Severe hepatic coma carries a substantial risk of death or permanent neurological disability. Levy and colleagues encountered 51 patients with 85 hepatic coma in their prospective analysis of nontraumatic coma of at least 6 hours' duration. In that group, 49 percent showed no sign of recovery over the first year after diagnosis, whereas 27 percent regained the ability to live independently and made a good neurological recovery. Among the remainder, 2 percent developed a persistent vegetative state, 14 percent were left with severe disability, and 8

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percent remained with moderate disability over a 1-year period. These patients probably represent a worst-case group because of the requirement for very deep and prolonged coma that had to be satisfied prior to enrollment in the study. Orlandi and associates studied a less severely affected population and reported a mortality rate of 6.1 percent for patients with 86 grade 1 encephalopathy, rising to 27 percent in patients with grade 2 or higher. An identifiable precipitating factor and a short duration were favorable indicators, whereas hyperbilirubinemia, prolongation of the prothrombin time, ascites, and cachexia predicted an unfavorable outcome. Previous

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Aminoff: Neurology and General Medicine: Other Neurological Disor...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 15 Other Neurological Disorders Associated With Gastrointestinal, Liver, or Pancreatic Diseases VINAY CHAUDHRY • WILLIAM J. RAVICH •

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NEUROLOGICAL COMPLICATIONS OF GASTROINTESTINAL DISORDERS Malabsorption Syndromes Celiac Disease Chronic Idiopathic Inflammatory Bowel Disease Infectious Diseases Campylobacter Enteritis and Guillain–Barré Syndrome Whipple's Disease Liver and Neurological Disease Peripheral Neuropathy Acquired Hepatocerebral Degeneration Pancreas and Neurological Disease GASTROINTESTINAL MANIFESTATIONS OF NEUROLOGICAL DISEASES Dysphagia Neurological Diseases With Dysphagia Evaluation of Dysphagia Management of Dysphagia Motility Disorders

Neurological disorders associated with gastrointestinal (GI), liver, or pancreatic diseases are poorly recognized. In consequence, their diagnosis and treatment are often unnecessarily 1–3 delayed and costly. Neurological manifestations may be secondary to the presence of a known GI disorder. Conversely, GI disturbances may complicate known neurological disorders. These two aspects are discussed separately, but there is a considerable overlap between the two, so that patients with undiagnosed GI disease may first be seen by a neurologist, and vice versa. NEUROLOGICAL COMPLICATIONS OF GASTROINTESTINAL DISORDERS

Malabsorption Syndromes The term malabsorption is used to describe a variety of disorders in which ingested nutrients are not absorbed. These disorders in turn are commonly divided into disturbances of

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digestion (maldigestion) in which ingested foods are inadequately broken down into absorbable components and disorders of absorption proper (malabsorption) in which there is a failure of the normal transport of the nutrients through the intestines. Malabsorption syndromes can cause neurological abnormalities both through specific nutritional deficiencies 4 and through multisystem involvement associated with specific disorders. Table 15-1 summarizes the neurological manifestations of nutritional deficiencies of vitamins and electrolytes caused by various malabsorption syndromes. A detailed discussion of individual vitamin deficiencies can be found in Chapter 17. The manifestations of deficiency of a specific nutrient are the same whether the deficiency occurs from reduced dietary intake, impaired intraluminal digestion, or disorders of intestinal transport. Unexplained confusion, memory changes, numbness, weakness, and gait ataxia should lead to a suspicion of malabsorption, especially if associated with diarrhea or weight loss. Glossitis, cheilosis, and stomatitis may also be noted. Laboratory studies demonstrating deficiencies of minerals and vitamins, including determination of serum iron, ferritin, vitamin B12, vitamin D (25-OH vitamin D), vitamin E, thiamine, folic acid, calcium, and phosphorus, may suggest but are not specific for malabsorption. Deficiency of water-soluble vitamins (thiamine, riboflavin, niacin, and pyridoxine) is more likely to result from dietary deficiencies than from malabsorption syndromes, whereas deficiency of fat-soluble vitamins (vitamins D, E, and B12) is more likely to be the result of absorptive problems. Click here to view this table.... The differential diagnosis of malabsorption disorders is quite broad and can be divided into the following, often overlapping, groups: 1. Mucosal disorders, such as celiac disease, collagenous sprue, nongranulomatous ulcerative jejunoileitis, eosinophilic gastroenteritis, immunoproliferative small intestinal disease, lymphoma, lymphangi ectasia, Crohn's disease, radiation enteritis, and chronic mesenteric ischemia 2. Infectious disorders, such as bacterial overgrowth, tropical sprue, Whipple's disease, parasitic diseases (e.g., Giardia, Cryptosporidium, tapeworm infestations), and Mycobacterium avium-intracellulare infection 3. Maldigestive disorders, such as pancreatic exocrine insufficiency, hepatic or biliary tract disease with bile acid deficiency, Zollinger–Ellison syndrome, and drug effects (cholestyramine, colchicine, laxatives) 5

4. Postoperative malabsorption, such as following gastric surgery or extensive intestinal resection (short gut syndrome) 5. Lymphatic obstruction from disorders such as lymphoma and tuberculosis 6

6. Other disorders, including abetalipoproteinemia, malabsorption in the elderly, diabetic 7 8 collagen vascular disease, and acquired immunodeficiency diarrhea, amyloidosis, 9 syndrome (AIDS) Unexplained confusion, memory changes, numbness, weakness, and gait ataxia should lead to a suspicion of malabsorption, especially if associated with diarrhea or weight loss. Common symptoms of malabsorption include foul-smelling, greasy stools, weight loss, 10 flatulence, and bloating. Glossitis, cheilosis, and stomatitis may also be noted. Most patients with malabsorption describe a change in their stools. The hallmark of malabsorption is steatorrhea, loss of excessive fat in the stool. Most patients with steatorrhea have diarrhea, but about 10 percent of patients have steatorrhea without diarrhea. Typical characteristics of steatorrhea include a pale color, excessive bulk, greasiness, a tendency to float (due to incorporated fat), and stool that leaves a greasy film on the toilet bowl surface after flushing. A spot qualitative assay of fecal fat using Sudan staining may be used. The presence and severity of steatorrhea is confirmed by fecal fat collection, usually over a 3-day 11 period. The patient must be ingesting an adequate amount of fat. Commonly, the patient is placed on a high (100 g) fat diet for a number of days before collection begins, but the test can be satisfactorily performed during ingestion of lower amounts of fat (e.g., 70 g). The important issue is to make sure that the fat is ingested. With an adequate fat diet and with moderate to marked malabsorption, the test usually correlates fairly well with a quantitative assay of fat malabsorption and can provide rapid data that can direct subsequent diagnostic testing. Steatorrhea is defined as the loss in the stool of more than 7 percent of ingested fat. Once steatorrhea is confirmed, a d-xylose test in which the blood or urine level of d-xylose is

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measured helps to determine whether the malabsorptive process is due to a mucosal 12 disease or intraluminal digestion. A positive test, showing low levels of d-xylose absorption, indicates either an abnormality of mucosal processing or bacterial overgrowth (bacteria compete for d-xylose), whereas a normal test indicates an abnormality of intraluminal digestion, most often due to pancreatic disease. Other laboratory tests that may suggest malabsorption are not specific; they include determination of serum iron, ferritin, vitamin B12, vitamin D (25-OH vitamin D), vitamin E, thiamine, folic acid, calcium, and phosphorus. A small bowel biopsy may be needed for a definitive diagnosis of a mucosal, infective, or infiltrative cause of malabsorption. Celiac Disease Celiac disease (nontropical sprue, gluten-sensitive enteropathy) is a malabsorptive condition in which an allergic reaction to the cereal grain protein gluten causes small bowel injury resulting in malabsorption. Celiac disease deserves to be discussed separately given its numerous neurological manifestations that may occur even without clinically evident 13,14 malabsorption of nutrients. The age at onset of celiac disease is bimodal, being either in the first decade of life or between 40 and 50 years of age. Women are affected more often than men (2:1). The clinical presentation is with the symptoms of malabsorption described earlier. Some patients may 14 have minimal GI symptoms or none at all at the onset of their neurological illness. Although neurological symptoms are rare in children, as many as 36 percent of adult patients have 15 been reported to have neurological manifestations. Dementia, cerebellar ataxia, myelopathy, brainstem encephalitis, progressive leukoencephalopathy, seizures, vasculitis, and occipital calcification make up the central nervous system (CNS) manifestations of celiac 2,13 Hadjivassiliou and associates reported the presence of antigliadin antibodies in disease. 16 41 percent of patients with idiopathic ataxia. Neuropathological examination has shown Purkinje cell loss in the cerebellum and in the brainstem nuclei. The deep gray matter and 17 spinal cord may also show pathological changes. This pattern of involvement is not influenced by nutritional therapy and differs from the changes seen in alcohol-related cerebellar degeneration and from subacute combined degeneration due to vitamin B12 deficiency. Epilepsy manifesting as partial seizures has been reported in as many as 5.5 18 percent of patients with celiac disease. Some of these cases were refractory to antiseizure medications until a gluten-free diet was initiated. The neuromuscular manifestations of celiac disease include polymyositis, dermatomyositis, 14 and inclusion-body myositis. All the myopathies described have the classic features of a primary inflammatory process, with proximal muscle weakness, high serum creatine kinase (CK) levels, the electromyographic (EMG) features of a myopathy, and necrotizing features with primary inflammation on muscle biopsy. A sensory-motor axonal peripheral neuropathy with length-dependent features affecting lower limbs more than upper limbs has also been reported with celiac disease as an independent association, again even without malabsorption or nutritional deficiencies. In a study by Chin 19 and co-workers, 5 percent of 400 screened patients with neuropathy had celiac disease. Of 9 patients described by Hadjivassiliou and colleagues, 3 had peripheral neuropathy, and 1 each had axonal motor neuropathy, mononeuropathy multiplex, inclusion-body myopathy, 14 and neuromyotonia. These authors emphasize that gluten sensitivity is common and should be searched for in all patients with neurological disease of unknown cause, including peripheral neuropathy, mononeuritis multiplex, and myopathy. By contrast, a study of 27 patients with cerebellar ataxia and 32 with peripheral neuropathy concluded that the presence of food antibodies is a nonspecific finding, casting doubt on 20 the nosological status of “gluten ataxia” and “gluten neuropathy” as discrete disease entities. The diagnostic test for celiac disease is a small intestinal biopsy that reveals loss of villi and flattening of the mucosa, which is composed of cuboidal cells in place of the normal columnar cells. In addition, the crypts are elongated, and there is an increase in inflammatory cells in the intestinal biopsy specimen. Laboratory tests for circulating IgA anti–tissue transglutaminase and anti-endomysial antibodies in the serum are relatively sensitive and specific for the diagnosis of celiac disease. A falsely negative test may result from IgA deficiency, which is more common in celiac disease than in the general population. Despite the high degree of test specificity, most authorities would require confirmation of celiac disease by small intestinal biopsy. A gluten-free diet, which consists of removal of all substances containing wheat, rye, and barley, is the mainstay of treatment. Even small amounts of dietary gluten will sustain the mucosal injury. Once a gluten-free diet is initiated, malabsorptive symptoms usually improve

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within 1 to 2 weeks, but the mucosal architecture may take 1 to 2 months to return to a near-normal state. It is not clear, however, whether neurological symptoms are necessarily improved, stabilized, or even prevented by a gluten-free diet. Overall, convincing evidence of a causal association of celiac disease with specific neurological conditions has not been established. Routine screening for celiac disease in 20 patients with idiopathic neurological syndromes cannot be recommended. Chronic Idiopathic Inflammatory Bowel Disease Ulcerative colitis and Crohn's disease are the two main diseases in this category. Ulcerative colitis is a chronic disease characterized by inflammation of mucosal and submucosal portions of the rectum, extending proximally for a variable distance along the colon. It generally presents with symptoms of bloody and urgent diarrhea. Crohn's disease is also a chronic disease that, unlike ulcerative colitis, can result from inflammation of any region of the GI tract. Also unlike ulcerative colitis, Crohn's disease generally affects all layers of the involved region of the bowel. It presents as abdominal pain, with nonbloody and less urgent diarrhea. Neurological involvement is uncommon in inflammatory bowel disease (3%) and either is due to21–23 malabsorption (Table 15-1) or is a part of the extra-intestinal complications. Neurological manifestations of ulcerative colitis include the acute inflammatory demyelinating 24 25 polyneuropathy form of Guillain–Barré syndrome (GBS) and polymyositis. 21A patient with myasthenia gravis was also reported in the series by Lossos and associates, although this association may have been coincidental. The diarrhea that occurs in ulcerative colitis may cause symptoms due to potassium deficiency (Table 15-1). Crohn's disease has been associated with sensorimotor axonal neuropathy independent of 26 Myopathy has also been associated with Crohn's any deficiency of specific nutrients. 21 disease. In most cases, the myopathy is thought to be inflammatory with an immune basis 27 and, in about half the cases, seems to be correlated with the activity of the bowel disease. Crohn's disease may also lead to neurological symptoms from malabsorption of nutrients resulting in hypokalemia, hypocalcemia, hypomagnesemia, and vitamin B12 deficiency. The malabsorption may relate to length of mucosal involvement or surgical resection, loss of the terminal ileum, or bacterial overgrowth. Peripheral neuropathy in Crohn's disease is often associated with vitamin B12 deficiency due to the disease or to resection of the intestine. Gondim and colleagues reported peripheral neuropathy unassociated with nutritional26 deficiency in 18 patients with Crohn's disease and 15 patients with ulcerative colitis. Axonal sensory (small- or large-fiber), axonal sensorimotor, and demyelinating neuropathies responsive to immunotherapies were noted by these authors. Treatment of the disease often requires corticosteroids or metronidazole, each of which has potential neurological side effects. Thromboembolic complications are well-known complications of both ulcerative colitis and 28,29 Transient Crohn's disease and may manifest neurologically as cerebral vein thrombosis. ischemic attacks, ischemic strokes, and cerebral hemorrhage also occur. Cerebral arterial occlusions have been described as affecting the internal carotid, middle cerebral, or posterior cerebral vessels. In a prospective study, magnetic resonance imaging (MRI) of the brain showed hyperintense focal white matter changes in 40 to 50 percent of patients with 30 inflammatory bowel disease compared with age-matched control subjects. None of the patients, however, had neurological symptoms. Lossos and colleagues noted 5 patients with 21 slowly progressive myelopathy.

Infectious Diseases Campylobacter Enteritis and Guillain–Barré Syndrome Campylobacter jejuni is a leading cause of acute gastroenteritis in humans and is now recognized to be the most frequent antecedent pathogen leading to Guillain–Barré syndrome (GBS). GBS is the most common cause of acute generalized paralysis and is characterized by an acute polyneuropathy, with areflexia and albuminocytological dissociation in the cerebrospinal fluid (CSF). The epidemiological link between preceding C. jejuni infection and 31 GBS has been confirmed in many parts of the world, occurring in between 15 and 75 percent of GBS cases in different places. Patients developing GBS after C. jejuni infection 32 have autoantibodies to GM1 ganglioside in the acute phase of the illness. The C. jejuni and GBS association represents an example of molecular mimicry between C. jejuni lipopolysaccharides that carry ganglioside-like epitopes and ganglioside-like moieties present

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on nerve fibers. Infection by C. jejuni that bears the GM1-like lipopolysaccharides associated with the serotypic determinant of PEN 19 induces high production of IgG1 and IgG3 anti-GM1 antibodies with the help of T cells. IgG anti-GM1 antibody binds to motor nerve terminal axons, inhibits motor neuron excitability, and leads to development of GBS. The bacterial 31 gene responsible for this has been determined (cst-II). Whipple's Disease Whipple's disease is a rare, chronic, multisystem infectious disease that is caused by Tropheryma whippelii infection, a weakly gram-positive actinomycete. Whipple's disease is more common in men (80%) than in women, with the mean age of onset being 50 years. Although the disease can affect any organ, its predominant manifestations are in the GI tract and are characterized by abdominal pain, diarrhea (steatorrhea), and weight loss. Variable fever, relapsing-remitting arthralgia, arthritis, and lymphadenopathy may also occur. Neurological involvement occurs in 4 to 11 percent of patients with Whipple's disease. Among neurological symptoms, mental status changes including dementia, confusion, and behavioral and personality changes are the most frequent manifestations. Abnormalities of eye movements are the next most frequent presentation and may include supranuclear (vertical more than horizontal) ocular palsy, conjugate gaze paresis, and nystagmus. Oculomasticatory myorrhythmia and oculofacial-skeletal myorrhythmia (slow convergent-divergent nystagmus combined with rhythmic33movements of the jaw, mouth, and limbs) are said to be pathognomic for Whipple's disease. Other movement disorders, including myoclonus of the extremities, twitching of the facial muscles, and bruxism, have been described. Seizures and hypothalamic, cerebellar, spinal cord, and basal ganglia involvement may also occur and lead to a wide range of reported manifestations, such as polydipsia, hyperphagia, hypersomnolence, seizures, cerebellar ataxia, myelopathy (spastic quadriparesis), parkinsonism, aseptic meningitis, stupor, and coma. Ocular involvement may be manifested by uveitis, vitritis, keratitis, optic neuritis, or papilledema. Peripheral manifestations include myopathy, peripheral neuropathy, and compressive neuropathy. The multifocal involvement resembles cerebral vasculitis or CNS sarcoidosis. The CSF is generally normal, although pleocytosis and mild elevations in protein concentration have been reported. Spinal fluid or tissue (duodenum) assay by polymerase chain reaction for Tropheryma whippelii is important for confirming the diagnosis. Magnetic resonance imaging of the brain can reveal atrophy, hydrocephalus, and multiple areas of abnormal signal intensity in deep white matter, hypothalamus, medial temporal lobes, basal ganglia, and 34 pons. If the disease is suspected, a duodenal biopsy is necessary. The presence of PAS-positive foamy macrophages on light microscopy and of the characteristic morphology of the bacilli on electron microscopy establishes the diagnosis. The availability of polymerase chain reaction (PCR) assays has made diagnosis easier. Treatment of Whipple's disease should be with antibiotics that can cross the blood–brain barrier. At present, the favored method of treatment is the daily parenteral administration of 1.2 million units of benzylpenicillin (penicillin G) and streptomycin, 1 g, for a period of 2 weeks. This is followed by treatment with cotrimoxazole35,36 (trimethoprim, 160 mg, and Ceftriaxone parenterally for 1 sulfamethoxazole, 800 mg) twice daily for 1 to 2 years. 37 month, followed by oral cefixime for 2 years, has also been recommended. Symptomatic treatment of seizures and movement disorders may be required. PCR assays of the CSF are helpful in monitoring treatment. The response to treatment has been variable. Established neurological manifestations are difficult to reverse, and a relapse may occur once antibiotics are discontinued.

Liver and Neurological Disease Fulminant acute hepatic failure and reversible hepatic encephalopathy (also called portal systemic encephalopathy) are discussed in Chapter 14. This section, therefore, focuses on the peripheral neuromuscular manifestations of liver disease. Acquired hepatocerebral degeneration, a topic not covered in Chapter 14, is also discussed. Peripheral Neuropathy Although peripheral neuropathy may occur in patients with liver disease, there is controversy 38 regarding a causal relationship. Some authors doubt the existence of hepatic neuropathy, 39–41 whereas others report an incidence ranging from 19 to 100 percent. A prospective study

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of 58 patients with end-stage liver disease found that peripheral neuropathy was frequent, 41 occurring in 71 percent of these patients. In most patients, the neuropathy was either subclinical or associated with minimal symptoms. Examination showed distal sensory loss and loss of distal reflexes consistent with a length-dependent neuropathy. Quantitative sensory testing revealed abnormalities of small-fiber function (cooling threshold) more than large-fiber function (vibration threshold). Nerve conduction studies showed length-dependent loss of sensory and motor response amplitudes with relatively preserved conduction velocities, confirming that axonal loss was responsible. Median neuropathy at the wrist (carpal tunnel entrapment) was common, occurring in one third of patients. Some authors have reported that the neuropathy is predominantly demyelinating in 39,40,42 On careful analysis of these reports, the conduction velocities were rarely in the nature. range suggestive of demyelination and can be explained by large-fiber axonal loss. Furthermore, entrapment neuropathies were not excluded as possible explanations for the reduced conduction velocities. Similarly, a few pathological studies have suggested that the neuropathy is associated with demyelination on the basis of sural nerve biopsies showing 40 thinly myelinated fibers and short internodes. However, no active demyelination or inflammatory cells were reported, and the thinly myelinated fibers and small internodes may have been a reflection of axonal degeneration followed by regeneration. The causal relationship between liver disease and neuropathy has been questioned because certain systemic illnesses that cause liver dysfunction are also independent causes of peripheral nerve dysfunction. This applies to alcohol-induced cirrhosis, porphyria, polyarteritis nodosa, certain intoxications, primary biliary cirrhosis, and amyloidosis. However, the severity of neuropathy correlates with severity of liver disease independently of its etiology, suggesting 39 that the peripheral neuropathy is caused by the liver disease. Moreover, patients with cryptogenic liver disease also develop peripheral neuropathy of varying severity. In addition to hepatocellular damage, portosystemic shunting has been incriminated in the genesis of 43 hepatic neuropathy. However, others have found no differences between cirrhotic patients related to portacaval shunt, and an experimental study of portacaval anastomosis in rats also 44 favored hepatocellular failure as the principal cause of hepatic neuropathy. Reports are increasing that hepatitis C may be associated with neuromuscular complications. Two groups of patients with hepatitis C may develop peripheral neuropathy. Patients with cryoglobulinemia may have a fulminating vasculitic syndrome and develop a mononeuropathy 45,46 Patients with chronic liver disease in the absence of cryoglobulinemia may multiplex. 39 develop a length-dependent oligosymptomatic distal peripheral neuropathy. Both acute neuropathy (GBS) and chronic demyelinating neuropathies sometimes occur in the setting of 47–49 Myalgia is a common symptom of unknown cause in infectious hepatitis; viral hepatitis. muscle weakness is rarely present. Polymyositis is increasingly being reported as an immune 50 response to hepatitis C, although a clear causal relationship remains to be established. In addition, interferon therapy for hepatitis C infection may precipitate or aggravate the 51 myopathy. Patients with chronic liver disease secondary to primary biliary cirrhosis form a separate group. These 52 patients have pure sensory neuropathy with or without xanthomatous infiltration of the nerves. 53

Autonomic neuropathy occurs frequently in chronic liver disease. In one study, autonomic 41 dysfunction was found in 48 percent of patients. Abnormalities of heart-rate variation with deep breathing and with the Valsalva maneuver are more likely than an orthostatic decline in blood pressure, suggesting predominant parasympathetic dysfunction. Most patients with autonomic dysfunction have evidence of a somatic neuropathy. The prevalence and severity of autonomic dysfunction relates to the severity of hepatic dysfunction and is independent of 54 its etiology. Acquired Hepatocerebral Degeneration Acquired (non-Wilsonian) hepatocerebral degeneration occurs in the setting of 2,55 The decompensated acquired liver disease or extensive portosystemic shunts. characteristic clinical presentation resembles Wilson's disease and includes dysarthria, ataxia, tremor, choreoathetosis, and altered mental status. Parkinsonism may occur (p. 1113). Typically, patients experience several episodes of hepatic encephalopathy before developing the extrapyramidal manifestations. Tremor of the outstretched arms is followed by gait ataxia, dysarthria, and rigidity. Intention myoclonus, nystagmus, varying degrees of dementia, and spastic myelopathy may also be noted. Wilson's disease needs to be excluded if an acquired etiology for chronic liver disease is not obvious. Unlike Wilson's disease, patients with acquired hepatocerebral degeneration will have normal serum and urinary

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copper levels, normal serum ceruloplasmin, and absence of Kayser–Fleischer rings. T1-weighted magnetic resonance imaging sequencing shows hyperintensity in the lenticular 56 nucleus, although this is not a specific finding. The pathogenesis is poorly understood, although it is presumed to be secondary to toxic metabolites bypassing the liver circulation. Increased manganese deposition in the basal ganglia has been documented. Histologically, prominent astrocytic hyperplasia, white matter spongy degeneration, and pseudolaminar cortical necrosis have been found. The disorder is not responsive to conventional therapy for hepatic encephalopathy and tends to be irreversible. A few case reports of patients improving with liver57transplant have been described, although the improvement has not been sustained.

Pancreas and Neurological Disease Pancreatic encephalopathy is a term used to describe a range of neuropsychiatric symptoms 2,58 associated with acute pancreatitis. These symptoms are similar to those of any other metabolic encephalopathy and may include fluctuating mental status, hallucinations, decreased attention span, restlessness, delirium, anxiety, slurred speech, spasticity, and seizures. In a59prospective study of 17 cases of acute pancreatitis, encephalopathy was found in 6 patients. A direct relationship was found between the pancreatic encephalopathy and an increase in CSF lipase. The electroencephalographic (EEG) changes were nonspecific. The encephalopathy was not related to severity of the pancreatitis, did not affect the course of the pancreatitis, and showed no relationship to type of treatment. Several hypotheses have been proposed to explain the pathogenesis of cerebral dysfunction in acute pancreatitis, but 60 none has been proved. Fat embolism, intravascular coagulation, hyperosmolarity, and hypoxia all have been regarded as etiopathogenic mechanisms of pancreatic encephalopathy. Wernicke's encephalopathy should be included in the differential diagnosis in the setting of pancreatitis. Treatment with thiamine (100 mg/day) should be considered even if the classic triad (nystagmus, ataxia, and confusion) of Wernicke's encephalopathy is lacking. Chronic pancreatitis from any cause, including cystic fibrosis, may cause neurological symptoms due to malabsorption, as noted earlier. Alcoholism is a common etiology of chronic pancreatitis and may independently cause peripheral neuropathy (from nutritional deficiency of thiamine) and myopathy. Diabetes mellitus occurs in as many as 30 percent of patients with chronic pancreatitis and in up to 70 percent of patients with diffuse pancreatic calcifications. In this setting, neuropathy is as frequent as in other patients with diabetes. Hypoglycemic neuropathy is an entity that is encountered in relation to insulinoma or the accidental or deliberate injection of insulin. Although the predominant manifestation of this is 61 an encephalopathy, distal paresthesias and weakness have been reported. GASTROINTESTINAL MANIFESTATIONS OF NEUROLOGICAL DISEASES

Dysphagia Swallowing involves a coordinated act that has oral, pharyngeal, and esophageal phases. In the oral phase, the tongue partitions the bolus and pushes a portion into the pharynx. In the pharyngeal phase, the nasopharynx closes so that food does not go into the nasal passages, the epiglottis tilts downward, the larynx elevates, and the vocal cords approximate to prevent entry of food into the airway, and the upper esophageal sphincter relaxes to allow unimpeded bolus passage. In the esophageal phase, a progressive contraction of the circular muscle layer is coordinated with relaxation of the lower esophageal sphincter to push the swallowed food bolus down the length of the esophagus and into the stomach. Patients with oral and pharyngeal dysphagia often complain of difficulty in controlling the oral bolus, difficulty in initiating swallowing, coughing during swallowing, or the feeling of food sticking in the throat. Associated symptoms of facial, tongue, jaw, and pharyngeal weakness, such as nasal regurgitation, coughing during swallowing, and dysarthria (nasal speech) are usually present. Patients with oral and pharyngeal dysphagia often localize the sensation of food-stick to the lower neck. Neurological Diseases With Dysphagia Oral- and pharyngeal-phase dysfunction is often due to neurological diseases (Table 15-2). Neurogenic dysphagia may result from cortical (generally bilateral) lesions; lesions of the pyramidal tracts; movement disorders; cerebellar disorders; lesions of the brainstem nuclei of cranial nerves V, VII, IX, X, and XII; and lesions of these cranial nerves, their neuromuscular

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junctions, or the oral, pharyngeal, or esophageal striated muscles that they innervate (Table 62 15-2). Dysphagia may be the first or presenting symptom of the neurological disorder or may develop during the course of the neurological disease. Click here to view this table.... Cerebrovascular disease is the most common cause of neurogenic dysphagia, which occurs 63 in up to 50 percent of patients with stroke. Brainstem strokes and bilateral anterior circulation strokes are more likely to result in dysphagia, although swallowing dysfunction 63 may also occur in unilateral hemispheric strokes involving either side. Isolated dysphagia is uncommon from stroke, although it has been reported with lacunar infarcts in the 62 periventricular white matter and with discrete brainstem lesions. The mechanism of dysphagia is an upper or lower motor neuron disturbance involving the bulbar muscles, with oral masticatory and transit phases of swallowing being affected. Video radiography using barium contrast often shows premature leakage of oral contents into the pharynx, delayed initiation of swallowing, asymmetric weakness of the pharyngeal constrictor mus cles, nasopharyngeal incompetence, incomplete laryngeal closure, or poor opening of the pharyngo-esophageal segment. The consequence of these abnormalities includes nasal regurgitation, penetration of barium into the larynx, and pharyngeal retention. The risk of aspiration is high when the patient's sensorium is altered and may necessitate intubation to protect the airway. Dysphagia as a result of a stroke is usually transient, with most patients able to swallow within 2 weeks. Movement disorders such as Parkinson's disease, progressive supranuclear palsy, Huntington's disease, Wilson's disease, and spasmodic torticollis have all been associated with dysphagia, although it is rarely severe enough to affect nutrition or warrant a feeding tube. Reduced tongue motility, delayed initiation of swallowing reflex, and decreased peristaltic movement have been described in Parkinson's disease. Dysphagia in Parkinson's disease is often associated with tongue tremor, pharyngeal peristaltic dysfunction, and 64 impaired opening of the upper esophageal sphincter. Drooling and difficulty in handling the secretions are manifestations of dysphagia, rather than secondary effects of increased secretions, even though treatment is often directed at the latter. As many as one third of parkinsonian patients experience coughing, choking, or nocturnal dyspnea due primarily to the dysphagia. Abnormal swallowing is also common in multiple sclerosis, although it is often asymptomatic 65 and does not compromise nutrition. It is associated with disordered brainstem or cerebellar function, bilateral pyramidal tract disease, overall disability, depressed mood, and low vital capacity. Multiple sclerosis impairs the oral and pharyngeal stages of swallowing by spasticity, ataxia, and weakness. palsy and Dysphagia in amyotrophic lateral sclerosis (ALS) is due to bulbar or pseudobulbar 66 occurs in as many as 25 percent of patients at the onset of the disease. Eventually almost all patients with ALS have at least some degree of dysphagia. The oral and pharyngeal components of swallowing are predominantly affected. Weakness of oral muscles (orbicularis oris, buccinator, pterygoids, masseter, and tongue) results in poor lip seal, reduced ability to chew (poor bolus formation), food particles collecting in the buccal sulcus, poor secretion control, poor propulsion of food, coughing, and choking before swallowing. Pharyngeal constrictor muscle weakness along with impaired laryngeal elevation results in symptoms of aspiration, such as choking or coughing during or immediately after swallowing. Symptoms are progressive and rapidly affect nutritional intake, and the risk of aspiration pneumonia is high. Dysarthria, either flaccid or spastic, frequently accompanies the dysphagia. Although clinical distinction between bulbar and pseudobulbar palsy is often made, the findings are often mixed. Sialorrhea (drooling), often resulting from impaired pharyngeal clearance rather than an increase in salivation, also accompanies bulbar symptoms in patients with ALS. A percutaneous endoscopic gastrostomy (PEG) tube should be considered early in ALS, before vital capacity declines to less than 50 percent, as an alternative or supplemental route for nutrition. The indications for PEG include inadequate oral intake (with weight loss) because of either difficulty in swallowing or fear of choking. Two studies suggested that PEG 66,67 placement prolongs survival, although there has been some debate on this issue. Patients with ALS also show delayed colonic transit times compared with healthy control subjects and a prolonged gastric emptying time. Bowel dysfunction does not occur, but constipation is common as the result of altered dietary intake, medications, and reduced mobility. Dysphagia due to infection of the bulbar neurons (brainstem lower motor neurons) during acute paralytic poliomyelitis is now rare, but after several years survivors may develop

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dysphagia as part of the postpolio syndrome. Dysphagia is slowly progressive and is severe in patients who initially had acute bulbar poliomyelitis. Sonies and Dalakas found clinical or subclinical evidence of dysphagia in most (31 of 32 patients examined) patients with the 68 postpolio syndrome (defined by onset of new weakness in the limbs). Aspiration is rare, and simple modifications of swallowing position, a change to soft food, and introduction of compensatory techniques were sufficient to control symptoms in all patients. Many postpolio patients are unaware of any difficulty with swallowing, since they have learned to68make gradual compensations in the way they swallow and take longer to finish a meal. Approximately 33 percent of patients with myasthenia gravis will have significant fatigable 69,70 Patients dysphagia, with oral and pharyngeal phases of swallowing being affected. typically do not have chewing or swallowing difficulty at the beginning of a meal, but tire easily as the meal progresses. They should be instructed to time the dosing of their cholinesterase inhibitors so that they are taken approximately 30 minutes prior to food intake. Botulism 71,72 presents with prominent bulbar symptoms of dysphagia and dysarthria, associated with blurred vision, diplopia, ptosis, descending paralysis, constipation, and autonomic symptoms, including ileus. Dysphagia for both solids and liquids is prominent in polymyositis and 62,73 inclusion-body myositis. The pharyngeal and esophageal phases of swallowing are affected. Nasal regurgitation is rare, and dysarthria and chewing difficulties are not primary complaints. To avoid aspiration, patients spend a long time in chewing their food. Oculopharyngeal muscular dystrophy is an autosomal-dominant myopathy that usually manifests itself with bilateral symmetric ptosis. Dysphagia usually occurs subsequently, although this symptom first brings the patient to seek medical attention. The dysphagia is at the upper sphincter level, at the junction of pharynx and esophagus, and is usually accompanied by pharyngo-oral and pharyngo-nasal regurgitation, which often causes social embarrassment to the point that patients no longer enjoy eating. Tracheal aspiration occurs frequently. Patients with myotonic muscular dystrophy may also have prominent dysphagia with myotonia; ptosis; facial weakness; and atrophy and 74 weakness of temporalis, sternocleidomastoid, masseter, and distal limb muscles. Cataracts, frontal balding, testicular atrophy, cardiac conduction defects, mental dullness, and sleep apnea are associated features. Pharyngeal and palatal weakness in myotonic dystrophy also lead to nasal dysarthria. Dysphagia occurs in as many as 25 to 85 percent of patients in different series. There is a high incidence of aspiration pneumonia. Involvement of the smooth muscle at several levels of the GI tract can occur (Table 15-3). Some of these patients have “unexplained abdominal pain,” which may lead to unnecessary laparotomy and even cholecystectomy. Click here to view this table.... Evaluation of Dysphagia Dysphagia should always be a concern in neurological patients with weight loss, since patients with mild to moderately severe dysphagia may not be aware of their symptoms. Drooling, aspiration, interrupted sleep, and change of diet to softer foods may suggest the presence of dysphagia. Patients with neurogenic dysphagia tend to have difficulty in the early phases of swallowing in contrast to patients with mechanical obstruction that localizes to mid-sternum or the xiphoid process. Also in contrast to mechanical causes of dysphagia, liquids are often harder to swallow than solids. A simple bedside slurp test consists of timing the patient as754 oz. of water in a cup are sucked through a flexed straw. Normal adults take 7 to 9 seconds. The patient should be observed for nasal regurgitation, aspiration, choking, effortful swallowing, leakage from the mouth, and apraxia. A video pharyngoesophagogram, in which the structure and movement of the oral cavity, pharynx, larynx, and esophagus are 76 visualized during swallowing, is the gold standard. The basic diagnostic study is often performed by a radiologist. A modification of the video study (the modified barium swallow) determines the impact of differing volumes and viscosities as well as the timing and head position during swallowing on swallowing safety and the efficiency of oral and pharyngeal function. The study is often performed jointly by a speech pathologist with specialized training in swallowing therapy and a radiologist. The impact of different food types, different food consistencies, and various therapeutic maneuvers on pharyngeal clearance and severity of aspiration can be determined. During the radiographic examination, the patient is also asked to flex the neck, extend the neck, and turn the head to one side in order to design postural strategies (e.g., chin down to prevent aspiration) to provide compensation for dysphagia. Management of Dysphagia

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Management depends on the results of the video study, diet modifications, postural strategies, and teaching supraglottic swallow (see later), which can be used to improve the efficiency and safety of swallowing. Diet modifications are based on observations during the video fluoroscopic swallowing study as to whether liquids, semisolids, or solids are safer and easier for the patient. Adjustment of the head position (“chin tuck”) during chewing and swallowing can help patients with difficulty in moving the food from mouth into the pharynx, and with premature leakage of the oral contents into the pharynx. Finally, some patients, especially those who retain food in anatomical spaces, may benefit from a supraglottic or safe-swallow procedure. The patient is instructed to inhale prior to swallowing, swallow the food (cough if needed), and then exhale immediately after swallowing. Sedatives should be avoided. Drooling in parkinsonian and ALS patients is due to dysphagia rather than to excessive production of saliva. Although anticholinergics may help reduce the saliva output, they may aggravate the dysphagia by making the secretions thicker and forming a mucous plug. Suction machines are often helpful. Other helpful measures include avoiding dry and 62 sticky foods and eating foods of uniform consistency. Cricopharyngeal myotomy, a surgical procedure in which the cricopharyngeal muscle (the major contributor to the upper esophageal sphincter) is cut, may be useful but only in an extremely well-selected group of patients with dysphagia due to neuromuscular disorders. It is likely to be more helpful if the video study shows failure of relaxation of the upper esophageal sphincter. It has been used successfully in oculopharyngeal muscular dystrophy and is reported to be useful in dysphagia with other neuromuscular disorders. In our experience, however, the procedure is not useful for most patients with neuromuscular diseases causing oral or pharyngeal weakness. Weight loss, malnutrition, and aspiration pneumonia are the feared complications of dysphagia. To avoid these complications, enteral feeding is often required by either nasogastric tube or PEG and jejunostomy tubes. A PEG is placed under local anesthesia (and sedation) by an endoscopist or a radiologist. The tube is placed through a small incision into the skin overlying the stomach on the anterior abdominal wall. Verification of the tube's position in the stomach lumen is obtained endoscopically and radiologically. Although it is thought by most neurologists that a PEG tube will prevent aspiration, the risk of aspiration remains high in patients with neurogenic dysphagia even after tube placement.

Motility Disorders Gastric and bowel motility is controlled by parasympathetic and sympathetic nerves that stimulate or inhibit the enteric neurons of the gut, which are organized as ganglionated plexuses and innervate the smooth muscles of the GI tract. The parasympathetic control of GI motility is from vagal and sacral nerves (S2, S3, S4) and the sympathetic outflow is from the intermediolateral column of the spinal cord (T5 to L3) through superior and inferior mesenteric ganglia. Neurological lesions affecting the sympathetic or parasympathetic pathways, or the smooth muscle, may affect the motility of the GI tract, resulting in gastroparesis, symptoms of small bowel obstruction, diarrhea, or constipation. These disorders are discussed in detail in Chapter 16, and brief comment here is made about only certain of them. Chagas' disease, also known as American trypanosomiasis, causes GI disease due to 77 intrinsic lesions of bowel innervation. Megacolon, megarectum, and mega-esophagus are common in rural areas of central Brazil, where the disease is endemic. Chronic constipation, abdominal distention, and dysphagia, at times so severe as to produce cachexia, are the clinical manifestations of intestinal dilatation. Loss of esophageal myenteric neurons occurs in this condition. Patients complain of dysphagia with the bolus being “stuck” or “hung up” at the level of the suprasternal notch, even though the level of obstruction is well below that. Hollow visceral myopathy is a term used to describe the motility disorder ascribed to 78 myopathic processes affecting the smooth GI muscle. Acute gastric dilatation has been described in patients with muscular dystrophy. Abdominal pain, tenderness, and distention, followed by vomiting, dehydration, gastric perforation, and peritonitis, have all been reported to occur, rarely with a fatal outcome. It is thought that dystrophic changes in the smooth muscle of the stomach wall may be responsible, but these have yet to be convincingly demonstrated. Myotonic muscular dystrophy can affect all levels of the GI tract (Table 74 15-3). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by ophthalmoparesis, peripheral neuropathy, leukoencephalopathy, and gastrointestinal symptoms of recurrent nausea, vomiting, or diarrhea due to intestinal dysmotility, and 79 histologically abnormal mitochondria are present in the muscle. Two defects of innervation also need to be considered under the heading of motility

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disorders. Achalasia is a disorder of esophageal motility characterized by aperistalsis and failure of the lower esophageal sphincter to relax. It presents with dysphagia and regurgitation. It is diagnosed by manometry or barium esophagogram. Although the esophageal findings are similar to those of Chagas' disease, the abnormalities in achalasia are restricted to the esophagus. Good long-term symptomatic relief can be achieved with pneumatic dilatation and Heller myotomy, although intrasphincteric injection of botulinum 80 toxin is also an effective treatment. Hirschsprung's disease is a motility disorder of the colon due to absence of autonomic ganglia that may involve the rectum only or variable lengths of the colon. The lack of ganglion cells results in a condition in which the affected area of colon fails to relax. This results in the development of megacolon and severe constipation beginning soon after birth. Genetic factors are involved in some cases.

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Aminoff: Neurology and General Medicine: Disturbances of Gastrointe...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 16 Disturbances of Gastrointestinal Motility and the Nervous System MICHAEL CAMILLERI • ADIL E. BHARUCHA •

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INTERACTIONS BETWEEN THE EXTRINSIC NERVOUS SYSTEM AND THE GUT COMMON GASTROINTESTINAL SYMPTOMS IN NEUROLOGICAL DISORDERS Dysphagia Gastroparesis Chronic Intestinal Pseudo-obstruction Constipation Diarrhea Fecal Incontinence EXTRINSIC NEUROLOGICAL DISORDERS CAUSING GUT DYSMOTILITY Brain Diseases Stroke Parkinsonism Head Injury Autonomic Epilepsy and Migraine Amyotrophic Lateral Sclerosis Postpolio Dysphagia Brainstem Tumors Autonomic System Degenerations Pandysautonomias or Selective Dysautonomias Idiopathic Orthostatic Hypotension Postural Orthostatic Tachycardia Syndrome Shy–Drager Syndrome Spinal Cord Lesions Spinal Cord Injury Multiple Sclerosis Peripheral Neuropathy Acute Peripheral Neuropathy Chronic Peripheral Neuropathy GENERAL MUSCle DISEASES CAUSING GUT DYSMOTILITY IDENTIFICATION OF EXTRINSIC NEUROLOGICAL DISEASE IN PATIENTS WITH GASTROINTESTINAL SYMPTOMS OF A MOTILITY DISORDER MANAGEMENT OF GASTROINTESTINAL MOTILITY DISORDERS CONCLUDING COMMENT

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The nervous system modulates normal gut function through the extrinsic neural supply and the enteric nervous system of the gastrointestinal tract. Disorders of the nervous system affecting gastrointestinal tract function are manifested primarily as abnormalities in motor, rather than absorptive or secretory, functions or other digestive processes. The normal neural–gut interactions, common clinical manifestations of gut dysmotility encountered in neurological disorders, and the assessment of gastrointestinal functions that might be used to assess extrinsic autonomic control of viscera are reviewed in this chapter. Finally, the main features in the diagnosis and treatment of neurological diseases affecting the gut are discussed. INTERACTIONS BETWEEN THE EXTRINSIC NERVOUS SYSTEM AND THE GUT Normal motility and transit through the gastrointes-tinal tract result from an intricately balanced series of control mechanisms (Fig. 16-1): the electrical and contractile properties of the smooth muscle cell; control by the intrinsic nervous system through chemical transmitters, such as acetylcholine, biogenic amines, gastrointestinal neuropeptides, and nitric oxide; and regulatory extrinsic pathways (sympathetic and parasympathetic nervous systems). The neuropeptides may act as circulating hormones or at the site of their release (paracrine or neurocrine functions).

FIGURE 16-1 Control of gut motility: interactions between extrinsic neural

pathways and the intrinsic nervous system (“enteric brain”) modulate contractions of gastrointestinal smooth muscle. Interactions between transmitters (e.g., peptides and amines) and receptors alter muscle membrane potentials by stimulating bidirectional ion fluxes. In turn, membrane characteristics dictate whether the muscle cell contracts. (From Camilleri M, Phillips SF: Disorders of small intestinal motility. Gastroenterol Clin North Am 18:405, 1989, by permission of Mayo Foundation.) The electrical properties of gut smooth muscle cells result from transmembrane fluxes of ions; as in other excitable muscular organs, these fluxes alter the membrane potential and result in muscle contraction or relaxation. In some parts of the digestive tract, such as the stomach and small bowel, a contraction occurs once a threshold potential is exceeded by a spike potential. In other regions (e.g., internal anal sphincter), no such spike occurs, but contractions are nevertheless observed and associated with altered basal electrical rhythm. Infiltrative or degenerative processes that affect the excitability of the smooth muscle cells of the gut are typically manifestations of myopathic disorders and prevent normal contractions, resulting in gastrointestinal dysmotility. In the mammalian digestive tract, the intrinsic (or enteric) nervous system contains about 100 million neurons, approximately the number present in the spinal cord. This integrative system is organized in ganglionated plexuses (Fig. 16-2), which include the interstitial cells of Cajal (the gastrointestinal pacemakers), and is separate from the sympathetic and parasympathetic portions of the autonomic nervous system. It has several components: sensory mechanoreceptors and chemoreceptors; interneurons that process sensory input and control

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effector (motor and sensory) units; and effector secretor or motor neurons involved in secretory or motor functions of the gut. Preprogrammed neural circuits serve to integrate motor function within and between different regions and thereby control the coordinated functions of the entire gastrointestinal tract, such as the peristaltic reflex and probably the interdigestive migrating motor complex (Fig. 16-3). The synaptic pathways in the gut wall are capable of autonomous adjustment in response to sensory input. They can also be modulated by the extrinsic nervous system at prevertebral ganglia, spinal cord, or higher centers, so that excitation results from the activity of vagal preganglionic fibers, and inhibition from sympathetic activity.

FIGURE 16-2 The enteric plexuses in the intestinal layers. The chief neural

plexuses are in the submucosal and intermuscular layers.

FIGURE 16-3 Interaction between extrinsic neural control, sensory pathways,

and enteric plexuses. Vagal command fibers synapse with preprogrammed circuits having “hard-wired” functions that drive motor and secretory processes. The vagus is composed of preganglionic cholinergic fibers that synapse with preprogrammed circuits in the ganglionated enteric plexuses. These enteric neurons include myenteric cholinergic neurons that, in turn, excite smooth muscle cells to contract, or surface epithelial cells to absorb or secrete fluids and electrolytes. Since there is a great disparity between the limited number of extrinsic nerve fibers and the millions of enteric plexus neurons, it is currently believed that motor or secretory programmed circuits are controlled by command vagal preganglionic or sympathetic postganglionic fibers. Thus, there are approximately 40,000 preganglionic vagal fibers (many of which are afferent, not efferent) at the level of the diaphragm; in contrast, 100 million neurons populate the enteric nervous system. The sympathetic supply inactivates neural circuits that generate motor activity while allowing intrinsic inhibitory innervation by the enteric nerves. Extrinsic vagal fibers also synapse with noradrenergic inhibitory intramural neurons in the gut, which produce transmitters such as nitric oxide, vasoactive intestinal peptide, and somatostatin. Loss of the sympathetic inhibitory supply (“the brake”) results in excessive or uncoordinated phasic pressure activity in the gut that may manifest with gut motor overactivity, including diarrhea. The extrinsic innervation of the gut consists of the parasympathetic vagal and sacral (S2, S3, and S4) nerves and the sympathetic outflow from the intermediolateral column of the spinal cord between the fifth thoracic and upper lumbar levels. The sympathetic nerves synapse in the prevertebral celiac, superior mesenteric, and inferior mesenteric ganglia; sympathetic fibers follow the respective arterial trunks.

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Extrinsic nerves are intimately involved in the control of the striated muscle portions of the esophagus and the external anal sphincter. Although the smooth muscle portion of the gut can function fairly normally without the extrinsic nerves, the latter modulate the intrinsic neural circuits, integrate activity in widely separated regions of the gastrointestinal tract, and appear to influence greater control in certain regions (e.g., the stomach and distal portion of the colon) than in others (e.g., the small bowel). COMMON GASTROINTESTINAL SYMPTOMS IN NEUROLOGICAL DISORDERS

Dysphagia Dysphagia is the sensation of difficult swallowing. Oropharyngeal, or transfer, dysphagia is 1 the inability to initiate a swallow or propel food from the mouth to the esophagus. The hold-up occurs in the cervical area and is generally caused by a lesion affecting any level of the swallowing pathway rather than by a process affecting the oropharyngeal mucosa. However, even patients with distal esophageal obstruction may experience a sensation of hold-up of food in the pharynx or at the level of the neck. Stroke and Parkinson's disease are the neurological disorders most commonly associated with dysphagia. Pharyngeal weakness may also occur in brainstem disease (e.g., bulbar polio, Arnold–Chiari malformations, tumors) or muscle diseases, such as dystrophies and mitochondrial cytopathy. In contrast to oropharyngeal dysphagia, esophageal dysphagia is caused by abnormal esophageal peristalsis. In esophageal smooth muscle disorders (e.g., progressive systemic sclerosis), abnormal peristalsis may be due to incoordination during early stages, accompanied by reduced amplitude of contractions during later stages of the disease. Idiopathic achalasia is a primary esophageal motor disorder characterized by aperistalsis of the esophageal body and impaired lower esophageal sphincter relaxation during swallowing. While degeneration of ganglion cells within the myenteric plexus is the primary disturbance and seems to be responsible for abnormal esophageal function, the injury can extend to the vagal nerve endings within the esophagus and neuronal bodies within the dorsal motor nucleus of the vagus. Dysphagia that is restricted to solids suggests a mechanical cause or narrowed lumen that blocks the bolus passage through the esophagus. Dysphagia restricted primarily to liquids is suggestive of oropharyngeal disease or achalasia. Neuromuscular dysphagia typically results in dysphagia to both liquids and solids, and aspiration into the upper airways. Physical examination shows evidence of the co-existing neurological disease, such as abnormal palatal or pharyngeal movements or a brisk jaw jerk, suggesting pseudo-bulbar palsy. Barium videofluoroscopy or a fiberoptic endoscopic evaluation of swallowing (FEES) is essential, can identify the motor disturbance, and can provide the basis for interventions to lessen the problem. However, these tests only indirectly assess the sensory component. Airway protective reflexes may not be properly initiated in patients with sensory deficits of the larynx or pharynx, leading to dysphagia and aspiration. Thus, sensory testing (ST), accomplished by FEES-ST 2 may help stratify the risk of aspiration in patients with pharyngeal weakness. Pharyngoesophageal motility studies, preferably using solid-state pressure transducers, also complement the diagnosis. Re-education of the swallowing process is feasible in many patients, often in a program that incorporates speech therapy. Nutritional support and prevention of bronchial aspiration are predominant considerations in planning therapy for those with more severe dysphagia not responding to these conservative measures. This may require placement of a gastrostomy feeding tube, either permanently or temporarily, while swallowing is rehabilitated. Since swallowing may improve considerably in the first 2 weeks after a stroke, long-term decisions should be delayed for that period.

Gastroparesis Gastric motor dysfunction resulting in delayed gastric emptying is a common gastrointestinal 3,4 manifestation of autonomic neuropathies such as that associated with diabetes mellitus. Symptoms range from vague postprandial abdominal discomfort to recurrent postprandial emesis, resulting in weight loss and malnutrition. Iatrogenic gastroparesis is induced by surgical vagotomy, including laparoscopic fundoplication, and by numerous medications, most commonly narcotic analgesics and tricyclic antidepressants. There may be a succussion splash on physical examination. It is essential to exclude gastric outlet obstruction by a barium or gastroscopic study. Scintigraphic gastric emptying tests confirm the impaired emptying of solids5 from the stomach; the tests may be extended over time to assess small bowel transit too. Gastric stasis may result from obstruction or from abnormal motility of the

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6

stomach or small bowel, and studies of pressure profiles by manometry or solid-state pressure transducers placed in the distal stomach and small bowel can help identify abnormality of motor function (Fig. 16-4A), differentiate neuropathic from myopathic 7 processes (Fig. 16-4B), and exclude mechanical8 obstruction that may have been missed on previous radiographic studies of the small bowel.

FIGURE 16-4 A, Tracing showing normal upper gastrointestinal motility in the fasting and fed states. The fasting tracing shows phase III of the interdigestive migrating motor complex. B, Manometric tracings showing the myopathic pattern of intestinal pseudo-obstruction due to systemic sclerosis (left panel). Note the low amplitude of phasic pressure activity compared with control (middle panel). A manometric example of neuropathic intestinal pseudo-obstruction in diabetes mellitus shows the absence of antral contractions and persistence of cyclical fasting-type motility in the postprandial period (right panel). (A from Malagelada J-R, Camilleri M, Stanghellini V: Manometric Diagnosis of Gastrointestinal Motility Disorders. Thieme, New York, 1986, by permission of Mayo Foundation. B from Camilleri M: Medical treatment of chronic intestinal pseudo-obstruction. Pract Gastroenterol 15:10, 1991, with permission.)

Prokinetic agents and use of a more easily digestible diet (low in fat with insoluble, large-particle [>5 mm] fibers) may be beneficial in the treatment of gastroparesis. Since cisapride has been withdrawn from the market, metoclopramide and erythromycin are the only available prokinetic agents. Because it can cause occasionally irreversible, extrapyramidal side effects, metoclopramide must be used judiciously. Erythromycin increases gastric motility by stimulating motilin receptors. A feeding gastrostomy or jejunostomy with a percutaneously placed tube, often possible via upper gastrointestinal endoscopy, may be required. Gastric electrical stimulation may also improve symptoms but not gastric emptying in gastroparesis. A total gastrectomy with esophago–Roux-en-Y jejunostomy is the last resort for patients with gastroparesis who have had previous gastric surgery.

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Chronic Intestinal Pseudo-obstruction Chronic intestinal pseudo-obstruction is a syndrome characterized by nausea, vomiting, early satiety, abdominal discomfort, weight loss, and altered bowel movements suggestive of intestinal obstruction in the absence of a mechanical cause. These symptoms are the consequence of abnormal intestinal motility rather than of mechanical obstruction. The syndrome may result from a number of neurological diseases extrinsic to the gut (e.g., disorders at any level of the neural axis), from dysfunction of neurons in the myenteric 3 plexus, or from degeneration of gut smooth muscle in familial or sporadic hollow visceral myopathy (Table 16-1). The pathophysiology of these diseases can be broadly subdivided into myopathic (e.g., infiltrative amyloidosis, hollow visceral myopathy, metabolic myopathies, muscular dystrophies) and neuropathic processes (Table 16-1). Click here to view this table.... The patient's accompanying clinical features may suggest an underlying disease process: these features include postural dizziness, difficulties in visual accommodation in bright lights, and sweating abnormalities suggestive of an autonomic neuropathy; alternatively, the occurrence of urinary symptoms such as recurrent urinary infections and problems with bladder voiding suggest genitourinary involvement by a generalized visceral neuromyopathic disorder, and accompanying peripheral sensory or motor symptoms suggest an associated peripheral neuropathy. The combination of external ophthalmoplegia, high dysphagia, peripheral neuromyopathy (e.g., increased serum creatine kinase) and acidosis (e.g., increased lactate, pyruvate) suggests mitochondrial myopathy, a rare disorder associated 9 with small bowel pseudo-obstruction and diverticulosis. Patients should be questioned about the use of narcotics, phenothiazines, antihypertensive agents such as clonidine, tricyclic antidepressants having anticholinergic effects, and calcium-channel blockers. The physical examination should pay particular attention to evaluation of pupillary reflexes to light and accommodation, measurement of the blood pressure and pulse with the patient lying and standing, and a search for abdominal distention or a succussion splash. Plain radiographs and barium studies are often nonspecific; dilatation of the small intestine was found in about 60 percent of one series of patients with chronic idiopathic intestinal 10 pseudo-obstruction, but it is probably more frequent in later stages of myopathic than neuropathic disorders. Contrast studies of the small bowel are important in ruling out mechanical obstruction but rarely lead to an etiologic diagnosis. Motility studies (Fig. 16-4) help differentiate myopathic and neuropathic processes and may also suggest the presence 8 of mechanical obstruction, even in the presence of an underlying neuromuscular disorder. When the motility tracing is suggestive of a neuropathic process, assessment of autonomic function and radiological and serological tests should be performed to identify the cause of the autonomic neuropathy or cerebrospinal disease (see later). The goals of treatment of chronic intestinal pseudo-obstruction include the restoration of hydration and nutrition, stimulation of normal intestinal propulsion, and suppression of bacterial overgrowth. Specific medications are discussed later.

Constipation Constipation is a common complaint and may be perceived by the patient as infrequent bowel movements, excessively hard stools, the need to strain excessively during defecation, or a sense of incomplete evacuation after defecation. Broadly, constipation in neurological disorders may be caused by potentially reversible factors (e.g., inadequate dietary fiber intake, lack of exercise, medications), slow colonic transit or pelvic floor dysfunction (i.e., a defecatory disorder)11that may be related to the neurological disorder, or another disease (e.g., colon cancer). When stool enters the rectum, rectal distention induces rectal contractions, the desire to defecate, and involuntary relaxation of the internal anal sphincter. Thereafter, defecation is accomplished by increased intra-abdominal pressure coordinated with relaxation of the anal sphincters and pelvic floor muscles (Fig. 16-5). Many neurological diseases (e.g., Parkinson's disease, multiple sclerosis, spinal cord injury, and autonomic neuropathies) can affect colonic transit and pelvic floor functions. In multiple sclerosis and Parkinson's disease, pelvic floor dysfunction may result from disordered coordination, owing to which patients cannot relax or paradoxically contract the anal sphincter or pelvic floor muscles (or both) during defecation. Because the desire to defecate is necessary to initiate the process, diminished rectal sensation (e.g., due to a neuropathy or spinal cord injury) can also affect defecation.

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FIGURE 16-5 Schema showing normal alternations of pelvic floor, rectoanal angle, and

sphincters during defecation. (Adapted from Camilleri M, Thompson WG, Fleshman JW, et al: Clinical management of intractable constipation. Ann Intern Med 121:520, 1994, with permission.) Patients use the term constipation to describe a variety of disturbances: a careful history can contribute significantly to understanding the cause. For example, the need for enemas or finger evacuation to expel the stool from the lower rectum suggests a disturbance of the pelvic floor or anorectum. The coexistence of incontinence and lack of rectal sensation suggests a pudendal neuropathy and is common among patients with diabetic neuropathy. The presence of blood in the stool with constipation necessitates further tests to exclude colonic mucosal lesions, such as polyps, or perianal conditions, such as hemorrhoids. Even when the clinical features suggest that constipation is due to an underlying neurological disorder, anatomical abnormalities (i.e., tumors, megacolon, and megarectum) that may require surgery should be excluded by colonoscopy or imaging (i.e., barium enema or computed tomography colonography). Potentially reversible factors (e.g., physical inactivity, inadequate dietary caloric or fiber intake, and neglect of the urge to defecate) should be addressed. Most constipated patients respond well to fiber, bulking agents, and stool softeners. Slow colonic transit occurs frequently in wheelchair- or bed-bound patients and may not respond to fiber supplementation, therefore requiring the addition of stimulant cathartics or prokinetic medications. Patients with spinal cord injuries usually respond to a combination of bulk laxatives and scheduled enemas daily or on alternate days. In patients with paraplegia, computer-assisted sacral anterior root stimulation has been used to evoke a coordinated sequence of sigmoid and rectal contractions and sphincter relaxation, thereby 12 simulating the dynamic events occurring during defecation. This has been shown to reduce the interval between defecations and the time taken to defecate. A dorsal rhizotomy must be performed to avoid general stimulation of autonomic responses. However, few centers have experience with this approach. When constipation does not respond to dietary fiber supplementation or osmotic laxatives, consideration should be given to assessing colonic transit and anorectal functions. Colonic 13 14 transit can be measured by radiopaque markers or by radioscintigraphy. Because pelvic floor dysfunction may result in outlet obstruction and thereby delay colonic transit, slow colonic transit does not necessarily indicate colonic motor dysfunction. The anorectal functions contributing to defecation can be tested by measuring resting anal pressure, by assessing for the rectoanal inhibitory reflex during rectal distention, and by measuring the 11,15 If clinically indicated, anorectal recto-anal pressure gradient during simulated evacuation. imaging during rectal evacuation of barium (i.e., defecation proctography) or ultrasound gel (i.e., MR proctography) should 16,17 be performed to identify occult mucosal prolapse, rectoceles, Pelvic floor retraining by biofeedback therapy, using or excessive perineal descent. surface electromyography (EMG) sensors or manometry, can improve recto-anal coordination during defecation in patients with an “idiopathic” functional defecatory disorder 18 (i.e., not due to neurological disease). Although biofeedback therapy can improve rectal sensation, partially preserved rectal sensation is necessary to participate in biofeedback therapy. Therefore, it is unclear whether patients with neurological disorders (e.g., multiple sclerosis), who often have reduced rectal sensation and impaired volitional control of the

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pelvic floor muscles, can benefit from pelvic floor retraining by biofeedback therapy. Surgery is reserved for patients with intractable symptoms. A colostomy or subtotal colectomy with ileorectostomy may be necessary for colonic inertia. Other surgical procedures may be necessary to correct a rectal prolapse or a rectocele.

Diarrhea Diarrhea is loosely defined as passage of abnormally liquid or unformed stools at an increased frequency. For adults on a typical Western diet, a stool weight exceeding 200 g/day probably reflects diarrhea. The duration of diarrhea guides the differential diagnosis. Diarrhea may be further defined as acute if less than 2 weeks, persistent if 2 to 4 weeks, and chronic if more than 4 weeks in duration. Acute diarrhea is most frequently caused by infectious agents or is secondary to20medications. The differential diagnosis of chronic diarrhea is discussed in detail elsewhere. In autonomic neuropathies (e.g., diabetes), chronic diarrhea may be caused by rapid intestinal transit due to sympathetic denervation or by bacterial overgrowth secondary to gut dysmotility. Osmotic agents (e.g., artificial sweeteners) may also cause or aggravate diarrhea. Dysautonomic diarrhea, as in patients with diabetic neuropathy, is often multifactorial and may be associated with secretion, malabsorption secondary to rapid transit, or bacterial overgrowth and high-amplitude propulsive contractions in the colon that result in 20–22 urgency and sometimes incontinence of stool. A careful history and physical examination are extremely important to guide diagnostic tests. Secretory diarrhea persists with fasting, whereas osmotic diarrhea does not. Features of fat malabsorption (e.g., greasy, difficult-to-flush stools, weight loss) should prompt a 24- to 48-hour stool collection with quantitation of stool fat. The coexistence of diarrhea and neurological manifestations may be explained by autonomic dysfunction (e.g., in diabetic neuropathy), the neurological consequences of malabsorption (e.g., myopathy or neuropathy in celiac disease), and rare diseases with neurological manifestations (e.g., Whipple's disease). After excluding a structural cause (e.g., inflammatory bowel disease) and malabsorption, most patients with diarrhea due to disordered motility can be treated effectively with loperamide, beginning with 2 mg taken 30 minutes before meals, and titrated to control symptoms up to a maximum of 16 mg daily. Patients should be tested and treated for bacterial overgrowth. The α2-adrenergic agonist clonidine also reduces diarrhea by improving intestinal absorption and inhibiting intestinal and colonic motility.

Fecal Incontinence Common neurological disorders associated with fecal incontinence include multiple sclerosis, Parkinson's disease, multiple system atrophy, Alzheimer's disease, strokes, diabetic neuropathy, and spinal cord lesions. In addition to generalized neuropathies (e.g., diabetes), obstetrical trauma and stretch-induced pudendal nerve injury related to excessive straining in 23 constipated patients are other causes of a pudendal neuropathy. Thus, a subset of patients with chronic constipation develop excessive perineal descent, a stretch-induced pudendal neuropathy, and ultimately anal sphincter weakness, culminating in fecal incontinence. An alteration in bowel habits (i.e., diarrhea) frequently precedes the transition from asymptomatic pelvic floor injury to fecal incontinence. Symptoms may provide clues to the etiology of fecal incontinence. Incontinence occurring only at night suggests internal anal sphincter dysfunction (e.g., progressive systemic sclerosis); stress incontinence during coughing, sneezing, or laughing suggests loss of external sphincter control, typically from the pudendal nerve or S2, S3, and S4 root lesions. Leakage of formed stool suggests more severe sphincter weakness than leakage of liquid stool alone. Examination of the incontinent patient should include inspection of the anus with and without straining to detect rectal prolapse; a digital rectal examination to exclude impaction or mucosal disease; and proctoscopy and barium enema or colonoscopy to exclude mucosal lesions. Anal examination may disclose normal (e.g., multiple sclerosis) or reduced (e.g., diabetes mellitus, scleroderma) anal resting tone. The external sphincter and puborectalis contractile response during squeeze is often reduced. Perineal weakness is often manifested by excessive perineal descent (>4 cm) on straining. The perianal wink reflex is absent in lesions of the sacral reflex arc. In evaluating such patients, it is important first to exclude overflow incontinence due to fecal impaction. Similarly, overuse of laxatives or other medications, such as magnesium-containing antacids, may result in reversible incontinence. If these fail to identify the cause of incontinence, further tests may be necessary: anorectal manometry,

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assessment of rectal sensation, and the ability to expel a balloon from the rectum. Anal sphincter defects and atrophy can be visualized by endoanal ultrasound or magnetic resonance imaging (MRI). Rectal evacuation and anatomical abnormalities (e.g., rectocele, rectal intussusception) can be assessed by a barium defecating proctogram or by dynamic MRI. In contrast to defecating proctography, dynamic MRI can visualize global pelvic floor motion (anterior, middle, and posterior compartments) in real-time without radiation exposure. EMG provides a sensitive measure of denervation (fibrillation potentials) and can usually identify myopathic damage (small polyphasic motor unit potentials), neurogenic damage (large polyphasic motor unit potentials), or mixed injury. Anal EMG should be considered in patients with clinically suspected neurogenic sphincter weakness, particularly if there are 24 features suggestive of proximal (i.e., sacral root) involvement. Neurogenic changes isolated to the external anal sphincter may be caused by injury at any level along the lower motor neuron, that is, from motor neurons in the sacral spinal cord to the nerve fascicles entering the anal sphincter (e.g., caused by local or obstetrical trauma). Therefore, a pudendal neuropathy can be diagnosed with certainty only when neurogenic changes diffusely affect the anal sphincter (i.e., anterior and posterior quadrants) or when the changes affect the anal sphincter and ischiocavernosus muscle. 25

It is important to maintain perianal hygiene and integrity by perianal protective devices. Medical management is focused on restoring regular bowel habits. In contrast, biofeedback therapy has little impact on anal resting tone or on squeeze responses in patients with weakness of the pelvic floor muscles. In patients with reduced rectal sensation (e.g., due to diabetes), biofeedback retraining can restore rectal sensation and improve fecal continence. A colostomy may be necessary in patients with medically refractory fecal incontinence. It is important to exclude mucosal prolapse in association with incontinence; surgical correction of the prolapse may at least temporarily improve continence by permitting better function of the 26 external sphincter. Though more complex surgical procedures (i.e., artificial anal sphincter, dynamic graciloplasty) may improve fecal continence, these procedures are associated with considerable morbidity and are not routinely performed in the United States. Uncontrolled studies suggest that sacral nerve stimulation can improve symptoms,27anal pressures, and rectal sensation even in patients with neurogenic fecal incontinence. EXTRINSIC NEUROLOGICAL DISORDERS CAUSING GUT DYSMOTILITY It is possible to distinguish disorders that affect the gut muscle (“myopathic disorders”), those involving the myenteric plexus, and diseases of the extrinsic path-ways that supply the gut. 28 Certain diseases affect both intrinsic and extrinsic neural control. This review concentrates on diseases of extrinsic neural control and smooth muscle. Diseases affecting the enteric 29 nervous system are reviewed elsewhere.

Brain Diseases Stroke Dysphagia may result from cranial nerve involvement and may cause malnutrition or aspiration pneumonia. Videofluoroscopy of the pharynx and upper esophagus typically shows 30 transfer dysphagia or tracheal aspiration. Colonic pseudo-obstruction occurs rarely. Percutaneous endoscopic gastrostomy is usually the most effective method to provide nutrition without interfering with rehabilitation; feedings can be given in the form of boluses or by infusion at night. Swallowing improves in a majority of survivors over time. Over 50 percent of affected individuals improve significantly within 1 week, and most improve within 3 months. 31 The severity of the initial neurological deficit is the strongest predictor of eventual recovery. The gastrostomy tube can be removed when oral intake is shown to be sufficient to maintain caloric requirements. Parkinsonism Patients with Parkinson's disease or progressive supranuclear palsy may have oropharyngeal 32 dysfunction with impaired swallowing. Shy–Drager syndrome, or multiple system atrophy, is considered later. Patients may have mild to moderate malnutrition; moderate dysphagia may be diagnosed by videofluoroscopy. In the absence of severe malnutrition or significant aspiration, conservative treatment with attention to the consistency of food (thickened liquids) and to adequate caloric content of meals will suffice. Feeding through a percutaneous gastrostomy is an appropriate alternative for severe dysphagia. 32

Constipation is common in patients with parkinsonism 34and may be the result of slow colonic 33 transit or of pelvic floor or anal sphincter dysfunction. Gastrointestinal hypomotility,

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generalized hypokinesia, associated autonomic dysfunction, and the effects of various anticholinergic and dopamine agonist medications may all play a role. The bioavailability of other medications can be altered considerably by the effects of parkinsonism on gut transit and delivery of medications to the small bowel for absorption. Head Injury Immediately following moderate to severe head injury, most patients develop transient delays in gastric emptying. The underlying mechanism is unknown, although a correlation exists between the severity of injury, increased intracranial pressure, and severity of the gastric stasis. These patients are frequently intolerant of enteral feeding and require parenteral nutrition to meet their increased metabolic demands. In practice, enteral nutrition can often 35 be reintroduced within 2 to 3 weeks as the gastric stasis resolves. Autonomic Epilepsy and Migraine Autonomic epilepsy and migraine are infrequent causes of upper abdominal symptoms, such as nausea and vomiting. Treatment is of the underlying neurological disorder. Amyotrophic Lateral Sclerosis Patients with amyotrophic lateral sclerosis (ALS) and progressive bulbar palsy have 36 predominant weakness of the muscles supplied by the glossopharyngeal and vagus nerves. Dysphagia is a frequent complaint, and patients may have respiratory difficulty while eating as a result of aspiration or respiratory muscle fatigue. Rarely, patients 37 with vagal dysfunction will show features of a chronic intestinal pseudo-obstruction syndrome. Physical examination reveals the cranial nerve palsies and muscle fasciculations. An exaggerated jaw jerk may be present in ALS. Videofluoroscopic barium swallow of liquids and solids is employed to evaluate swallowing, determine whether aspiration occurs, and guide decisions about the route to use for nutritional support (oral feeding or a percutaneous gastrostomy). Cervical esophagostomy or cricopharyngeal myotomy has been performed in selected cases for significant cricopharyngeal muscle dysfunction. Postpolio Dysphagia Patients with postpolio syndrome frequently have dysphagia and aspiration, especially if there was bulbar involvement during the initial attack. Videofluoroscopy is useful for screening and monitoring progression of disease. Attention to the position of the patient's head during swallowing and alteration of food consistency to a semisolid state can decrease the 38 prevalence of choking and aspiration. Brainstem Tumors Brainstem lesions can present with isolated gastrointestinal motor dysfunction. In the absence of increased intracranial pressure, such symptoms are probably the result of a direct mass effect in the brainstem, with distortion of the vomiting center on the floor of the fourth ventricle. Motor dysfunction is typically evident on manometric or radionuclide studies of the 39 the most common symptom, colonic or stomach and small bowel. Although vomiting is 40 anorectal dysfunction has also been described. The presence of more widespread autonomic dysfunction, particularly if preganglionic sympathetic nerves are involved, necessitates a search for a structural lesion in the central nervous system (CNS).

Autonomic System Degenerations Pandysautonomias or Selective Dysautonomias Pandysautonomias are characterized by preganglionic or postganglionic lesions affecting both the sympathetic and parasympathetic nervous systems. Vomiting, paralytic ileus, constipation, and a chronic pseudo-obstruction syndrome have been reported in acute, 41 subacute, and congenital pandysautonomia. Motor disturbances have been substantiated in the esophagus, stomach, and small bowel. Selective cholinergic dysautonomia may also impair upper and lower gastrointestinal motor activity. This picture usually follows a viral 42 infection such as infectious mononucleosis.

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Idiopathic Orthostatic Hypotension Idiopathic orthostatic hypotension is sometimes associated with motor dysfunction of the gut, such as esophageal dysmotility, gastric stasis, alteration in bowel movements, and fecal 43,44 Cardiovascular and sudomotor abnormalities usually precede gut incontinence. involvement. The precise site of the lesion causing the gut dysmotility is unknown. Postural Orthostatic Tachycardia Syndrome About one third of patients with postural orthostatic tachycardia syndrome (POTS) have 45 gastrointestinal manifestations including pseudo-obstruction syndrome. It is important to exclude dehydration, deconditioning, and functional disorders that produce similar clinical features. A collaborative approach by experienced neurologists and gastroenterologists and cautious interpretation of objective measurements are essential. Shy–Drager Syndrome In the original description by Shy and Drager, constipation and fecal incontinence were 46 included among the classic features of the disorder named after them. Other reports have documented substantial reduction in fasting and postprandial antral and small bowel motility. Abnormal esophageal motility was demonstrated by videofluoroscopy and by the occurrence 43 of frequent, simultaneous, low-amplitude peristaltic waves during esophageal manometry.

Spinal Cord Lesions Spinal Cord Injury Dysphagia after47acute cervical spinal cord injury generally improves during the initial hospitalization. Compression of the brainstem and lower cranial nerves can cause potentially life-threatening neurogenic dysphagia in patients with Chiari malformations. Early recognition of dysphagia, which often precedes other brainstem symptoms, is important to avoid irreversible brainstem injury, to preserve48nutrition and pulmonary functions, and to maximize restoration of function after surgery. Ileus is a frequent finding soon after spinal cord injury, but it is rarely prolonged. In the chronic phase after injury, disorders of upper gastrointestinal motility are uncommon, whereas colonic and anorectal dysfunction are common. The latter probably result from interruption of supraspinal49,50 control of the sacral parasympathetic supply to the colon, pelvic floor, and anal There is a decrease in colonic compliance and an absence of postprandial sphincters. 51 colonic motor and myoelectric activity in patients with thoracic spinal cord injury. The loss of voluntary control of defecation may be the most significant disturbance in patients who rely on reflex rectal stimulation for stool evacuation. Loss of control of the external anal sphincter commonly results in fecal incontinence in patients with spinal cord injury. The usual management for irregular bowel function is a combination of bulking agents and scheduled enemas. Computerized stimulation of the sacral anterior roots has been 12 proposed as a method to restore normal function to the pelvic colon and anorectal sphincters ; however, relatively few patients have been treated by this means on a long-term basis. Multiple Sclerosis Severe constipation frequently accompanies urinary bladder dysfunction in patients with 52 advanced multiple sclerosis. In one study, colonic transit of radiopaque markers was prolonged in 14 of 16 patients with multiple sclerosis and urinary bladder involvement; 10 patients also had evidence of fecal incontinence, and 5 had spontaneous rectal contractions. The studies performed to date have not been sufficiently detailed to assess the extent to which such symptoms relate to sympathetic and parasympathetic denervation. Pelvic colonic dysfunction is probably due to impaired function of the supraspinal or descending pathways that control the sacral parasympathetic outflow. Further studies are needed to address the mechanism of impaired gut transit in multiple sclerosis, which, as with spinal cord53injury, results in motility disturbances more frequently in the lower than in the upper gut.

Peripheral Neuropathy

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Acute Peripheral Neuropathy Autonomic dysfunction associated with certain acute viral infections may result in nausea, vomiting, abdominal cramps, constipation, or a clinical picture of pseudo-obstruction. In the Guillain–Barré syndrome, visceral involvement may include gastric distention or adynamic ileus. Persistent gastrointestinal motor disturbances may also occur in association with herpes zoster, Epstein–Barr virus infection, or botulism B. The site of the neurological lesion is uncertain. Cytomegalovirus has been identified in myenteric plexus in some patients with 54 chronic intestinal pseudo-obstruction. Selective cholinergic dysautonomia (with associated gastrointestinal dysfunction) has been reported to develop within a week of the onset of 42 infectious mononucleosis. Diarrhea induced by human immunodeficiency virus (HIV) may be another manifestation of autonomic dysfunction (see later), but the data require confirmation. Chronic Peripheral Neuropathy Chronic peripheral neuropathy is the most commonly encountered extrinsic neurological disorder that results in gastrointestinal motor dysfunction. Diabetes Mellitus

Diabetic autonomic neuropathy of the gut has been studied extensively and has been 55 reviewed elsewhere. In patients with type I diabetes seen at university56medical centers, gastrointestinal symptoms, particularly constipation, are quite common. However, a questionnaire-based Finnish study in a randomly selected population suggests that the occurrence and spectrum of gastrointestinal symptoms in middle-aged subjects with insulin(IDDM) and57non–insulin-dependent diabetes mellitus do not differ from those of the general population. A similar U.S.-based study in the community showed that constipation with or without the use of laxatives was the only gut symptom more frequent in IDDM patients than in age- and gender-matched controls. Patients with constipation tended 58,59 to be taking some medications that cause the symptoms, or to have bladder symptoms. Gastric emptying of digestible or nondigestible solids is abnormal in patients with diabetes mellitus and gastrointestinal symptoms (“gastroparesis”). Studies in humans have demonstrated a paucity of distal antral contractions during fasting and postprandially; small 6 with an “autovagotomy,” bowel motility may also be abnormal. These features are consistent 60 a concept originally proposed in studies of gastric secretion, or loss of the interstitial cells of Cajal, the pacemaker cells of the gastrointestinal tract. Constipation is a frequent, although often unreported, symptom in patients with diabetes. 61 Colonic motor dysfunction is associated with constipation. Streptozotocin-treated rats develop abnormal colonic compliance and selective deficiencies of certain neurotransmitters (e.g., calcitonin gene-related peptide) in the myenteric plexus. However, in a small study of patients with diabetes and constipation selected randomly from among community diabetics, 62 the pathophysiology included equally slow transit, normal transit, or pelvic floor dysfunction. Diarrhea or fecal21incontinence (or both) may result from several mechanisms (reviewed in detail elsewhere ): dysfunction of the anorectal sphincter or abnormal rectal sensation, osmotic diarrhea from bacterial overgrowth due to small bowel stasis, and rapid transit from uncoordinated small bowel motor activity. Rarely, an associated gluten-sensitive enteropathy or pancreatic exocrine insufficiency is present. These associated conditions should be sought, since they are potentially reversible. Histopathological studies of the vagus nerve have revealed a reduction in the number of unmyelinated axons; surviving axons are usually of small caliber. In patients with diabetic diarrhea, there are giant sympathetic neurons and dendritic swelling of the postganglionic neurons in prevertebral and paravertebral sympathetic ganglia as well as reduced fiber 63,64 density in the splanchnic nerves. Peripheral cholinergic agonists (such as metoclopramide, bethanechol, and cisapride) and α2-adrenergic agonists (such as clonidine) have been used, respectively, to treat gastric 65 stasis and diarrhea secondary to diabetic gut neuropathy. Available therapeutic options have resulted in only transient relief. Erythromycin (administered intravenously) stimulates motilin receptors on cholinergic neurons and gastric muscle cells and is useful during the 66 is acute phase, but few patients tolerate it beyond 2 weeks. Pancreas transplantation 67 reported to restore normal gastric emptying in patients with diabetic gastroparesis. Long-term results are not available, however, and we have certainly observed persistent gastric stasis in patients with an autonomic neuropathy that preceded the pancreas

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transplant. Paraneoplastic Neuropathy

Autonomic neuropathy and gastrointestinal symptoms have been reported in association with 68 small cell carcinoma of the lung or pulmonary carcinoid. In the largest published series, all seven patients suffered constipation, six had gastroparesis, four had esophageal dysmotility suggestive of spasm or achalasia, and two had other evidence of autonomic neuropathy that 68 IgG affected bladder and blood pressure control. Investigators detected a circulating 69 antibody (called ANNA-1 or anti-Hu) directed against enteric neuronal nuclei, suggesting that the enteric plexus is the major target of this paraneoplastic phenomenon. However, 68,70 suggesting a several patients have also had evidence of extrinsic visceral neuropathies. more extensive neuropathological process. The chest x-ray is frequently normal in these patients; a chest computed tomography (CT) scan is therefore indicated when the syndrome is suspected, typically in middle-aged smokers with recent onset of nausea, vomiting, or feeding intolerance. Ganglionic receptor-binding antibodies have also been found in a subset of patients with idiopathic, paraneoplastic, or diabetic autonomic neuropathy and idiopathic gastrointestinal dysmotility; the antibody titer correlated with more severe autonomic 71 autoimmune model of gastrointestinal dysmotility has been replicated in dysfunction. This 72 an animal model. Amyloid Neuropathy 73

Amyloid neuropathy may lead to constipation, diarrhea, and steatorrhea. Patients have 42 to uncoordinated nonpropagated contractions in the small bowel. These features are similar 74 the intestinal myoelectric disturbances observed in animals subjected to ganglionectomy. Familial amyloidosis may also affect the gut. Manometric studies and monitoring of the acute effects of cholinomimetic agents can distinguish between neuropathic (uncoordinated but normal-amplitude pressure 73 activity) and myopathic (low-amplitude pressure activity) types of amyloid gastroenteropathy. These strategies may identify patients (i.e., those with the neuropathic variant) who are more likely to respond to prokinetic agents. Chronic Sensory and Autonomic Neuropathy of Unknown Cause

This is a rare, nonfamilial form of slowly progressive neuropathy that affects a number of 75 autonomic functions. Patients may exhibit only a chronic autonomic disturbance (e.g., abnormal sudomotor, vasomotor, or gastrointestinal function) for many years before peripheral sensory symptoms develop. Autonomic dysfunction is probably responsible for functional gastrointestinal motor disorders when these develop prior to the onset of more obvious features of dysautonomia. This28may account for a subset of patients with symptoms suggestive of irritable bowel syndrome. Some investigators have reported familial cases of intestinal pseudo-obstruction with degeneration of the myenteric plexus 29 and evidence of sensory or motor neuropathies affecting peripheral or cranial nerves. Porphyria

Acute intermittent porphyria and hereditary coproporphyria frequently present with abdominal 76,77 Porphyric polyneuropathy may lead to dilatation pain, nausea, vomiting, and constipation. and impaired motor function in any part of the intestinal tract, presumably because of autonomic dysfunction. Effects of porphyria on the enteric nervous system have not been described. Human Immunodeficiency Virus Infection

It is well known that neurological disease may manifest at any phase of HIV infection. Chronic 78 or damage diarrhea may result from increased extrinsic parasympathetic activity to the gut 79 to adrenergic fibers within the enteric plexuses. Further studies are needed to characterize these abnormalities; it is, of course, important to exclude gut infections and infestations in patients with HIV seropositivity and diarrhea. GENERAL MUSCLE DISEASES CAUSING GUT DYSMOTILITY

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At an advanced stage, progressive systemic sclerosis and amyloidosis result in an infiltrative replacement of smooth muscle cells in the digestive tract. Rarely, Duchenne or Becker 80,81 82,83 and polymyositis or dermatomyositis have been associated with muscular dystrophy gastroparesis. There are a number of case or family reports of chronic intestinal pseudo-obstruction, sometimes in association with an external ophthalmoplegia, secondary 9,84–86 87 Patients with myotonic dystrophy may have megacolon ; to a mitochondrial myopathy. anal sphincter dysfunction also occurs and is88consistent with an expression of myopathy, muscular atrophy, and neural abnormalities. The myopathic nature of these disorders is reflected by the low-amplitude contractions that occur at affected levels of the gut, as studied 89–91 Myopathic disorders may be complicated by bacterial especially in systemic sclerosis. overgrowth and small bowel diverticula; pneumatosis cystoides intestinalis and spontaneous pneumoperitoneum sometimes occur in progressive systemic sclerosis. However, it is worth noting that the latter disorder affects the gut from the distal two thirds of the esophagus to the anorectum; thus, it may present with dysphagia (which may also be due to reflux esophagitis and stricture), gastric stasis, chronic intestinal pseudo-obstruction, steatorrhea due to bacterial overgrowth, constipation, incontinence 26 (particularly at night, owing to involvement of the internal anal sphincter), and rectal prolapse. Skeletal muscle EMG or biopsy may be needed to 83–85 establish the nature of the generalized neuromuscular disorder, as in mitochondrial myopathy. Treatment includes restoration of nutrition (which may necessitate total parenteral nutrition), suppression of bacterial overgrowth, and treatment of complications such as gastroesophageal reflux (with an H2-receptor antagonist or proton pump inhibitor) or esophageal strictures (by endoscopic dilatation). Colonic dilatation and intractable constipation may necessitate subtotal colectomy with ileorectostomy. Prokinetics are rarely 92 improves effective but should at least be tried. The somatostatin analogue octreotide 93 However, octreotide symptoms in the short term and may suppress bacterial overgrowth. 94 retards postprandial small bowel transit, and we use it only once per day, at least 3 hours after the last meal, to induce migrating motor activity and clear residue from the stomach and small bowel. IDENTIFICATION OF EXTRINSIC NEUROLOGICAL DISEASE IN PATIENTS WITH GASTROINTESTINAL SYMPTOMS OF A MOTILITY DISORDER Patients with lesions at virtually any level of the nervous system may have symptoms of gastrointestinal motor dysfunction. Therefore, a strategy is necessary in the diagnostic evaluation of disordered gastrointestinal function (Fig. 16-6). Here there is convergence of the paths of the neurologist and gastroenterologist. Patients should undergo further testing, particularly if they have clinical features suggestive of autonomic or peripheral nerve dysfunction or a known underlying neuromuscular disorder. It is essential to record the use of all medications that influence gut motility.

FIGURE 16-6 Algorithm for the investigation of suspected gastrointestinal (GI)

dysmotility. ANA, antinuclear antibodies; ANNA, antineuronal enteric antibodies; CK, creatine kinase; CXR, chest radiograph; Ig, immunoglobulin; TSH, thyroid-stimulating hormone. (From Camilleri M: Study of human gastroduodenojejunal motility: applied physiology in clinical practice. Dig Dis Sci 38:785, 1993, with permission.) Gastrointestinal motility and transit measurements help the clinician to objectively confirm the

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disturbance in the motor function of the gut and distinguish between neuropathic and myopathic disorders. Tests of autonomic function (see Chapter 8) are useful for identifying the extent of involvement and localizing the anatomical level of the disturbance in extrinsic neural control. There is generally good agreement between abnormalities of abdominal vagal function, including the plasma pancreatic polypeptide response to95modified sham feeding (Fig. 16-7) and cardiovagal dysfunction in patients with diabetes. When a defect of the sympathetic nervous system has been identified by conventional tests, the effect of intravenous administration of edrophonium on plasma norepinephrine levels may provide further assessment of the96,97 integrity of postganglionic sympathetic nerves, many of which supply the digestive tract.

FIGURE 16-7 Assessment of abdominal vagal function by the plasma

pancreatic polypeptide (PP) response to modified sham feeding by chewing and spitting a bacon-and-cheese toasted sandwich. Once visceral autonomic neuropathy is identified, further tests are needed to identify any occult causes of the neuropathy; examples include lung tumors (CT of the chest), porphyria (uroporphyrinogen-1-synthase and coproporphyrinogen oxidase in erythrocytes), and amyloidosis (special protein studies in blood and urine, fat, or a rectal biopsy specimen). Imaging of the brain and spinal cord is needed when autonomic tests indicate a central lesion, as when a thermoregulatory sweat test is abnormal but tests of postganglionic nerves (e.g., the quantitative sudomotor axon reflex test, or plasma norepinephrine response to 70 edrophonium) are normal. MANAGEMENT OF GASTROINTESTINAL MOTILITY DISORDERS The principles of management of any gastrointestinal motility disorder are restoration of hydration and nutrition by the oral, enteral, or parenteral route; suppression of bacterial overgrowth (e.g., with oral tetracycline); use of prokinetic agents or stimulant laxatives; and resection of localized disease. In patients with a neurological cause of constipation, it is important to ensure adequate hydration. Osmotic laxatives (e.g., milk of magnesia tablets, 2 tablets three times daily, or lactulose, 10 to 20 ml up to four times per day) may be helpful, as may increasing bulk (as with a high-fiber diet, ispaghula, or psyllium) and a stimulant laxative. If such a regime does not work, scheduled enemas every 1 to 2 days are necessary. In a recent trial, transanal irrigation with a specialized system was more effective than conservative management for alleviating symptoms in patients with spinal cord injury and constipation or fecal 98 incontinence. Sacral anterior root stimulation is worthy of further research and trials in patients with disturbances in the neural control of defecation. Future therapies may include 99 100 neurotrophins such as recombinant brain-derived neurotrophic factor or neurotrophin-3. The prokinetic effects of metoclopramide (a peripheral cholinergic agonist and dopamine D2 antagonist) are limited to the esophagus and stomach. Its clinical efficacy is restricted by the relatively high frequency of side effects, and especially of changes in affect, extrapyramidal disorders, and hyperprolactinemia (which may result in altered menstrual function and galactorrhea). Bethanechol (10 to 25 mg, 4 times daily) is a cholinergic agonist that is not specific for the

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gastrointestinal tract. It is helpful only in mild cases of gastroparesis and is now seldom used; it is sometimes prescribed in combination with metoclopramide. Tegaserod (Zelnorm) is a partial 5-HT4 receptor agonist that was previously approved for short-term treatment of women with constipation-predominant irritable bowel syndrome and for men and women with chronic constipation. Tegaserod accelerates small bowel transit and tends to accelerate colonic transit in patients with constipation-predominant irritable bowel 101 syndrome. A trend toward increased satisfaction with bowel habits and improved abdominal discomfort was also observed in a small controlled study of 15 patients with 102 constipation and Parkinson's disease. The drug is generally well tolerated; headache and diarrhea are the main side effects. A numerical imbalance in the number of cardiovascular events in patients on tegaserod compared to placebo, however, has led to recent withdrawal of the drug. Lubiprostone was recently approved by the U.S. Food and Drug Administration (FDA) for treating constipation. This drug belongs to a new class of bicyclic fatty acid compounds called prostones that are derived from a metabolite of prostaglandin E1. It activates type 2 chloride 103 channels (ClC-2), increases intestinal secretion, and thereby increases intestinal motility. At the recommended dose of 24 μg twice daily, 31.1 percent of patients receiving lubiprostone reported nausea, and 8.7 percent discontinued treatment due to nausea; 13.2 percent reported diarrhea; and 3.4 percent reported severe diarrhea. The incidence of nausea may be reduced by taking lubipro-stone with food or by reducing the dose to 24 μg once daily. Erythromycin, a macrolide antibiotic, stimulates smooth muscle motilin receptors in the gastrointestinal tract. It has a role in relieving acute gastric stasis but, because of 66 tachyphylaxis, is of little benefit beyond 2 weeks of treatment. Perhaps it is preferable to administer erythromycin as a suspension rather than tablets in patients with delayed gastric emptying. Because it is metabolized by the cytochrome P450 3A4 system, there is a potential for drug interactions, the long Q-T syndrome, and rarely torsades de pointes. 83

Octreotide's efficacy has been tested predominantly in patients with systemic sclerosis. It does not usually induce normally propagated activity in the small bowel, but it may help clear residue by virtue of the intensity of contractions and increased duration of the migrating 104 complex that it induces in the small bowel. The role of surgery for motility disorders due to neurological disease is restricted to those patients with intractable colonic or rectal symptoms, particularly incontinence. There is no good rationale for vagotomy or for partial or total gastrectomy in patients with chronic neuropathies causing gastric stasis. In patients with severe colonic inertia, subtotal colectomy with ileorectostomy is usually successful, but this treatment has been used only rarely in patients with neurological or muscle disease. Surgery for local complications of severe constipation may be necessary, as in patients with rectal intussusception or prolapse. CONCLUDING COMMENT Gastrointestinal motor abnormalities result when extrinsic nerves are disturbed and are unable to modulate the motor functions of the digestive tract, which depend on the enteric nervous system and the automaticity of the smooth muscles. Disorders at all anatomical levels of the extrinsic neural control system and degenerations of gut smooth muscle have been reported in association with gut motor dysfunction and illustrate the important role of the nervous system in the etiology of gastrointestinal symptoms. Although much emphasis in the literature is laid on dysphagia and constipation in neurological disorders, more recent studies have highlighted incontinence, vomiting, and abdominal distention in the symptomatology of such patients. Strategies that evaluate the physiological functions of the digestive tract and the function of the extrinsic neural control are available and aid in the selection of rational therapies for patients, including physical and biofeedback training (e.g., for dysphagia or incontinence), prokinetic agents (for neuropathic forms of gastroparesis, intestinal pseudo-obstruction, or slow-transit colonic disorders), and nutritional support using the enteral or parenteral route. Electrical or magnetic stimulation of lumbar sacral roots may alleviate certain symptoms, such as constipation in paraplegics. Previous

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Aminoff: Neurology and General Medicine: Nutritional Disorders of t...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 17 Nutritional Disorders of the Nervous System ELLIOTT L. MANCALL •

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RETINOL (VITAMIN A, β-CAROTENE) B COMPLEX OF VITAMINS THIAMINE (VITAMIN B1) Nutritional Polyneuropathy Wernicke–Korsakoff Syndrome Wernicke's Encephalopathy Korsakoff's Syndrome Cortical Cerebellar Degeneration Nutritional Amblyopia Subacute Necrotizing Encephalomyelopathy NIACIN (NICOTINIC ACID) PYRIDOXINE (VITAMIN B6) COBALAMIN (VITAMIN B12) CALCIFEROL (VITAMIN D) TOCOPHEROL (VITAMIN E) FOLIC ACID OTHER DISORDERS WITH A POSSIBLE NUTRITIONAL BASIS Marchiafava–Bignami Disease Central Pontine Myelinolysis Jamaican Neuropathy HYPERALIMENTATION

Nutritional disorders of the nervous system, although changing to some extent in character and distribution over the years, remain remarkably common. Affecting people from birth—or before—to old age, such disorders are of universal concern. Widely recognized 1in the urban United States, particularly in the nutritionally depleted adult alcoholic population, nervous system diseases due to dietary deprivation appear under circumstances as diverse as famine; extreme poverty; incarceration in prisoner-of-war camps; intestinal malabsorption due to disorders such as sprue or to major gastrointestinal surgery including gastric plication; administration of metabolic antagonists such as isonicotinic acid hydrazide (INH); anorexia nervosa; and food fads, perhaps especially among adolescents. As a general rule, affections of the nervous system due to nutritional depletion present in a

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symmetric distribution, both clinically and pathologically, and in a stereotyped and thus readily identified fashion. These features are common to many metabolic disorders of the nervous system. The precise factors underlying development of such neurological disease have been well established in only some instances, such as the Wernicke–Korsakoff syndrome. Often the exact nutrient lacking cannot be defined with certainty, and it is not unlikely that a combination of dietary defects may be necessary for a given disease to develop. The complex inter-relationship between total caloric intake, relative balance of carbohydrate/protein/fat in the diet, and lack of one or more specific nutrients appears important under some circumstances; extreme caloric deprivation alone may not be a sufficient explanation for these disorders. At times, totally unanticipated factors—for example, autoimmune mechanisms, as documented for pernicious anemia, or inherent genetic defects, as have been suggested in the Wernicke–Korsakoff syndrome—may be of fundamental pathogenetic significance. Difficulties encountered in establishing a clear-cut dietary history and practical problems in the documentation of deficiencies of, for example, isolated vitamins in the clinical laboratory, add yet more complications to the assessment of nutritional disorders as a whole. Finally, our understanding of these disorders is impeded by the fact that data derived from animal investigations cannot always be translated successfully to naturally occurring disease in the human. In view of the lack of precision related to establishing the pathogenesis of many of these disorders, no classification can be entirely satisfactory. Because most clearly defined nutritional diseases reflect depletion of a vitamin or vitamins (most commonly the group B vitamins), the presentation of these disorders that follows adheres to an outline based on specific vitamins whenever possible. The ambiguities and uncertainties of such an approach cannot, however, be ignored. Perhaps not surprisingly, many of these disorders occur in combination with one another, rendering any classification still more arbitrary and incomplete. 2

The therapeutic use of vitamins is itself not without hazard ; potentially toxic complications of hypervitaminosis are most prominent with vitamins A and B6, as discussed later in this chapter. RETINOL (VITAMIN A, β-CAROTENE) A deficiency of vitamin A is remarkably common in parts of the world, such as Southeast Asia, Africa, and the Middle East, where extreme poverty and nutritional depletion are 3 endemic. Hypovitaminosis A leads most importantly to a variety of ophthalmic disorders, 4 loosely grouped under the rubric xerophthalmia. An early manifestation of such depletion is night blindness, reflecting the importance of retinol in the production of rhodopsin (visual purple). After light absorption in the rods, retinol is released from rhodopsin and is available for recycling, with continuous regeneration of rhodopsin. The rods, which are present in the more peripheral portions of the retina but not in the macula and which subserve vision in conditions of low illumination, use rhodopsin as their primary chemical photoreceptor. A defect in vitamin A leads directly to deficient rod performance and thus to night blindness. The potential additive or potentiating role of protein malnutrition (e.g., kwashiorkor) remains insufficiently explored. A continuing severe deficiency of vitamin A results in progressive changes in both the conjunctiva and cornea. Corneal ulceration and keratomalacia lead ultimately to irreversible corneal damage and blindness. Hypovitaminosis A has also been implicated, albeit rarely, in 4 the development of pseudotumor cerebri during infancy (discussed later). Recommended daily allowances of vitamin A are 4,000 USP units in female subjects and 5,000 in male subjects; both parenteral and oral preparations of retinol are available for management of documented hypovitaminosis A, but great care must be used to avoid toxicity when administering this agent chronically. An excess of vitamin A results from a diversity of factors, including ingestion of carotene-rich polar bear liver or excessive amounts of vitamin A itself, ingested either as a food fad or as treatment for a host of dermatological conditions. A daily intake of as little as 7.5 mg retinol over time may produce toxic manifestations; acute hypervitaminosis A may follow the ingestion of 500 mg retinol in the adult, and less in infants and children. Such an excess is among the identified causes of the syndrome of pseudotumor cerebri (benign intracranial hypertension), a disorder characterized by generalized brain swelling associated with clinical features of increased intracranial pressure. Patients experience headache and at times slowed intellectual function; examination reveals papilledema, enlargement of the physiological blind spot, and occasionally nonspecific sixth nerve palsies. The cerebrospinal fluid (CSF) pressure is elevated, but the spinal fluid itself is otherwise normal. Computed tomography (CT) scanning or magnetic resonance imaging (MRI) demonstrates diffuse brain

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swelling with symmetrically placed ventricles, which may be small, normal, or (uncommonly) mildly enlarged. This condition represents a major threat, particularly to vision, because consecutive (“secondary”) optic atrophy may lead to progressive visual loss. Every effort must be made to prevent this complication by reducing the intracranial pressure. Therapeutic measures include the use of diuretics, corticosteroid preparations such as dexamethasone, repeated lumbar puncture, and a surgically established subarachnoid-extracranial shunt or optic nerve fenestration. Surgical cranial decompression should be avoided, if possible, and rarely requires serious consideration. B COMPLEX OF VITAMINS A number of factors in the B group of vitamins are of clinical importance with regard to neurological disease. These vitamins include thiamine (vitamin B1), niacin (nicotinic acid), pyridoxine (vitamin B6), and cobalamin (vitamin B12). Although each is considered separately here, in many instances deficiencies of these and other vitamins occur in combination and may lead to complex clinical disturbances. THIAMINE (VITAMIN B1) Thiamine pyrophosphate, or cocarboxylase, functions as a cofactor in intermediary carbohydrate metabolism. It serves as a coenzyme in the decarboxylation of α-keto acids, that is, α-ketoglutaric acid and pyruvate dehydrogenase; it also acts as a cofactor to the enzyme transketolase in the hexose monophosphate shunt. Deficiency of thiamine in animals results in accumulation of lactic acid and reduction in oxygen uptake, especially in the 5,6 brainstem, and depression of transketolase activity, again most strikingly in the brainstem. Such observations are intriguing in light of the known predilection of the lesions of Wernicke's encephalopathy for brainstem structures. In developed countries, thiamine deficiency in humans has been studied particularly in 7,8 chronic alcoholics. In this context, alcohol plays a secondary role, essentially serving to displace food in the diet. For the most part, observations in alcoholics appear readily transposed to those in nutritionally depleted nonalcoholics. Such discrepancies as do exist may well be explained on the basis of multiple vitamin deficiencies and varying ethnic and regional dietary habits and susceptibilities. Two disorders that appear most clearly related to thiamine deficiency are nutritional polyneuropathy and the Wernicke–Korsakoff syndrome. Two others, cortical cerebellar degeneration (“alcoholic cerebellar degeneration”) and nutritional amblyopia, are probably not related to thiamine deficiency alone but nevertheless seem intimately related to thiamine lack and are considered here as well. It is of interest that an epidemic deficiency of thiamine, and of other B vitamins, including B12 and folate, on a background of excessive intake of alcohol, heavy cigarette smoking, and chronic and severe food shortages, appeared in Cuba in the early 1990s, involving more than 50,000 individuals. Clinical manifestations included retrobulbar optic neuropathy, myelopathy with spastic paraparesis, spastic bladder, deafness, and sensory neuropathy with autonomic involvement. These features are reminiscent of those of so-called Jamaican neuropathy or Strahan's syndrome, discussed later. Following recognition of the nutritional basis of this disorder, multivitamins and folate were distributed by the government to the entire population 9–11 of the island; the epidemic thereafter subsided.

Nutritional Polyneuropathy Nutritional polyneuropathy (neuritic or dry beriberi, alcoholic neuropathy) is the most common of all nutritional disorders of the nervous system. Whether it relates to isolated deficiency of thiamine or more accurately reflects deficiencies of multiple vitamins in the B group, including pyridoxine and pantothenic acid, remains unsettled. It is clear, however, that thiamine deficiency plays a dominant role in the pathogenesis of polyneuropathy in both the alcoholic and nonalcoholic population. Clinically, nutritional polyneuropathy presents as a largely symmetric, mixed sensorimotor neuropathy. The onset of symptoms is usually insidious and progression is slow, but evolution is occasionally rapid. The lower extremities tend to be involved earlier and more severely than the upper extremities, and in many cases the arms appear to be spared. The distal portions of the limbs are characteristically affected more than the proximal segments. Complaints include numbness or tingling paresthesias distally in the limbs, frequently accompanied by pain. Although it is usually dull and aching in quality, the pain is sometimes sharp and lancinating, reminiscent of the pain of tabes dorsalis. (At times it is sufficiently

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severe to warrant the appellation pseudotabes.) Cramps in the feet and calves are common. Patients may complain of severe burning pain in the feet (“burning feet syndrome”) or of restless legs, and they often experience prominent and at times disabling dysesthetic sensations that are so uncomfortable that simple weight-bearing may become impossible. Examination demonstrates variable weakness, at times amounting to virtual paralysis of the legs. Footdrop with a resultant steppage gait is frequent, and the distal muscles atrophy. The muscles may be tender to palpation, especially in acute cases. The tendon reflexes are reduced or lost. Sensory examination demonstrates reduction or loss of vibratory sense, particularly at the ankles. Proprioception may be impaired, at times profoundly. Reduction of cutaneous sensation usually takes the form of a distal impairment of pain and light-touch appreciation in a glove-and-stocking distribution; thermal sensibility is reduced in a corresponding manner. The hypalgesic areas are not crisply defined, the border between normal and abnormal portions of the limbs tending to be indistinct (in contrast to the sharply delineated glove-and-stocking sensory loss found in the patient with a conversion reaction). Not all sensory modalities are involved to an equal degree, the severity and extent of loss exhibiting considerable variability from patient to patient. Signs and symptoms of dysfunction of the autonomic nervous system are sometimes encountered as well, including vocal cord paralysis with hoarseness, dysphagia, pupillary abnormalities, and hypotension. Hyperhidrosis of the hands and feet is common. Examination of the CSF usually demonstrates at most only a mild increase in protein content. Electrophysiological studies demonstrate findings suggestive of an axonal polyneuropathy, but there may also be features of superimposed compressive mononeuropathies. Pathologically, the primary change is segmental demyelination associated with axonal degeneration, affecting particularly the distal portion of the peripheral nerves. Changes in the sympathetic nervous system may also occur. In long-standing cases, retrograde changes may be found in the spinal cord, including chromatolytic changes in the anterior horn cells and secondary (ascending) degeneration in the posterior columns. Restoration of a well-balanced diet with supplemental vitamins of the B group, especially thiamine, is the keystone of therapy. The parenteral use of vitamin preparations is advisable in the early stages of treatment. Although the minimum daily requirement of thiamine in the adult is only approximately 1 mg, injections of 50 to 100 mg daily may be used early in therapy, with 50 to 100 mg subsequently taken by mouth several times daily. Symptomatic management includes the use of analgesics, amitriptyline (25 to 50 mg or more at bedtime), or carbamazepine (up to 800 mg or more per day as required) for relief of pain. The therapeutic benefit of either gabapentin or pregabalin in patients with nutritional painful neuropathy has not been adequately documented. Sympathetic block may be necessary in instances of severe and intractable burning. Unfortunately, recovery tends to be slow and incomplete; residual and at times severe sensory and motor alterations are common, even in individuals who maintain a normal dietary intake with vitamin supplementation.

Wernicke–Korsakoff Syndrome Although Wernicke's encephalopathy and Korsakoff's syndrome are traditionally viewed as two distinct entities, they are best regarded as representing simply two aspects of the same disease, separable chronologically into acute (Wernicke's encephalopathy) and chronic 12 (Korsakoff's syndrome) phases. Considerable evidence has accumulated to support the notion that these two disorders are indeed intimately linked. Thus, the typical mental changes of Korsakoff's syndrome may be present from the earliest stages of acute Wernicke's encephalopathy or may emerge during the treatment of that disorder as other clinical manifestations recede. Furthermore, examination of patients with classic Korsakoff's psychosis often reveals residual features of previous, perhaps unrecognized, Wernicke's encephalopathy, such as nystagmus and truncal ataxia. Finally, both the nature and the distribution of the pathological changes appear identical in the two conditions, such differences as do exist being accounted for by differences in the chronology of the lesions rather than reflecting a fundamental difference in kind. There can be little doubt as to the central role of acquired thiamine deficiency in the pathogenesis of this disorder. Such deficiency is found most commonly, although certainly not invariably, on a background of long-standing dietary insufficiency conditioned by the excessive use of alcohol, at least in Western society. Thiamine deficiency associated with 13 as well as in Wernicke–Korsakoff syndrome has also been recorded in patients on dialysis 14 and carcinoma those with acquired immunodeficiency syndrome, hyperemesis gravidarum, 15 treated with the chemotherapeutic agent fluoropyrimidine dexifluridine, and after 16,17 The possibility of an inherent gastroplasty performed for management of obesity.

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predisposition to Wernicke's encephalopathy, reflecting a genetically determined error in transketolase, has been suggested as of significance in at least some instances of the 18–20 disease. Wernicke's Encephalopathy Wernicke's disease, or encephalopathy, is an acute or subacutely evolving disorder. Appearing on a background of chronic and severe undernutrition, it is frequently preceded by some additional metabolic stress related, for example, to serious trauma or infection. A carbohydrate load is the immediate precipitating factor in some patients. Characteristic clinical features of this disorder include the following. 1. Abnormal mental status. Some patients appear apathetic and listless, with a short attention span, little spontaneity of speech, mental confusion, and excessive drowsiness. Coma is rare. Other patients have perceptual distortions, hallucinations, agitation, confusion, and other clinical features reminiscent of delirium tremens. Still others exhibit features of an amnestic dementia (i.e., of the typical mental alteration of Korsakoff's syndrome) with an otherwise clear sensorium. 2. Ophthalmoplegia. Ocular palsies are a hallmark of Wernicke's encephalopathy. Bilateral sixth nerve palsies are most common, but virtually any pattern of restricted ocular motility may be found, including conjugate gaze palsies and internuclear ophthalmoplegia. Diplopia is characteristically experienced and, in fact, often represents the first subjective manifestation of the disease. Involvement of the pupils is rare. 3. Nystagmus. Nystagmus is typically encountered in both the horizontal and vertical planes. In the presence of severe abducens palsies, however, nystagmus may be lacking in the abducting eye, becoming apparent only in the course of treatment as the ophthalmoplegia itself subsides. 4. Ataxia. Patients with Wernicke's encephalopathy typically evidence ataxia of trunk and gait, at times associated with severe truncal titubation. Only modest ataxia is observed with the heel-to-knee test, and the arms tend to be involved little if at all. In some patients ataxia is minimal, being evident only with attempts at tandem walking. Autonomic changes such as postural hypotension and altered cardiac function may also be encountered in Wernicke's encephalopathy, although not with sufficient frequency to be considered characteristic of the disease. Hypothermia is well described. True beriberi heart disease is infrequent, but sudden death may occur from acute cardiovascular collapse, 21 so-called shoshin beriberi. The clinical 12 course of Wernicke's encephalopathy is dramatically altered by the administration of thiamine. Within hours of the parenteral administration of 25 to 50 mg thiamine, the ophthalmoplegia improves, and ocular palsies generally disappear entirely within several days. Nystagmus similarly improves but less dramatically, and most patients are left with permanent horizontal nystagmus of modest amplitude. The truncal ataxia also improves, but again rather slowly and often incompletely; one half of the patients continue to exhibit at least mild residual ataxia. In contrast, improvement in the mental status is less predictable. Patients with a quiet confusional state or delirium tend to improve over a period of weeks; all too often, however, memory impairment, the hallmark of Korsakoff's syndrome, appears in the course of recovery and may persist thereafter. After initial management with parenteral thiamine in doses of 50 to 100 mg, patients are maintained on an oral dosage at 50 to 100 mg three or four times daily. The pathological alterations of Wernicke's encephalopathy are found in a remarkably stereotyped distribution, predominantly involving brainstem and hypothalamus. The characteristic lesion is one of subtotal tissue necrosis involving neurons, axons, and myelin to variable degrees. Lesions are typically found centrally disposed in the mammillary bodies, along the walls of the third ventricle, in the medial dorsal nucleus of the thalamus, in the periaqueductal gray matter of the mesencephalon, in the floor of the fourth ventricle, and in the superior cerebellar vermis. Within the lesions there is a glial response that is chronologically appropriate to the age of the destructive lesions. Inflammatory changes are lacking. In some cases fresh hemorrhages are found (responsible at least in part for the name Wernicke himself gave to this disease, i.e., polioencephalitis hemorrhagica superioris). It is probable that these hemorrhagic changes are secondary rather than primary events. Vascular proliferation is occasionally encountered. In terms of clinicopathological correlation, it is likely that the ophthalmoplegias are caused by lesions in the periaqueductal gray matter

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and pontine tegmentum, nystagmus by lesions typically involving the vestibular complex at the pontomedullary junction, and truncal ataxia by lesions in the superior cerebellar vermis. The alterations in attention, cognition, and memory are probably caused by lesions in the mammillary bodies and medial and posterior thalamus. Korsakoff's Syndrome Korsakoff's syndrome, or psychosis, the chronic form of the Wernicke–Korsakoff syndrome, is characterized primarily by an amnestic dementia, that is, a profound disorder of memory with relative preservation of cognitive abilities per se. The core of the defect appears to be an impairment of the ability to acquire new information (i.e., to establish new memories); thus, anterograde amnesia results. Patients with Korsakoff's psychosis also typically have some degree of retrograde amnesia, extending backward over a variable period of time before onset of the disease. Memories of events in the more remote past are often retained, but commonly in chronological disarray. The most striking impairment is without doubt the inability to learn newly presented information. Confabulation, probably representing, in large part, suggestibility on the part of the patient, is frequently encountered in Korsakoff's syndrome, but not invariably so. Because confabulation also occurs in other states of mental incapacity, it cannot be looked on as specific or in any way pathognomonic of Korsakoff's syndrome. The degree to which conscious mechanisms enter into confabulation under any circumstances remains unclear. Although the primary defect in Korsakoff's syndrome centers about memory, other cognitive impairment may be found, although usually of lesser severity. Thus, defects may be evident in visual and verbal abstracting ability, shifting mental sets, and concept formation, which are functions in which memory does not play a major role. In addition, the behavior of many patients with Korsakoff's syndrome is abnormal, being characterized by apathy, lack of interest, and listlessness, but without a clear defect in attention or vigilance. On careful examination, most patients with Korsakoff's syndrome show other clinical features of the Wernicke–Korsakoff syndrome, including horizontal nystagmus and variable gait ataxia. Not unexpectedly, many also demonstrate features of an associated nutritional polyneuropathy. The outlook for patients with established Korsakoff's syndrome is discouraging. Only a relatively small proportion of these patients recover memory function to any significant degree, although many evidence at least modest return, permitting them to function to a limited extent in society. One would anticipate that if vigorous therapy with thiamine were to be instituted during the acute phase of the disease (i.e., early in the course of Wernicke's encephalopathy), there would be a greater chance of either avoiding or appreciably lessening the ultimate memory defect; unfortunately, this has not been well documented. It is clear, however, that with continuing administration of thiamine in an oral dosage of 50 to 100 mg three or four times daily over many months, some patients who originally show little or no improvement may demonstrate gradual and at times remarkably complete functional recovery. The neuropathological changes in Korsakoff's syndrome are essentially identical in distribution and histological character to those of Wernicke's encephalopathy. The only noteworthy difference is that of a more chronic (i.e., astrocytic) form of glial reaction, in keeping with the more protracted clinical course. In terms of the anatomical substrate for the memory defect, the lesions in the mammillary bodies and thalamus appear to be of particular importance. The studies of Victor and associates have clearly demonstrated that the lesions in the medial dorsal and perhaps posterior nuclei of the thalamus are central to the memory 12 defect. In a large series of pathologically documented cases, they were able to demonstrate lesions invariably in the thalamus in patients with Korsakoff's syndrome, whereas lesions in the mammillary bodies were not consistently observed. Although cortical atrophy is a commonplace observation in the brains of chronic alcoholics, it is doubtful that a cortical pathological process plays a significant role in producing the mental changes of classic Korsakoff's syndrome.

Cortical Cerebellar Degeneration Cortical cerebellar degeneration, or “alcoholic cerebellar degeneration,” appears intimately linked to Wernicke's encephalopathy. Although a primary role for thiamine deficiency has not been convincingly established, this disorder is clearly of nutritional origin, and its close association with Wernicke's disease warrants its inclusion here.

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Cortical cerebellar degeneration is a relatively frequent complication of chronic alcoholism 22,23 Usually beginning in and is the most common of the acquired cerebellar degenerations. midlife and almost always on a background of long-standing and excessive ethanol abuse and chronic nutritional depletion, the onset of the disease is commonly marked by complaints of disordered gait or truncal stability. The gait disability worsens in subacute fashion for a period of several weeks or months or even longer, but it ultimately stabilizes, usually when patients become abstinent and improve their nutritional status. At times the disorder evolves episodically, seemingly in relation to severe systemic illness. Examination demonstrates that the primary defect is referable to the gait and stance. Truncal instability is common, and a wide-based ataxia of gait with ataxia of individual leg movements is characteristic. The patient is unable to make rapid postural adjustments and walks in tandem fashion only with difficulty. At times the ataxia is so severe that the patient cannot stand unaided, even on a wide base; most patients require at least some support for either standing or walking. In contrast to the severe affection of the lower extremities, the arms are affected little if at all. There may be ocular dysmetria, but other features suggestive of cerebellar dysfunction are either minimal or entirely lacking: dysarthria, when present, tends to be mild, and nystagmus is uncommon. Features of other neurological disorders, particularly those of Wernicke's encephalopathy and nutritional polyneuropathy, are often present. After stabilization, patients may show modest improvement as their nutrition improves, especially if supplemental vitamins are taken. However, a significant cerebellar deficit invariably remains and persists for years thereafter. Pathological changes predominate in, and may be confined to, the anterior and superior portions of the cerebellar vermis and hemispheres. Occasional lesions are also found elsewhere in the cerebellar cortex. In almost all cases the lingula, central lobule, and culmen and adjacent declive are affected in the vermis, whereas in the hemispheres it is the more anterior portion of the anterior lobes that is most commonly affected. Within these areas, all neurocellular elements are destroyed, although to variable degrees; the Purkinje cells appear to be especially vulnerable. Secondary changes may be found in the cerebellar white matter, deep cerebellar nuclei, and related brainstem nuclei, such as the olivary complex. The typical histological features of Wernicke's encephalopathy are conjoined in many cases. Well-documented cases of a similar form of cerebellar degeneration occurring in conditions 24 of severe nutritional depletion unrelated to the abuse of alcohol have been reported, suggesting that “alcoholic” cerebellar degeneration is in fact of nutritional origin. The appearance of similar clinical and pathological features in the course of Wernicke's encephalopathy, and the occurrence of characteristic features of Wernicke's encephalopathy in otherwise straightforward instances of cerebellar degeneration, suggest that the two disorders are closely linked. It is therefore tempting to ascribe the cerebellar disease also to thiamine deficiency, but this cannot be stated with certainty at this time. The significance of the reportedly low CSF levels of thiamine in certain inherited ataxias, and specifically in 25 olivopontocerebellar atrophy and Friedreich's ataxia, remains unclear in this respect. The transient cerebellar syndrome encountered as an evanescent ataxia of gait in acute alcoholic intoxication (or rarely in withdrawal states) is not associated with any fixed cerebellar lesions. The cerebellar dysfunction that occurs in these circumstances presumably reflects a reversible biochemical lesion that conceivably also relates to thiamine deficiency, although this relationship remains to be established.

Nutritional Amblyopia Nutritional amblyopia (deficiency amblyopia, nutritional retrobulbar neuritis, tobacco-alcohol amblyopia) appears most frequently in the chronically malnourished alcoholic and appears 26 firmly established as a deficiency disorder of the B group of vitamins. As its name implies, it is characterized primarily by defective vision. Its onset is insidious and its course progressive. Initial impairment of the ability to read small print or to distinguish colors leads eventually to serious impairment of visual acuity, but with few (if any) other subjective ocular complaints. Examination typically demonstrates a bilateral and fairly symmetric loss of visual acuity, with bilateral central, cecocentral, or paracentral scotomas. Peripheral fields are unaffected. Funduscopic examination is usually unrevealing, although in advanced stages there may be mild optic atrophy. Signs of other disorders of nutritional origin (e.g., polyneuropathy or the Wernicke–Korsakoff syndrome) may be found. The salient pathological changes are found in the optic nerves, chiasm, and tracts in a position that corresponds to the location of the papillomacular bundles. Trans-synaptic degeneration is sometimes seen in the nerve cells of the lateral geniculate body, and in severe cases there may be loss of ganglion cells in the

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macular region of the retina. The primary site of involvement, however, is the conducting pathways themselves, in contrast to the amblyopia of methyl alcohol toxicity, which is due to primary degeneration of the retinal nerve cells. This disorder is encountered worldwide among undernourished alcoholics, in conditions of naturally occurring famine, and among incarcerated groups of people such as prisoners of war. Although there is widespread agreement that deficiency of group B vitamins is important 27 in the pathogenesis of nutritional amblyopia, it does not necessarily imply a central role for thiamine alone; a similar syndrome may appear in patients with deficiency of vitamin B12 and perhaps of riboflavin. Despite the term tobacco-alcohol amblyopia traditionally applied to this condition, it is unlikely that either tobacco or ethyl alcohol plays a significant role as a directly toxic agent. Dramatic improvement in vision, with complete return to normal acuity and fields, follows the timely introduction of treatment with group B vitamins, even if the patient continues to smoke and consume ethanol as before. If the disease is not recognized early and treated promptly, the visual changes become irreversible, with permanent blindness and optic atrophy.

Subacute Necrotizing Encephalomyelopathy The relationship of subacute necrotizing encephalopathy of childhood (Leigh's disease) to Wernicke's disease itself remains unclear. Inherited as an autosomal-recessive or X-linked trait or exhibiting a pattern of maternal inheritance, Leigh's disease typically develops within 28 the first 2 years of life. An adult form has been described. It is characterized by weakness, hypotonia, intellectual deterioration, seizures, deafness, optic atrophy and blindness, irregular respirations, ataxia, ophthalmoplegia, vomiting, and nystagmus. The disease is usually fatal within several months, but occasional patients have pursued a much more chronic course. Clinically, it thus bears no obvious relation to Wernicke's encephalopathy. However, lesions reminiscent of Wernicke's disease are found in the thalamus and brainstem; necrotic lesions may also be found in the optic nerves and posterior columns of the spinal cord. The mammillary bodies and hypothalamus are involved only infrequently. In view of this at least superficial pathological resemblance to Wernicke's encephalopathy, 29,30 the possibility that Leigh's disease relates to thiamine deficiency has been raised, 31 particularly in light of the observation of elevated blood pyruvate and lactate levels and of 32 lactic acidosis, suggesting a defect in pyruvate decarboxylation in at least some cases. Pincus and colleagues observed an absence of thiamine triphosphate in the brain of a patient dying of this disorder and noted the presence in blood, urine, and CSF of a factor inhibiting the conversion of thiamine pyrophosphate to thiamine triphosphate (and therefore inhibiting 33 the action of thiamine pyrophosphate–adenosine triphosphate phosphotransferase). Reduction in thiamine triphosphate content has been documented in other cases as well, and temporary benefit has been noted after the administration of thiamine in large amounts in at least some instances. It has become clear, however, that the fundamental defect in Leigh's disease is in fact impairment of cerebral oxidative metabolism; cytochrome c oxidase deficiency may be the most important of the numerous biochemical/enzymatic alternatives 34,35 Although thiamine may play some role in pathogenesis, a that have been described. simple dietary lack of thiamine does not appear to be of significance. NIACIN (NICOTINIC ACID) A deficiency of nicotinic acid or of its metabolic amino acid precursor tryptophan is widely accepted as the cause of pellagra. Relatively uncommon today, pellagra is occasionally encountered as a neuropathological curiosity in chronic alcoholics. It is not rare, however, in institutionalized mentally retarded or demented patients. In its fully developed clinical form, pellagra comprises a host of symptoms referable to the gastrointestinal tract (anorexia, nausea, vomiting, diarrhea), skin, and nervous system. Both central and peripheral nervous systems may be affected. Evidence of involvement of the central nervous system (CNS) includes irritability, insomnia, depression, mania, confusion, intellectual deterioration, and memory impairment. Extrapyramidal or cerebellar deficits may develop, and the optic nerves may be involved. The appearance of a polyneuropathy, usually of mild to moderate degree, indicates peripheral involvement. The clinical features are typical of most metabolic polyneuropathies and include tenderness of nerve trunks and muscles, cramps, distal weakness of the limbs, depressed tendon reflexes, and distal impairment of cutaneous sensibility. Loss of proprioception and vibratory sense may reflect either the neuropathy or an associated myelopathy whose presence is suggested by the occasional appearance of extensor plantar responses. The corneal reflexes may be decreased and the pupillary light reflexes impaired. Pathological changes in pellagra are found in the cerebrum, spinal cord, and peripheral

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nerves and roots. Chromatolytic changes in neurons (the “central neuritis” of Adolph Meyer) are encountered, involving most prominently the large Betz cells of the motor cortex; a similar neuronal change may be found ubiquitously throughout the central gray matter. Degenerative changes are found symmetrically in the posterior and lateral columns of the spinal cord. The peripheral nerves show a patchy loss of myelin and axons. Although it is widely held that all the clinical manifestations of pellagra are due to niacin deficiency, the neurological changes are remarkably resistant to treatment with niacin alone, even when 25 mg is administered intravenously twice daily. Deficiency of other vitamins such as thiamine may be important, particularly in the pathogenesis of the polyneuropathy. Furthermore, Victor and Adams have demonstrated the appearance of the typical neuronal 36 changes of pellagra in experimental pyridoxine deficiency. It is therefore possible that the full clinical syndrome of pellagra reflects deficiency of several vitamins in the B group. A reversible syndrome of niacin deficiency termed nicotinic acid deficiency encephalopathy also occurs, predominantly although not exclusively in the literature of the 1940s. This poorly understood syndrome appears to involve particularly the elderly. It is characterized by mental confusion, stupor, cogwheel rigidity, and the appearance of primitive reflexes (e.g., forced grasping). The exact nature of this disorder has never been clarified, and there are reservations as to its relationship to nicotinic acid deficiency as such because most affected patients appear to have experienced much broader nutritional defects. Finally, a relationship of nicotinic acid deficiency to Hartnup's disease is suggested by the similarity of the clinical picture of this infantile, recessively inherited familial disorder to pellagra. A genetically determined defect in intestinal transport of the nicotinic acid precursor tryptophan (and other amino acids) and reported benefit from the administration of nicotinic acid are features of Hartnup's disease that support the notion of such a relationship. PYRIDOXINE (VITAMIN B6) Neurological disorders reflecting both pyridoxine deficiency and pyridoxine excess have been recognized. Pyridoxine is a water-soluble vitamin that is converted by the enzymes pyridoxal kinase and pyridoxine phosphate oxidase to its active form, pyridoxal phosphate, a coenzyme involved in a number of decarboxylation and transamination reactions. Excessive intake of pyridoxine may saturate either of these enzyme systems, with a resultant accumulation of (inactive) pyridoxine, which occupies binding sites on the appropriate apoenzymes and thus acts as a competitive inhibitor for pyridoxal phosphate. In essence, an excess or overdose of pyridoxine leads to a deficiency of pyridoxal phosphate. Deficiency of dietary pyridoxine causes a mixed distal symmetric polyneuropathy. The lack of pyridoxal phosphate functioning as a coenzyme for serine palmityltransferase (as required for the synthesis of sphingomyelin) or amino acid decarboxylase, or both, may be responsible for the polyneuropathy. Polyneuropathy due to pyridoxine deficiency is found in patients treated 37 for tuberculosis with INH, an agent that inhibits pyridoxine phosphorylation. Patients treated with INH commonly describe numbness and tingling in the limbs, particularly involving the lower extremities, together with tenderness in the calves and pain (often burning) distally in the limbs. Examination demonstrates reflex loss, impairment of superficial sensation, and weakness in the lower extremities, with little, if any, affection of the arms. At times, INH neuropathy is extraordinarily severe, especially in seriously malnourished tubercular patients and particularly in those who are also chronic alcoholics. This finding suggests the likelihood of multiple nutritional deficiencies acting synergistically to produce a devastating neuropathy. Of additional interest in this connection is the observation that the typical central features of pellagra may appear in patients receiving INH, along with the classic dermatological and 38 intestinal manifestations of the naturally occurring disease. Neuropathy caused by INH may be prevented by the concomitant administration of pyridoxine. Although the minimum daily requirement of pyridoxine is only approximately 2 mg in adults, 50 mg/d or more may be required for successful therapy in the deficiency states. A predominantly sensory neuropathy or neuronopathy has also been recognized as a result 39,40 Female subjects are affected almost exclusively, perhaps reflecting of pyridoxine abuse. the widespread use of pyridoxine in the management of premenstrual symptoms. All exhibit symmetric and distal sensory loss; vibratory and position sense may be markedly impaired, and sensory ataxia is often prominent. The legs are usually more severely involved than the arms, reflecting the fact that the disorder is primarily a distal axonopathy. Muscle weakness has been described in a few patients. The Achilles reflexes are invariably lost. Electrophysiological studies demonstrate absent or severely reduced sensory nerve action potentials, with mild slowing of sensory nerve conduction velocities. Compound muscle action

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potential amplitudes and motor nerve conduction velocities are normal. Improvement occurs after discontinuation of pyridoxine. Complete recovery may occur in patients with a mild neuropathy who had been taking only low doses of the vitamin. During infancy, pyridoxine deficiency results in seizures, excessive irritability, tremulousness, and poor psychomotor development. This disorder appears due to an inherited metabolic defect transmitted in an autosomal-recessive manner. The seizures presumably result from depletion of γ-aminobutyric acid, the normal conversion of glutamic acid being thwarted by the absence of the coenzyme pyridoxal phosphate, acting in concert with the apoenzyme glutamic acid decarboxylase. The administration of pyridoxine arrests seizures and may also foster normal development. Finally, some patients with childhood homocystinuria, inherited as an autosomal-recessive 41 characteristic and reflecting a deficiency of cystathionine synthase, are pyridoxine responders, and may be treated effectively with fairly large doses of vitamin B6. COBALAMIN (VITAMIN B12) As is well known, pernicious anemia, which is characterized by malabsorption of vitamin B12, reflects a lack of intrinsic factor associated with gastric atrophy and gastric achlorhydria. It may have an autoimmune basis, as suggested by the fact that many patients with pernicious anemia have antibodies against gastric parietal cells as well as antithyroid antibodies; immunoglobulin G antibodies against intrinsic factor itself may also be demonstrated. Further supporting the notion of autoimmune causation is the occasional association of pernicious anemia with myasthenia gravis, a disorder of known autoimmune cause. Vitamin B12 malabsorption and deficiency may also occur under a number of other circumstances, including fish tapeworm infestation, celiac disease, sprue, gastric malignancy, chronic gastritis, thyrotoxicosis, myxedema, an extreme vegetarian diet, chronic pancreatic insufficiency, and after gastrectomy or gastrojejunostomy. Whatever its cause, vitamin B12 deficiency may lead to serious disease involving both central and peripheral nervous systems, although the precise pathophysiological mechanisms remain unclear. The most widely recognized CNS disorder resulting from vitamin B12 deficiency is subacute combined degeneration of the spinal cord, often erroneously referred to as posterolateral sclerosis or combined system disease. Clinically it presents with tingling paresthesias involving the feet, subsequently associated with weakness and stiffness of the legs and a spastic gait. As the disease progresses, the upper extremities are involved. Loss of vibratory sense, particularly in the feet, and impairment of proprioception with a resultant sensory ataxia are characteristic features. Hyperreflexia and extensor plantar responses may give way to areflexia as an associated polyneuropathy appears. Signs of a hypertonic bladder are frequent. On occasion, segmental impairment of cutaneous sensibility is observed over the torso. In addition to such features of myelopathy, many patients with subacute combined degeneration develop impairment of vision, reflecting involvement of the optic nerves; altered visual evoked potentials are common. Primary optic atrophy may appear. Central or cecocentral scotomas may be documented with visual field examination. A variety of mental changes may also be seen, ranging from depression to paranoid states, and, most important, progressive dementia with impairment of both memory and cognitive function. On MRI, an increased T2-weighted signal, decreased T1-weighted signal, and contrast enhancement of the posterior and lateral columns of the spinal cord may be found, mainly in 42 the cervical and upper thoracic regions. Pathologically, the earliest changes in the spinal cord are in the posterior columns of the thoracic cord; these changes are characterized by patchy, eventually confluent areas of myelin swelling and degeneration, ultimately with loss of axons. As the disease progresses, patchy demyelination appears in the lateral columns and sometimes spreads to involve the white matter of the cord in its entirety. The process extends to the cervical cord as the disease evolves. Demyelination may be encountered in the cerebral white matter—presumably accounting for the psychological changes found in the disease—and in the optic nerves. 43,44

Disease of the peripheral nervous system is observed in vitamin B12 deficiency as well, but the frequency of polyneuropathy is not clear. Clinical criteria alone may be insufficient to establish a diagnosis in that complaints of numbness or paresthesias, which are typical symptoms of a sensory neuropathy, are also encountered in patients with disease of the posterior columns. In addition to loss of posterior column sensibility attributable to myelopathy, however, some patients exhibit distal impairment of cutaneous sensibility in a glove-and-stocking distribution. This sensory change, coupled with loss of tendon reflexes in

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the legs, may be taken as evidence of polyneuropathy appearing either independently of or superimposed on the myelopathy. There is also45abundant electrophysiological evidence of polyneuropathy occurring in pernicious anemia. A decrease in distal sensory nerve conduction velocity is characteristic and in keeping with the observation of a reduction in the number and diameters of myelinated axons in the distal portion of peripheral nerves in patients with subacute combined degeneration. In general, the electrophysiological features in these patients are suggestive of a mixed demyelinating and axonal neuropathy; reversal of such abnormalities occurs to a variable extent with vitamin B12 treatment. Electrophysiological evidence of subclinical polyneuropathy may also be found in patients with vitamin B12 deficiency. Vitamin B12 deficiency, marginal or overt, has been implicated as a possible cofactor in the pathogenesis of cognitive alterations in patients with human immunodeficiency virus 46,47 48 although the evidence for such a relationship is not compelling. Vitamin B12 infection, deficiency has also been noted in some cases of multiple sclerosis and documented by depressed levels in both blood and CSF and elevation of plasma homocysteine and R-binder 49,50 There is anecdotal evidence of clinical improvement in some patients with capacity. multiple sclerosis treated with vitamin B12 supplements. Features of both central and peripheral nervous system disease similar to those encountered in classic subacute combined degeneration51with associated polyneuropathy may occur as a reflection of deficiency in R-binder protein, one of the two carriers responsible for extracellular transport of vitamin B12 in plasma. Attention has been drawn to the appearance of subacute combined degeneration in a patient with an abnormal plasma B12-binding 52 protein, with high serum vitamin B12 levels. In patients with neurological dysfunction secondary to deficiency of vitamin B12, therapy must be prompt and aggressive. At the outset, 1,000 μg cyanocobalamin should be administered intramuscularly daily. This dose should be continued on a daily basis, or at least several times weekly, for several months, while the patient's neurological progress is monitored. Subsequently, 1,000 μg cyanocobalamin should be given intramuscularly every 2 weeks indefinitely to patients with pernicious anemia. CALCIFEROL (VITAMIN D) The exact role of vitamin D in neuromuscular function is unclear. This nutrient appears to be involved in muscle metabolism and contractility by virtue of action either on the 2+ Ca -dependent myosin ATPase system or directly on the phospholipid component of the sarcolemmal membrane. A deficiency in vitamin D has been held responsible at least in part for the weakness, fatigability, and muscular atrophy encountered in patients with hyperparathyroidism and renal tubular acidosis. Intestinal malabsorption or dietary insufficiency may lead to vitamin D deficiency, with resultant hypocalcemia, osteomalacia, muscle weakness, and tetany; minor myopathic features may be noted histologically. 53

Hearing loss has also been reported as a reflection of hypovitaminosis D. Of particular interest is the often unappreciated development54–56 of hypovitaminosis D with hypocalcemia in including phenytoin, phenobarbital, and the course of prolonged use of anticonvulsants, carbamazepine. A depression of vitamin D levels is not invariable, however, even in the 57,58 presence of significant hypocalcemia. TOCOPHEROL (VITAMIN E) There has been growing awareness of the role of acquired vitamin59–61 E deficiency in the The exact role of production of neurological dysfunction in both children and adults. vitamin E in the nervous system is not known, although it appears important in maintaining the integrity of biological membranes and has antioxidant properties. On a background of chronic fat malabsorption—as occurs, for example, in cholestatic liver disease, cystic fibrosis, or celiac disease—a deficiency of vitamin E results in a remarkable constellation of neurological abnormalities referable to both central and peripheral nervous 62–70 Features of both spinocerebellar degeneration and polyneuropathy have been systems. recognized clinically, including progressive gait ataxia, incoordination of the limbs, ophthalmoplegia, dysarthria, extensor plantar responses, loss of reflexes in the legs, limb weakness, and marked impairment of vibratory and position sense. The occurrence of 71 seizures has been recorded, and there may be involvement of the autonomic nervous system. Vitamin E deficiency has also been documented in several instances of infantile 72 motor neuron disease (Werdnig–Hoffman disease) although without demonstrable intestinal malabsorption. When the typical clinical features of vitamin E deficiency are associated with

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retinitis pigmentosa, acanthocytosis, and abetalipoproteinemia, the rubric Bassen–Kornzweig syndrome is used. A lack of73tocopherol has been demonstrated in peripheral nerves in vitamin E–deficient patients. Electrophysiological studies demonstrate reduced sensory action potentials and at least mild abnormalities of peripheral sensory conduction velocity, reverting to normal after 74 treatment with vitamin E. Somatosensory evoked potentials exhibit a central delay in conduction, in keeping with pathological changes in the posterior columns, and there may be a prolonged P100 latency in visual evoked potentials. Pathological studies demonstrate loss of large-caliber myelinated axons in the peripheral nerves; accumulation of lipid pigment in nerve cells bodies in the dorsal root ganglia, anterior horns, and brainstem motor nuclei; degenerative changes in the cerebellar cortex; and, most strikingly, degeneration of the posterior columns and, to a lesser extent, the spinocerebellar tracts. There is remarkable plate- or disc-like swelling of axons in the posterior columns, in Clarke's column, and in the cuneate nuclei of the brainstem. Such axonal swelling, referred to as neuroaxonal dystrophy, is also found in experimental vitamin E deficiency. Similar disc-like swellings of axons are found in Hallervorden–Spatz disease, but no definite alteration of vitamin E absorption has been documented in that disorder; furthermore, the vitamin E deficiency disorders fail to demonstrate deposition of iron in the basal ganglia, which is the hallmark of Hallervorden–Spatz disease. Variable improvement in the clinical and electrophysiological manifestations of vitamin E deficiency has been observed after the administration of tocopherol either orally or, perhaps preferably, parenterally. Intramuscular injection of 50 to 100 mg of vitamin E, given every 3 to 7 days for up to 44 months, may arrest the evolution of the neurological disease but not 75 necessarily reverse the clinical symptomatology. Chronic oxygen neurotoxicity, perhaps in association with a loss of calcium homeostasis, may be a pathogenetic factor of possible significance in degenerative diseases of the nervous system such as Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and Alzheimer's76disease. The demonstration of a genetically determined deficiency of superoxide dismutase, an enzyme that detoxifies oxygen free radicals, in familial instances of amyotrophic lateral sclerosis underscores the potential importance of this concept. As a corollary, the antioxidant properties of α-tocopherol and of ascorbic acid and β-carotene as free radical scavengers have prompted their consideration as therapeutic agents in such degenerative disorders. However, in preliminary studies, any benefit from the use of these antioxidants appears conjectural at best. FOLIC ACID Reduced serum folate levels have long been recognized in patients with subacute combined degeneration of the spinal cord and vitamin B12 deficiency, and the association of maternal dietary folate deficiency in pregnancy with fetal neural tube defects is well established. Reversible depression and cognitive decline have frequently been reported in individuals with 77,78 A folate deficiency, especially the elderly, and perhaps related to homocysteine levels. link to Alzheimer's disease has been suggested, though never adequately demonstrated. A single case of Kearns–Sayre syndrome associated with reduced plasma and cerebrospinal 79 fluid folate has been reported. An infantile sporadic cerebral folate deficiency syndrome has been defined, recently 80 suggested as being due to the presence of autoantibodies to folate receptors. The disorder develops ordinarily within 4 to 6 months postpartum and is characterized clinically by psychomotor retardation, ataxia, signs of upper motor neuron dysfunction, and a variety of abnormal movements. Some patients have seizures, and a small number with mental retardation appear autistic. Visual failure with optic atrophy may be manifested late in the course. At least some clinical abnormalities appear to respond to the administration of folinic acid. OTHER DISORDERS WITH A POSSIBLE NUTRITIONAL BASIS

Marchiafava–Bignami Disease Marchiafava–Bignami disease, or primary degeneration of the corpus callosum, is a rare disorder encountered largely, although not exclusively, in nutritionally depleted chronic 23,81 Originally it was thought to appear particularly in middle-aged or elderly men of alcoholics. Italian descent addicted to drinking crude red wine, but now it is clear that the most important factor underlying its appearance is actually chronic and severe nutritional depletion.

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Characteristic changes of the disease have been noted in association with disorders of clearly recognized nutritional origin such as Wernicke's encephalopathy and pellagra; in several well-documented, pathologically verified instances, there has been no history of 82 alcohol ingestion. It is unfortunately not possible to define more precisely the specific nutritional defect in this disease, although it has been suggested that thiamine deficiency is of primary importance. The clinical features of Marchiafava–Bignami disease, which are nonspecific, include a variety of psychiatric symptoms, dementia, aphasia, seizures, heightened muscle tone, tremor, paralysis, stupor, and coma. The course of the disease may be measured in terms of months, occasionally years. Although progressive in an overall sense, patients have occasionally exhibited clinical plateaus or even frank remissions in their clinical course. The fundamental pathological change is a symmetric degeneration of the myelin sheaths in the mid-zone of the corpus callosum, with relatively good preservation of axons and without appreciable inflammatory changes. Such degenerative changes are not confined to the corpus callosum; similar changes may be found in the anterior commissure, symmetrically disposed in the cerebral white matter, the optic chiasm, or the middle cerebellar peduncles. Although Marchiafava–Bignami disease was once looked on as a neuropathological curiosity not diagnosable during life, the lesions may be readily identified with CT scanning or MRI.

Central Pontine Myelinolysis 83

First described in 1959 but reported in large numbers since, central pontine myelinolysis is characterized clinically by a rapidly evolving flaccid quadriplegia with bulbar paralysis; pathologically it is identified by demyelination confined for the most part to the basal portion of the middle and upper pons and symmetrically distributed about the midline. Extrapontine myelinolysis has been observed in a number of instances. Consciousness is preserved, and patients may be able to communicate by moving the eyelids, the only motor activity remaining in extreme cases; the term locked-in syndrome is appropriately applied to cases of this sort. The course of the disease is rapid, and patients usually84die within 3 weeks of the onset. Clinical recovery has been observed in rare instances. Although originally looked on as nutritional in origin, it has become apparent that many if not most cases of 85 central pontine myelinolysis are in fact due to overly vigorous correction of the 86,87 or hyponatremia, as frequently encountered in the neglected, malnourished alcoholic, under other circumstances, as discussed in detail in Chapters 19 and 37 and ranging from 88 ornithine carbamoyl transferase deficiency in childhood to orthotopic liver transplantation 89,90 It has been suggested that in most cases an with concomitant use of cyclosporine. osmotic shift may be more important in producing demyelination than the serum level of 91 sodium per se. It is unclear whether chronic nutritional depletion plays a specific role in the pathogenesis.

Jamaican Neuropathy In 1897, Strachan described a group of patients in Jamaica who presented with numbness and burning in the limbs, girdle pains, impaired vision and hearing, muscle weakness and wasting, hyporeflexia, and sensory92ataxia in association with a mucocutaneous lesion such cases were subsequently reported in a as angular stomatitis and glossitis. Virtually identical 93 variety of circumstances of nutritional depletion. The clinical features are predominantly those of a sensory neuropathy. Pathological alterations have been described in the peripheral nerves, posterior columns, spinocerebellar tracts, and optic nerves. Similar clinical features 94 and occurring in association with spasticity were later described by Denny-Brown 95 Cruickshank. In the spastic form of the disease, severe degeneration of both the pyramidal tracts and posterior columns of the spinal cord has been documented, with involvement of the spinocerebellar and spinothalamic pathways in some cases. It is unclear whether the neuropathic disorder of Strachan and the myelopathic variety of Cruickshank represent different entities or simply different manifestations of the same process. The designation Jamaican neuropathy is often applied indiscriminately to all such instances. Those disorders characterized by myelopathic features (i.e., spasticity) are, however, sometimes referred to titers to human T-lymphotrophic as tropical spastic paraparesis; in the latter group, antibody 96–98 retrovirus type I have been documented repeatedly, and it is presumed on this basis that viral infection plays a major role in pathogenesis, as discussed in Chapter 47. Whether nutritional depletion plays any role in either form of the disease remains unclear. The use of clioquinol has been implicated in the development of subacute myelo-opticoneuropathy, a similar disorder occurring most commonly in Japan. HYPERALIMENTATION

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Parenteral hyperalimentation using a central venous catheter, usually placed in a jugular vein, is widely used in the management of chronic nutritional depletion at all ages. A number of 99 neurological disorders appear in such patients, reflecting either mechanical or metabolic problems. Complications attributed to mechanical factors, with or without sepsis, include 100 101 cortical vein thrombosis, infected subdural collections, cerebral air embolization, 102 103–105 pseudotumor cerebri, and, in infants, communicating hydrocephalus. Metabolic alterations are usually held responsible for a variety of encephalopathic, neuropathic, or myopathic manifestations, virtually all of which are reversible when the underlying metabolic defect is identified and treated appropriately. Encephalopathy is attributed most commonly to 106,107 108 or hyperammonemia ; hyperosmolarity has also been implicated hypophosphatemia and appears to be of particular 109 importance in experimental models of the disorder. Biotin deficiency has been described. Patients receiving prolonged parenteral nutrition without thiamine supplementation are at110 risk for development of an acute and fatal encephalopathy resembling Wernicke's disease. Severe hypophosphatemia has also been blamed for the appearance of a peripheral neuropathy characterized by weakness, areflexia, and paresthesias and sensory 111 impairment. Ataxia, cranial nerve palsies, ophthalmoplegia, blurred vision, and respiratory failure have all been described. At times, the clinical evolution of this disorder is sufficiently 112,113 114 Chromium and linolenic acute to suggest a diagnosis of Guillain–Barré syndrome. 115 acid deficiency have been documented in individual cases. Selenium deficiency has been 116–118 associated with a reversible myopathy, evidenced by proximal muscle weakness and tenderness and an elevated serum creatine kinase level. Selenium deficiency may relate to parenteral or enteral nutrition, or malabsorption; insufficient selenium intake in low soil-selenium areas; and chronic conditions associated with oxidative stress, such as chronic 118 alcohol abuse and human immunodeficiency virus (HIV) infection. Selenium supplementation usually reverses myopathic symptoms when the cause is parenteral or enteral nutrition, or malabsorption; when deficiency occurs in low soil-selenium areas, other factors may also be important, as selenium supplementation and placebo have similar effects 118 on muscle symptoms. Patients with copper deficiency may present with gait disturbances from a sensory ataxia related to posterior column dysfunction. Lower-limb spasticity is common and a polyneuropathy is generally present, so that the clinical picture resembles that of vitamin B12 deficiency. The syndrome has followed prolonged total parenteral hyperalimentation, copper deficiency in enteral feeding, gastric surgery, malabsorption, and excessive zinc 119–121 but a cause cannot always be identified. Serum zinc level may be elevated absorption, and the diagnosis is suggested by low ceruloplasmin and copper levels in the absence of evidence for Wilson's disease. Anemia (macrocytic, normocytic, or microcytic), leukopenia, and thrombocytopenia may occur; the hematological findings may resemble a sideroblastic anemia or myelodysplastic syndrome. Abnormalities of somatosensory evoked potentials and of MRI, when present, help to demonstrate involvement of the posterior columns of the spinal cord. Copper supplementation may arrest the course of the disorder, which should therefore be excluded in patients with an ataxic spastic paraparesis or neuromyelopathy of uncertain cause. Previous

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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 18 Neurological Dysfunction and Kidney Disease MICHAEL J. AMINOFF •

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UREMIC ENCEPHALOPATHY Pathophysiology Clinical Features Investigations Treatment of Uremic Convulsions UREMIC NEUROPATHY Polyneuropathy Pathophysiology Clinical Features Treatment Autonomic Neuropathy OPTIC NEUROPATHY NEUROLOGICAL COMPLICATIONS OF DIALYSIS Entrapment Mononeuropathies Carpal Tunnel Syndrome Ulnar Nerve Lesions Ischemic Neuropathy Dialysis Dysequilibrium Syndrome Wernicke's Encephalopathy Dialysis Dementia Clinical Aspects Pathogenesis Treatment COMPLICATIONS OF TRANSPLANTATION Femoral and Related Neuropathy Tumors Brain Tumors Central Nervous System Infections HEREDITARY DISORDERS OF THE NERVOUS SYSYEM AND KIDNEYS Fabry's Disease von Hippel–Lindau Disease Polycystic Kidney Disease

The neurological aspects of renal disease and the neurological complications of dialysis and

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renal transplantation are discussed in this chapter. The neurological complications of renal carcinoma are not considered, but paraneoplastic complications of malignancy are considered in Chapter 27, and the neurological consequences of radiation and chemotherapy in Chapter 28. The subject itself is complicated because many of the causes of renal failure lead to neurological complications that also occur in uremia. Thus, collagen vascular diseases are commonly associated with encephalopathy or seizures, and diabetes with neuropathy or encephalopathy. Attention here is directed primarily to complications that are a direct consequence of the renal failure and its treatment rather than to the underlying cause of the kidney disease. In addition, however, certain hereditary disorders that affect both the nervous system and the kidneys are considered. UREMIC ENCEPHALOPATHY The neurological consequences of uremia resemble other metabolic and toxic disorders of the central nervous system (CNS). Thus, the clinical features of the encephalopathy that occurs in uremic patients include an impairment of external awareness that ranges from a mild confusional state, with diminished attention and concentration, to coma. The presence of coma may indicate severe uremia or reflect a complication 1–3 such as hypertensive encephalopathy, posterior reversible leukoencephalopathy, fluid and electrolyte disturbances, seizures, or sepsis. Other causes of an encephalopathy in uremic patients include dialysis, thiamine deficiency, drug toxicity, and transplant rejection. Finally, the encephalopathy and renal impairment may both relate independently to the same underlying systemic illness, such as diabetes or connective tissue diseases. All these factors complicate clinical assessment. In addition to an alteration in external awareness, patients with uremic encephalopathy may have seizures, dysarthria, gait ataxia, asterixis, tremor, and multifocal myoclonus. As with all metabolic encephalopathies, symptoms and signs typically fluctuate in severity over short periods of time, such as over the course of a day or from day to day.

Pathophysiology In early studies, various pathological changes were described in the brain of uremic patients, but these probably did not relate directly to the uremia. Thus, neuronal degeneration and necrosis of the granular cell layer of the cerebellar cortex probably related to preterminal hypoxia, and focal demyelination 4and necrosis to coexisting hypertensive cerebrovascular disease that led to small infarcts. Glycolysis and energy utilization are reduced in the brain, probably as a consequence of a disturbance of synaptic transmission that leads to decreased 4 neuronal interaction and thus to reduced cerebral oxygen consumption. Uremic encephalopathy almost certainly relates to a variety of metabolic abnormalities, with the accumulation of numerous metabolites, imbalance in excitatory and inhibitory neurotransmitters, and hormonal disturbances leading to cerebral dysfunction. The European Uremic Toxin Work Group has listed 90 compounds considered to be uremic toxins; 68 have a molecular weight less than 5,6 500 Da, 12 exceed 12,000 Da, and 10 have a molecular weight between 500 and 12,000 Da. A few merit brief discussion here. Retention of urea occurs; urea clearance, even in well-dialyzed patients, amounts to only one sixth of physiological 6 clearance. Accumulation of guanidinosuccinic acid, methylguanidine, guanidine, and creatinine, all of which are guanidine compounds, in the serum and cerebrospinal fluid (CSF) 7–9 of uremic patients, may play a role in causing uremic seizures and cognitive dysfunction. Activation of N-methyl-d-aspartate (NMDA) receptors and inhibition of γ-aminobutyric acid-A 7 (GABAA) transmission may be involved, on the basis of studies in animals. Guanidinosuccinic acid may inhibit transketolase, a thiamine-dependent enzyme involved in 8,9 the pentose phosphate pathway and in the maintenance of myelin. It remains unclear whether 10 low-level aluminum overload in renal failure causes gradual deterioration in cerebral + + triphosphatase function. Abnormalities of the membrane pumps for both Na ,K –adenosine 11,12 and may be of and calcium ions have been described in experimental studies in animals clinical relevance. Hormonal changes may also be important in the pathogenesis of uremic encephalopathy. Serum concentrations of parathyroid hormone, growth hormone,13prolactin, luteinizing hormone, insulin, and glucagon are elevated in uremic patients. Parathyroid hormone levels increase with the severity of the encephalopathy, and alterations in brain calcium could influence neurotransmitter release, the sodium-potassium pump, intracellular enzyme activity, and intracellular metabolic processes, and thereby may affect cerebral function. Experimental studies show that the calcium content of the cerebral cortex is greatly increased in uremia, and this is unrelated to alterations in calcium concentration in the plasma16or cerebrospinal 14,15 Both clinical and electroencephalographic (EEG) abnormalities, and changes in fluid.

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cerebral calcium concentration,


are improved by parathyroidectomy.

In contrast to the process in subjects with normal kidneys, the removal of uremic toxins in dialysis is achieved by a one-step, membrane-based process and is intermittent. The resulting stepwise variation in plasma concentrations of uremic toxins contrasts with the 6 continuous function of normal kidneys.

Clinical Features The clinical features of uremic encephalopathy do not show a good correlation with any single laboratory15abnormality but can sometimes be related to the rate at which renal failure develops. Thus, stupor and coma are relatively common in acute renal failure, whereas symptoms may be less conspicuous and progression more insidious despite more marked laboratory abnormalities in chronic renal failure. Dialysis relieves or prevents some of the more severe features of this encephalopathy. The most reliable early indicators of uremic encephalopathy are a waxing and waning 2 reduction in alertness and impaired external awareness. The ability to concentrate is impaired, so that patients seem preoccupied and apathetic, with a poor attention span; they become increasingly disorientated with regard to place and time and may exhibit emotional lability and sleep inversion. An impairment of higher cognitive abilities, such as of executive function, becomes evident, and patients become increasingly forgetful and apathetic. With progression, patients become more obtunded so that it may then be necessary to shout or gently shake them to engage their attention and elicit any responses, which are likely to be of variable accuracy and relevance. Delusions, illusions, and hallucinations (typically visual) often develop, and patients may become agitated and excited, with an acute delirium that eventually is replaced by stupor and a preterminal coma. Tremulousness may be conspicuous and usually occurs before asterixis is found. A coarse postural tremor is seen in the fingers of the outstretched hands, and a kinetic tremor is also common. Asterixis is a nonspecific sign of metabolic cerebral dysfunction. An intermittent loss of postural tone produces the so-called flapping tremor of asterixis after several seconds when the upper limbs are held outstretched with the elbows and wrists hyperextended and fingers spread apart; irregular flexion-extension occurs at the wrist and of the fingers at the metacarpophalangeal joints, with flexion being the more rapid phase. There is complete electrical silence in the wrist flexors and extensors during the downward (flexor) movements, followed by electrical activity in the extensors as they restore the limb's posture. The axial structures, including the trunk or neck, may also be affected. Asterixis can also be demonstrated in the lower limbs, and flapping may even be elicited in the face by forceful eyelid closure, strong retraction of the corners of the mouth, pursing of the lips,4 or protrusion of the tongue, provided that some degree of voluntary muscle control persists. In obtunded or comatose patients, or others in whom voluntary effort is limited, asterixis can still be 7 elicited, but at the hip joints. With the patient lying supine, the examiner grasps both ankles of the supine patient and moves the feet upward toward the patient's body, flexing and abducting the thighs: irregular abduction–adduction movements at the hips indicate asterixis. Spontaneous and stimulus-sensitive myoclonus is common in uremia and in other metabolic encephalopathies and reflects increased cerebral excitability. The myoclonus is typically multifocal, irregular, and asymmetric; it may be precipitated by voluntary movement (action myoclonus). The myoclonic jerks may be especially conspicuous in the facial and proximal limb muscles. Uremic myoclonus in humans resembles the reticular reflex form of postanoxic 17 action myoclonus. It is usually not associated with EEG spike discharges, although such discharges have sometimes been encountered with the myoclonus. The myoclonus may respond to clonazepam. Multifocal myoclonus is sometimes so intense that muscles appear 4 to be fasciculating (uremic twitching). Tetany may occur. Seizures are common. They are usually generalized convulsions, may be multiple, and are often multifactorial in etiology. In acute renal failure, convulsions commonly occur several days after onset, during the anuric or oliguric phase. In chronic renal failure, they tend to occur with advanced disease, often developing preterminally; they may relate to the uremia itself or to electrolyte disturbances, medications (such as penicillin, aminophylline, or isoniazid), or an associated reversible posterior leukoencephalopathy syndrome (characterized by vasogenic white-matter edema predominantly localized to the posterior cerebral hemispheres on imaging studies, as shown in Figure 18-1). Their incidence has declined, perhaps because of more effective treatment of renal failure and its complications. Seizures also occur in patients undergoing hemodialysis in the dialysis dysequilibrium syndrome (discussed on p. 335). Focal seizures sometimes occur. Occasional patients develop nonconvulsive status epilepticus that may not be recognized unless an EEG is

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18,19

obtained.

FIGURE 18-1 Imaging findings of a patient with seizures who was diagnosed

with posterior reversible leukoencephalopathy. A, Axial computed tomography (CT) scan demonstrates bilateral low-density involvement of the occipital lobes. B, Axial T2-weighted magnetic resonance imaging (MRI) shows high signal intensity lesions without mass effect involving white matter bilaterally in the occipital lobes. (Courtesy of William P. Dillon, MD, University of California, San Francisco.)

FIGURE 18-2 Electroencephalogram (EEG) showing a diffusely slowed

background with triphasic waves in a patient with uremic encephalopathy. During the early stages of uremia, patients may be clumsy or have an unsteady gait. Paratonia (gegenhalten) a variable, velocity-dependent resistance to passive movement, especially rapid movement, is common, and grasp and palmomental reflexes may be present, presumably as a result of a depression of frontal lobe function. As uremia advances, extensor muscle tone increases and may be asymmetric; opisthotonos or decorticate posturing of the limbs may eventually occur. Motor deficits may include transient or alternating hemiparesis that shifts sides during the course of the illness, flaccid quadriparesis related to hyperkalemia, or distal weakness from uremic neuropathy. The tendon reflexes are generally brisk unless a significant peripheral neuropathy is present and may be asymmetric; Babinski signs are often present. Encephalopathy may occur in uremic patients for reasons other than uremia, such as in relation to dialysis, thiamine deficiency, electrolyte imbalance, medication-related toxicity, and graft rejection. These disorders are considered in later sections of this chapter.

Investigations Laboratory studies provide evidence of impaired renal function but are of limited utility in monitoring the course of the encephalopathy. Furthermore, abnormal renal function tests do not exclude other causes of encephalopathy. An underlying structural lesion must be excluded in uremic patients who have had seizures, especially when focal or multiple

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seizures have occurred. The CSF is commonly abnormal, with a pleocytosis that is unrelated to the degree of azotemia and an increased protein4 content that sometimes exceeds 100 mg/dl. In the older literature, summarized by Raskin, up to 30 percent of uremic patients were found to have neck stiffness and Kernig's sign, and in this context the finding of abnormal CSF may lead to the erroneous conclusion that the patient has a meningitic or encephalitic illness. The EEG is diffusely slowed, with an excess of intermittent or continuous theta and delta waves that may show a frontal emphasis, perhaps reflecting a decreased cerebral metabolic rate. Triphasic waves are often present, with an anterior predominance (Fig. 18-2). Bilateral spike-wave complexes may be present either in the resting EEG or with photic stimulation, as in 14 percent of the patients on a chronic hemodialysis program reported by Hughes, none of 20 whom had experienced a seizure. The EEG becomes increasingly slowed with progression of the encephalopathy, so that delta activity becomes more continuous; the findings correlate best with the level of retained nitrogenous compounds, although no clear relationship exists between the EEG and a specific laboratory abnormality. Similarly, there are delays of visual, 21 reveal auditory, and somatosensory evoked cerebral potentials. Event-related potentials 13 abnormalities even in asymptomatic patients, with an increase in P3 latency. In a study involving transcranial magnetic stimulation, 36 patients with end-stage renal disease were 21 evaluated at different stages of the disease and under different treatment. Patients on conservative treatment showed a significant reduction of short-interval intracortical inhibition that could be reversed by hemodialysis, peritoneal dialysis, or renal transplantation. After hemodialysis, intracortical facilitation increased, and this was inversely correlated with the decline in plasma osmolarity induced by the dialytic procedure. In other words, patients showed alterations in cortical excitability that were reversed by treatment of the renal disease. Cerebral imaging studies are of limited help except in excluding other, structural causes for the encephalopathy. They may reveal a reversible, predominantly posterior 2,3 leukoencephalopathy, with subcortical edema without infarction. There may be multiple areas of symmetric edema in the basal ganglia,1brainstem, or cerebellum, with—in severe cases—focal infarcts, sometimes hemorrhagic.

Treatment of Uremic Convulsions Treatment involves correction of renal failure and related metabolic abnormalities. In patients who have had seizures, anticonvulsant medication may be required, especially when the convulsions are of uncertain cause. If status epilepticus occurs, it is managed as in other circumstances. Various considerations make anticonvulsant therapy difficult to manage in uremia. As 22 discussed in Chapter 58 and also reviewed elsewhere, plasma protein binding and renal excretion are reduced, and dialysis may remove drugs from the circulation. Phenytoin is often used in this context: reduced protein binding leads to a greater volume of distribution and lower serum concentrations, but the proportion of unbound (active) phenytoin increases and maintains the benefit of a given dose. Free phenytoin rather than total plasma levels are used to monitor treatment; the optimal therapeutic range is 1 to 2 μg/ml. The total daily dose generally need not be changed, but it is probably best taken divided rather than in a single 23 24 dose. Dialysis does not remove phenytoin from the circulation to any significant extent. Valproic 23 acid is helpful for treating myoclonic seizures and generalized convulsions in uremic 24 patients. Protein binding decreases, but the free fraction remains constant. Dialysis does not necessitate additional doses. Plasma phenobarbital levels are unaffected by renal insufficiency. Lower doses of phenobarbital are used for long-term maintenance therapy, however, because the drug may 23,24 24 ; additional doses may be required after dialysis. Primidone and its accumulate 23 metabolites may also accumulate, causing toxicity in uremic patients. Serum 24 carbamazepine levels are unchanged, and dosing does not need alteration. Impaired renal function leads to decreased clearance of felbamate, gabapentin, topiramate, levetiracetam, vigabatrin, pregabalin, and oxcarbazepine. Gabapentin, pregabalin, and topiramate are 25–27 and the daily dose will need to be reduced in uremic excreted mainly by the kidneys, 28 Hemodialysis necessitates patients; dosing of zonisamide may also need reduction. 29 additional doses of levetiracetam (typically 250 to 500 mg) and gabapentin (200 to 300 mg); 27 26 supplemental doses of topiramate and pregabalin after hemodialysis may also be required. Extra doses of zonisamide may not be necessary if this drug is given in a single 30 show little daily dose after dialysis sessions. Tiagabine and lamotrigine pharmacokinetics31,32 change even in severe uremia, and dosage adjustment is usually unnecessary.

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UREMIC NEUROPATHY

Polyneuropathy Peripheral nerve function becomes impaired at glomerular filtration rates of less than 12 13 ml/min, with clinical deficits developing at rates of about 6 ml/min. More than 50 percent of patients with end-stage renal disease have clinical (neuropathic symptoms or signs) or electrophysiological abnormalities, the exact number depending on the series and diagnostic criteria utilized. Pathophysiology Because uremic neuropathy improves with dialysis, uremic neuropathy has been attributed to the accumulation of dialyzable metabolites. Hemodialysis regimes sufficient to control urea or creatinine may neverthe-less fail to prevent the development of neuropathy, and this observation led to the “middle molecule” hypothesis. In particular, the lower prevalence of neuropathy in patients on peritoneal dialysis than on hemodialysis suggested that the responsible substance was better dialyzed by the peritoneum, and it was proposed that these substances might be in the middle-molecule range (500 to 12,000 Da), which is poorly cleared by hemodialysis membranes. The adoption of dialysis strategies4,33 to improve the Babb and clearance of middle molecules reduced the rates of severe neuropathy. colleagues have reviewed the data both supporting and conflicting with the middle molecule hypothesis; the preponderance of evidence supports the hypothesis, although convincing 34 studies are lacking. The identity of the responsible neurotoxin has remained elusive. Some evidence exists for the neurotoxicity of parathyroid hormone, as was discussed earlier. Parathyroid hormone prolongs motor conduction velocities in dogs perhaps through accumulation of calcium in peripheral nerves; parathyroidectomy of three dogs with chronic renal failure was associated with reversal of the motor conduction abnormalities and calcium content of nerve despite an 35 of parathyroid additional period of renal failure. Studies in uremic patients of the effect 36 and conflicting hormone on peripheral nerves, however, have yielded both supporting 37 results. On the basis of the published literature, Bostock and colleagues have emphasized that for a substance to be accepted as a uremic neurotoxin, it must satisfy certain criteria, namely, (1) it must be an identifiable chemical; (2) its concentration in the blood should be increased in patients with uremia; (3) a direct relationship should exist between its blood level and neurological dysfunction; (4) it should be neurotoxic in animals at appropriate blood levels; (5) its removal from the blood should abolish neurological dysfunction; and (6) dialysis should 38 remove the substance from the body, but more slowly than it removes urea. If these criteria are accepted, the middle molecule hypothesis cannot be accepted at this time because no identifiable chemical with established neurotoxicity has been demonstrated, with a clear relationship between its blood level and neurological dysfunction, except for parathyroid hormone, which is not dialyzable. These authors proposed instead that mild hyperkalemia was responsible. It is known that hyperkalemia typically recurs within a few hours of a dialysis session as a result of re-equilibration between intracellular and extracellular fluid 39 Prolonged hyperkalemia may disrupt 33,38 normal ionic gradients and activate compartments. ++ Ca -mediated processes that are damaging to axons. 40

41

Motor and sensory nerve excitability has been studied in relation to changes in serum levels of potential neurotoxins, including calcium and potassium ions, urea, uric acid, and certain middle molecules. Predialysis measures of nerve excitability were abnormal, consistent with axonal depolarization, and correlated strongly with serum potassium levels, suggesting that hyperkalemic depolarization may underlie the development of uremic neuropathy. The severity of symptoms also correlated with excitability abnormalities. Most 40,41 The findings support the nerve excitability parameters were normalized by hemodialysis. belief that hyperkalemia is primarily responsible for uremic depolarization and probably + + contributes to the development of neuropathy. There is no evidence of significant Na /K 42 pump dysfunction, despite earlier suggestions to the contrary. If hyperkalemia does indeed have a role in mediating these abnormalities, measures of dialysis adequacy based solely on blood urea or creatinine concentrations may be inadequate for determining whether dialysis will prevent neurotoxicity. Monitoring the serum potassium level and ensuring that it is maintained within normal limits between periods of dialysis may be more relevant in this regard.

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Clinical Features Uremic neuropathy is more common in men than women and in adults than children. It is characterized by a length-dependent, symmetric, mixed sensorimotor polyneuropathy of axonal type that resembles other axonal metabolic-toxic neuropathies. Its clinical manifestations, severity, and rate of progression are variable. As with uremic encephalopathy, its severity correlates poorly with biochemical abnormalities in the blood, but neuropathy is more likely to develop in chronic or severe renal failure. Initial symptoms commonly consist of dysesthesias distally in the legs; muscle cramps may also be troublesome. The restless legs syndrome often develops before or with the clinical onset of neuropathy, and its occurrence may therefore indicate incipient peripheral nerve involvement. As with many other neuropathies, the earliest clinical signs are of impaired vibration appreciation and depressed or absent tendon reflexes distally in the legs, indicating involvement of large-diameter myelinated fibers. Progression is typically insidious over many 43,44 Thus, a more months but occasionally is rapid, leading early to severe disability. progressive, predominantly motor subacute neuropathy may occur in uremic patients with diabetes and lead to severe weakness over a few weeks or months; nerve conduction studies 44 but may show demyelination typically demonstrate features of an axonal neuropathy 43 43 to transplantation or to a switch from features, and the neuropathy may respond 44 conventional to high-flux hemodialysis. The course may be arrested at any time despite continuing or worsening renal failure. It is hard to predict the likely clinical course in individual patients. Most patients are left with distal motor and sensory deficits, but some become severely disabled with a flaccid quadriparesis or paraparesis. Severe neuropathy has become less prevalent with the introduction of dialysis and transplantation techniques but remains common. Histopathological examination of nerve biopsy specimens confirms that the neuropathy is a length-dependent axonal degeneration accompanied by secondary demyelination, although in 45 some cases the demyelination seems the predominant finding ; damaged endoneural blood capillaries may also be found and support an ischemic theory as one mechanism in the 46 pathogenesis of uremic neuropathy. Nerve conduction studies also support an axonal process, with reduced conduction velocities and response amplitudes; abnormalities are common even in clinically unaffected nerves. The amplitude of the sensory nerve action potential is affected particularly, especially that of the sural nerve. Large fibers are affected 47 more often than small fibers, but in occasional patients a predominantly small-fiber neuropathy has been reported. Thus, impaired thermal discrimination was the first sign of neuropathy in 15 percent of one series of 64 nondiabetic uremic patients, indicating that a 48 small-fiber uremic neuropathy may exist as a separate entity. The findings on nerve 49 conduction studies may 50 improve after effective treatment51of the underlying renal failure, sometimes very rapidly, but this is not always the case ; sensory nerve conduction velocities in the median, ulnar, and sural nerves may be the most sensitive 52 electrophysiological indices of the beneficial effect of hemodialysis. Needle electromyography (EMG) may reveal evidence of denervation, particularly in the distal muscles of the legs. Abnormalities of late responses (F waves and H reflexes) are frequent and may be helpful early in the53,54 course of renal failure, when standard nerve conduction study results are sometimes normal. Laaksonen and colleagues examined the clinical severity of uremic neuropathy in 21 patients, using a modified version of the neuropathy symptom score combined with results of 55 electrophysiological studies. They found that 81 percent of uremic patients were diagnosed with neuropathy: the neuropathy was asymptomatic in 19 percent, associated with nondisabling symptoms in 48 percent, and accompanied by disabling symptoms in 14 percent. Patients with the restless legs syndrome develop an irresistible urge to move the legs that is worse at night and during periods of inactivity. They complain of curious sensations—often described as creeping, crawling, prickling, or itchy feelings—in the lower limbs, and these tend to be worse in the evening or when the limbs are not in motion. Such sensations are experienced most commonly in the legs but occasionally occur in the thighs or feet; the upper limbs are also sometimes involved. Low hemoglobin levels, high serum phosphorus levels, high anxiety levels, and a great degree of emotion-oriented coping seem to be related to the 56 presence of restless legs syndrome in uremic patients undergoing hemodialysis. Treatment of restless legs syndrome is with clonazepam,57dopamine agonists, levodopa, or opioids (propoxyphene or codeine) taken at bedtime. In addition, coexisting anemia and hyperphosphatemia should be corrected.58,59 Successful renal transplantation may ameliorate or eliminate symptoms within a few weeks.

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Treatment Uremic polyneuropathy may stabilize or even show some improvement with dialysis, but mild 51,60,61 Renal progression is not uncommon and recovery of severe neuropathy is unlikely. 62 transplantation improves uremic neuropathy, sometimes very rapidly and with a negative correlation between electrophysiological change and serum creatinine and myoinositol50 concentrations, suggesting that metabolic factors may underlie the rapid improvement ; in other instances, improvement is more gradual over a number of months, is characterized electrophysiologically by improvement in motor and sensory conduction velocities, and is often incomplete, perhaps because the main reason for improvement is segmental 49 remyelination, with some fibers remaining degenerate in severe neuropathies.

Autonomic Neuropathy Uremic patients may develop postural hypotension, impaired sweating, impotence, gastrointestinal disturbances, and other dysautonomic symptoms, which progress in some 63 with patients—but not all —despite continuing hemodialysis. The dysautonomia correlates 64 the presence or severity of peripheral neuropathy in many but not all patients and may be corrected by renal transplantation. The mechanism underlying the development of uremic 65 autonomic neuropathy is unknown. In patients with diabetic renal failure, dysautonomia may relate also to the diabetes. Studies of both cardiovagal and sympathetic function (discussed 63,64,66–70 that may be in Chapter 8) have revealed objective evidence of dysautonomia sub-clinical. Intradialytic hypotension is a frequent67,69 complication of hemodialysis and has been shown to regardless of whether a peripheral neuropathy is relate to67impaired autonomic function present ; however, there is no agreement on this point, and some investigators have found that hypotension-prone patients are not distinguished by impaired predialytic or intradialytic 71 Midodrine may have a role in the therapy of patients with control of the blood pressure. 72 intradialytic hypotension. 73,74

Dialysis may not benefit autonomic neuropathy. However, Vita and colleagues found that when patients were switched from acetate to bicarbonate dialysis, all the patients in a small 75 After renal transplantation, series eventually showed a reversal of autonomic damage. 65,73 but at a variable rate. autonomic function may improve or normalize OPTIC NEUROPATHY A progressive optic neuropathy may occur over several days; visual loss is accompanied by reduced pupillary response to light and by papillitis. Prompt hemodialysis and corticosteroid 76 therapy may restore vision in some patients. The optic neuropathy may be neurotoxic, ischemic, related to side effects of medication or intracranial hypertension, or inflammatory in 77 nature. In ischemic optic neuropathy, coexisting hypotension and anemia may be important risk factors, and treatment may require78intravenous saline or blood transfusions in addition to the other measures mentioned earlier. Calcific uremic arteriolopathy may also have an 79 etiological role. NEUROLOGICAL COMPLICATIONS OF DIALYSIS Dialysis has been associated with subtle cognitive alterations, possibly reflecting an early 80 manifestation of dialysis dementia at a reversible stage. More commonly, psychological studies have shown significant improvement in short-term memory both after onset of maintenance dialysis and when comparisons are made between the day before and after an individual dialysis treatment session; attentional functions also seem to improve after dialysis 81 as well. Subdural hematoma (Fig. 18-3) may occur in patients on maintenance 82 hemodialysis and its symptoms attributed to dysequilibrium syndrome or dialysis dementia. Its occurrence may relate to anticoagulation used to maintain the patency of the conduit for hemodialysis; platelet function may be impaired in uremia but, in itself, is unlikely to be responsible. A rare case of manganese-induced parkinsonism has been described in a patient on maintenance hemodialysis and was attributed to long-term ingestion of a health supplement; the clinical, laboratory, and magnetic resonance imaging (MRI) findings were 83 abnormal, but the patient improved on edetic acidinfusion therapy. These complications will receive no further discussion here.

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FIGURE 18-3 Axial noncontrast CT scan shows a mixed-density left subdural

hematoma producing marked mass effect on the left hemisphere and midline shift. The low density within the subdural hematoma is a feature of active hemorrhage. (Courtesy of William P. Dillon, MD, University of California, San Francisco.) Muscle cramps are common, tending to occur toward the end of a dialysis session: their etiology is uncertain, but plasma volume contraction and hyponatremia are among the factors that have been incriminated. Headache, nausea, and vomiting may also occur during dialysis, sometimes as the initial manifestations of the dysequilibrium syndrome (discussed later). The risk of cerebrovascular disease is increased in patients undergoing dialysis and seems related to accelerated cerebrovascular disease and the high incidence of malnutrition, 84,85 Presentation may be hypertension, diabetes, and hyperlipidemia among these patients. with hypertensive encephalopathy, transient ischemic attacks, or occlusive or hemorrhagic 86 stroke. Infarcts may show a predilection for the vertebrobasilar arterial territory. The osmotic demyelination syndrome may occur after hemodialysis, leading clinically to convulsions, an alteration in the level of consciousness, and quadriparesis with hyperactive tendon reflexes and bilateral Babinski87responses. MRI shows findings of demyelination in pontine and often extrapontine regions. The effects of dialysis on uremic encephalopathy and neuropathy have already been discussed, but dialysis may cause other neurological disturbances that merit comment.

Entrapment Mononeuropathies Carpal Tunnel Syndrome It was originally believed that carpal tunnel syndrome occurred because of increased venous pressure in the distal limb when an arteriovenous shunt had been placed for hemodialysis, the increased extravascular volume within the carpal tunnel or steal being held responsible for the median nerve compression. Recent studies support an etiological role for arteriovenous fistulas. Thus, in one study, carpal tunnel syndrome was diagnosed significantly less frequently in the contralateral wrist than that ipsilateral to the arterio-venous fistula, and a positive correlation was found between the duration of the fistula and development of carpal tunnel syndrome; in contrast to such clinical assessment, however,

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electrodiagnostic studies indicate no significant association between the frequency of carpal 88 tunnel syndrome and arteriovenous fistula or its duration. The occurrence of β2-microglobulin amyloidosis is probably more important etiologically in 89–91 Amyloid fibrils have been this context, particularly in patients on long-term hemodialysis. isolated from amyloid-laden tissues inside the carpal tunnel and the protein identified as 90 β2-microglobulin. Circulating β2-microglobulin presumably cannot be removed by conventional hemo dialysis and accumulates in tissues; the consequent formation of amyloid fibrils appears to have a 90 relatively high affinity for the region of the carpal tunnel, leading to carpal tunnel syndrome. A significant increase in carpal tunnel width and thickness in the palmoradiocarpal ligament, correlating with duration of long-term hemodialysis, has been 92 reported based on ultrasound examination of the wrists of hemodialysis patients. The prevalence of carpal tunnel syndrome and the severity of symptoms have been improved by 93 maneuvers to reduce the levels of β2-microglobulin. Uremic tumoral calcinosis may also be 94,95 responsible in some instances. Treatment is as in other patients, with decompressive surgery if symptoms fail to respond to conservative measures. Ulnar Nerve Lesions A high prevalence (between 41% and 60%) of ulnar neuropathy in patients has recently been 96 reported in patients receiving hemodialysis for end-stage renal disease. This may relate to arm positioning during hemodialysis, underlying polyneuropathy, upper-extremity vascular 96,97 access, and uremic tumoral calcinosis.

Ischemic Neuropathy A shunt for access during chronic hemodialysis and inserted between the radial artery and cephalic vein in the upper arm was reported by Bolton and colleagues to have caused a distal, ischemic neuropathy in two patients; electrophysiological evidence was present of axonal degeneration of sensory fibers with mild ischemia, and of both motor and sensory 98 nerve fibers with more severe ischemia. This has been attributed to shunting of arterial blood away from the limb distally, with the nerves being selectively affected because of their greater vulnerability to ischemia. Other cases of this so-called ischemic monomelic 99 neuropathy have since been reported, and the disorder is particularly 100 likely in diabetics with renal failure and preexisting peripheral vascular disease or neuropathy. Multiple upper-limb mononeuropathies98–101 develop, leading to burning pain and to sensory and motor deficits in the Motor conduction block may be detected electrophysiologically forearm and hand. shortly after the onset of symptoms, preferentially involving the median nerve, with clinical 102 and electrophysiological improvement following ligation or revision of the shunt. In some instances, more widespread signs of upper-extremity ischemia may be found distal to the 103 fistula, such as established or impending tissue loss or nonhealing wounds.

Dialysis Dysequilibrium Syndrome Several neurological disturbances may arise during or after hemodialysis or peritoneal dialysis, including headache, nausea, anorexia, muscle cramps, irritability, restlessness, agitation, confusion, coma, and seizures; increased intracranial pressure may lead to papilledema. Such symptoms tend to occur at the beginning of a dialysis program and were particularly conspicuous in the past when patients with advanced uremia were dialyzed aggressively; patients now enter dialysis programs at an earlier stage of renal failure and have shortened dialysis times, and this may account for the reduced incidence of the disorder, which seems more common in children and the elderly than in other age groups. Marked104 metabolic acidosis and the presence of other CNS disease may also be predisposing factors. Symptoms typically appear toward the end of a dialysis session, sometimes 8 to 24 hours later, and subside over several hours. When an agitated confusional state develops, it may persist for several days. Many patients manifest exophthalmos and increased intraocular pressure at the height of the syndrome, which may be helpful clinically for diagnostic 4 purposes. Headache is the most common symptom reported by patients undergoing dialysis, and migrainous episodes may be precipitated during or after hemodialysis in patients with preexisting migraine. Headache is otherwise usually diffuse and throbbing in quality. Subdural hematoma sometimes mimics the dysequilibrium syndrome and requires 82 exclusion.

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Movement of water into the brain leads to cerebral edema. According to the hypothesis known as the reverse urea effect, a rapid reduction in blood urea level lowers the plasma osmolality, thereby producing an osmotic gradient between blood and brain. Although urea is able to permeate cell membranes, this may take several hours to reach completion; accordingly, there is not enough time for urea equilibration when the blood urea level is reduced rapidly by hemodialysis. There is thus an influx of water into the cells. This results in increased intracranial pressure and cerebral edema. Alternatively or additionally, the osmotic gradient between brain and blood may not reflect simply the movement of urea; unidentified osmotically active substances (“idiogenic osmoles”) are present in the brain of 105 dialyzed uremic animals (but not dialyzed nonuremic animals) and may be responsible. It has been suggested that a decrease in cerebral intracellular pH, reflecting an 104 increased production of organic acids that are osmotically active, is important in this regard. A number of other disorders, such as uremic encephalopathy, intracranial infection or hemorrhage, cerebral infarction, hyponatremia, hypoglycemia, and medication-related encephalopathy must be excluded before the diagnosis is made with confidence. Prophylactic measures involve the gradual reduction in blood urea level by attention to the hemodialysis technique. In patients with established dialysis dysequilibrium syndrome, mild symptoms usually clear spontaneously over several hours, and symptomatic and supportive measures are all that are required; however, it may be necessary to slow or discontinue the dialysis session. Dialysis is stopped in patients with seizures or an altered level of conscious-ness and, if necessary, the plasma osmolality can be raised with either hypertonic saline or mannitol. Management is otherwise supportive, and improvement can be expected over the following day.

Wernicke's Encephalopathy Thiamine is a water-soluble vitamin that passes through dialysis membranes. However, 106,107 and no dialysis does not remove more thiamine than is normally excreted in the urine, consistent change occurs after hemodialysis in plasma levels of the B vitamins. Wernicke's encephalopathy has occurred in patients on chronic dialysis but is relatively infrequent. It has been related to anorexia, vomiting, a diet low in thiamine-containing foods, and intravenous alimentation without thiamine supplementation; other potential causes in uremia are infections that may stress thiamine reserves and the use of repeated infusions of glucose, 107 insulin, and bicarbonate to lower the serum potassium level. Among five patients undergoing dialysis in whom Wernicke's encephalopathy developed in the absence of alcoholism or other precipitating factors and was diagnosed at autopsy, 107 triad of ophthalmoplegia was evident in only one instance, but in other instances the full108 ophthalmoplegia, ataxia, 109 and an altered level of consciousness were encountered. Hypothermia is common. Intravenous administration of thiamine reverses the clinical deficit. Given the reversible nature of the disorder, it is important to consider it in all patients on hemodialysis who exhibit at least one of its classic features; dialysis dysequilibrium syndrome, dialysis dementia, and uremic encephalopathy have each been diagnosed 108 erroneously in patients who were subsequently found to have Wernicke's encephalopathy. Indeed, in one series of 30 consecutive patients on regular hemodialysis or peritoneal dialysis who were admitted with an alteration in mental status, 10 had an unexplained encephalopathy after initial evaluation and were eventually 110 found to have thiamine deficiency; nine responded to thiamine supplementation and one died.

Dialysis Dementia Clinical Aspects There has been a decline in the incidence of this progressive encephalopathy, which may occur in patients undergoing long-term dialysis. The first symptom is often a stammering hesitancy of speech that eventually progresses to speech arrest, dysarthria, and expressive aphasia. The speech disorder is intensified during and immediately after dialysis and initially may occur only at these times. Other manifestations such as tremor, myoclonus, asterixis, seizures, and dementia become apparent as the disorder advances, and hallucinations and delusional thinking round out the clinical picture. Focal neurological abnormalities are found occasionally. Symptoms initially occur immediately after dialysis and then clear, but eventually they fail to resolve and the patient becomes increasingly demented.111The EEG shows abnormal bursts of high-voltage slow activity and spikes anteriorly. The CSF is normal. The differential diagnosis includes other causes of dementia, but metabolic encephalopathy and 82 structural lesions such as subdural hematoma, normal-pressure hydrocephalus, hypertensive encephalopathy, multi-infarct dementia, and stroke require exclusion.

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Pathogenesis A clustering of cases in areas with aluminum-contaminated water was noted originally, and water-purification measures have led to a substantial reduction in the incidence of the disorder. The disorder results from accumulation of aluminum in the brain and is now rarely 112 encountered because 113 of elimination of aluminum in the dialysate. Phosphate retention occurs in renal failure, leading eventually to hyperparathyroidism, and reduction of the serum phosphate concentration with phosphate binders is therefore important. The substitution of phosphate binders such as calcium carbonate and calcium acetate, and of nonmineral-containing phosphate binders, for oral aluminum-containing114phosphate binders has also been important in reducing the aluminum content in the brain. Although parathyroid hormone increases aluminum absorption from the gut, parathyroidectomy has not 4 affected the course of dialysis dementia. The toxicity of aluminum may involve disruption of the inositol phosphate system and115 calcium regulation, facilitation of oxidative injury, and disruption of basic cell processes. Postmortem immunochemical analysis of frontal cortex of 15 dialysis patients treated with aluminum showed changes in tau protein processing in the brain resembling those seen in Alzheimer's disease, although none had signs of dialysis 116 dementia. Treatment Diazepam is initially helpful in treating the myoclonus and seizures and in improving speech, but it is less effective later. Increased dialysis time and renal transplantation have not altered 4 the natural history. In untreated patients, death usually occurs within a year of the onset of symptoms. The chelator deferoxamine can remove excess aluminum and thereby reverse acute encephalopathy, as well as the osteomalacia and anemia that may also be associated with aluminum overload. However, its introduction was associated with visual and auditory toxicity and with increased neurological and other side effects from acute aluminum toxicity (presumably because of the rapid mobilization of stored aluminum) in occasional patients; some patients developed a rapidly progressive and fatal systemic or rhinocerebral 117 mucormycosis. Experimental studies in animals suggest that deferoxamine enhances the pathogenicity 118,119 of the responsible organism and reduces the effectiveness of treatment with Nevertheless it is the mainstay of treatment for established dialysis amphotericin. dementia. Several protocols for the administration of deferoxamine have been proposed, and the 120 National Kidney Foundation has published guidelines. A baseline serum aluminum level is determined: normal levels are 6 ± 3 μg/L, but excess aluminum deposition is unlikely when values are less than 20 μg/L. If baseline levels are increased, a low-dose deferoxamine test is performed by administering 5 mg/kg 1 hour before the end of dialysis if aluminum overload (serum aluminum levels of 60 to 200 μg/L) is present or toxicity is suspected clinically. Deferoxamine can be given to symptomatic patients in a single dose of 1 to 6 g (30 to 40 mg/kg) once weekly in the last hour of a dialysis session; however, to avoid the risk of deferoxamine neurotoxicity, it is not given to patients with very high plasma aluminum levels (exceeding 120 μg/L) until the level is first lowered by withdrawal of aluminum exposure. When serum aluminum levels exceed 200 μg/L, daily hemodialysis using high-flux membranes and a low dialysate aluminum concentration, and withdrawal of all aluminum-containing oral agents, is necessary; a low-dose deferoxamine test (5 mg/kg) is given after 4 to 6 weeks of such treatment to determine the timing of further treatment. 120 The length of treatment required is uncertain, but it Further details are given elsewhere. 4 Many cases of dialysis dementia have been stabilized or may need to be for many months. 121,122 The need for treatment is unclear in patients with an improved by deferoxamine. asymptomatic increase in aluminum levels. COMPLICATIONS OF TRANSPLANTATION Various neurological complications are caused by the neurotoxicity of immunosuppressive agents, as discussed in Chapter 46. When acute rejection encephalopathy occurs, patients experience headache, confusion, and seizures, sometimes accompanied by papilledema, increased CSF pressure, and computed tomography (CT) evidence of diffuse cerebral edema. The EEG is diffusely slowed and may show focal features. Treatment of the rejection episode leads to improvement.

Femoral and Related Neuropathy Femoral neuropathy is a common complication of renal transplantation in the iliac fossa, 123 occurring ipsilateral to the transplant surgery with an incidence on the order of 2 percent.

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Nerve compression typically occurs intraoperatively, for example, with prolonged use of retractors. When compression leads to neurapraxia, recovery is likely to be rapid and complete, as in most patients; severe compression or nerve ischemia leads to axonal loss, 124 delayed recovery, and residual deficits. In patients undergoing renal transplantation involving either the internal or external iliac artery, sensory disturbances may be the sole manifestation and are not necessarily confined to the territory of the femoral nerve: in one series of 20 patients in which the internal iliac artery was used, for example, sensory 125 complaints were in the anterior thigh in 15, lateral thigh in 3, and anterolateral thigh in 2, suggestive of involvement of the lateral femoral cutaneous nerve.

Tumors The rates of malignancies among 35,765 first-time recipients of deceased or living donor kidney transplantations between 1995 and 2001 was examined by Kasiske and associates 126 using Medicare billing claims. For common tumors, such as of the colon, lung, prostate, stomach, esophagus, pancreas, ovary, and breast, cancer rates were approximately twice as high after kidney transplantation than in the general population. Melanoma, leukemia, hepatobiliary tumors, cervical, and vulvovaginal tumors were each increased about 5-fold; testicular and bladder cancers about 3-fold; kidney cancer (typically of the native kidney) 15-fold; and Kaposi's sarcoma, non-Hodgkin's lymphomas, and nonmelanoma skin cancers more than 20-fold. Thus, cancer screening and attention to prophylactic measures are important after kidney transplantation. The development of such neoplasms may involve the nervous system directly by metastatic spread, may lead to a paraneoplastic syndrome, or may produce secondary neurological abnormalities as a consequence of treatment (Chapters 27 and 28).

Brain Tumors Non-Hodgkin's lymphoma constitutes more than 90 percent of lymphomas in transplant 127 recipients. Most of these lymphomas are of the B-cell type and follow B-cell proliferation related to infection with Epstein–Barr virus in patients who are chronically immunosuppressed. Extranodal involvement after organ transplantation occurs commonly 128 and—in almost one quarter of patients —involves the CNS (Fig. 18-4). Involvement of the transplanted kidney may also occur, causing renal failure. The degree of 129 immunosuppression, age (greater in those younger than 25 years), time since transplant (greater in the first year), race (greater in Caucasians than in African Americans), and130 serological status regarding Epstein–Barr virus infection influence the risk of disease. The development of mental status changes or new neurological abnormalities should raise concern about the possibility of CNS involvement. Imaging studies (CT or MRI) of the head, CSF analysis for Epstein–Barr virus and cytological examination for malignant cells, and brain biopsy generally lead to the diagnosis. In one autopsy study of 10 patients, all had tumor infiltration in CNS regions that were normal on imaging studies, indicating that MRI may 131 underestimate the extent of the tumor. Bulky disease is seen as a contrast-enhancing lesion because of disruption of the blood–brain barrier, but microscopic tumor infiltration may 131 cause T2 hyperintensity or show no imaging abnormality.

FIGURE 18-4 A, Axial post-contrast T1-weighted MRI demonstrates an

enhancing mass located in the right lateral recess of the fourth ventricle. B, Coronal post-contrast T1-weighted image shows an enhancing subependymal

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mass involving the left lateral ventricle. The findings are most consistent with CSF spread of lymphoma. (Courtesy of William P. Dillon, MD, University of California, San Francisco.) The use of corticosteroids, which alter the imaging and histopathological findings, may confound interpretation. Since the advent of modern chemotherapeutic regimens, the natural history seems to have changed in that systemic metastases outside the CNS are uncommon, 127 and some patients may survive for much longer than in the past. 132

The incidence of primary CNS lymphoma is increasing, especially among the elderly. The tumor is located supratentorially in more than two thirds of instances and typically is periventricular and involves deep subcortical structures such as the basal ganglia and corpus callosum (Fig. 18-5); subependymal spread is common. Abnormal lymphocytes may disseminate along CSF pathways and subsequently spread throughout the CNS. The eye may also be involved. As with systemic lymphoma, the high incidence of primary CNS lymphoma in transplant recipients receiving immunosuppressants indicates involvement of the immune system in its pathogenesis and, again, the Epstein–Barr virus may have a role. Presenting symptoms depend on the location of the lesion. Supratentorial lesions may cause headaches (sometimes from increased intracranial pressure or meningeal involvement), personality changes, cognitive abnormalities, blurred vision, or focal motor or other deficits. Convulsions are relatively uncommon. Cranial neuropathies, ataxic syndromes, and other signs of brainstem involvement occur with infratentorial intracranial involvement. Meningeal involvement is relatively common as the disease advances and leads to multifocal disease with cranial and spinal neuropathies, headaches, signs of meningeal irritation, and, occasionally, hydrocephalus. In rare instances of primary spinal involvement, there is weakness, sensory loss, and sphincter dysfunction, depending on the site and extent of the lesion. Spinal lesions are more often intramedullary, whereas in patients with systemic lymphoma diffuse leptomeningeal involvement or extradural nodules are more likely. Recurrence is usually within the brain, but systemic dissemination occurs occasionally and tends to involve extranodal organs, such as kidneys or skin.

FIGURE 18-5 MRI of a patient with biopsy-proven primary lymphoma of the

brain. Axial post-contrast T1-weighted MRI shows an enhancing mass involving the splenium of the corpus callosum as well as two satellite nodules

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within the white matter of the left posterior frontal lobe. (Courtesy of William P. Dillon, MD, University of California, San Francisco.) The CSF usually shows nonspecific findings, but cytology may reveal malignant cells, especially if repeated examinations are performed. The absence of such cells does not exclude the diagnosis. CT usually shows a mass much larger than that suggested by the clinical findings; there are usually isodense, hyperdense, and hypodense areas, with contrast enhancement. On T2-weighted MRI, the mass may appear isointense to hypointense, enhances homogeneously with contrast administration, may be associated with extensive133 edema, is often in contact with the subarachnoid space, and typically is without necrosis. 134 One third of these tumors are multifocal. Tumors may be missed by one imaging modality and detected by the other; both may miss meningeal disease. MRI or myelography detects spinal disease. A definitive diagnosis is made by histopathological examination after stereotactic biopsy. Extensive resection of the tumor is usually not attempted given its deep location and often multifocal nature and because of the high surgical morbidity. Treatment is by radiation therapy plus corticosteroids. The role of chemotherapy is under reexamination, and various regimens have been advocated. Meningeal lymphoma is treated by intrathecal methotrexate. Most patients die within a few weeks to months after diagnosis.

Central Nervous System Infections In renal transplant recipients, the risk of infections (and neoplasia), with135their attendant mortality and morbidity, increases with increasing immunosuppression rather than with the use of a specific immunosuppressive agent. It is important to bear this in mind when the addition of a potent immunosuppressive agent is under consideration for the treatment of acute rejection episodes. The risk of infection is also influenced by environmental exposure, by the presence of indwelling catheters that may serve as a conduit for infection, and by whether peritoneal dialysis rather than hemodialysis was utilized prior to transplantation (as the former is associated with a higher risk of infection). Other factors that bear on the issue are coexisting diseases such as diabetes that render patients more prone to infection, poor nutritional status, metabolic abnormalities such as uremia, and infection with immunomodulating viruses such as Epstein–Barr and human immunodeficiency virus. CNS infections are an important consideration in transplant recipients. When acute meningitis occurs, it is usually caused by Listeria monocytogenes, whereas subacute or chronic meningitis is commonly caused by Cryptococcus neoformans, although systemic infection with M. tuberculosis, L. monocytogenes, H. capsulatum, N. asteroides, and certain 136 other organisms may have a similar presentation. Signs of meningeal irritation may be subtle or absent in patients with meningitis as a consequence of the anti-inflammatory effects 136 of immunosuppressants. Fever, headache, and impairment of consciousness may also be due to CNS lymphoma, which must therefore be distinguished, as described earlier. The presence of unexplained fever and headache in transplant recipients mandates brain imaging by CT scan or MRI and examination of the CSF. Brain abscesses (Fig. 18-6) are well described in transplant recipients and, in most instances, the primary source of infection is the lung. CT of the chest is therefore important, especially when chest radiographs are normal or unhelpful, for diagnostic purposes in differentiating fungal brain abscess from brain tumor in transplant recipients. Aspergillus has a predilection for dissemination to the brain and accounts for most fungal brain abscesses; such fungal infections usually lead to multiple 137 brain abscesses and have a poor prognosis. Abscess may also result from L. monocytogenes, Toxoplasma gondii, or N. asteroides. With Listeria infection, abscesses are 138 also commonly multiple, with a high mortality. The clinical presentation is often with 139 neurological deficits or seizures of abrupt onset or with a worsening confusional state. The CT scan may show poorly circumscribed, low-absorption areas with minimal or no contrast 139,140 MRI shows ring-enhancing lesions with surrounding enhancement and little mass effect. edema; distinction from tumor is sometimes difficult, but diffusion-weighted imaging is helpful in this regard. The CSF may be unrevealing. Brain biopsy is sometimes the only reliable way to establish a diagnosis. Treatment is discussed in later chapters.

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FIGURE 18-6 A, Axial post-contrast T1-weighted image demonstrates a ring-enhancing mass lesion in the right frontal lobe with surrounding vasogenic edema. B, Axial T2-weighted fluid-attenuated inversion recovery (FLAIR) image demonstrates a mass surrounded by a zone of increased signal intensity consistent with vasogenic edema. The mass itself consists of several layers of abnormal signal. Within the center of the mass, a zone of lower signal is seen, surrounded by alternating zones of higher and lower signal. The capsule of the mass shows low signal and is the area that enhances with contrast material (see A). C, Axial diffusion-weighted image. The central portion of the mass shows high signal, consistent with restricted diffusion. The appearance of a ring-enhancing mass containing material with restricted diffusion is most consistent with a cerebral abscess. D, Axial diffusion-weighted image at the level of the lateral ventricles shows abnormal high-signal layering within the right lateral ventricle and in the sulci of the left hemisphere, consistent with both meningeal and intraventricular extension of abscess material. (Courtesy of William P. Dillon, MD, University of California, San Francisco.)

Progressive multifocal leukoencephalopathy (Fig. 18-7) due to JC virus infection has been described in transplant recipients and leads to cognitive changes, seizures, and focal neurological deficits. In one reported case, immunosuppression was discontinued and the patient returned to hemodialysis; his neurological symptoms and imaging abnormalities 141 gradually re-solved completely. Similar clinical deficits may relate to other viral infections, such as herpes simplex or Epstein–Barr virus, or may reflect toxicity of immunosuppressants such as cyclosporine or tacrolimus.

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FIGURE 18-7 A, An immunosuppressed patient with alteration of mental status.

Axial T2-weighted fluid-attenuated inversion recovery MRI demonstrates several discrete areas of T2 prolongation involving the right and left thalamus and the left posterior frontotemporal area. Despite the large size of the lesion, no mass effect is present. B, Axial post-contrast T1-weighted image demonstrates well-circumscribed low-intensity lesions without contrast enhancement. Subsequent brain biopsy confirmed the diagnosis of progressive multifocal leukoencephalopathy. (Courtesy of William P. Dillon, MD, University of California, San Francisco.) West Nile virus infection manifests similarly in transplant recipients as in other patients, but 142 neurological damage tends to be especially severe. HEREDITARY DISORDERS OF THE NERVOUS SYSYEM AND KIDNEYS Various uncommon inherited disorders affect both the kidneys and the nervous system, meriting brief discussion here.

Fabry's Disease Fabry's disease is an X-linked lysosomal storage disease resulting from deficiency of ceramide trihexosidase (αgalactosidase), which catalyzes the hydrolytic cleavage of the terminal galactose from143 globotriaosylceramide. It relates to mutations of the α-galactosidase A (GLA) gene at Xq22. It leads to a small-fiber neuropathy, with severe neuropathic or limb pain and dysautonomic symptoms, accompanied by evidence of other organ involvement from glycosphingolipid accumulation, including in the kidneys. Renal involvement leads to polyuria and polydipsia; progressive renal failure typically develops in adulthood. Kidney function is worse in patients with undetectable α-galactosidase activity compared to those with some residual activity. Cerebrovascular involvement is associated with transient ischemic attacks and strokes: the vertebrobasilar circulation was symptomatic in 67 percent of hemizygotes and 60 percent of the heterozygotes in one meta-analysis, and elongated, ectatic, tortuous vertebral and basilar arteries were the most common angiographic and 144 pathological findings. The MRI may show white matter lesions in affected males and in female carriers. A fatal outcome is common in middle life from uremia or cerebrovascular disease Treatment of neuropathic pain with gabapentin, carbamazepine, or amitriptyline may be helpful. Nonsteroidal anti-inflammatory agents are usually ineffective, and narcotics are best avoided. Treatment with recombinant α-Gal A may provide symptomatic benefit but is 145 not curative.

von Hippel–Lindau Disease In autosomal-dominantly inherited von Hippel–Lindau disease, the responsible gene maps to chromosome 3p25 and is a tumor suppressor gene. Renal cysts and cancers occur in patients with CNS and retinal hemangioblastomas (often bilateral), and sometimes with pancreatic cysts and pheochromocytoma. The CNS hemangioblastomas commonly involve the cerebellar hemispheres and may be asymptomatic; spine and brainstem lesions are also

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well described (Fig. 18-8). A variety of visual complications may occur, mandating the need for regular ophthalmological screening. Monitoring for the development of renal lesions by CT scan and ultrasound, and for CNS lesions by gadolinium-enhanced MRI of the entire neuraxis, also is important. Treatment is surgical or by radiation therapy.

FIGURE 18-8 Sagittal post-contrast T1-weighted image through the cervical

spinal cord and lower cerebellum demonstrating several intensely enhancing pial-based hemangioblastomas (arrows) associated with nonenhancing cysts. (Courtesy of William P. Dillon, MD, University of California, San Francisco.)

Polycystic Kidney Disease At least two different genetic loci for autosomal-dominant polycystic kidney disease have been identified. The renal manifestations of this disorder includehypertension, urinary tract infection, polyuria, hematuria, nephrolithiasis, pain in the flank, and progressive renal failure. Hypertension also may occur in relation to the kidney disease. Intracranial arterial aneurysms, sometimes multiple and unrelated to the occurrence of hypertension, are associated, and rupture may lead to subarachnoid or intracerebral hemorrhage. In a retrospective study of 77 patients from 64 families with ruptured (71 instances) or unruptured (6) aneurysms, mean age at the time of rupture was 39.5 years (range, 15 to 69 years), renal function was normal in half of the patients, and 11 percent were on renal replacement therapy. The ruptured aneurysm was usually located on the middle cerebral artery; in 31 percent of the patients, additional intact aneurysms were found. On long-term follow-up, 27 (38%) were left with severe disability. Five patients bled from another aneurysm 2 days to 14 146 years after initial rupture. Treatment of ruptured aneurysms is as for aneurysmal subarachnoid hemorrhage occurring for other reasons, involving emergency CT scanning, four-vessel angiography, and surgery or endovascular treatment. Screening by MR angiography or high-resolution CT angiography at periodic intervals for the presence of aneurysms is probably worthwhile, at least in high-risk patients, such as those with previous aneurysmal rupture or a positive family history of an intracerebral bleed, but no clear

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guidelines exist for the frequency with which this should be undertaken. The value of widespread screening for intracranial aneurysms in patients with polycystic kidneys has otherwise been questioned because most intracranial aneurysms detected by presymptomatic screening in this population are small, and follow-up studies do not suggest an increased risk for growth and rupture, compared to intracranial aneurysms in the general 147 population. Previous

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Keyword Index

Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 19 Neurological Manifestations of Electrolyte Disturbances JACK E. RIGGS •

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SODIUM Hyponatremia Subarachnoid Hemorrhage and Unselected Intracranial Disease Central Pontine Myelinolysis (Osmotic Myelinolysis) Hypernatremia POTASSIUM Hypokalemia Hyperkalemia CALCIUM Hypercalcemia Hypocalcemia MAGNESIUM Hypomagnesemia Hypermagnesemia

Electrolyte disturbances are common in clinical practice and are associated with a1variety of characteristic central or peripheral (including muscle) neurological manifestations. Since electrolyte disturbances are typically secondary processes, effective management requires identification and treatment of the primary disorder in addition to correction of the electrolyte abnormality. The neurological consequences of electrolyte disorders are usually functional rather than structural. Consequently, the neurological manifestations of electrolyte disturbances are usually reversible, particularly if corrected and effectively managed at an early stage. The neurological manifestations of abnormalities of serum sodium, potassium, calcium, and magnesium are reviewed in this chapter. SODIUM Extracellular fluid volume is directly dependent on total body sodium, the principal osmotic component of that fluid compartment. Consequently, most patients with hyponatremia are hypo-osmolar, and those with hypernatremia are hyperosmolar. The symptomatic neurological manifestations of serum sodium abnormalities typically involve the central, rather than the peripheral, nervous system and reflect, respectively, hypo-osmolarity in hyponatremia and hyperosmolarity in hypernatremia. Because of the brain's ability to adapt to changes in serum osmolarity, the propensity of hyponatremia or hypernatremia to produce

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neurological symptoms generally depends on the rapidity with which the sodium disturbance 1 develops.

Hyponatremia Hyponatremia with normal osmolarity (pseudohyponatremia) occurs, although relatively infrequently, in the setting of hyperlipidemia or hyperproteinemia. Hyponatremia with hyperosmolarity usually occurs in the setting of hyperglycemia. Hyponatremia is most often associated with hypo-osmolarity and is classified into three categories, depending on whether the extracellular fluid volume is decreased, normal, or increased. Hypo-osmolar hyponatremia with hypovolemia results from excessive renal sodium loss (e.g., from diuretic usage, or in association with mineralocorticoid deficiency, salt-losing nephropathy, and osmotic diuresis) or extrarenal sodium loss (e.g., by vomiting, diarrhea, and third-space losses). Hypo-osmolar hyponatremia with normovolemia (no edema) results from conditions such as the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), glucocorticoid deficiency, hypothyroidism, and stress, or in response to various drugs, including carbamazepine and many psychotropic agents. Hypo-osmolar hyponatremia with excess extracellular fluid (edema) occurs in conditions such as cirrhosis, cardiac failure, nephrotic syndrome, and acute or chronic renal failure. The separation of hypo-osmolar hyponatremia into these three categories based on the extracellular fluid volume status has therapeutic implications. In normovolemic and hypervolemic hypo-osmolar hyponatremia, the fundamental principle of therapy is water restriction, whereas in hypovolemic hypo-osmolar hyponatremia the basis of therapy is replacement of water and sodium (generally with 1–3 isotonic saline). Among hospitalized patients, the incidence of hyponatremia is about 1.0 percent and 4,5 increases the risk of death 7 to 60 times that of hospitalized patients without hyponatremia. However, the increased mortality associated with hyponatremia may reflect the seriousness 1 of underlying disorders rather than the hyponatremia per se. Neurological symptoms related to hyponatremia are seen much more frequently in patients 1–3 with acute, rather than chronic, hyponatremia. For example, a serum sodium concentration of 130 mEq/L may produce neurological symptoms if it developed rapidly, whereas a serum sodium concentration of 115 mEq/L may be asymptomatic if it developed slowly. An alteration in mental status is the most common neurological manifestation of hyponatremia and ranges from mild confusion to coma. The encephalopathy is associated with nonspecific generalized slowing on the electroencephalogram (EEG). The occurrence of convulsions in the setting of acute hyponatremia (typically with a serum sodium concentration less than 115 mEq/L) is ominous and portends a mortality rate exceeding 50 percent. The occurrence of seizures in patients with acute hyponatremia represents a medical emergency and necessitates rapid, but only partial, correction of the serum sodium concentration. Control of hyponatremic seizures can obtained by the judicious use of 3 percent saline (4 to 6 ml/kg) in an attempt to 6 raise the serum sodium concentration by small 3 to 5 mEq/L increments. Occasionally, focal neurological signs and symptoms are seen in the setting of hyponatremia and include hemiparesis, monoparesis, ataxia, nystagmus, tremor, rigidity, aphasia, and unilateral 1 corticospinal tract signs. These focal abnormalities often represent an aggravation of an underlying structural lesion and remit with resolution of the hyponatremia. Although occasional muscle twitches and fasciculations may be seen in acute hyponatremia, muscle 7 symptoms other than cramps are not common. The central nervous system (CNS) manifestations of acute hyponatremia are related to cerebral edema, but understanding is incomplete regarding the factors that mitigate hyponatremic osmotic brain swelling and 8–11 reduction in the brain's intracellular organic osmolytes. The use or restriction of fluids may have profound effects on the eventual outcome of patients with hyponatremia and acute neurological disease. Subarachnoid Hemorrhage and Unselected Intracranial Disease Hyponatremia frequently develops in patients with subarachnoid hemorrhage due to ruptured saccular aneurysms and is often attributed to SIADH. Clinicians manage SIADH by instituting some degree of fluid restriction. This measure may not be entirely unwarranted, since some patients with subarachnoid hemorrhage may do better when fluid is restricted early in the 12 course of the disorder. In a retrospective study of 134 consecutive patients from the Netherlands, 44 patients developed hyponatremia between the second and tenth days 13 following subarachnoid hemorrhage. Hyponatremia was defined as a serum sodium level below 135 mEq/L on at least two consecutive days. Of the 44 hyponatremic patients, 25 fulfilled the laboratory criteria for SIADH. Cerebral infarction, defined as a focal neurological

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deficit with or without computed tomography (CT) confirmation or deterioration in the level of consciousness with CT confirmation of ischemic changes, occurred in 46 of the 134 patients. Of the cerebral infarcts, 27 occurred in the 44 hyponatremic patients (61.4%), but only 19 occurred in the 90 normonatremic patients (21.1%). Of the 44 hyponatremic patients, 26 were fluid-restricted; of these, 21 developed infarcts (80.8%). Of the 18 hyponatremic patients who were not fluid-restricted, only 6 developed infarcts (33.3%). Of the 25 patients who fulfilled the laboratory criteria for SIADH, 17 were fluid-restricted; of these, 15 developed infarcts (88.2%). Thus, fluid restriction in hyponatremia following subarachnoid hemorrhage, particularly in those thought to have SIADH, appears to markedly increase the risk of cerebral infarction. Some insight has been gained into the basis for this risk in fluid restriction in patients with subarachnoid hemorrhage who develop hyponatremia. In a study of 12 unselected neurosurgical patients with intracranial disease who fulfilled the laboratory criteria for SIADH, 14 absence of hypovolemia 10 had significant decreases in their total blood volume. Because 15 is considered one of the criteria for making the diagnosis of SIADH, the finding of decreased blood volume in patients with hyponatremia and intracranial disease suggests that these patients did not have SIADH. In a prospective study of 21 patients with aneurysmal subarachnoid hemorrhage, plasma volume decreased by more than 10 percent in 11 of the 16 patients. Serum sodium decreased in 9 of the 21 patients. Plasma volume decreased by more than 10 percent in 6 of 9 patients with hyponatremia, and a similar decrease occurred in 5 of 12 patients with normal serum sodium. Eight of the 9 patients with hyponatremia had a negative sodium balance, whereas only 4 of the 12 patients with normal serum sodium had a negative sodium balance. Finally, 10 of the 12 patients with a negative sodium balance had a decrease in plasma volume of more than 10 percent. Hyponatremia following from 16,17 as aneurysmal subarachnoid18hemorrhage appears to be related to cerebral salt-wasting, was originally suggested, and is not due to SIADH. Fluid restriction instituted to correct hyponatremia attributed to presumed SIADH in patients with subarachnoid hemorrhage appears to exacerbate an already volume-depleted state and subjects the patient to an even greater risk of ischemic cerebral damage from vasospasm. Central Pontine Myelinolysis (Osmotic Myelinolysis) Central pontine myelinolysis was recognized as a distinct clinical entity in 1959 in four cases 19 occurring on a background of alcoholism and malnutrition. Its pathological features are symmetric noninflammatory demyelination in the base of the pons with relative sparing of neurons and axons. The classic clinical presentation includes pseudobulbar palsy and spastic quadriparesis. Following the original description, many additional cases were reported in rapid succession, suggesting that central pontine myelinolysis is not a rare disorder. Many cases of central pontine myelinolysis were not associated with alcoholism or malnutrition. It may, for example, occur in subjects with extensive burns (p. 1032). By 1964, the relatively 20 was noted, and this was validated by high frequency of small subclinical lesions (Fig. 19-1) 21,22 subsequent reports.

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FIGURE 19-1 Macrosection of the pons demonstrating central demyelination, an

incidental finding of subclinical central pontine myelinolysis in a patient with a history of electrolyte abnormalities and diuretic use (Luxol fast blue). In 1963, Aleu and Terry suggested that central pontine myelinolysis must be related to 23 recently introduced factors. Also in 1963, the initial suggestion that an24“electrolyte imbalance may be a contributing factor” in its development was made. The observation was subsequently made that acute cases of central pontine myelinolysis (i.e., acute quadriparesis) developed only in hospitalized patients who were being hydrated. From an analysis of 12 acute cases in 1980, Leslie and associates noted that there had been a recent rapid rise of 25 serum sodium in each patient. They suggested that central pontine myelinolysis “is an iatrogenic disorder that in most25cases is caused by a rapid correction of serum sodium rather than by hyponatremia per se.” The factors that led to the appearance of the disorder during the 1950s were the introduction of diuretics, the liberal use of intravenous fluids, and the 1 ability to rapidly measure serum electrolytes. Prospective magnetic resonance imaging (MRI) studies have now demonstrated the development of characteristic pontine lesions in patients treated for hyponatremia in whom the rate of correction of the hyponatremia was 26 rapid. Of undefined significance, in one retrospective study of published reports of patients with central pontine myelinolysis in whom initial values of sodium and potassium were given, 27 all patients who developed thedisorder were also hypokalemic initially. Patients who develop hyponatremia following liver transplantation may be particularly vulnerable to central 28 pontine myelinolysis if their hyponatremia is rapidly corrected. Sterns and colleagues, in a review of their experience, noted neurological complications in 29 eight patients whose serum sodium had been corrected by more than 12 mEq/L per day. Conversely, patients with hyponatremia that was corrected more slowly made uncomplicated recoveries. In a review of the literature, these authors found 80 patients with severe hyponatremia (serum sodium 12 mEq/L per day), 22 (58%) had some type of neurological complication. Of these 22 patients 14 (64%) were suspected of having central pontine myelinolysis. Of the 13 patients who were corrected slowly (350 mOsm/kg). Virtually all patients with hyperosmolar hyperglycemic state show some degree of renal 94 dysfunction, which potentiates the development of hyperglycemia. There is no significant associated ketoacidosis. The small amount of insulin activity present100 in these patients is believed to be sufficient to prevent hepatic activation of ketogenesis. 101

Many patients show some degree of metabolic acidosis due to either lactic acidosis or an unidentified anion. Some have small amounts of keto acids present; indeed, rather than being two pathophysiologically distinct entities, diabetic ketoacidosis and hyperosmolar hyperglycemic state probably represent extremes of a continuum, the metabolic result of decreased or absent insulin effect and increased glucagon effect. A large proportion of patients in a hyperosmolar hyperglycemic state have accompanying serious medical conditions, which in some cases may have triggered the metabolic changes. These include gram-negative pneumonia, myocardial infarction, stroke, gastrointestinal 101,102 hemorrhage, gram-negative sepsis, pulmonary embolism, uremia, and pancreatitis. These illnesses may contribute to the inadequate hydration and lack of recognition of symptoms during progression of the syndrome and are the major reason for the high 67,101 mortality rate. Hyperosmolar hyperglycemic state has also been reported in association with corticosteroid

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104


therapy, thiazide diuretics, renal dialysis, and severe burns, precipitating or associated factors.

or without clear

Progressive lethargy leading to unresponsiveness is the most common reason for seeking 101 medical attention, but a number of other neurological symptoms and signs may be the presenting feature. Seizures and focal neurological deficits are quite common, unlike in 74 106 94 diabetic ketoacidosis. Focal and generalized seizures may occur, and stroke-like 102 syndromes are common, sometimes with radiological evidence107,108 of cerebral infarction. A hallucinations, and flapping tremor of the upper extremities, hemichoreoathetosis, hemianopia have also been reported. A patient who died in a hyperosmolar hyperglycemic state developed lateral pontine and extrapontine myelinolysis, presumably owing to the rapid 109 increase in serum osmolality. Alterations in the patient's level of consciousness are more prevalent in hyperosmolar hyperglycemic state than diabetic ketoacidosis. In one series, 30 of 34 patients had a 102 decreased level of consciousness, reflecting both the higher serum osmolality (due to glucose and sodium) and the compounding effects of associated medical illness on the encephalopathy. Despite the very high serum osmolalities reached, with serum glucose sometimes surpassing 2,000 mg/dl and osmolality greater than 450 mOsm/kg, treatment with insulin and fluids has only rarely resulted in cerebral edema, such as that encountered in diabetic ketoacidosis. 94 Arieff described five cases, all of which involved rapid lowering of plasma glucose to below 300 mg/dl in the first 24 hours of therapy. This situation, he believed, produces an 75,94 accumulation of “idiogenic osmoles” within the brain, thereby producing cerebral edema. Little or no insulin appears to be required to correct the hyperglycemia of the hyperosmolar 110 hyperglycemic state once fluid replacement is undertaken. Lactic acidosis is more common in diabetics than in the general population, but accurate 67 study, 50 percent of the reported cases of figures on its incidence are not available. In one 111 idiopathic lactic acidosis occurred in diabetics. The reason for this association is not clear, but vascular disease and congestive heart failure predisposing to tissue ischemia may be responsible. In past years, administration of the biguanide oral hypoglycemic agent phenformin was associated with an increased incidence of lactic acidosis. This agent has not been available for a number of years. Treatment should be directed at reversing the underlying cause of lactic acid accumulation whenever possible and to correcting severe acidemia, which sometimes requires large 112 that bicarbonate treatment may amounts of sodium bicarbonate. It has been suggested 113 worsen lactate levels by increasing lactate production. Hypoglycemia Hypoglycemia may occur in a large number of different conditions, but excessive doses of insulin for the treatment of diabetes are the most common cause of severe hypoglycemic coma. In addition, patients with early diabetes114 and diabetics with renal insufficiency may show spontaneous mild postprandial hypoglycemia, and both insulin and oral hypoglycemic agents may produce hypoglycemia of variable severity with a corresponding range of neurological symptoms and signs. Newer, rapidly acting insulin analogues have not had a 115 significant effect on the rate of hypoglycemic episodes in diabetics. Not only are diabetics more prone to developing hypoglycemia, but they also may be particularly sensitive to it. There is evidence that chronically high blood glucose produces a reduction in the number and activity of glucose transporters in the brain, so that glucose 111 transport is lower at a given low plasma glucose level. Clinically, this correlates with the “hypoglycemic” symptoms that occur despite blood glucose levels in the normal range in diabetics after rapid reduction from hyperglycemia. Intensively treated diabetics with tight control seem to be at greater risk of both severe and symptomatic hypoglycemia. One study has shown that the epinephrine and other counter-regulatory responses were delayed and diminished in these patients, and electroencephalographic changes compatible with hypoglycemia were more commonly seen than in poorly controlled or nondiabetic patients with similar blood glucose levels. The metabolic alterations underlying the brain dysfunction and pathological changes that occur in hypoglycemia are not completely understood. Many comparisons have been drawn 116,117 Notable differences include the profound between anoxic and hypoglycemic damage. functional changes in brain activity early in hypoglycemia, with alterations in consciousness despite relative maintenance of cerebral blood-flow, oxygen utilization, and high-energy

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phosphate stores, as well as the remarkable capacity for recovery even after prolonged hypoglycemic coma. It appears that energy failure is not the cause of the alteration in consciousness in hypoglycemic patients. It is probable that some other aspect of glucose metabolism is rapidly impaired despite high energy stores. The ongoing oxidative metabolism suggests that other substrates are being utilized, such as endogenous glycogen, and this may contribute to the patient's capacity for recovery. Striking similarities have been noted among the pathological changes in anoxia, status 116 epilepticus, and hypoglycemia with respect to the nature and distribution of cell changes. All exhibit “selective neuronal vulnerability,” with damage predominating in certain layers of 117 the cerebral cortex, areas of the hippocampus, parts of the striatum, and the cerebellum. Some differences exist on the subcellular level and in topographical distribution between hypoglycemia and anoxia or status epilepticus, but the similarities are so great as to suggest a common pathophysiological mechanism in all three instances. A great deal of evidence has been gathered implicating increased intracellular calcium and excitatory neurotransmitters as possible mediators of this selective cellular injury. Intracellular acidosis and toxic free radical 17 formation may also be involved. If strict control is attempted, an occasional “insulin reaction” is unavoidable. Diabetics are familiar with the typical symptoms of the “sympathetic” phase of hypoglycemia, which usually occurs at plasma glucose levels of less than 40 to 50 mg/dl. This phase includes dizziness, 118 Such warning signs may weakness, tremor, and palpitations due to epinephrine release. 118 be absent in diabetics with autonomic dysfunction or may be neglected because of intervening “neuroglycopenic” symptoms affecting behavior and judgment. One study showed nocturnal hypoglycemia in 22 of 39 poorly controlled diabetics; it lasted more than 3 hours in 119 17 patients. Although family members reported daytime behavioral abnormalities, only 6 patients were aware of hypoglycemia. Recurrent nocturnal hypoglycemia has produced the 119 clinical picture of dementia, which was reversed with appropriate treatment. In other patients, repeated or prolonged hypoglycemic attacks may produce dementia and irreversible 120 pathological changes. The neurological effects of hypoglycemia have been described as progressing in a reverse 121 phylogenetic order, with the cerebral hemispheres affected first and most commonly, and patients subsequently progressing to diencephalic, mesencephalic, and finally medullary phases of dysfunction. This ordered topographical progression is not always borne out in clinical experience; instead, different areas of the brain appear to be most affected in different attacks. Four forms of acute metabolic encephalopathy have been described in hypoglycemia: (1) delirium, either quiet or manic; (2) multifocal brainstem dysfunction with neurogenic hyperventilation and decerebrate spasms, but with preserved oculocephalic and oculovestibular responses; (3) stroke-like events with or without coma, with focal deficits that may shift from one side to the other, tend to resolve, and may occur without evidence of 122,123 ; and (4) seizures, single or multiple, which may underlying vascular or other pathology be the only manifestation of124 hypoglycemia. Hypothermia is common and may be a clue to the presence of hypoglycemia. Although there is not a tight correlation between plasma glucose levels and neurological 120 symptoms, confusion and behavioral changes generally appear at levels below 30 to 40 mg/dl, with stupor and seizures occurring as the level declines further, and profound coma 125 with levels below 10 mg/dl. In milder cases, hypoglycemic symptoms are quickly reversed by oral or intravenous glucose. In some cases, however, coma may persist despite restitution of normoglycemia, for reasons that are not clear. In general, complete recovery is the rule, even after an hour or more of 120 and repeated coma. There may be some residual focal neurological signs after recovery, 120,125 severe attacks are known to produce cognitive decline. In addition to the behavioral changes, alterations in consciousness, and focal hemispheric and brainstem signs described earlier, 126 hypoglycemia has also been reported to cause recurrent or persistent choreoathetosis (presumably reflecting susceptibility of the basal ganglia to hypoglycemia) and recurrent focal neurological deficits in the distribution of a 127 stenosed atherosclerotic vessel (probably reflecting disruption of borderline perfusion and substrate delivery in the normoglycemic state).

Cerebrovascular Disease Stroke is two to six times more common in diabetics than in nondiabetics and is involved in 128 about 25 percent of diabetic deaths. Although much of129this increase in incidence of stroke is attributable to an increase in cerebral atherosclerosis, other factors also are probably

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important. Hypertension is common in diabetics and, in addition to contributing to atherosclerosis, also promotes both intracranial small-vessel disease and heart disease, 130 which can lead to lacunar and embolic infarction, respectively. Atherosclerotic heart 131 disease and congestive heart failure are more common in diabetics than in nondiabetics. Metabolic and hematological abnormalities occurring in diabetes may aggravate the damage resulting from any of these ischemic insults. Hemorrhagic stroke is not increased in incidence 132,133 in diabetes and may actually be less frequent. It was believed until recently that cerebrovascular disease and stroke were not more common in diabetics than in the general population. Large autopsy studies, however, have shown an increase in encephalomalacia (cerebral infarcts) in diabetics, with 1.5 to 2.0 times the 134 incidence of infarcts, particularly in small, deep, and infratentorial areas, suggesting small-vessel disease. The increase over nondiabetics was more apparent in subjects younger than 60 years. Hypertension did not account for all the increased incidence of encephalomalacia in diabetics. Furthermore, in all of these studies, hemorrhagic stroke was found to be less frequent in diabetics than in nondiabetics, which would not be expected if hypertension were the only pathogenetic influence. Diabetes is an important risk factor for 135 African Americans, stroke in blacks. Both diabetes and hypertension are more common in 135 resulting in stroke being the third leading cause of death in U.S. blacks. A recent meta-analysis of all available randomized trials suggests that improved diabetes control 136 reduces the risk of stroke in both type 1 and 2 diabetic patients. Hypertension and Arteriolosclerosis Hypertension is known to be a major risk factor for cerebral infarction. It contributes to the pathogenesis of lacunar and atherothrombotic infarction and also to that of cardioembolic brain infarcts as a result of related heart disease and atrial fibrillation. Hypertension is 1.5 to 3 times more common in diabetics than in the general population. One half of129,137 diabetics have a medical history of hypertension, and it is controlled in only 30 to 50 percent. Arteriolosclerosis is associated with hypertension. It is characterized by thickening of the arteriolar wall (“hyaline degeneration”) and in some cases permeation of plasma into the wall, 138,139 This process appears to be rendering it an amorphous mass (“fibrinoid necrosis”). physiologically related to aging but is accelerated by hypertension and is also increased in 138,139 In brain, it diabetic tissue, where it may be seen even in the absence of hypertension. has been 140 found to be increased in proportion to the increased frequency of hypertension in diabetics. The clinical correlate of arteriosclerosis is infarction, particularly of deep structures supplied by end-arterioles (so-called lacunar infarction). Intraparenchymal hemorrhage, another common consequence of hypertensive small-vessel disease, is actually reduced in incidence in diabetics, as noted earlier. One study found arteriolar necrosis, which may lead to hypertensive hemorrhages, to be significantly less common in diabetics than in nondiabetics of equivalent hypertensive status. It has been suggested that some specific diabetic changes protect the arterioles from hypertensive damage. Large-vessel atherosclerosis is also promoted by hypertension. Atherosclerosis Atherosclerosis is known to be more common in diabetics, to be more severe at an earlier 128,129,141 The vessels of the lower age, and to involve smaller vessels than in nondiabetics. extremities, heart, and brain all are affected. Comparison of atherosclerosis in the circle of Willis as a function of sex, age, and diabetic status showed striking increases in the frequency and severity of atherosclerosis in diabetes, especially in women, who, by the fourth 138 decade, surpassed diabetic men in this regard. These data were not corrected for the presence of hypertension, which is more common in diabetics and certainly contributes to the increase in atherosclerosis. The epidemiology of vascular disease in diabetics has been thoroughly reviewed 142 elsewhere. In those with onset of diabetes before 40 years of age, the influence of the duration of diabetes on the severity of vascular disease is striking, with very few patients free from significant disease after 20 years of diabetes. Autopsy studies have provided many data but are not necessarily representative of the population as a whole. Population studies have 132,133,138,140,143,144 and have shown confirmed the excess risk of atherosclerosis in diabetes that the usual measurable associated risk factors cannot account for the total increase in symptomatic arteriosclerotic disease in diabetics.

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Stroke in Diabetics In an individual patient, determining whether a stroke has occurred (and, if so, its pathogenesis) is difficult. This leads to methodological problems in epidemiological studies of stroke and diabetes. Although CT scans are a major help in distinguishing hemorrhagic events, they usually are negative in acute ischemic stroke. The best criterion for determining that a stroke has occurred is a neurologist's clinical evaluation at the time of the acute events. An attempt should be made to determine the subtype of ischemic stroke: large-vessel occlusive disease due to atherothrombosis, lacunar infarction due to arteriolar disease, or embolic stroke due to cardiac disease. Diabetes and related conditions may contribute to each of these. The increased incidence of stroke in diabetics has been well documented in epidemiological 132,133,143 145 It is now accepted as an independent risk factor. Although one study studies. 146 showed no increased risk of stroke in normotensive diabetics, this same study did find an increased risk of stroke in hypertensive diabetics compared with hypertensive nondiabetics. Furthermore, a number of large prospective studies, including the Honolulu Heart Program, the Gothenburg Cohort Study, and the Framingham Study, have found diabetes to provide a 132,133,143 separate risk of stroke, independent of associated risk factors. 132,143

The relative risk of stroke due to diabetes itself is about twice normal. Even high-normal serum glucose levels in 132 those not carrying a diagnosis of diabetes are associated with an increased risk of143 stroke. Including all risk factors, the relative risk of stroke in diabetics is higher in133women and may be as high as 13 times the normal risk in the younger age groups. In addition to increased frequency of stroke in diabetes, the resulting impairment tends to be greater and survival poorer in diabetic than in nondiabetic stroke patients. In a study of patients with peripheral vascular disease, the incidence of stroke with permanent neurological deficit was twice as high in diabetics as in nondiabetics with equivalent atherosclerotic 146 cerebrovascular disease, as determined by noninvasive tests. Nondiabetics, however, had more transient ischemic attacks (TIAs), and the total numbers of ischemic events in the two groups were equivalent. This suggests that diabetics are more prone to irreversible destruction of ischemic brain tissue. In another study, diabetic patients followed for 5 years after their first stroke or TIA showed only a 20 percent 5-year survival, compared with 40 147 percent in matched or random nondiabetic stroke patients. Thus, diabetes provides an independent risk of ischemic stroke, separate from other risk factors. In addition, it appears to increase the morbidity and mortality following stroke. This may be mediated in part by an increase in the severity of atherosclerosis in diabetics. It is possible that some risk factors serve to increase atherosclerosis in diabetics even beyond the increase that would be expected on the basis of known associated risk factors, such as hypertension, hyperlipidemia, and obesity. The possibilities include an atherogenic effect of hyperglycemia itself or of insulin, alterations in blood coagulability and viscosity, possible effects of microvascular disease on arterial walls, and a genetic predisposition to enhanced 128,129,140 atherogenesis in diabetics. It is the clinical impact of cerebrovascular disease, rather than the severity of atherosclerosis, that is measured in epidemiological studies. Although the rate of stroke may reflect an actual increase in vascular disease per se, it may also reflect an increased tendency to stroke on the basis of blood or tissue factors. Certain features common in diabetes may serve to enhance the rate of atherogenesis, promote thrombosis, or reduce the ability of brain tissue to tolerate an ischemic insult. Hyperglycemia, for example, has been associated with an increased morbidity after stroke, and in animals it enhances the extent and degree of brain damage from controlled degrees of 148 cerebral ischemia. This has been shown to result from intracellular lactic acidosis in tissue receiving a trickle of flow rich in glucose. Because hyperglycemia is common following stroke 149 even in patients not previously diagnosed as diabetic, it clearly may aggravate the morbidity due to stroke; furthermore, stroke and TIA occur more frequently in patients with 150 may act in another manner to promote stroke, in poorly controlled diabetes. Hyperglycemia 151,152 Alterations in platelet adhesiveness, coagulation that it may promote atherogenesis. 153 factors, and fibrinolytic activity have been documented in diabetics. Through their relation to endothelial cell function, these factors may be involved in the pathogenesis of 154 97 atherosclerosis. Clearly, they may also lead to the thrombotic complications of diabetes. A prospective study showed a significantly increased risk of arterial occlusion in diabetic men, with increased spontaneous platelet aggregation or abnormalities in fibrinogen or von 155 Willebrand's factor.

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Thus, diabetes, with its associated metabolic and vascular abnormalities, greatly increases the risk of ischemic stroke. Some of the abnormalities may not be modifiable, but a significant part of this increased risk may be amenable to treatment, with good control of hyperglycemia 136,142 and hypertension.

Other Central Abnormalities The most common CNS abnormalities in diabetics result from cerebrovascular disease and metabolic derangement, as described earlier. Whether there are, in addition, primary abnormalities of the CNS inherent to diabetes is less clear. 156

A number of autopsy studies have documented spinal cord lesions in diabetics. Many show degeneration of the posterior columns, which probably is secondary to disease of the dorsal 157 Corticospinal tract degeneration has been related to root ganglia or the peripheral nerves. 158,159 Some authors believe that diabetic myelopathy lesions higher in the nervous system. 160 exists as a distinct entity. The existence of a primary diabetic encephalopathy is similarly unclear. Several reports document 161–164 slowing of conduction velocity in brainstem auditory or somatosensory evoked but it is possible that this is due to ischemic microvascular damage. Overall, potentials, there is no convincing clinical or pathological evidence to suggest brain dysfunction or lesions 120,138,139 that could not be explained on the basis of previous metabolic or vascular insults. Some of the peripheral complications of diabetes can lead indirectly to alterations in brain function. Autonomic neuropathy may produce syncope from orthostatic hypotension. Generalized cerebral hypoperfusion and decreased levels of consciousness may occur with a 165 painless myocardial infarction. Uremic encephalopathy should be considered in a diabetic with nephropathy. Other CNS changes reported in diabetes include abnormal hypothalamic regulation of166growth hormone in poorly controlled diabetes, focal seizures with isolated hypomagnesemia, 167 and pituitary insufficiency. The prevalence of migraine is reported to be lower in diabetics, and it has been167 suggested that the diminished vasodilatory capacity in diabetic brain may be Diabetics may be at increased risk of developing neuroleptic-induced tardive protective. 168–170 dyskinesia. Certain other neurological entities are associated with secondary diabetes, including Friedreich's ataxia and myotonic dystrophy. An increased prevalence of diabetes has also 171 been shown in Huntington's disease. A large proportion of patients with stiff-person syndrome are diabetic, with anti–islet cell antibodies and antibodies172 directed against glutamic acid decarboxylase that are strongly associated with this condition. Although it has commonly been held that diabetics are more prone to infection, presumably on the basis of impaired neutrophil function, epidemiological data do not confirm a significant 173,174 Certain unusual infections, increase in infection in diabetics other than bacteriuria. 173 however, are seen essentially only in diabetics. Rhinocerebral mucormycosis is the only one affecting the CNS. This fungal infection of the nose and orbit may invade the brain, with 131 It is neurological sequelae, or it may invade locally to produce peripheral facial weakness. 131 more common in acidotic patients but may occur in any diabetic. Although the greatest impact of diabetes is on the peripheral nervous system, there are significant effects on central neurological function, mediated by vascular disease and metabolic derangements. Neurological disease in a diabetic should be viewed with this in mind. ACKNOWLEDGMENTS The secretarial assistance of Judith C. Boldt is greatly appreciated. The work of the authors is supported by the National Institutes of Health (NS36778 and NS38849), UPDATE, the Juvenile Diabetes Research Foundation (JDRF) Center for the Study of Complications in Diabetes, a grant from the American Diabetes Association, and the Program for Neurological Research and Discovery. Previous

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Aminoff: Neurology and General Medicine: Sex Hormones and the Ne...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 22 Sex Hormones and the Nervous System HYMAN M. SCHIPPER •

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SEX STEROID–NEURAL INTERACTIONS Organizational Effects Activational Effects HUMAN MENSTRUAL CYCLE AND HORMONAL CONTRACEPTIVES MIGRAINE STROKE EPILEPSY MOVEMENT DISORDERS Chorea Parkinsonism Wilson's Disease Other Movement Disorders NERVOUS SYSTEM NEOPLASMS Meningiomas Gliomas Other Tumors MULTIPLE SCLEROSIS ALZHEIMER'S DISEASE NEUROPSYCHIATRIC DISORDERS The Porphyrias Premenstrual Syndrome Depression and Psychosis SLEEP DISORDERS INTRACRANIAL HYPERTENSION NEUROMUSCULAR DISEASES Catamenial Sciatica Other Neuromuscular Disorders CONCLUDING COMMENTS

The effects of sex steroids on neurological function in health and disease constitute a rich and rapidly expanding area of basic and clinical neuroscience. Several factors account for the burgeoning of this field over the past several decades. First, the development of radioimmunoassay, autoradiography, immunocytochemistry, and in situ hybridization has permitted meticulous determinations of circulating hormone profiles and mapping of steroid

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hormone binding sites within the nervous system. Second, ample evidence has accumulated attesting to the potent modulatory effects of sex hormones on monoaminergic, cholinergic, and peptidergic neurotransmission and the role of such interactions in diverse normal and pathophysiological states. Finally, there is the recognition by clinicians that many neurological conditions are influenced by hormonal fluctuations associated with the menstrual cycle, pregnancy, the menopause, and use of oral contraceptives. A growing appreciation of these relationships is currently being rewarded by the development of specific hormonal and antihormonal therapies for neurological disorders as disparate as catamenial epilepsy and acute intermittent porphyria. SEX STEROID–NEURAL INTERACTIONS In mammals of both sexes, estrogens, progestins, and androgens represent the three major classes of endogenous sex steroids (Fig. 22-1). Prototypical hormones in each class include 17β-estradiol, progesterone, and testosterone. Plasma sex hormones are secreted directly from ovaries, testes, and adrenal glands but may also be derived from enzyme-mediated conversions from prohormones in extraglandular tissues (Fig. 22-2). Important examples of 4 the latter include the aromatization of the androgens Δ -androstenedione and testosterone to estrone and 17β-estradiol, respectively, in brain and adipose tissue. Approximately 98 percent of the circulating sex hormone pool is protein bound and functionally inert. The remaining “free” fraction is highly lipophilic and readily penetrates the blood–brain barrier and neuronal cell membranes. Within the cytoplasm or nucleus of the target cells, sex hormones form complexes with specific receptor proteins. Subsequent binding of these complexes to steroid response elements within the promoter regions of various genes induces or suppresses the transcription of these genes. In neurons, sex steroids modulate the biosynthesis of enzymes and structural proteins concerned with cell membrane function, energy metabolism, hormonal sensitivity, and neurotransmission. In addition, steroid hormones are capable of far more rapid1,2 modulation of neuronal firing by direct (nongenomic) interactions with nerve cell membranes.

FIGURE 22-1 Sex steroids, nonsteroidal estrogens, and steroid antagonists.

(Courtesy of Dr. E. E. Baulieu, Faculté de Médecine de Bicêtre, France, with modifications. From Schipper HM: Neurology of sex steroids and oral contraceptives. Neurol Clin 4:721, 1986.)

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4

FIGURE 22-2 The brain-pituitary-ovarian axis. Δ A, delta-4-androstenedione;

ACh, acetylcholine; DA, dopamine; E1, estrone; E2, estradiol; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; 5-HT, 5-hydroxytryptamine (serotonin); LH, luteinizing hormone; NE, norepinephrine; P, progesterone; T, testosterone. In rodents and primates of both sexes, estrogen-binding neurons are located in the preoptic area, medial basal hypothalamus, medial amygdala, and circumventricular organs. Estrogen-binding neurons also reside, albeit to a lesser extent, in the basal forebrain, hippocampus, several thalamic nuclei, sensory regions of the brainstem and spinal cord, and 3,4 target neurons the neonatal neocortex. The topographies of the progestin and androgen 3 exhibit considerable overlap with the estrogen-concentrating populations.4,5In addition to and undergo neurons, some periventricular astrocytes also contain estrogen receptors 6 morphological and histochemical changes after sex hormone exposure. These latter observations may be important insofar as some human glial tumors appear to be responsive to sex hormones.

Organizational Effects Organizational effects refer to the irreversible dif-ferentiation of neural circuitry resulting from exposure to sex steroids during critical periods of brain development. This is perhaps best exemplified by the role sex steroids play in the gender-specific organization of the 7 hypothalamic-pituitary-gonadal axis in neonatal rodents (Fig. 22-3). Sexually dimorphic regions have been defined in the human brain, including the sexually dimorphic nucleus of the preoptic area, subregions of the hypothalamic suprachiasmatic nucleus, the bed nucleus 8 of the stria terminalis, and certain white matter tracts. Clinical and experimental evidence

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suggests that abnormal exposure to circulating sex hormones in utero or during infancy, as might occur after maternal exposure to diethylstilbestrol (Fig. 22-1) or in children with congenital adrenal hyperplasia, may result in altered development of one8or more sexually dimorphic brain regions and expression of gender-associated behaviors. Whereas during the neonatal and peripubertal periods estrogens and aromatizable androgens induce trophic (synaptogenic) changes in the rodent hypothalamus, in later life estrogens accelerate aging-related changes in the endocrine hypothalamus that may contribute to the onset of reproductive senescence.

FIGURE 22-3 The classic organizational hypothesis. Female (left panel): During

the first week of life (neonatal critical period) in female rodents, ovary-derived estradiol (E2) is bound to circulating α-fetoprotein (αFP) and does not readily cross into the brain. The hypothalamic circuitry subserving pituitary gonadotropin regulation is intrinsically “female” in organization and releases gonadotropin-releasing hormone (GnRH) in a pulsatile (phasic) fashion. The latter is necessary for stimulating the luteinizing hormone (LH) surge that sustains ovulation. αFP levels progressively decline after birth, permitting ovarian estrogen to modulate the brain-pituitary axis after puberty. Testosterone administered to female rodents during the critical period does not bind to αFP and thus gains access to the developing hypothalamus, where it is converted to E2 by the enzyme aromatase. This E2 (ironically) “masculinizes” the gonadotropin-regulating hypothalamic pathways, resulting in permanent nonpulsatile (tonic) release of GnRH and LH. At puberty, in the absence of LH surges, the animal develops irreversible anovulatory sterility and multicystic ovaries. Male (right panel): Testosterone secreted from neonatal testes during the critical period does not bind αFP, undergoes aromatization to E2 within the hypothalamus, and reorganizes the intrinsically “female” circuitry to express “male” (tonic) patterns of GnRH and LH secretion. This nonpulsatile pattern of LH release suffices to maintain normal levels of testicular androgen production at puberty. In genetic males, “female” (pulsatile) patterns of GnRH-LH secretion occur at puberty if the animals are castrated at birth or treated with antiestrogens or aromatase inhibitors during the critical period.

Activational Effects The activational effects of sex steroids encompass a myriad of largely reversible neurophysiological influences exerted by gonadal hormones on the mature nervous system. Such interactions are essential for regulation of the brain-pituitary-gonadal axis and the establishment of normal patterns of sexual, aggressive, cognitive, and autonomic behaviors. Furthermore, by impacting the metabolism and release of various central neurotransmitters and neuromodulators, hormonal fluctuations associated with (1) specific phases of the menstrual cycle, (2) pregnancy, (3) the meno-pause, and (4) exposure to exogenous sex hormones may induce or modify a host of neurological and neuropsychiatric disorders.

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HUMAN MENSTRUAL CYCLE AND HORMONAL CONTRACEPTIVES Sex steroid fluctuations in the course of a typical menstrual cycle are depicted in Figure 22-4A. Plasma estradiol levels increase during the late follicular phase of the cycle and peak just before ovulation. A smaller but more sustained elevation in circulating 17β-estradiol occurs during the luteal phase. Progesterone levels are negligible during the follicular phase and rise markedly during the luteal phase in synchrony with the second 17β-estradiol surge. In the late luteal phase, a decline in sex hormone levels triggers the menstrual flow. High concentrations of circulating sex steroids resulting from ingestion of oral contraceptives inhibit ovulation through a negative feedback action on the hypothalamic-pituitary unit (Fig. 22-2). In the most widely used combined oral contraceptives, fixed doses of estrogen and progestin are administered for 21 days, followed by a 7-day placebo period during which time menstruation occurs. The estrogenic component of “the pill” consists of either ethinyl estradiol or mestranol (which is metabolized to ethinyl estradiol). Commonly used progestogens include ethynodiol diacetate, norethindrone, norethynodrel, norgestrel, norgestimate, gestodene, and desogestrel. The synthetic steroids are readily absorbed from the gut, freely traverse the blood–brain barrier, and are metabolized by the microsomal enzyme system in the liver. Common minor adverse effects of “the pill” include nonvascular headaches, dysphoria, and decreased libido. The remainder of this chapter is concerned with major neurological complications of endogenous sex steroids and oral contraceptives. Wherever possible, a distinction is made between “high-dose” (≥50 μg) and the more recently introduced “low-dose” (20 to 35 μg) estrogen preparations because there appear to be significantly fewer neurological and non-neurological complications with use of the latter. MIGRAINE Although no gender difference in the prevalence of migraine is apparent before puberty, the 9 condition is three times as common in adult women (18%) as in men (6%). Approximately 60 percent of women with migraine experience perimenstrual exacerbations of their headaches (catamenial migraine). The late luteal phase decline in plasma estradiol (but not 10 progesterone) appears to play an important role in the precipitation of catamenial migraine (Fig. 22-4). The frequency or severity (or both) of migraine attacks often diminishes with 11 gestation, particularly in patients whose headaches are linked to the menstrual cycle. The absence of rhythmic estrogen “withdrawal” characteristic of the pregnant state is believed to be responsible for the reduction in migraine activity. Indeed, many women whose headaches are attenuated by pregnancy experience relapses at the time of parturition, when sex 12 In some patients, migraine arises de novo or appears to hormone levels fall precipitously. 13 14 worsen during gestation or the perimenopausal period. A first approach to the management of gestational migraine should be nonpharmacological (e.g., relaxation training, biofeedback), especially during the first trimester when risks of teratogenicity and embryotoxicity are greatest. For severe attacks, acetaminophen with codeine or nonsteroidal anti-inflammatory drugs (NSAIDs) can be used. Further discussion is provided in Chapter 35. For status migrainosus in pregnancy, chlorpromazine, meperidine, morphine, or prednisone 15 may need to be administered. Perimenopausal migraine often responds to standard estrogen replacement therapy, but this must be weighed against the risk of developing breast 14 cancer in individual patients.

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FIGURE 22-4 A, Daily plasma concentrations of estradiol and progesterone throughout a normal menstrual cycle in a woman with premenstrual migraine (vertical arrow indicates onset of headache). B, Plasma estradiol concentrations during a normal and estradiol-treated cycle in a woman with premenstrual migraine. (From Somerville B: The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology 22:355, 1972, with permission.)

An association between migraine and “the pill” is frequently encountered in general and neurological practices. Women often exhibit new-onset or exacerbation of migraine while taking oral contraceptives. Attacks tend to manifest during the first few cycles (particularly on placebo days in accord with the estrogen withdrawal hypothesis) and usually, but not invariably, resolve on discontinuation of the medication. A qualitative change in the pattern of migraine is noted in some patients. For example, a migraineur may develop a focal prodrome for the first time while taking oral contraceptives. Women in this category may be at high risk of infarction in regions reflecting the distribution of their auras. Amelioration of migraine after exposure to oral contraceptives is observed in a few women. Psychological factors, such as the diminished fear of accidental pregnancy, may in part contribute to the improvement. The pathophysiology of estrogen-related migraine is incompletely understood. Estrogens may act directly on vascular smooth muscle as well as modulate the activity of vasoactive substances at the neurovascular junction. 16 In addition, by altering central prostaglandin, serotonin, opioid, or prolactin metabolism, premenstrual changes in circulating estrogens may activate vasoregulatory elements in the brainstem or hypothalamus, which, in turn, may 17 trigger symptomatic alterations in cerebrovascular tone. First-line therapy for menstrual migraine should include the standard pharmacological, dietary, and psychological modalities employed in the general migraine population.

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Sumatriptan and related serotonin 5-HT1D (presynaptic autoinhibitory) receptor agonists are 18 equally effective for noncatamenial and menstrual migraine. Refractory cases of severe catamenial migraine may benefit from late luteal phase therapy with19prostaglandin inhibitors (e.g., naproxen, 250 to 500 mg orally twice daily) and mild diuretics. Various hormonal interventions in catamenial migraine have been largely unsuccessful and often complicated by unpleasant side effects. Oral contraceptives usually exacerbate migraine and probably should not be used in20the treatment of this disorder. The use of estrogen implants has yielded contradictory results. The risk-benefit ratio accruing to long-term estrogen therapy must be carefully assessed before such treatment can be advocated for this relatively benign 22 21 condition. The antiestrogen tamoxifen (Fig. 22-1) may either alleviate or precipitate catamenial migraine. The beneficial effect of tamoxifen21may be due to inhibition of calcium 23,24 danazol (200 uptake or prostaglandin E synthesis in these subjects. In several reports, mg twice daily for 25 days), a testosterone derivative used in the management of endometriosis, aborted or ameliorated premenstrual migraine for the duration of treatment. Catamenial headaches resumed on discontinuation of this medication. Continuous bromocriptine therapy (2.5 mg three times daily) resulted in a 72 percent decline in headache 25 frequency in a study involving 24 women with menstrual migraine. STROKE “The pill” has been implicated as a significant risk factor in thromboembolic cerebral 26 infarction, subarachnoid hemorrhage, and cerebral venous thrombosis. In 1969, American 27 and British case-control studies revealed, respectively, a 19- and 6-fold increased risk of ischemic stroke in young women related to the use of oral contraceptives. Hypertension, migraine, and age older than 35 years were associated, 28 but independent, risk factors for cerebral infarction in patients taking oral contraceptives. Cigarette smoking by women on “the pill” was found to increase further the likelihood of hemorrhagic but not thromboembolic stroke. Ingestion of lower dose (30 μg) estrogen preparations appears to be responsible for a 29 decline in rates of thromboembolic disease among users of oral contraceptives. In a population-based case-control study, the odds ratio of ischemic stroke in current users of low-dose estrogen contraceptives (20 to 35 μg) was only 1.18 in comparison with former 30 users or women who were never exposed to oral contraceptives. However, the risk of stroke remains unacceptably high in low-dose oral contraceptive users if they smoke and are 31 older than the age of 35. Although less often implicated than estrogens, progestins may contribute to the danger of cerebral infarction by promoting hypertension, hypercoagulability, 32,33 and adverse serum lipoprotein levels. Ischemic strokes in users of oral contraceptives have been localized to the carotid (usually the middle cerebral artery or its deep penetrating branches) and vertebrobasilar distributions. There is usually no radiological or pathological evidence of disseminated vascular disease in 34 young women with oral contraceptive–related stroke. Cerebral thromboembolism resulting from estrogen-induced hypercoagulability is a likely etiology for such strokes. Estrogen increases plasma levels of fibrinogen and clotting factors VII, VIII, IX, X, and XII. The steroid also enhances platelet aggregation and suppresses antithrombin III activity and the fibrinolytic system. A host of estrogen-regulated genes that may 35 impact the risk of ischemic stroke, either positively or negatively, are listed in Table 22-1. Elam and associates have reported an increased prevalence of mitral valve prolapse among users of oral contraceptives with 36 ischemic stroke. The combination of a fixed valvular anomaly and an estrogen-related hypercoagulable state may render patients particularly vulnerable to thromboembolic complications. Sex hormone–induced hypercoagulability is thought to play an important role in the pathogenesis of cerebral venous thrombosis complicating pregnancy, the puerperium, 37 and use of hormonal contraceptives. Click here to view this table.... Data concerning the impact of hormone replacement therapy (HRT) on stroke incidence and severity are conflicting, with reports of neutral, increased, and decreased stroke risk accruing from this intervention. In some observational studies, HRT-related stroke risk was significantly 38 modified by the presence or absence of associated factors such as hypertension or smoking. Importantly, several large randomized controlled studies indicated that HRT with conjugated equine estrogen or 17β-estradiol, alone or combined with medroxyprogesterone acetate, does not protect against stroke (or coronary artery disease) in women with39,40 established vascular disease and may actually worsen outcomes in this high-risk In healthy women without prior cerebrovascular history enrolled in the population. Women's Health Initiative (WHI) study, an increased risk of ischemic but not fatal or 41 hemorrhagic stroke was again attributed to 17β-estradiol replacement therapy. Interestingly, men with the common ESR1 c.454-397CC variant of the estrogen receptor-alpha (ESRa) gene may be more prone to ischemic stroke than men bearing other ESRa genotypes after

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adjusting for age, hypertension, diabetes, blood lipid levels, and smoking status.

42

In a study by the Royal College of General Practitioners, the relative risks for subarachnoid hemorrhage in former users, current users, or subjects who had ever used moderate- to 43 high-dose oral contraceptives were 4.5, 3.2, and 4.0, respectively. The odds ratio for hemorrhagic stroke in current users of low-dose estrogen contraceptives (20 to 35 μg) in comparison with former users or nonusers is negligible (1.14). As in the case of ischemic stroke, cigarette smoking and age older than 35 years substantially increase the risk of 30,43 Female sex hormones may subarachnoid hemorrhage in users of oral contraceptives. predispose to bleeding from both aneurysms and arteriovenous malformations, although the 34 pathophysiological mechanisms underlying these phenomena remain controversial. By analogy to their effects on endometrial spiral arteries, fluctuating sex hormone levels may compromise the integrity of cerebral arterial walls, rendering them more susceptible to 44 rupture. During pregnancy, hemodynamic changes may facilitate engorgement and bleeding from cerebral arteriovenous malformations. In addition, sex hormones may exert direct trophic influences on these malformations analogous to their effects on other highly 45 46 vascularized lesions such as spider angiomas, gingival epulis, and meningiomas (discussed later). Rarely, subarachnoid hemorrhage is secondary to cyclic bleeding from 47 hormone-sensitive ectopic endometriomas of the spinal canal. EPILEPSY 48

Normal reproductive processes may be disrupted by seizure disorders49and their therapies. Abnormal limbic discharges may be responsible for the hyposexuality and increased 48,50 noted in prevalence of hypogonadotropic hypogonadism and polycystic ovary syndrome patients with temporal lobe epilepsy. Pregnant epileptic women experience higher rates of maternal and fetal complications, including vaginal hemorrhage, prematurity, low birth weight, 51 and perinatal mortality. As discussed in Chapter 35, anticonvulsant therapy in women of childbearing age may result 52 expected oral in failure of oral contraceptives and in teratogenicity. On the basis of the 53 Coulam and contraceptive failure rates reported for the general population by Tietze, 54 Annegers calculated a 25-fold increased risk of oral contraceptive failure in patients concomitantly exposed to anticonvulsants. Phenytoin, phenobarbital, primidone, 55,56 ethosuximide, and carbamazepine have been implicated in oral contraceptive failure. These anticonvulsants induce the hepatic cytochrome P450 microsomal enzyme system, which, in turn, accelerates catabolism of endogenous and exogenous sex hormones. In addition, the anticonvulsants augment the synthesis of sex hormone–binding globulins, 57 resulting in reduced levels of circulating free (active) hormone. Anticonvulsants may also promote the clearance of sex hormones by influencing sulfate conjugation and 55 glucuronidation of the latter in the gut wall and liver. Oral contraceptive failure does not occur with valproic acid, which may actually inhibit cytochrome P450 enzymes, causing elevations in plasma steroid concentrations. Valproic acid, however, may cause 48,58 Of the newer antiepileptic medications, hyperandrogenism and polycystic ovaries. lamotrigine, gabapentin, vigabatrin, and clobazam do not induce the hepatic P450 microsomal enzyme system, and56,59 oral contraceptive failure has not been reported with Topiramate and felbamate have modest effects on sex concomitant use of these drugs. 60 hormone pharmacokinetics and may affect contraceptive efficacy. Although breakthrough bleeding has been reported with tiagabine, the impact of this drug on ovarian hormone 61 metabolism is believed to be minimal. The course of epilepsy and its management may be greatly influenced by specific phases of the reproductive cycle and exposure to steroid contraceptives. A variety of seizure disorders have been documented to worsen around the time of ovulation or premenstrually (catamenial 62,63 64 65,66 Data amassed from human and animal studies epilepsy) and during pregnancy. indicate that58estrogens and progestins have epileptogenic and anticonvulsant properties, respectively (Table 22-2). Estrogen augments glutamatergic and suppresses GABAergic neurotransmission, favoring epileptogenesis, whereas progesterone has the opposite 58 effects. Conceivably, a rising estrogen:progesterone ratio during the late luteal phase triggers catamenial seizure activity. Furthermore, the markedly elevated estrogen:progesterone ratio characteristic of the polycystic ovary syndrome may, in part, contribute to the relatively frequent association of this reproductive disorder with temporal 50 lobe epilepsy. Exposure to oral contraceptives consisting of estrogen-progestin 56 combinations does not appear to worsen seizure control significantly. Management strategies for catamenial epilepsy include (1) premenstrual or periovulatory supplemen-tation of anticonvulsant doses or addition of an adjunctive antiepileptic drug such as clobazam; (2) cyclic administration of acetazolamide, a mild diuretic with weak antiepileptic activity; and (3) 67,68 progesterone supplementation by mouth or suppository.

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Click here to view this table.... With respect to gestational epilepsy, factors such as maternal sleep deprivation, stress, and inadequate anticonvulsant levels are probably more important than direct hormonal epileptogenesis. During pregnancy, serum levels of phenytoin, phenobarbital, and valproic acid may decrease by 30 to 40 percent of pregestational levels, with a lesser decline in carbamazepine. Primidone levels are reportedly stable during69pregnancy, but the concentration of primidone-derived phenobarbital is reduced. Decreased drug compliance, bioavailability, and protein binding, as well as an increased volume of distribution and metabolic clearance, are factors contributing to the fall in anticonvulsant levels during 67 preparations on pregnancy. The influences of the menstrual cycle and of oral contraceptive 70 anticonvulsant disposition appear to be of minor clinical significance. MOVEMENT DISORDERS

Chorea Pregnancy and steroid contraceptive therapy have infrequently been complicated by the acute or subacute development of choreiform movements of the face and extremities associated with limb hypotonia and pendular reflexes. Fever, dysarthria, and neuropsychiatric symptoms may complete the clinical picture. Gestational and oral contraceptive–related 34 chorea have a close association with previous rheumatic fever. Contraceptive-related chorea has also been reported in71,72 patients with a history of congenital cyanotic heart disease Pharmacological, epidemiological, and pathological and Henoch–Schönlein purpura. evidence suggests that altered hormonal patterns characteristic of pregnancy and ingestion of oral contraceptives may unmask latent chorea by augmenting dopaminergic neurotransmission in basal ganglia previously damaged by rheumatic or hypoxic 17 encephalopathy. Estrogens may facilitate dopaminergic neurotransmission by upregulation of postsynaptic dopamine receptors, by inhibition of central monoamine oxidase activity, and possibly through conversion to catechol-estrogens (Fig. 22-1). The latter may compete for the catecholamine degrading enzyme, catechol O-methyltransferase, resulting in the excessive 73 accumulation of dopamine and other neurotransmitters within the affected brain regions. In most cases, chorea gravidarum and oral contraceptive–related dyskinesias resolve completely by the end of pregnancy or after discontinuation of the medication, respectively. As many as 20 percent of women experience recurrences of chorea with subsequent 74 at increased risk of later developing oral pregnancies. Patients with chorea75gravidarum are 76 contraceptive–related dyskinesias, and vice versa. In patients with suspected chorea gravidarum, appropriate clinical and laboratory investigations may be required to exclude other causes of chorea, such as acute rheumatic fever, systemic lupus erythematosus, hyperthyroidism, and Wilson's disease. Chorea gravidarum is usually self-limited, and abortion or premature delivery is rarely indicated. Judicious use of neuroleptics or other medications may afford symp-tomatic relief in severe cases. Women with a history of gestational or oral contraceptive–induced chorea should probably minimize further exposure to any estrogen-containing medications.

Parkinsonism There are anecdotal reports in the early clinical literature of motor deterioration in idiopathic and neuroleptic-induced parkinsonism after exposure to exogenous estrogen. Furthermore, premenopausal women were reportedly more susceptible to drug-induced parkinsonism than 77 men of similar age. These observations argued for a potentially antidopaminergic role of estrogen in this condition. Yet, in two studies of premenopausal women with idiopathic Parkinson's disease, motor symptoms were noted to worsen premenstrually when estrogen 78,79 Data titers were falling, favoring a stimulatory influence of estrogen on striatal dopamine. from several investigations suggest 80,81 that postmenopausal estrogen replacement is beneficial In other studies, postmenopausal estrogen therapy in women with Parkinson's disease. 82 or was associated with worsening motor either had no significant dopaminergic effect 83 (natural or surgical) scores. Recent epidemiological studies suggest that early menopause 84,85 and that the latter may may be a risk factor for the development of Parkinson's disease 86 be offset by post-menopausal estrogen replacement. In a Swedish population, polymorphisms of the estrogen receptor–beta gene (an important mediator of estrogenic effects on the nigrostriatal pathway), although not associated with an overall risk of contracting Parkinson's disease, may have an impact on the age of symptom onset in this 87 condition.

Wilson's Disease

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Wilson's disease is an inborn error of copper metabolism that is characterized by hepatic cirrhosis and degenerative changes in the basal ganglia. Patients with this rare condition exhibit decreased serum ceruloplasmin levels, increased plasma levels of nonceruloplasmin copper, and reduced biliary excretion of the heavy metal. Movement disorders, seizures, and 88 psychosis result from the toxic effects of excessive copper deposition in neural tissues.89 In normal individuals, serum ceruloplasmin and copper levels increase during pregnancy and 17 after administration of estrogen or estrogen-progestogen contraceptives. The rise in ceruloplasmin resulting from exposure to oral contraceptives is responsible for the green-tinged serum occasionally noted in these women. In patients with Wilson's disease, increased serum ceruloplasmin levels occur during pregnancy and after treatment with exogenous estrogens. Effects on serum copper, however, are inconsistent. Normalization of serum ceruloplasmin levels by estrogen administration has no therapeutic benefit, and such exposure may lead to neurological deterioration in some individuals. Exposure to hormonal contraceptives may yield “falsely normal” 17 ceruloplasmin levels in patients with Wilson's disease, resulting in a delay in diagnosis.

Other Movement Disorders A broad spectrum of movement disturbances appear to be influenced by changes in the sex steroid milieu. Included are cases of posthypoxic and hereditary myoclonus, dominantly inherited myoclonic dystonia, tardive dyskinesia, a pyramidal-extrapyramidal syndrome, hemiballismus, ill-defined tremors and drop attacks, familial episodic ataxia, Gilles de la 17,90,91 Tourette's syndrome, and the neuroleptic malignant syndrome. NERVOUS SYSTEM NEOPLASMS

Meningiomas Sex steroids may play an important role in the biology of meningiomas. These tumors occur 92 before puberty or during more frequently in women than in men and are rarely diagnosed 93 the senium, corresponding94to the time of maximal gonadal activity. Meningiomas are more 95 common in obese women and in patients with hormone-dependent breast carcinoma. The greater prevalence of these tumors in obese individuals may be related to higher circulating96 estrogen levels derived from the aromatization of androstenedione to estrone in adipocytes (Fig. 22-2). Meningiomas have been documented clinically and radiologically to undergo relatively rapid expansion during pregnancy, followed by spontaneous regression 17,97 Some women suffer exacerbations of symptoms in the luteal phase of the postpartum. menstrual cycle. These fluctuations in tumor size have been attributed to steroid-induced fluid retention by the lesion, increased vascular engorgement of the tumor, and direct trophic 98,99 effects of gonadal hormones on meningioma cells. Numerous investigators have demonstrated the presence of progestin- and, to a lesser extent, estrogen- and androgen-binding proteins in a significant number of human 17 meningioma specimens. These observations suggest that progestins and possibly other gonadal steroids may directly modify the growth and differentiation of these tumors. The presence of progestin receptors may indicate a more favorable prognosis because progesterone receptor–negative meningiomas have been associated with a greater tendency 100 and shorter disease-free for brain invasiveness, higher mitotic indices and necrosis, 101 intervals. In an early study, the antiestrogen tamoxifen (Fig. 22-1) did not102appreciably affect tumor size or neurological status in patients with inoperable meningiomas. By contrast, the antiprogestin RU486 (Fig. 22-1) has been reported to induce stabilization or regression of meningiomas in a cohort of patients,103 suggesting that antiprogesterone therapy may be useful the effects of progestins and RU486 on in the management of these tumors. However, 104–106 and patients chronically treated with 107 meningioma growth in vitro are contradictory, RU486 may require glucocorticoid replacement to counteract its antiglucocorticoid effects.

Gliomas There are anecdotal reports of astrocytomas enlarging during pregnancy, only to shrink 108 spontaneously in the puerperium. As in the case of meningiomas, certain human gliomas may selectively bind estrogens, progestins, and androgens. Some of these tumors may also contain enzymes 109,110 (e.g., 17β-oxidoreductase and aromatase) that catalyze steroid hormone interconversions. The origin of putative steroid receptors in glial cell tumors is obscure, although significant numbers of normal astrocytes in certain brain regions possess estrogen 4,5 receptors. Astroglial tumors predominantly express estrogen receptor–beta, and 111 expression levels reportedly decline with increasing histological grade of malignancy. High-dose tamoxifen therapy (Fig. 22-1) may result in clinical and radiological stabilization of

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http://www.merckmedicus.com/pp/us/hcp/printpage.jsp 112–114

astrocytomas and glioblastoma multiforme in some patients. These benefits are more 112,113 or its role as a likely due to the115inhibitory effects of tamoxifen on protein kinase C radiosensitizer than to any accruing antiestrogenic activity. Human oligodendrogliomas have also been reported 116 to contain sex steroid receptors and could theoretically be subject to hormonal manipulations.

Other Tumors 117

Responsiveness to 118 sex hormones has been reported in cases of acoustic neuromas, 119 pituitary adenomas, and breast cancer metastases to the nervous system. Sex steroid receptors have also been reported in hemangioblastomas, anaplastic ependymomas, malignant lymphomas, and primitive neuroectodermal tumors, suggesting that the natural 120,121 history of these neoplasms may be influenced by sex hormones and their antagonists. MULTIPLE SCLEROSIS Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system (CNS) that often afflicts men and women during their reproductive years. An ESR1 gene polymorphisms and MS has been reported in some association between specific 122,123 124 studies but not others and may be population dependent. Physicians are often asked by young women with MS whether their condition will be worsened by pregnancy. Contrary to medical dogma promulgated before World War II, initial epidemiological studies have indicated that the overall effect of one or more 125,126 As discussed in Chapter 35, subsequent pregnancies on MS-related morbidity is nil. studies involving larger patient cohorts have amply demonstrated a tendency for MS exacerbation during the first 3 postpartum months that is counterbalanced by significant 127,128 Indeed, the approximately 70 suppression of disease activity in the third trimester. percent reduction in the relapse rate of MS in the third trimester is more robust than that 129 accruing from interferon-beta, glatiramer acetate, or intravenous immunoglobulin therapy. Immunomodulation that is necessary to prevent rejection of the semiallogenic fetus is probably responsible for the dampening of third trimester disease activity in MS and other immune-mediated conditions. Factors that have been implicated in gestational immunosuppression include estradiol, progesterone, human chorionic gonadotropin, human placental lactogen, cortisol, 1,25-dihydroxyvitamin D3, α-fetoprotein, pregnancy-associated 129,130 glycoprotein, “blocking antibodies,” immunocomplexes, and interleukin-10. In animals, pregnancy significantly delays the onset of experimental allergic encephalomyelitis (a model 131,132 If for MS) after inoculation with spinal cord homogenate or myelin basic protein. necessary, intravenous steroids can be used for MS attacks in pregnancy. Interferon-beta should be discontinued 3 months before planned conception and should not be used during 129 pregnancy or while breast-feeding. In one study, none of 14 pregnant women with relapsing-remitting MS who received prophylactic intravenous immunoglobulins immediately 133 postpartum exhibited disease relapse in the first 6 months after delivery. ALZHEIMER'S DISEASE Alzheimer's disease is a common dementing illness characterized by progressive neuronal degeneration, gliosis, marked depletion of acetylcholine and other neurotransmitter disturbances, and the accumulation of senile (amyloid) plaques and neurofibrillary tangles in 134 discrete regions of the basal forebrain, hippocampus, and association cortex. At the time of publication of the third edition of this book (2001), there were promising reports suggesting that estrogens play an important role in normal human cognition, have a salutary effect on the manifestations of Alzheimer's disease, 135 and may even protect against the development of this estrogens neurodegenerative disorder in women. Fundamental research indicated that 136 exert trophic influences on cholinergic neurons of the rodent basal forebrain, induce dendritic spines (synapses) and functional N-methyl-d-aspartate receptors (important for 137 memory) in adult rat hippocampus, and induce massive neuritic growth in rodent 138 hypothalamic explants. In addition, estrogens were shown to manifest antioxidant properties, reduce the deposition of fibrillar β-amyloid, modulate apolipoprotein E expression, 139–141 suppress inflammatory responses implicated in neuritic plaque formation, and increase cerebral blood-flow and glucose utilization (which are deficient in subjects with Alzheimer's 139,140 The 1990s brought to light evidence that estrogens improve cognitive disease). behaviors in rats and monkeys, psychometric performance in women is influenced by menstrual cycle phase, cross-gender hormone therapy affects cognition in transsexual men and women, and estrogen replacement therapy augments verbal memory scores in normal 139,142–144 Moreover, early clinical studies suggested that estrogen menopausal women. replacement therapy may improve cognitive performance, especially language function, 139,142,144,145 verbal memory, and attention, in menopausal women with Alzheimer's disease,

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and enhance the146,147 likelihood of a beneficial response to acetylcholinesterase inhibitors in 148–150 In several case-controlled studies, in153 initial prospective affected151,152 women. and in a meta-analysis of 12 observational studies, postmenopausal studies, estrogen replacement therapy appeared to be associated with a significantly decreased risk of developing Alzheimer's disease. There was also some indication that postmenopausal estrogen replacement therapy protected against the development of dementia in women with 154 Parkinson's disease and that androgen (testosterone) treatment conferred cognitive 155,156 benefits in elderly men with Alzheimer's disease and mild cognitive impairment. The results of recent, large, randomized, placebo-controlled prospective trials evaluating the potential benefits of sex hormone replacement therapy in preventing the dementia of Alzheimer's disease have been disappointing. In a substudy of the Heart and Estrogen/Progestin Replacement Study (HERS), age-adjusted cognitive function scores were no different in women with coronary artery disease who received estrogen and progestin (n = 157 517) than in placebo-treated controls. Surprisingly, in the Women's Health Initiative Memory Study (WHIMS) involving over 6,000 participants, the hazard ratios for development of dementia were 1.49 for women randomized to receive 0.625 mg conjugated equine estrogen and 2.05 for those receiving 0.625158 mg estrogen plus 2.5 mg medroxyprogesterone acetate relative to placebo-treated controls. On the basis of current knowledge, and despite initial optimism to the contrary, the third Canadian Consensus Conference for the Diagnosis and Treatment of Dementia (2006) recommended against the use of estrogen/progestin replacement therapy for reducing the risk of dementia in postmenopausal women. It was also concluded that there is insufficient evidence for or against prescription of androgen replacement for cognitive dysfunction in elderly men. NEUROPSYCHIATRIC DISORDERS

The Porphyrias The porphyrias are characterized by the excessive production of porphyrins and porphyrin precursors resulting from specific enzymatic defects in the heme biosynthetic pathway. Neurological manifestations, when present, include seizures, neuropsychiatric symptoms, and sensorimotor and autonomic neuropathies. Estradiol and other steroids with a 5β configuration induce the enzyme δ-aminolevulinic acid synthase and may thereby precipitate porphyric crises. Oral contraceptives increase urinary excretion of this enzyme in normal individuals, and it has been suggested that asymptomatic relatives of patients with porphyria should avoid “the pill.” In many women with acute intermittent porphyria, cyclic attacks of variable severity may occur during the late luteal phase or, less commonly, at ovulation. Paradoxically, some patients exhibit prolonged remissions after suppression of ovarian 17 cyclicity with oral contraceptives. Although acute treatment with GnRH agonists, such as d-His or leuprolide, stimulates the pituitary-ovarian axis (Fig. 22-2), chronic administration of these agents downregulates gonadotrope GnRH receptors, resulting in long-term 159 suppression of pituitary-ovarian function. In the first reported case, d-His administration (5 μg subcutaneously daily) yielded complete remission of severe premenstrual acute intermittent porphyria for the duration (8 months) of therapy (Fig. 22-5). Similar benefits were 160 and hereditary observed in subsequent cases of catamenial acute intermittent porphyria 161 GnRH coproporphyria in response to GnRH analogue therapy. Side effects of long-term 159,161 GnRH treatment include hot flashes, diminished breast size, and bone demineralization. analogs, unlike sex159 steroids, do not appear to induce porphyrin accumulation in chick embryo hepatic cell culture and provide a rational approach to the management of catamenial porphyria.

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FIGURE 22-5 Course of symptoms, menses, and plasma hormone levels in a patient

with acute intermittent porphyria during 8 months of treatment with an agonist (d-His) of luteinizing hormone–releasing hormone. (From Anderson KE, Spitz IM, Sassa S, et al: Prevention of cyclical attacks of acute intermittent porphyria with a long-acting agonist of luteinizing hormone–releasing hormone. N Engl J Med 311:643, 1984, with permission.)

Premenstrual Syndrome The premenstrual syndrome occurs in approximately 30 percent of women during their reproductive years. Common neuropsychiatric symptoms of this disorder include headache, fatigue, depression, irritability, increased thirst or appetite, and craving for sweet or salty 162 foods. Symptoms typically begin toward the end of the luteal phase of the cycle and usually, but not invariably, resolve with the onset of flow. The pathophysiology of this disorder remains obscure. An increased luteal phase estrogen:progesterone ratio, hyperprolactinemia, disturbances of the renin-angiotensin-aldosterone axis, hypothyroidism, and abnormal 162 secretion of opioid peptides are among the causes considered for this enigmatic condition. Numerous hormonal and nonhormonal therapies—including natural progesterone, oral contraceptives, bromocriptine, GnRH agonists, diuretics, prostaglandin inhibitors, vitamin B6, and lithium—are prescribed for the management of premenstrual syndrome. However, with the possible exception of the GnRH agonists,163none has proved to be unequivocally 162 effective. In a double-blind crossover trial, induction of “artificial menopause” with a GnRH agonist (d-Trp-Pro-NEt-Gn-RH, 50 μg per day subcutaneously) relieved both physical and neuropsychiatric symptoms in eight women with rigorously defined premenstrual syndrome. Although the authors reported no side effects (except for hot flashes in one patient), prolonged hypoestrogenemia resulting from the long-term use of these agents may predispose to osteoporosis. Such therapy should probably be reserved for patients with incapacitating symptoms, and low-dose estrogen replacement may have to be considered when the duration of treatment exceeds several months.

Depression and Psychosis Depression and other major affective disorders may surface in relation to the menstrual cycle, the puerperium, and menopause. In patients with postmenopausal depression, mood 1 elevation and anxiolysis often occur promptly in response to estrogen replacement. 164 Paradoxically, oral contraceptives may precipitate depression in susceptible individuals. Estrogen has also been implicated in the pathogenesis of anorexia nervosa in view of the high preponderance of this condition in women and the potent anorexic effects of estrogen in 165 animals. Psychotic disorders characterized by extreme agitation, hallucinations, paranoid delusions, 166 incoherent speech, and mood lability may arise during the postpartum period or may recur consistently during the late luteal phase of the cycle. Such disorders may be refractory to

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conventional therapies (neuroleptics, lithium, electroconvulsive treatment) but may respond 167 well to specific hormonal interventions, including the use of oral contraceptives, 168 169 intramuscular progesterone, and danazol. “Menopause” induced by GnRH analogs may also be of considerable benefit in the management of cyclical psychosis. SLEEP DISORDERS Estrogen and progestin replacement may shorten mean sleep latencies, extend the duration of rapid-eye-movement sleep periods, and diminish nocturnal movement arousals, thereby 170–172 The GABA-active metabolites improving sleep in hypogonadal women. allopregnanolone and pregnanolone may mediate the reduction in vigilance during 173 wakefulness observed after the administration of progesterone to healthy men. Progestins may also provide stimulatory drive to brainstem respiratory centers in subjects with central 174 sleep apnea and thereby improve hypoventilation. The hypocapnic apnea threshold is lower in women than in men, and testosterone administration increases this threshold in 175 in a nonobese premenopausal women. In one case, obstructive sleep apnea resolved 176 woman after removal of a benign testosterone-producing ovarian tumor. INTRACRANIAL HYPERTENSION Progesterone has been shown to suppress post-traumatic cerebral edema and intracranial hypertension in rodents. This progestational effect has been attributed to reduction in blood–brain barrier permeability and inhibition of cerebrospinal fluid production by the choroid 177–179 Estrogens, by contrast, appear to180,181 enhance cerebral endothelial cell permeability plexus. Estrogenic attenuation of the and post-traumatic brain edema in female rats. blood–brain barrier may also play a role in the pathogenesis of pseudotumor cerebri (benign intracranial hypertension) in humans and explain the robust female predilection for this 180 disorder. NEUROMUSCULAR DISEASES

Catamenial Sciatica Ectopic endometrial tissue (endometriosis) is hormone sensitive and undergoes epithelial sloughing and hemorrhaging at the time of menses. Ectopic endometrial tissue may destroy lumbar vertebrae, producing back pain; invade the lumbosacral plexus in the retro-peritoneal 17,182 The latter causes radicular pain space; and implant within the sheath of the sciatic nerve. in the distribution of the nerve that usually begins 2 to 3 days before the onset of menses and may continue for a variable duration after cessation of flow (catamenial sciatica). In addition to pain, there is often numbness, weakness, and loss of ankle reflexes. In contrast to far more common discogenic radiculopathy, endometriotic sciatica is less likely to respond to bed rest and the imaging findings are usually unimpressive. There may or may not be evidence of endometriosis elsewhere, and surgical exploration of the sciatic nerve may be required for diagnosis. In positive cases, the nerve appears blue and a dark, hemorrhagic fluid is expressed after incision of the sheath. Biopsy specimens reveal characteristic 182 glandular elements. Symptoms of catamenial sciatica may show dramatic improvement with standard therapy for endometriosis, including danazol, progestins, and in refractory 47,182 cases, bilateral oophorectomy.

Other Neuromuscular Disorders Endogenous and administered sex hormones (mainly estrogens) may influence the natural 41 history of Bell's palsy, recurrent brachial plexopathy, and the carpal tunnel syndrome. Abnormally high estrogen levels have been reported in male patients with amyotrophic lateral sclerosis, Kugelberg–Welander disease, bulbo-spinal muscular atrophy (Kennedy's syndrome), Duchenne muscular dystrophy, and the Crow–Fukase syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein,17,183 and skin changes [POEMS It is unclear whether syndrome], usually associated with plasma cell dyscrasias). hyperestrogenemia plays any significant role in the pathogenesis of these neuromuscular disorders. In an anecdotal report, high-dose testosterone therapy yielded considerable 184 symptomatic improvement in a patient with bulbospinal muscular atrophy. The authors conjectured that the testosterone therapy may have ameliorated some toxic gain of function ascribed to the mutated androgen receptor in this condition. Finally, Mastrogiacomo and co-workers have hypothesized that dysfunction of testicular peritubular myoid cells and corpus cavernosum smooth muscle may be contributing to the hypergonadotropic 185 hypogonadism and impotence that complicate myotonic dystrophy in men. CONCLUDING COMMENTS

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Sex hormones influence a broad spectrum of normal and abnormal neurological functions. Relationships between endogenous and exogenous sex hormones and many neurological conditions, such as migraine, stroke, and chorea, are well established. In other diseases, including such diverse entities as primary CNS neoplasms and various movement disorders, this relationship has not been confirmed but appears likely in the light of rapidly accumulating clinical, epidemiological, and biochemical data. Fluctuating sex hormone levels also influence the expression of certain neuropsychiatric states and neuroendocrine disorders. The ubiquitous nature of these interactions warrants routine inquiry into potential symptom modifications associated with the menstrual cycle, pregnancy, menopause, and hormonal contraceptive exposure in women with neurological and psychiatric illness. A more thorough understanding of the mechanisms mediating sex hormone–related neural function and dysfunction should facilitate the refinement of rational hormonal and antihormonal therapies for many of the conditions discussed in this chapter. ACKNOWLEDGMENT The author thanks Adrienne Liberman for assistance in preparation of this manuscript. Previous

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Aminoff: Neurology and General Medicine: Other Endocrinopathies a...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 23 Other Endocrinopathies and the Nervous System CHERYL A. JAY • GARY M. ABRAMS •

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PITUITARY GLAND Sellar and Parasellar Lesions Anterior Pituitary Prolactin Growth Hormone Adrenocorticotropic Hormone and Cushing's Disease Thyroid-Stimulating Hormone Clinically Nonfunctioning Pituitary Adenomas Pituitary Apoplexy Posterior Pituitary Diabetes Insipidus Syndrome of Inappropriate Antidiuretic Hormone Secretion Cerebral Salt Wasting Hypopituitarism PARATHYROID GLANDS Primary Hyperparathyroidism Hypoparathyroidism ADRENAL GLANDS Cortex Hyperaldosteronism Cushing's Syndrome Adrenal Insufficiency Medulla Pheochromocytoma and Related Disorders

The endocrine and nervous systems interact in intricate ways, and hence it is not surprising that disorders in one system may cause clinically evident dysfunction of the other. For example, anterior pituitary tumors produce symptoms principally as the result of hormonal hyperfunction when small and of either hypersecretion or hyposecretion and dysfunction of 1 adjacent cranial nerves or hemispheric structures when large. The protean clinical features of hormonal2,3 excess and deficiency states include both central and peripheral nervous system dysfunction. Conversely, various cerebral disorders may cause posterior pituitary dysfunction, such as diabetes insipidus and the syndrome of inappropriate secretion of antidiuretic hormone.

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In general clinical practice, the most common endocrine disorders causing neurological disease are likely diabetes mellitus and thyroid disease, topics addressed in Chapters 20 and 21. Specific central or peripheral nervous system complications may develop on a background of known diabetes mellitus or thyroid disease, or the neurological syndrome may suggest a diagnosis of these endocrine disorders. The same is true for the neurological manifestations of parathyroid and adrenal disorders, whose numerous systemic and neurological manifestations can make diagnosis of these less common, yet treatable, disorders quite challenging. Finally, hormonal therapy or its cessation influences the course of various neurological disorders and may lead to specific central and peripheral nervous system complications. The neurological aspects of sex hormones are reviewed in Chapter 22. Prescribed for diverse systemic and neurological indications, corticosteroid administration or withdrawal is a common cause of hyperadrenalism or hypoadrenalism. In this chapter, disorders of the pituitary, parathyroid, and adrenal glands are reviewed, with particular focus on features relevant to neurological practice. PITUITARY GLAND The complex anatomy of the sellar region influences the clinical features of pituitary 4 disorders. The pituitary gland, or hypophysis, sits in the sella turcica, a bony depression in the posterior sphenoid bone. The tuberculum sellae and anterior clinoid processes form the anterior boundary of the sella turcica, and the dorsum sellae forms its posterior margin. Dural reflections border the pituitary superiorly and laterally. The diaphragma sellae, which contains a central opening that allows passage of the pituitary stalk into the pituitary fossa, forms the roof of the sella turcica. Adjacent to the pituitary bilaterally are the cavernous sinuses, which drain the ophthalmic and middle and inferior cerebral veins, and the sphenopalatine sinus. In addition, the carotid artery and cranial nerves III, IV, V1, V2, and VI pass through the cavernous sinus. The anterior pituitary, or adenohypophysis, derives embryologically from Rathke's pouch, an evagination of the oropharyngeal membrane, which originates from ectoderm. The adenohypophysis is composed of three parts: pars distalis, constituting most of the anterior pituitary; pars tuberalis, a small extension of pars distalis adherent to the infundibulum; and pars intermedia, vestigial in adults and thought to have little functional significance in 4 humans. Hormones secreted by the anterior pituitary include prolactin, growth hormone (GH), adrenocorticotropic hormone (ACTH), thyrotropin (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The hypothalamus controls anterior pituitary hormone secretions through various hypophysiotropic substances, most of which are peptides (Table 5 23-1). The superior hypophysial artery, a branch of the internal carotid, supplies a hypothalamic capillary bed linked to the anterior pituitary capillary bed by portal veins that may be capable of bidirectional flow. Adenohypophysial capillaries also drain into the posterior pituitary and cavernous sinus. The unique vascular anatomy of the hypophysial-portal system provides the basis for feedback loops that regulate the 6 hypothalamic-pituitary axis. Click here to view this table.... The posterior pituitary, known also as the neurohypophysis or pars nervosa, derives from a neuroectodermal extension of diencephalon that fuses with Rathke's pouch. Also of neuroectodermal origin is the infundibulum, which directly links the pituitary to the hypothalamus at the median eminence, which also forms the floor of the third ventricle. The optic chiasm liessuperior to the pituitary and anterior to the pituitary stalk. Neurohypophysial hormones include oxytocin and antidiuretic hormone (ADH), or vasopressin. The inferior hypophysial artery, a branch of the cavernous carotid, supplies the neurohypophysis. The juxtaposition of the pituitary gland to hypothalamus, third ventricle, cavernous carotid arteries, and cranial nerves related to vision, extraocular movements, and mid- and upper facial sensation accounts for many of the neurological manifestations of lesions in and around the sella. Endocrine disturbances arising from excess or insufficient secretion of one or more pituitary hormones may also cause neurological as well as systemic symptoms, signs, and laboratory abnormalities. Improved neuroimaging techniques have greatly 4,7 facilitated assessment of sellar and parasellar lesions. A detailed discussion of the increasingly complex array of stimulation and inhibition studies used to assess the integrity of 5 specific elements of the hypothalamic-pituitary axis is beyond the scope of this chapter. However, a basic understanding of pituitary hormone physiology is essential to evaluating patients with mass lesions in and around the gland and is reviewed here after a discussion of the neurological symptoms and signs resulting from these lesions.

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Sellar and Parasellar Lesions Pituitary adenomas are the most common sellar region mass and account for 10 to 15 4,5 percent of intracranial neoplasms. Classification based on histological staining properties, which designated these anterior pituitary tumors as acidophilic, basophilic, or chromophobic, has given way to categorization by the hormone or hormones secreted and more recently by 1,8,9 Pituitary adenomas are also classified by size. Microadenomas (Fig. cytodifferentiation. 23-1A), lesions that are 10 mm or smaller, typically spare adjacent neural or vascular structures and generally come to medical attention during evaluation for symptoms and signs of hormone oversecretion. Lesions larger than 10 mm are called macroadenomas (Fig. 23-1B). In addition to causing manifestations of hormone excess, these larger tumors may impair normal glandular function, resulting in hypopituitarism, or compress adjacent neural or 1,8 vascular structures, causing neurological dysfunction. Common clinical symptoms include visual loss, ophthalmoparesis, facial sensory symptoms, and headache. Macroadenomas extending superiorly compress the optic chiasm, nerves, or tracts. Bitemporal hemianopia is10 the classic syndrome, although monocular visual loss or junctional scotoma also may occur. Because adenomas grow slowly, visual deficits may not be appreciated by the patient until they are quite advanced. Third ventricular extension occasionally causes acute or chronic hy drocephalus. Lateral extension, with subsequent cavernous sinus involvement, disturbs extraocular motility and sensation in the upper and middle face. Head pain may be quite5 nondescript, mimicking tension-type headache, and does not correlate with lesion size. Very large lesions involving inferior frontal or medial temporal lobes may cause cognitive impairment, behavioral changes, and seizures. A few pituitary tumors extend inferiorly, causing epistaxis or cerebrospinal fluid (CSF) rhinorrhea.

FIGURE 23-1 A, Microadenoma. Gadolinium-enhanced T1-weighted magnetic

resonance imaging (MRI) shows a small focus of decreased enhancement compatible with microadenoma in a young woman with galactorrhea-amenorrhea. B, Macroadenoma. Large sellar lesion, subsequently shown to be a nonsecretory adenoma, in a gadolinium-enhanced T1-weighted MRI obtained in a middle-aged man with progressive visual loss. The extensive differential diagnosis of sellar region masses includes other pituitary tumors, nonpituitary neoplasms, metastases, infectious and inflammatory disorders, vascular lesions, and cysts (Table 23-2). Most of these lesions are quite rare. Click here to view this table.... Craniopharyngiomas account for nearly 3 percent of intracranial tumors and arise from 4 epithelial cell rests of Rathke's pouch. Among malignant lesions, pituitary carcinomas are quite rare; metastases to the pituitary are recognized more frequently at autopsy than during 11 life. Among more common disorders, the empty sella syndrome is often associated with an incompetent diaphragma sellae, which allows arachnoid and CSF to herniate into the sella. Typically an incidental finding on neuroimaging studies, the empty sella syndrome is not 4,7 usually associated with endocrinopathy. Other non-neoplastic sellar lesions include granulomatous processes, such as tuberculosis or sarcoidosis, and vascular lesions, 1,5 particularly cavernous carotid aneurysms or cavernous sinus thrombosis. Magnetic resonance imaging (MRI) before and after gadolinium enhancement, with high-resolution thin sections in the sagittal and coronal planes, allows visualization of the pituitary stalk and surrounding neural and vascular structures, and is the test of choice for

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pituitary-region imaging. On T1-weighted images, high signal intensity in the posterior pituitary 4,7 is referred to as the bright spot and is believed to represent ADH in neurosecretory vessels. Pituitary adenomas typically enhance less intensely than normal glandular tissue (Fig. 23-1A). Dynamic imaging, which acquires images rapidly in a time-scale synchronous with the microcirculation, may improve detection of microadenomas. In patients who cannot undergo MRI, precontrast and postcontrast computed tomography (CT) images through the area can be obtained. A consequence of modern neuroimaging is detection of the 12 asymptomatic pituitary mass, the so-called pituitary “incidentaloma.”

Anterior Pituitary Prolactin Prolactin acts on mammary tissue to promote lactation, in addition5to inhibiting cyclic gonadotropin secretion and directly suppressing gonadal function. Hypothalamic control of basal prolactin secretion occurs primarily by inhibition, with the major inhibitory factor being dopamine. An important clinical consequence is that pituitary stalk disruption from lesions other than prolactinomas may elevate serum prolactin levels, although rarely above 200 5 mild ng/ml (normal 1:20,000. In type II, there is variable density that leads to characteristic “endobones” in the spine, iliac wings (“bone in bone” appearance), and skull 75 base. Both77types present in adulthood and are often found incidentally on routine radiographs. About 50 percent of patients are asymptomatic, and another 40 percent have fractures or osteomyelitis. Bone marrow failure does not occur. Neurological involvement occurs in 16 percent of cases; cranial nerve palsies occur as the result of bony 78 The second, seventh, and eighth cranial nerves are the most commonly encroachment. 74 affected. Type III, or “centrifugal osteopetrosis,” is characterized by sclerosis of the distal 75 appendicular skeleton and the skull with only minor involvement of the axial skeleton. Carbonic anhydrase II deficiency (also known as Guibaud–Vainsel syndrome or marble brain disease) is an autosomal-recessive disorder resulting in osteopetrosis, renal tubular acidosis, 75 and cerebral calcification. It presents in late infancy or early childhood with developmental delay, short stature, failure to thrive, dysmorphic features, weakness, cranial nerve compression, and a history of multiple fractures. Motor retardation occurs during the first year of life. Patients may have apathy, global hypotonia, or muscle weakness that may be explained by acidosis and diminished blood levels of potassium from their renal tubular acidosis. Rarely, hypokalemic weakness or paralysis occurs episodically. More than one half of all patients develop cranial nerve deficits, particularly optic atrophy, facial palsy, and 79 deafness. Plain radiographs show increased density in the long bones, vertebral bodies, pelvis, and skull. Cranial CT shows diffuse calcifications of the brain, particularly the basal 71 can be made by erythrocyte assay or by molecular probes for ganglia. The diagnosis 80 been found in the carbonic anhydrase carbonic anhydrase II. Five different mutations have 81 II gene on the long arm of chromosome 8 (8q22). Prenatal diagnosis must be made at the DNA level, because carbonic anhydrase II is not expressed in fetal erythrocytes. There is no established treatment for this condition, and bicarbonate treatment does not clearly reverse the growth retardation. Infantile neuroaxonal dystrophy is a rare autosomal-recessive disorder with widespread accumulation of neuroaxonal spheroids in cortex, basal ganglia, mesencephalon, brainstem, 75 and spinal cord, which has been reported in association with osteopetrosis. It presents during the first year of life with weakness, hypotonia, rigidity, pyramidal signs, diminished pain sensation, optic atrophy, and mental impairment. This is accompanied by hypocalcemia, hypomagnesemia, severe anemia, thrombocytopenia, hepatosplenomegaly, jaundice, and metabolic acidosis. Cranial CT shows agenesis of the corpus callosum and ventriculomegaly. This form of osteopetrosis is fatal within the first year of life.

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Aminoff: Neurology and General Medicine: Neurological Disorders A...


Transient infantile osteopetrosis that spontaneously resolved by the age of 28 months has been reported in a child. Unlike malignant osteopetrosis, the child was asymptomatic without abnormal physical findings or hematopoietic impairment. The osteoclasts appeared normal on bone biopsy, and the spontaneous resolution of radiographic abnormalities soon after birth 75 differentiated this transient osteopetrosis from the malignant form. PAGET'S DISEASE OF BONE Paget's disease is a focal disorder of bone turnover. There is excessive bone resorption coupled with abnormal new bone formation resulting in architecturally disorganized and 82 mechanically weak bone. It has a predilection for the axial skeleton and involves the cervical spine in 14 percent,82thoracic spine in 45 percent, lumbar spine in 58 percent, and studies skull in 42 percent of cases. The prevalence based upon autopsy and radiographic 83 is 3 to 3.7 percent, and it is found primarily in populations of Anglo-Saxon origin. Its 84 prevalence increases with age. There is a family history in 14 to 40 percent of patients. The etiology is poorly understood and may relate to a combination of 82 genetic susceptibility, environmental factors, and a viral agent such as paramyxovirus. Three genes are identified in familial Paget's disease and related disorders. They encode RANK, a receptor that regulates osteoclast activity; osteoprotegerin, a decoy receptor for RANK; and sequestosome 84 1, a scaffold protein in the NF-κB signaling pathway. Histologically, increased bone resorption is followed by a mixed osteolytic-osteoblastic phase, with deposition of poorly 82 organized bone with ineffective mineralization. The bones are thickened, with replacement of the marrow by highly vascularized fibrous tissue. Later, there is primarily abnormal bone deposition. 82

Most patients with Paget's disease are asymptomatic. The most common presentation in symptomatic patients is local bone pain with overlying skin warmth due to increased bone microvasculature. The pain is continuous and worse at rest. There may be obvious deformity of the bones. Skeletal complications include osteoarthritis, fractures, and sarcomatous 82 change. 82

Plain radiographs may show lytic lesions early in the disease. Later, there is a chaotic crisscross pattern with thickened cortical and trabecular bone, sometimes accompanied by pseudofractures. Bone scintiscanning may reveal lesions not seen by plain films. Markers of bone turnover are often elevated, including serum alkaline phosphatase and urine hydroxyproline. 82,85

Asymptomatic patients Treatment depends on the location and activity of the disease. often do not require treatment. Calcitonin inhibits osteoclast activity and can be effective in the acute setting. Relapses are common. Bisphosphonates produce a marked and prolonged inhibition of osteoclast function, and newer agents such as alendronate and risedronate are used for chronic treatment. The bisphosphonates are currently first-line therapy for active Paget's disease. A recent study showed alendronate had equivalent efficacy to intravenous 86 pamidronate in previously untreated patients (91% versus 86%). Alendronate resulted in biochemical remission in 86 percent of patients who did not respond to pamidronate. Adherence to oral bisphosphonates is impacted by the need to fast before and after treatment and to remain upright for at least 30 minutes after ingestion to reduce the risk of upper gastrointestinal side effects. A study comparing a single infusion of zoledronate to a 2-month course of daily risedronate therapy showed a therapeutic response in 96 percent 87 of patients receiving zoledronate compared to 74.3 percent of patients receiving risedronate. The relapse rate in the zoledronate group was significantly lower than in the risedronate group (0.9% versus 25.6%). Calcium supplementation is recommended to prevent symptomatic hypocalcemia. Surgical treatment is sometimes required to treat fracture, osteoarthritis, and bone deformity. Conventional bone scan is recommended prior to medical therapy and at 6 months and 12 months after medical therapy to monitor disease activity. Bone markers should be monitored every 3 to 6 months. Neurological involvement occurs as a result of the close anatomical relationship of bone with 82,88 Compression from the brain, spinal cord, cauda equina, spinal roots, and cranial nerves. expanding bone or fracture is the most common cause of neurological dysfunction. Less common causes include ossification of extradural structures, osteosarcoma, and epidural hematoma. Ischemia of the nervous system can occur owing to compression of vascular structures or a vascular steal phenomenon. Measurement of skeletal blood-flow by 18 F-clearance demonstrates that affected bone receives up to 18 percent of the cardiac 89 output compared with 5 percent in normal bone. Calcitonin reduces the abnormal skeletal blood-flow to normal. The incidence of neurological involvement from cranial disease is unknown. Irreversible

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82

hearing loss occurs in 13 percent of patients, but other neurological complications of cranial disease, such as headache, epilepsy, dementia, brainstem and cerebellar dysfunction, and 90 cranial neuropathies, are rare. Headache is severe, frequently occipital, and worsened by coughing, sneezing, or straining. Dementia occurs from direct compression of the cerebral 91–93 In its94extreme, dementia is accompanied by hemispheres or as a result of hydrocephalus. a paucity of motor activity resembling akinetic mutism. Epilepsy occurs as a result of 91 compression of the cerebral hemispheres. In advanced cranial disease, there is softening of the skull base that can result in an anatomical lowering of the skull onto the upper cervical vertebrae (basilar invagination). This leads to obstructive hydrocephalus and compression of the cerebellum, lower cranial nerves, corticospinal tract, and upper cervical nerves. The severity ranges from asymptomatic to acute tonsillar herniation and death. The typical presentation is that of slowly progressive ataxia, vertigo, tinnitus, dysphagia, dysarthria, and occipital headache. Basilar invagination can result in vertebrobasilar insufficiency as well as obstructed venous return. An unusual picture resembling amyotrophic lateral sclerosis has been reported in association with 90 cervical cord involvement. Any of the cranial nerves may be affected, but the olfactory and auditory nerves are95the most 90 commonly involved. Hearing loss is common, occurring in 37 percent of patients. It may be neuronal, conductive, or of mixed type. The cochlea is the most common site of involvement. The optic nerve may be affected at the optic foramen by compression or from compromise of the vasa nervorum. Clinically, there is diminished vision or 91 blindness, retinal hemorrhages, choroiditis, optic atrophy, papilledema, and angioid streaks. The oculomotor nerves (III, IV, and VI) are vulnerable as they pass through the superior orbital fissure, with resulting diplopia and pupillary abnormalities. Exophthalmos from direct impingement of the extraocular muscles rarely occurs. Trigeminal nerve involvement leads to facial numbness and trigeminal neuralgia. Involvement of the facial nerve (VII) may result in hemifacial spasm 95 or facial paresis with a frequency of 8.3 percent. 96

Osteosarcoma of the skull occurs in less than 1 percent of patients with Paget's disease. It usually presents as a partially fluctuant and locally painful skull mass with rapid neurological deterioration after long-standing “benign” bone disease. The prognosis is poor despite radiation therapy and 83 surgery. The occurrence of an associated sarcoma is linked to a gene on chromosome 18q. Epidural hematomas may cause acute compression of the spinal cord or brain and relate to the increased blood flow to bone and increased risk for 97–100 The prognosis in these cases is also poor, owing to excessive pathological fractures. bleeding during surgery. The spine is the second most common site of involvement in Paget's disease and may result 83 in symptoms of spinal stenosis. Mechanisms of neurological compromise include (1) direct compression of the spinal cord, cauda equina, or nerve roots by enlarged vertebrae or expansion of the facet joint; (2) pathological fractures or subluxation; (3) ossification of extradural structures; (4) diversion of the local blood supply to the highly vascular bone; and 88 (5) pressure on vessels as they pass through the intervertebral foramina. Compression of neural structures by the expanding pagetic vertebrae is the most common cause of 101,102 The onset of neurological dysfunction. Sarcomas or epidural hematomas are rare. continuous severe spinal pain and rapid neurological deterioration in association with an 93,103 affected vertebra should raise concern of osteosarcoma. 83

Back pain occurs in 11 to 43 percent of patients with involvement of the spine. Osteoarthritis is prevalent in this elderly population and can be hard to distinguish from 83,103 Other changes in the spine include Paget's disease as the cause of back pain. thickening of the pedicles and laminae, flattening of the vertebral bodies, and encroachment of the spinal canal by osteophytes. Involved vertebrae are increased in width and reduced in height. The most commonly involved levels are the upper and lower cervical, low thoracic, 103 and mid-lumbar vertebrae. Of the patients with involvement of the spine by plain radiographs, two thirds will have evidence of spinal stenosis by CT and104 half of those patients will have clinical evidence of myelopathy or a cauda equina syndrome. There is no association between number of vertebrae involved and presence of symptomatic spinal 83 stenosis. Low back pain may respond to treatment with bisphosphonates. Pain that does not respond to antipagetic therapy after 3 months should be treated with nonsteroidal anti-inflammatory agents. Spinal stenosis should first be treated with antipagetic therapy. Improvement or reversal of symptoms is 83 demonstrated with calcitonin, mithramycin, etidronate, pamidronate, and clodronate. Prompt surgical decompression is appropriate for patients who do not respond to pharmacological treatment. Preoperative assessment of bone vascularity by radionuclide bone blood-flow can help direct perioperative medical therapy and prevent massive bleeding.

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Extradural ossification of the ligamentum flavum and epidural fat can105–107 result in compression of Myelopathy and the spinal cord or nerve roots and requires surgical decompression. cauda equina syndrome can occur without evidence of compression on neuroimaging, however, and respond dramatically to medical therapy, suggesting that ischemia due to a 108–110 vascular steal phenomenon is responsible. Serum alkaline phosphatase concentrations and urine hydroxyproline are usually increased in patients with neurological complications, 111 but alkaline phosphatase levels are normal in almost one third of patients with spinal stenosis. Plain radiographs and radionuclide scans should be obtained to localize disease activity and identify pathological fractures. Cranial CT or MRI, and CT myelography or MRI of the spine are necessary to demonstrate compression of neural structures and to exclude other causes for symptoms (Fig. 24-4). Sarcomatous transformation is best assessed withMRI. The use of MRI perfusion scans to assess vascular steal may be of clinical value in the future. Patients with neurological complications should have serum alkaline phosphatase and urinary hydroxyproline level determinations every 6 months. Clinical monitoring of neurological function in symptomatic patients and repeat radiographs of the skull and weight-bearing long bones are recommended every 6 to 12 82 months in patients with osteolytic lesions.

FIGURE 24-4 Paget's disease of bone. Axial-view CT scan of the head with

bone windows. The white arrow shows thickened osteosclerotic bone anteriorly. The black arrow shows thickened hypodense osteolytic bone posteriorly. The type of treatment required for the neurological complications of Paget's disease depends on their location, basis, and clinical course. Asymptomatic disease affecting the skull or spine 82,85 Patients with neurological compromise may should be treated with bisphosphonates. 82,85,89,108,110,112–117 The respond to calcitonin, etidronate, and/or intravenous palmidronate. newer oral bisphosphonates, such as alendronate or risedronate, are recommended for patients with slowly progressive symptoms. Intravenous bisphosphonates are sometimes

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effective in cases where calcitonin or oral bisphosphonates fail ; decompressive surgery may otherwise be necessary. Rapidly progressive neurological deterioration should be treated with calcitonin or intravenous bisphosphonates before surgery to minimize bone hemorrhage intraoperatively. Obstructive hydrocephalus does not respond to medical therapy and requires the placement of a ventricular shunt. Hydrocephalic dementia with memory loss, gait disturbance, and 118,119 urinary incontinence may improve with shunting and bisphosphonate85therapy. Bisphosphonate treatment results in the stabilization of hearing loss. Memory loss and optic 114 neuritis may respond to a combination of etidronate and91calcitonin. Trigeminal neuralgia and hemifacial spasm are treated with carbamazepine. Hemifacial spasm may also 95 Facial nerve paresis sometimes responds to surgical respond to calcitonin or alendronate. 91 decompression, and there are older reports of benefit with suboccipital93craniectomy and upper cervical laminectomy for patients with lower cranial neuropathies. Botulinum toxin injection is an option for hemifacial spasm that is refractory to medical treatment. Surgical treatment of spinal disease is difficult because involvement is often at multiple levels, vascular bone leads to problematic bleeding, and patients are generally in an older age group. A review of 65 111 surgical cases showed some degree of benefit in 85 percent but an 11 percent mortality rate. Reoperation was required in 9 percent. Medical treatment (calcitonin or bisphosphonates) for symptomatic spinal stenosis has been reported to result in marked or complete110,113,117 reversal of myelopathy or cauda equina syndrome in more than 80 percent of Relapses may occur after calcitonin, bisphosphonates, or surgical patients. 108,111–113,115,116 and benefit may then follow repeating or changing therapy. treatment, VERTEBRAL OSTEOMYELITIS Infection of bone may be due to a wide variety of pathogenic microorganisms, including pyogenic bacteria, mycobacteria, and fungi. Although osteomyelitis of the long bones may occasionally involve injury to peripheral nerves, and infection of the facial and skull bones may lead to extradural abscess formation, meningeal infection, and venous sinus thrombosis, it is infection of the vertebrae that is most often associated with neurological complications. 120 Recent observations suggest an increasing incidence. Bacteria may reach the spine by hematogenous spread from a distant source of sepsis, may spread from a local focus of 121 contiguous infection, or may be introduced by direct penetrating trauma or surgery. The lumbar spine is most commonly affected, followed by the cervical spine. With hematogenous spread, septic emboli lodge in the metaphyseal subchondral area of the vertebra, often causing bone infarction. Ischemic necrosis may result in the formation of islands of devascularized bone (sequestra). Infection within the vertebral body tends to spread sequentially to involve the adjacent intervertebral disc and then the next adjacent vertebra (spondylodiscitis). This propensity to traverse the disc space distinguishes osteomyelitis from neoplasia, which tends to remain confined. Abscesses may form within the disc or in adjoining tissues when infection extends beyond the cortex of the vertebra. An epidural abscess may cause radicular injury or, more ominously, spinal cord compression. Extraspinal abscesses may track to a variety of sites (paraspinal, retroperitoneal, psoas). Chronic osteomyelitis is characterized by necrosis of bone, a predominantly mononuclear infiltrate, fibrosis, and few organisms. A sinus tract may develop between bone and skin. Osteomyelitis resulting from blood-borne bacterial seeding is almost always the result of infection by a single organism. Diabetes and chronic alcoholism are risk factors. More than half of infections are due to Staphylococcus aureus (in recent series, methicillin-susceptible staphylococci accounted for the majority) and are often associated with vascular catheters 122 and invasive medical procedures. Other organisms commonly involved include Escherichia coli and other gram-negative bacteria, Brucella, and fungi (Candida). Pseudomonas and staphylococcal infections are associated with intravenous drug use. Streptococci and 123,124 Tuberculous infection of the enterococci are frequently associated with endocarditis. spine is discussed separately. Trauma and spread of contiguous infection often produce polymicrobial (“mixed”) cultures. S. aureus is again commonly implicated, but gram-negative and anaerobic bacteria are also frequently involved. Back pain, often with local tenderness, is the most frequent presenting feature of spinal 125,126 The clinician should be alerted by pain that is not relieved by rest and that osteomyelitis. persists at night. The spine may be held rigidly, with paraspinal muscle spasm. In many patients, back pain is preceded by a subacute prodrome of constitutional symptoms—fever, fatigue, lethargy, anorexia—that may last for several weeks. By the time of initial presentation, however, the patient may be afebrile with few other signs of systemic ill health. Neurological deficit occurs in only approximately half the patients. Encroachment on sensory

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and motor roots gives rise to pain and segmental sensorimotor loss. A cauda equina syndrome may result from compression of multiple lumbosacral roots. Epidural abscess formation with compression of the spinal cord may develop acutely or subacutely over several weeks and requires immediate surgical decompression. Because of the frequency of back pain due to other etiologies and the nonspecific character of the clinical presentation, a high index of clinical suspicion is required for the prompt diagnosis of osteomyelitis; this is crucial, because effective antibiotic therapy may prevent necrosis of bone with permanent skeletal abnormality, but diagnosis is unfortunately often delayed. Plain radiography is frequently normal in the first 2 to 4 weeks, since lytic lesions are not apparent until significant bone loss has already occurred. Erosions may be seen at the endplates, and the disc space is narrowed. Spinal CT may provide additional details of bony anatomy, but MRI is necessary to define the anatomy of neural structures within the spinal canal and the surrounding soft tissues (Fig. 24-5). In early disease, vertebral body edema may be the sole imaging abnormality; other findings include spondylodiscitis, erosion of bone, and intra- and extra-vertebral collections. Radionuclide bone scanning is highly sensitive but not specific; it is particularly useful where MRI may be contraindicated because of spinal instrumentation. Scintigraphy also reflects the activity of a focus of infection, allowing a 127 measure of the response to therapy.

FIGURE 24-5 Osteomyelitis. Sagittal T1-weighted MRI of the lower thoracic

spine, with contrast. A septic focus is seen to involve the intervertebral disc and the two adjacent vertebral bodies. An epidural abscess compresses the thecal sac. Specimens for microbiological culture and anti-biotic sensitivity should always be obtained before the institution of antibiotic therapy. Blood culture may be positive in one third of cases. Material from the focus of infection may be obtained by needle aspiration or bone biopsy. Antibiotics are introduced in high dose and administered intravenously. Empirical treatment (usually a penicillinase-resistant penicillin plus a third-generation cephalosporin) may be necessary before the microbiology results are available. Further therapy is then guided by these results. Antibiotics are generally initiated intravenously and may be continued for an extended period of weeks to months before switching to an oral preparation once a favorable response has been achieved. Imaging abnormalities tend to persist despite clinical128and laboratory measures of improvement, and are not necessary for routine follow-up. Bed rest with external immobilization is generally enforced until back pain has receded. With appropriate antibiotic therapy, recovery is the rule; surgery is required in 10 to 20 percent of

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cases, in general for drainage of large abscesses, decompression in cases of progressive neurological deficit, fixation for spinal instability, and débridement in severe, unresponsive 129,130 Residual disability is seen in approximately one third of patients, particularly infection. 131 those with structural damage to the spine. Osteomyelitis resulting from trauma or contiguous infection is often polymicrobial and requires broad-spectrum antibiotic therapy and, frequently, surgical débridement. The management of chronic osteomyelitis is difficult and controversial, usually requiring complete surgical removal of the nidus of infection, together with long-term antibiotic therapy. There is no consensus regarding timing of surgery, operative approach, or the use of 132 instrumentation. POTT'S DISEASE Tuberculous spondylitis with kyphotic deformity of the spine was first reported in detail by Sir Percivall Pott in the late eighteenth century, although the condition had been133 recognized in antiquity, and Pott was not aware of the tuberculous etiology of the disease. The features of Pott's disease have been demonstrated in preserved human remains dating from Egyptian times. In early clinical series, tuberculous involvement of bone and joint tissues was seen in 8 to 9 percent of cases of extrapulmonary tuberculosis, with the spine as the most common site. The incidence of tuberculosis in the Western world has declined in recent times with the introduction of specific chemotherapy and the success of public health measures. In contrast to the patients first described by Pott, who were all infants and young children, Pott's disease in developed societies is largely a disease of adults. Tuberculosis has become increasingly prevalent in the immunosuppressed population, particularly those infected with the human 134 immunodeficiency virus. It is a treatable condition, with a significant likelihood of permanent disability if the diagnosis is delayed. Tuberculous infection of the spine, although occasionally a presenting manifestation of the underlying infection, is most often a late feature, representing reactivation of a focus of latent infection with hematogenous or lymphatic spread to the spine, often years after the initial pulmonary infection. Typically, the vertebral body is affected, most commonly in the thoracic and upper lumbar spine. This is followed by spread to adjacent vertebrae, often with involvement of the intervening disc, and loss of disc space height. Destruction of cancellous bone renders the involved vertebral body liable to compression fractures and vertebral body collapse. A wedge fracture in the anteroposterior plane may produce kyphosis. In advanced cases, both kyphosis and scoliosis produce a striking gibbous deformity. 135,136 Compression of the Such spinal cord is an unusual but devastating consequence of Pott's disease. compression may be seen in association with spinal deformity, but it may occur in its absence with the formation of an epidural abscess within the spinal canal. Extension of infection outside the spine may result in the formation of paravertebral collections at various sites including within the psoas muscle. Back pain, often with local tenderness, is the most common clinical manifestation of Pott's disease. A predilection for the thoracolumbar junction distinguishes it from degenerative disc disease, which is most commonly seen in the cervical or lumbosacral regions. Constitutional symptoms (lethargy, night sweats, weight loss) and systemic signs (anemia, low-grade fever) are frequent but may not be prominent. Neurological features are present in fewer than half of patients. Radicular symptoms and signs reflect involvement of the sensory and motor roots at the level of the lesion; myelopathic features may herald the development of spinal cord compression and represent a medical emergency. Paraplegia occurs in up to 10 percent of patients. The possibility of tuberculous infection of the spine may be a clear consideration in patients with recognized pulmonary tuberculosis, particularly when treatment was incomplete, or in immunosuppressed patients, but137only a minority of patients have a history of previous tuberculosis or tuberculous contacts. In other instances, a high index of clinical suspicion and appropriate (radiological) investigations are needed for recognition. In many series, diagnosis was delayed for 12 to 18 months after presentation. Differential diagnosis includes neoplastic disease of the spine, pyogenic and fungal osteomyelitis, inflammatory conditions, and sarcoid arthritis. There may be few clues to the diagnosis on routine tests: erythrocyte sedimentation rate and C-reactive protein are likely to be elevated, and the peripheral white count may be normal or slightly elevated.138Chest radiography is often completely normal, and sputum negative for acid-fast bacilli. Plain radiographs of the spine are often unremarkable but may show involvement of adjacent vertebral bodies, with reduction in the intervening disc space height representing disc involvement. CT scan and particularly MRI of the spine provide the greatest

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139,140

detail ; characteristic findings include involvement, often with heterogeneous enhancement, of several contiguous vertebral bodies, with either sparing or involvement of the intervening discs, and the presence of epidural and subdural collections. In contrast, pyogenic infections typically involve the disc (“spondylodiscitis”) and tend to enhance 138 homogeneously. Late-stage disease with kyphosis is the result of pathological fractures of the vertebral bodies and destruction of all elements of the motion segment. MRI is particularly helpful in demonstrating encroachment onto the spinal cord and roots. Radiological changes tend to persist, suggesting that imaging need not be repeated in patients with clinical and 128,141–144 laboratory measures of improvement. Confirmation of the tuberculous nature of such a radiographically identified lesion is usually straightforward (and is necessary in the absence of pulmonary manifestations for a definitive diagnosis). Biopsy (needle aspiration or open biopsy) demonstrates the characteristic caseating granulomatous histology with Langhans giant cells and acid-fast bacilli, and culture is frequently positive. In most cases, a purified protein derivative (PPD) skin test is positive. Treatment is with prolonged antituberculous chemotherapy. There is often a rapid response to treatment as judged by clinical and laboratory measures. Surgery is sometimes required in addition to drug therapy, particularly for those patients with spinal instability or severe 145,146 Spinal cord compression is a medical disease, but should not be routinely performed. emergency necessitating immediate surgical decompression. “Cold abscesses” at other sites may also require drainage. ANKYLOSING SPONDYLITIS Ankylosing spondylitis is an HLA-B27–associated chronic inflammatory disease affecting the 147 sacroiliac joints, spine, and peripheral joints. Pathologically, there is synovitis and inflammatory lesions of ligamentous attachments (enthesopathy) with local erosion of bone. This is followed by calcification and ankylosis of axial joints and supporting structures, 148 including ligaments and tendons. There may be accompanying osteoporosis. Extra-articular manifestations include acute anterior uveitis, aortic insufficiency, cardiac 147 conduction disturbances, inflammatory bowel disease, and renal amyloidosis. The prevalence of ankylosing spondylitis in the general population is 0.1 to 0.2 percent, and 1 to 2 percent of HLA-B27–positive individuals will have the disorder. HLA-B27 is present in 90 148 percent of Caucasian patients with ankylosing spondylitis. Serum IgA levels are elevated in 50 to 60 percent of patients, correlating with disease activity and the presence of peripheral 147 arthritis and inflammatory bowel disease. Intestinal pathogens such as Klebsiella pneumoniae may play a role in peripheral arthritis and inflammatory bowel disease. Clinical manifestations typically begin in late adolescence or early adulthood. Presentation 147,149 after 50 years of age is rare. There is a male predominance of 2 to 3:1. Women usually are less symptomatic, have less severe disease, and have more involvement of the cervical 148 symptoms are low back pain and stiffness, which occur in 90 to spine. The most common 148 95 percent of patients. The initial pain is felt deep in the gluteal region. It can be severe and is often referred along the iliac crest to the greater trochanteric region or down the dorsal thigh. It may be accentuated by cough, sneeze, or a twisting motion of the back. Five features help differentiate it from mechanical low back pain: onset of back discomfort before the age of 40 years, insidious onset, persistence for at least 3 months, associated morning stiffness, 149 and improvement with exercise. Within a few months, it becomes persistent and bilateral. Enthesopathy of the costosternal and manubriosternal joints results in chest pain with reduced mobility that may seem pleuritic. Ankylosing spondylitis is a chronic disease with periods of remission, and patients have excessive mortality compared with the general population. Severe fractures are infrequent. The clinical examination and radiographs of the sacroiliac joints are used to make the diagnosis of ankylosing spondylitis (Fig. 24-6). Physical examination findings include flattening of lumbar spine and loss of lumbar lordosis. There is limited motion of the axial skeleton, especially with hyperextension and lateral bending. Percussion over the sacroiliac joints elicits pain. Human leukocyte antigen testing is positive in 90 percent of patients but is not specific. The erythrocyte sedimentation rate (ESR) is increased in 80 percent of patients 148 with active disease. Antinuclear antibody and rheumatoid factor are usually absent. The characteristic radiological changes may not be apparent early in the disease. Erosion of the joints occurs, followed by widening of the joint. Late stages of sacroiliitis include complete ankylosis with total obliteration of the joint space. Calcification ofthe annulus fibrosus and anterior and posterior longitudinal ligaments can be seen.

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FIGURE 24-6 Ankylosing spondylitis. Plain radiograph of lumbosacral spine.

The characteristic “bamboo spine” with fusion of the intervertebral ligaments is evident. The arrows show fusion of the sacroiliac joint. No treatment has been shown to alter the course of the illness, particularly the loss of spinal 148,150 Therapies that have evidence-based beneficial effects for ankylosing mobility. spondylitis include physical therapy, nonsteroidal anti-inflammatory drugs, and 151 disease-modifying drugs including tumor necrosis factor alpha (TNF-α) inhibitors. Intensive 152 physical therapy and exercise are important to maintain mobility. Braces, splints, and corsets should be avoided. Nonsteroidal anti-inflammatory drugs are effective in suppressing inflammation and ameliorating pain and are recommended as a first-line drug. Continuous use may slow the progression of spine ankylosis. Sulfasalazine has a role for peripheral arthritis but no impact on spinal mobility. The TNF-α inhibitors include etanercept and infliximab. In one study, at 4 months, 75 percent of the etanercept group had improvement in 148 morning stiffness, pain, and function compared with 30 percent of the placebo 148,153 group. Similar improvement was seen in studies of infliximab compared with placebo. Patients who are positive for C-reactive protein are more likely to respond. Relapse is common after termination of either therapy. Potential complications include reactivation of tuberculosis, hematological disorders including malignancy, central and peripheral demyelinating disorders, congestive heart failure, elevated153 serum levels of liver enzymes, and is hypersensitivity and autoimmune reactions. Treatment with TNF-α inhibitors 151,153 recommended for patients with refractory, severe, and active disease. Surgical 148,150,151 There is a treatment plays a limited role when nonsurgical treatment has failed. significant risk of operative and perioperative complications. Neurological complications are uncommon and occur in 2.1 percent of patients with 154 ankylosing spondylitis. They include radiculopathy from foraminal stenosis or inflammation.

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Myelopathy can result from fracture-dislocation, atlantoaxial subluxation, pseudoarthritis, ossified intraspinal ligaments, or granulation tissue. Cauda equina syndrome is a late complication attributed to arachnoiditis. Sciatic nerve compression due to contraction of the piriformis muscle can occur secondary to inflammation of the attachment of the piriformis148 muscle to the sacroiliac joint, mimicking sciatica from root compression (pseudosciatica). There is an increased incidence of vertebral compression fractures in ankylosing spondylitis. The spine is brittle and prone to fracture. The fracture often goes entirely through the vertebral body and ossified ligaments, resulting in increased instability and neurological 148 damage. The most common location of fracture is the cervical spine (C6–C7). In one series, the risk for traumatic spinal cord injury in patients with ankylosing spondylitis was 11.4 155 times greater than expected for the population at large. Cervical myelopathy occurred in 84 percent of patients with ankylosing spondylitis who had traumatic spine injury compared with 48 percent of all patients with traumatic spine injury. Neurological dysfunction may not develop until several weeks following the initial spine trauma. Surgical intervention is 148 indicated in these patients, but as many as 85.7 percent will have a residual deficit. Patients with148,150 complete paraparesis for more than 2 hours do not respond to surgical intervention. Spinal stenosis with cord compression is rare. Patients may develop “radicular” pain without neurological symptoms or signs, and this usually resolves spontaneously. The cervical spine may be involved, resulting in atlantoaxial subluxation. The incidence of this complication 156,157 Ramos-Remus and co-workers found ranges from 2 to 21 percent in different series. atlantoaxial subluxation in 22 of 103 consecutive patients with ankylosing spondylitis 156 (21%). One third of these patients had clinical evidence of myelopathy, and two patients had surgical fusion because of severe myelopathy. Atlanto-occipital subluxation with vertebral occlusion, brainstem transient ischemic attack (TIA), and infarction are also described in 156–158 Aortic root disease and valve disease are more patients with ankylosing spondylitis. common in patients with ankylosing spondylitis than in age-matched controls (82% compared 159 with 27% in one study ). TIA or stroke occurred in 2 of 44 patients without a clear etiology. Studies of the natural history of ankylosing spondylitis have demonstrated that cerebrovascular disease is a common cause of mortality in patients younger than 60 years. Prophylactic antiplatelet therapy may be indicated. 160–163

Patients have an Cauda equina syndrome occurs in rare patients late in the disease. average of 32 years before the onset of cauda equina syndrome, and most patients are 154 male. The typical presentation includes insidious onset and progression of bowel and bladder symptoms, sensory loss (often asymmetric) in an L5–S4 distribution, pain radiating into a limb or the rectal area, and minimal weakness in muscles innervated by the L5–S2 segments. Bladder symptoms include decreased awareness of bladder sensation, decreased ability to empty the bladder, hesitancy, decreased force of urinary stream, urgency, and frequency. Radiography of the lumbar spine may show erosions of the lamina. Spinal MRI shows dorsal dural diverticula associated with a widened thecal sac and scalloped erosions 160,163 Nerve roots appear to deviate toward the of the laminae and spinous processes. diverticula. They may be displaced posteriorly and appear adherent to the arachnoid membrane and to each other, suggesting arachnoiditis. There is no enhancement with gadolinium. Spinal CT typically demonstrates asymmetric, multilevel erosions that selectively 164 involve the pedicles, laminae, and spinous processes of the lumbosacral spine. Infrequently, erosion of the posterior portion of the vertebral body is found, or involvement is unilateral or confined to one level. Myelography is technically difficult and possibly dangerous in patients with ankylosing spondylitis. Cerebrospinal fluid is normal or shows a slightly elevated protein concentration. The pathological findings depend on the timing of surgery or autopsy relative to the onset of 162 neurological symptoms. Early pathological findings include inflammation of the spinal ligaments, dura, and arachnoid. Over time, there is fibrosis and chronic arachnoiditis embedding atrophic nerve roots, with small sacral roots splayed and adherent to the dura. Compression of the nerve roots by diverticula has been described. Some roots appear normal, but others are fibrosed in the later stages. The cauda equina syndrome has been attributed to arachnoiditis. Arachnoid adhesions may lead to blind pouches into which cerebrospinal fluid is forced by the pumping action of arterial pulsation, with consequent enlarging arachnoid cysts and pressure erosion of the adjacent bone. A resorption defect of the cerebrospinal fluid has been documented and may contribute 165 to to thecal sac enlargement and other structural changes. Nerve root injury may relate 162 arachnoiditis with subsequent neuritis, vasculitis, adhesion formation, or tethering. The role of surgery and decompression of the cysts is unclear, but a meta-analysis of 86 patients reported in the literature showed worsening of all patients who received no treatment or

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154

corticosteroids. Nonsteroidal anti-inflammatory drugs result in improvement of back pain without improvement of neurological deficits. Patients may have improvement of neurological function or halting of progression with either lumboperitoneal shunting or laminectomy. 148 Neurological deficits may persist despite surgical intervention in 85.7 percent of patients. The clinical course is slowly progressive, although patients rarely lose the ability to walk. In the cohort described in the meta-analysis, weakness occurred in 62 percent, sensory loss in 154 96 percent, and loss of reflexes in 93 percent. Bowel dysfunction was seen in 80 percent and bladder dysfunction in 95 percent of patients. It was recommended that any patient with longstanding ankylosing spondylitis who develops sphincter dysfunction receive a careful neurological assessment. The response to lumboperitoneal shunting may suggest that the dural ectasia is in part a cause of the neurological deficits in these patients. Case reports suggest an association between ankylosing spondylitis and multiple 158,166 The incidence of multiple sclerosis in patients with ankylosing spondylitis sclerosis. followed at a referral center is approximately 1,000 per 100,000, which is significantly greater 167,168 In contrast, 2,000 members of the than that of the general population (50 per 100,000). National Ankylosing Spondylitis Society were reviewed without169 a clear association being evident between multiple sclerosis and ankylosing spondylitis. A definitive population study has not been done. RELAPSING POLYCHONDRITIS Relapsing polychondritis is an uncommon, multisystem disorder characterized by recurrent episodes of inflammation and eventual destruction of cartilaginous tissues, which may have delay an autoimmune basis. It is diagnosed on clinical grounds (Table 24-3), and the average 170 171 to diagnosis from symptom onset is 2.9 years. The prevalence is 3.5 per million. The reported age range is from 16 to 84 years, with a peak onset in the fifth decade. Most authors 172 report an equal prevalence in males and females, and it is described in all races. It can affect all types of cartilage including the ears and nose (most commonly), peripheral joints, fibrocartilage at axial sites, and the tracheobronchial tree (which can be life threatening). The eye, heart, blood vessels, and inner ear are rich in proteoglycans and can also be affected. There is evidence of HLA-DR4 linkage and frequent concurrence of other autoimmune diseases. More than 30 percent of patients with relapsing polychondritis have an associated rheumatological or hematological disorder. Antibodies to type II collagen are present during acute attacks, and immunocomplex deposition is found in cartilage. Experimental models suggest the binding of these antibodies to cartilage leads to complement-mediated inflammation and the release of inflammatory cytokines, including TNF-α. Monocyte chemoattractant protein 1, macrophage inflammatory 173 protein 1 beta, and interleukin-8 are also elevated in patients with relapsing polychondritis. Click here to view this table.... The clinical presentation is with the abrupt onset of ear pain, tenderness and swelling of the external auditory meatus, erythema, and a clear serous discharge from the ear. Ear involvement is the initial presenting symptom in 39 percent and ultimately occurs in 85 to 95 172 percent of patients. The noncartilaginous lobule is spared. Repeated bouts of inflammation result in afloppy ear (Fig. 24-7). Nasal pain, hoarseness, and difficulty in talking are also common. Repeated inflammation of the nasal cartilage results in a saddle-nose deformity. Systemic symptoms include fever, lethargy, and weight loss. The course is relapsing; over the course of the illness, progressive significant disability occurs in most patients. Inflammation of the trachea and larynx occurs in 50 percent of patients and may be fatal. Cardiovascular involvement includes myocarditis, pericarditis, silent myocardial infarction, 170 paroxysmal atrial tachycardias, and first-degree and complete heart block. The arthropathy is episodic, nonerosive, migratory, and asymmetric, lasting from weeks to months.

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FIGURE 24-7 Relapsing polychondritis. Example of a “floppy ear” from repeated

inflammation and destruction of the cartilaginous portion of the ear. Vertigo and conductive or sensorineural hearing loss are common and are present in 5 170 percent at the onset of the disease and in 13 to 50 percent over the course of the illness. The conductive hearing loss is due to closure of the eustachian tube from inflammation in the cartilaginous wall, auricular cartilage collapse, or edema in the canal with subsequent serous otitis media. The sensorineural hearing loss is attributed to vasculitis of the vestibular or cochlear branch of the internal auditory artery. The abrupt onset of hearing loss, sometimes accompanied by vertigo, nausea, vomiting, and imbalance, can mimic a posterior circulation stroke. Ocular involvement occurs in 65 percent of patients. Recurrent conjunctivitis, episcleritis, scleritis, iritis, and keratoconjunctivitis sicca are common. Chorioretinitis, retinal vasculitis, exophthalmos due to orbital pseudotumor, extraocular muscle palsies, and optic neuritis may occur but are rarer. Extraocular palsies occur either from direct extension of pseudotumor-like inflammation in the orbit or from vasculitic ischemia to the third, fourth, or 172 sixth cranial nerves. Vasculitis occurs in 11 to 56 percent of patients with relapsing polychondritis and affects the 174 skin, internal organs, or central nervous system (CNS). It can affect the large arteries, resembling Takayasu's arteritis (100 mm in 1 hour), and mild leukocytosis may be present. The cerebrospinal fluid is normal or shows pleocytosis. The electroencephalogram may be normal or slow or show focal epileptiform activity. Cranial CT often demonstrates cerebral and cerebellar atrophy but may be normal. There may be 178 focal areas of hypodensity. The MRI is suggestive of cerebral vasculitis, with increased signal in the periventricular white matter and185centrum semiovale, focal lesions in the gray of limbic encephalitis, the MRI shows matter, and wedge-shaped cortical infarcts. In cases181 increased signal in one or both medial temporal lobes. Brain biopsy in these cases revealed marked gliosis, perivascular cuffing, and destruction of the vascular wall. The diagnosis of relapsing polychondritis is made on clinical criteria. Biopsy of the ear cartilage may be diagnostically helpful and shows loss of basophilic staining of the matrix, perichondrial inflammation, and eventually destruction of cartilage with replacement by 186 fibrous tissue. Nonspecific laboratory findings include anemia, peripheral leukocytosis, or throm-bocytosis. Serum creatinine and urinalysis should be checked to assess renal involvement. Evaluation for associated rheumatological disorders should include a screen for rheumatoid factor, antinuclear antibodies, antineutrophil cytoplasmic antibodies (ANCA), and complement levels. The airway should be evaluated by radiography, pulmonary function tests, and high-resolution CT scans. The differential diagnosis includes Wegener's granulomatosis; distinguishing clinical features include involvement of the mucosa and lung parenchyma and a positive ANCA, which are not seen in uncomplicated relapsing polychondritis. Aseptic meningitis results in neutrophil-predominant pleocytosis in the cerebrospinal fluid, with elevated total protein and normal glucose levels. Mild inflammation of joints, ear, or nose can be managed with nonsteroidal anti-inflammatory drugs, dapsone, or colchicine. Treatment of the CNS vasculitis, meningoencephalitis, and aseptic meningitis includes high-dose corticosteroids, often with additional “corticosteroid sparing” agents during the course of the illness. These adjunctive therapies include azathioprine, cyclophosphamide, cyclosporine, penicillamine, plasma exchange, dapsone, and methotrexate. Relapses are common, with cumulative persistent deficits. Refractory relapsing polychondritis may respond to agents that interfere with TNF-α (etanercept or 187–189 infliximab). Previous

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Aminoff: Neurology and General Medicine: Otoneurological Manifesta...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 25 Otoneurological Manifestations of Otological and Systemic Disease JOSEPH M. FURMAN • MICHELE B. ST. MARTIN •

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NEUROLOGICAL MANIFESTATIONS OF OTOLOGICAL DISEASE Complications of Middle Ear Pathology Labyrinthine Disorders Eighth Nerve Lesions Cerebellopontine Angle Disorders Central Vestibular Disorders Central Auditory Processing Disorder OTONEUROLOGICAL MANIFESTATIONS OF SYSTEMIC DISEASE Infection Immune-Mediated/Connective Tissue Disease Neurocutaneous Syndromes Metabolic and Endocrine Disorders Diseases of Bone Drug-Induced Disorders Environmental Disorders Nutritional Disease Neoplastic Disease NEURO-OTOLOGICAL MANIFESTATIONS OF AGING Dysequilibrium of Aging Presbycusis

NEUROLOGICAL MANIFESTATIONS OF OTOLOGICAL DISEASE

Complications of Middle Ear Pathology 1,2

Intracranial complications occur in 0.25 to 0.5 percent of all cases of otitis media. The mortality rate of intracranial complications has decreased dramatically over the last century, 3–5 However, from approximately 90 percent in the pre-antibiotic era to 10 percent at present. 6 significant morbidity still exists despite the improvement in survival. Diagnosis of an intracranial complication of otitis media relies heavily on an accurate history. Important elements include determining whether the patient has acute or chronic otitis media, a prior history of otologic disease or surgery, a history of head trauma or temporal bone fracture, previous antibiotic treatment, and symptoms suggesting intracranial involvement such as

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http://www.merckmedicus.com/pp/us/hcp/printpage.jsp 2,6–8

headache, lethargy, visual changes, fever, and nausea or vomiting.

The differential diagnosis for a patient with otitis media and symptoms and signs of intracranial involvement is long, as potential complications are numerous. The list includes extradural abscesses or granulation tissue, dural venous sinus thrombophlebitis, petrous subdural apicitis (Gradenigo's syndrome; Fig. 25-1), intraparenchymal brain abscesses, 3,7,9 Otitic abscesses, and meningitis, with purulent meningitis being the most common. hydrocephalus may also occur; intracranial pressure is increased secondary to venous sinus thrombosis and may manifest with bilateral papilledema. Despite its name, the ventricles are not enlarged in otitic hydrocephalus. The triad of headache, high fever, and focal neurological deficits should lead the clinician to suspect a brain abscess. Focal signs depend on the 7 location of the abscess; visual field defects are often an early finding. Temporal lobe lesions can lead to an expressive aphasia when located in the dominant hemisphere. Other neurological signs include homonymous hemianopia, limb paralysis, or extraocular palsies from involvement of cranial nerves III, IV, or VI. Nystagmus, papilledema, and ipsilateral pupillary dilatation may also be seen. Signs of a cerebellar abscess include nystagmus and 9,10 ataxia of the ipsilateral limbs.

FIGURE 25-1 Computed tomography (CT) scan showing right petrous apicitis.

Upper scan: Soft tissue algorithm demonstrating enhancement at the tip of the petrous apex affecting Dorello's canal (arrow head). Lower scan: Bone algorithm demonstrating a lytic cell in the petrous apex with loss of septation (arrow). (Courtesy of Hugh D. Curtin, MD, Massachusetts Eye and Ear Infirmary, Boston.) The microbiology of the intracranial complications of otitis media varies with the duration of otitis as well as the type of complication. Complications of acute otitis media usually are secondary3,6,7 to Streptococcus pneumoniae or Haemophilus influenzae, as would be expected. Chronic otitis media frequently leads to complications with gram-negative 6,7 bacteria, such as Pseudomonas or anaerobes. Otitic meningitis is most commonly caused

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by S. pneumoniae, H. influenzae, Proteus, Pseudomonas, and Staphylococcus aureus. Brain 10 abscesses are typically polymicrobial. If an intracranial complication is suspected on the basis of history or physical findings, further evaluation should include computerized tomography (CT) of the temporal bones to evaluate for bony erosion, congenital malformation, or fracture; magnetic resonance imaging (MRI) to evaluate for enhancement of the meninges or brain abscess; and a lumbar puncture if no 1,7,10 The cerebrospinal fluid (CSF) will show increased mass effect is visualized on imaging. protein and decreased glucose concentrations, and organisms on Gram's stain in meningitis; in otitic hydrocephalus, the opening pressure will be increased, but the other studies will be 7 normal. A positive blood culture can indicate the presence of sigmoid sinus thrombophlebitis. Figure 25-2 shows the appearance of sigmoid sinus thrombosis on temporal bone CT.

FIGURE 25-2 Sigmoid sinus thrombosis. CT venography performed after

retromastoid craniectomy reveals a filling defect in the right transverse (dashed arrow) and sigmoid (solid arrow) sinuses, representing subocclusive thrombus. (Courtesy of Barton F. Branstetter, MD, University of Pittsburgh.) Treatment of intracranial complications of otitis media includes inpatient admission and medical stabilization. Broad-spectrum intravenous antibiotics should be initiated empirically. Complications due toacute otitis media may be treated with a second- or third-generation cephalosporin to target the usual three pathogens: H. influenzae, Moraxella catarrhalis, and S. pneumoniae. Gram-negative and anaerobic coverage should be added for complications of chronic otitis media. Corticosteroids such as dexamethasone (Decadron), when administered concurrently with intravenous antibiotics,7can reduce the chance of sensorineural hearing loss due to otogenic meningitis.

Labyrinthine Disorders Meniere's disease and benign paroxysmal positional vertigo are two of the most common labyrinthine disorders that cause vertigo and dysequilibrium. The pathophysiology of Meniere's disease is thought to be endolymphatic hydrops, which is usually idiopathic but can 11 occur following inner ear trauma or infection. Patients with Meniere's disease typically experience episodes of unilateral tinnitus, unilateral hearing loss, unilateral ear fullness, and vertigo lasting for minutes to hours. They do not experience neurological symptoms that cannot be attributable directly to the inner ear. However, some patients experience visual changes, especially blurred vision, during attacks of Meniere's disease, and headaches may

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occur during attacks. Other patients become anxious during attacks and may experience numbness and paresthesias. The first attack of Meniere's disease often prompts an evaluation in an emergency department that leads to brain imaging to exclude cerebellar hemorrhage or infarction. Treatment of Meniere's disease consists of sodium restriction and a diuretic, typically a combination of hydrochlorothiazide and triamterene. Benign paroxysmal positional vertigo (BPPV) is caused by free-floating otolithic debris in the 11 posterior semicircular canal. As with Meniere's disease, benign paroxysmal positional vertigo may follow inner ear trauma or infections but usually is idiopathic. Patients typically have positionally induced vertigo when rolling over in bed or looking up. Vertigo typically lasts for less than 1 minute but more generalized symptoms of dizziness and dysequilibrium may persist for several hours. Neurological symptoms other than vertigo and transitory visual difficulties are generally absent. On physical examination, the findings on Dix–Hallpike 12 maneuvers, illustrated in Figure 25-3, are diagnostic. Treatment (Fig. 25-4) consists of a particle repositioning maneuver, which is highly successful. Despite the “benign” nature of benign paroxysmal positional vertigo, the initial episode often leads to emergency medical care. Since several nonbenign conditions, such as posterior fossa tumors, may present with positional dizziness, a thorough neurological evaluation of all patients with positional vertigo is warranted.

FIGURE 25-3 Dix–Hallpike maneuver. The Dix–Hallpike test of a patient with

benign paroxysmal positional vertigo (BPPV) affecting the right ear. A, The examiner stands at the patient's right side and rotates the patient's head 45 degrees to the right to align the right posterior semicircular canal with the sagittal plane of the body. B, The examiner moves the patient, whose eyes are open, from the seated to the supine right-ear-down position and then extends the patient's neck slightly so that the chin is pointed slightly upward. The latency, duration, and direction of nystagmus, if present, and the latency and duration of vertigo, if present, should be noted. The arrows in the inset depict the direction of nystagmus in patients with typical BPPV. The presumed location in the labyrinth of the free-floating debris thought to cause the

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disorders is also shown. (With permission from Furman JM, Cass SPC: Benign paroxysmal positional vertigo. N Engl J Med 341:1590, 1999.)

FIGURE 25-4 Particle repositioning maneuver for the bedside treatment of a

patient with benign paroxysmal positional vertigo affecting the right ear. The presumed position of the debris within the labyrinth during the maneuver is shown in each panel. The maneuver is a three-step procedure. First, a Dix–Hallpike test is performed with the patient's head rotated 45 degrees toward the right ear and the neck slightly extended with the chin pointed slightly upward. This position results in the patient's head hanging to the right (A). Once the vertigo and nystagmus provoked by the Dix–Hallpike test cease, the patient's head is rotated about the rostral-caudal body axis until the left ear is down (B). Then the head and body are further rotated until the head is face down (C). The vertex of the head is kept tilted downward throughout the rotation. The maneuver usually provokes brief vertigo. The patient should be kept in the final, face-down position for about 10 to 15 seconds. With the head kept turned toward the left shoulder, the patient is brought into the seated position (D). Once the patient is upright, the head is tilted so that the chin is pointed slightly downward. (With permission from Furman JM, Cass SPC: Benign paroxysmal positional vertigo. N Engl J Med 341:1590, 1999.)

Eighth Nerve Lesions Eighth nerve lesions leading to neurological manifestations include auditory neuropathy and vestibular neuronitis. Auditory neuropathy is a recently defined entity in which the function of

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the cochlea's outer hair cells appears intact, but dysfunction or disturbed synchrony of the inner hair cells13,14 or cochlear nerve leads to hearing loss and impaired speech Risk factors for auditory neuropathy include prematurity, discrimination. 15 hyperbilirubinemia, and exposure to ototoxic medications. Genetics also13play a role. This type of hearing loss can be associated with other neurological diseases and may be seen in 16 up to 11 percent of children with sensorineural hearing loss. Vestibular neuronitis is an idiopathic inflammation of the vestibular portion of the eighth cranial nerve leading to acute symptoms of vertigo, nystagmus, nausea, and vomiting. Acute symptoms persist for several days and are often preceded by viral illness. Unilateral reduction in vestibular response is seen on caloric testing. Possible etiologies include viral infection, 17 immunological causes, or vascular occlusion. The superior or inferior vestibular nerve, or both, may be involved. If the auditory portion of the eighth cranial nerve is involved, which is uncommon, hearing loss will be present.

Cerebellopontine Angle Disorders Cerebellopontine angle masses can cause hearing loss, tinnitus, and vertigo. The most common type of mass found in this location is a vestibular schwannoma, commonly referred to as an acoustic neuroma. Symptoms arise from compression of the nerve and surrounding vessels as the tumor enlarges. Symptoms are typically of insidious onset, but sudden hearing loss or vertigo may occur. Additionally, facial weakness or numbness may be seen with large tumors due to compression of the facial or trigeminal nerves, respectively. Without treatment, lower cranial nerve involvement and brainstem compression may eventually occur (Fig. 25-5). The underlying lesion is detected by MRI. Acoustic neuromas are treated with surgical excision or stereotactic radiation; small tumors may be observed for evidence of growth. Other masses occurring in the cerebellopontine angle include meningiomas, epidermoid tumors, and metastases, which may cause similar symptoms due to compression.

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FIGURE 25-5 Magnetic resonance imaging (MRI) of a large acoustic neuroma

with brainstem compression. Axial contrast-enhanced T1-weighted MRI reveals a large, lobulated, enhancing mass (arrows) filling the left cerebellopontine angle, with compression of the pons and thinning of the brachium pontis. The patient was known to have neurofibromatosis type 2, and this lesion is most likely a schwannoma of the eighth cranial nerve. (Courtesy of Barton F. Branstetter, MD, University of Pittsburgh.)

Central Vestibular Disorders The most common central vestibular disorders include migraine-related dizziness, vascular disease affecting brainstem and cerebellar vestibular pathways, cerebellar degeneration, and Chiari malformations. Migraine-related dizziness, which can be considered a migraine variant, affects women more often than men, particularly women in their childbearing years. As with migraine headache, it is a diagnosis of exclusion, since there are no pathognomonic tests for this condition. Diagnostic criteria consist of a combination of the International Headache Society criteria for migraine headache and recently conceived criteria specifically 18 for migraine-related dizziness. Establishing a diagnosis of migraine-related dizziness requires a temporal association between dizziness and either migraine headache or typical migrainous symptoms and the absence of another diagnosis that can account for dizziness. The pathophysiology is uncertain but is likely to be related to serotonin effects on central vestibular structures. Treatment is similar to the treatment for migraine headache and includes both decreasing triggers for migraine and use of pharmacotherapy. For patients with frequent episodes of migraine-related dizziness, prophylactic medications are indicated and include antidepressants, beta-blockers, anticonvulsants, and calcium-channel blockers. Some patients may benefit from triptans. Central vestibular structures in the brainstem and cerebellum are supplied by the posterior inferior cerebellar artery (PICA) and the anterior inferior cerebellar artery (AICA). Infarction in the territory of the PICA leads to Wallenberg's syndrome, wherein one of two vestibular nuclear complexes is damaged, leading to central vestibular imbalance. Accompanying symptoms are caused by involvement of the ascending spinothalamic tract and descending sympathetic tracts. Patients with Wallenberg's syndrome may experience lateropulsion (i.e., a sense of being pushed or pulled to one side). Over time, symptoms largely resolve. Infarction in the territory of the AICA leads to a syndrome that can be quite similar to and sometimes indistinguishable from Wallenberg's syndrome except for the presence of unilateral hearing loss resulting from cochlear ischemia (the internal auditory artery arises from the AICA). Another condition to be considered in patients with acute vertigo and accompanying neurological disturbances referable to the brainstem and cerebellum is that of cerebellar hemorrhage or infarction with concomitant brainstem compression. This condition represents a neurosurgical emergency. The ability to ambulate, even with some difficulty, usually excludes a life-threatening cerebellar vascular event. However, brain imaging provides definitive diagnostic information. Vertebrobasilar insufficiency may present with various neurological symptoms including vertigo and changes in hearing as well as with neurological symptoms referable to parenchymal posterior fossa structures such as changes in vision, sensation, strength, or level of consciousness. Symptoms typically last for minutes. Isolated vertigo is rarely a result 19,20 Repeated episodes of vertigo in the absence of of vertebrobasilar insufficiency. accompanying neurological symptoms are never caused by vertebrobasilar insufficiency. Diagnostic imaging such as magnetic resonance angiography can be helpful in establishing a diagnosis of vertebrobasilar insufficiency. Treatment with antiplatelet agents and management of risk factors for cardiovascular disease are warranted. Cerebellar degeneration can be associated with dizziness and dysequilibrium. Some types of cerebellar degeneration (particularly SCA6) can also be associated with episodic features including episodic vertigo and dysequilibrium. In association with such symptoms, patients with cerebellar degeneration often manifest limb ataxia and sometimes long-tract signs. Chiari malformations sometimes present with “dizziness” and dysequilibrium. Physical examination may disclose down-beating nystagmus (i.e., vertical nystagmus with a downward fast component), which may reflect a central vestibular imbalance. Additionally, patients with Chiari malformations often have nonvestibular symptoms such as dysphagia and long-tract signs. A diagnosis of a Chiari malformation can be confirmed by sagittal MRI (Fig. 25-6). Treatment is surgical with suboccipital craniectomy.

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FIGURE 25-6 Chiari malformation. Sagittal T2-weighted MRI through the

cranio-cervical junction shows the cerebellar tonsils (solid arrow) extending far below the foramen magnum (dashed line). The medulla is compressed. (Courtesy of Barton F. Branstetter, MD, University of Pittsburgh.)

Central Auditory Processing Disorder Central auditory processing disorder, as its name implies, is characterized by defects in higher level processing of auditory information in the setting of normal hearing as measured by conventional audiometry (www.nidcd.nih.gov/health/voice/auditory.asp). This disorder leads to difficulty in understanding oral communication, particularly when there is background noise, and can be associated with attention deficit–hyperactivity disorder, learning disabilities, 21–23 Psycho-acoustic testing often identifies head trauma, and other neurological disorders. 24 specific deficits that correlate with patients' symptoms. Treatment consists of improving the signal-to-noise ratio with amplification or reduction of background noise, as well as auditory 23 training. OTONEUROLOGICAL MANIFESTATIONS OF SYSTEMIC DISEASE

Infection Many infections can cause otoneurological symptoms and signs. Viral infection, in particular 25,26 herpes simplexdvirus (HSV), is thought to be responsible for many cases of Bell's palsy. Figure 25-7 shows HSV-1 particles seen by electron microscopy in the geniculate ganglion of mice with experimentally induced Bell's palsy.27Viral infection is also thought to play a role in 28 idiopathic sudden sensorineural hearing loss and vestibular neuronitis. Corticosteroids with or without antiviral medication are used for treatment. Mumps, measles, and congenital 29 rubella infection may cause significant hearing loss.

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FIGURE 25-7 Herpes simplex virus (HSV) in a mouse model of Bell's palsy. A,

The intratemporal portion of the facial nerve from the paralyzed side showing a neuron in the geniculate ganglion. Replicating HSV-1 viruses in the rough endoplasmic reticulum of a neuron in the geniculate ganglion are indicated by the arrows. B, The geniculate portion of the facial motor nerve. Arrows indicate vacuolar changes in the cytoplasm of a Schwann cell. These resulted in demyelination. Scale bars: A, 1 μm; B, 5 μm. (Reproduced with permission from Takahashi H, Hitsumoto Y, Honda N, et al: Mouse model of Bell's palsy induced by reactivation of herpes simplex virus type 1. J Neuropathol Exp Neurol 60:621, 2001.) Another member of the herpesvirus family, varicella-zoster virus (VZV), causes herpes zoster oticus, often referred to as Ramsay Hunt syndrome. Ramsay Hunt syndrome, from reactivation of VZV in the geniculate ganglion, causes facial weakness, sensorineural hearing 30 The symptoms loss, vertigo, and vesicular lesions in the external auditory canal and auricle. 30 that the are typically preceded by otalgia. Recently, investigators have postulated 31 reactivation of VZV may occur in the vestibular and spiral ganglia as well. Ramsay Hunt syndrome may involve other cranial nerves; polymerase chain reaction has localized viral material to the CSF in some cases. MRI typically reveals enhancement of the geniculate ganglion on the affected side. Treatment is with antiviral agents and corticosteroids. The facial palsy associated with Ramsay Hunt syndrome has a poorer prognosis than that of 32 Bell's palsy. 33

Otosyphilis was first described in 1887 by Politzer. Following the introduction of penicillin, it became rare. However, with the emergence of human immunodeficiency virus (HIV) infection, syphilis has experienced a resurgence in the United States and Western Europe, as 34,35 Otoneurological manifestations may occur in secondary, discussed in Chapter 41. tertiary, or congenital syphilis. Sensorineural hearing loss and hydropic symptoms of episodic tinnitus and vertigo may occur. Treatment is with penicillin G and corticosteroids. 36

Lyme disease (Chapter 41) may cause sudden sensorineural hearing loss or facial palsy. 37 Vertigo is uncommon but has been reported. The mainstay of treatment is intravenous ceftriaxone; corticosteroids may be added for treatment of otoneurological manifestations.

Tuberculosis may affect the ear. As with syphilis, tuberculosis has become increasingly 38 38 common in patients with HIV infection. Fortunately, tuberculous otitis media remains rare. The classic description of mycobacterial39otitis media is of chronic otorrhea and multiple perforations of the tympanic membrane. Polyps and granulation tissue38may also be seen. Treatment is primarily medical, with surgery reserved for complications. Finally, HIV infection and immunodeficiency may cause otological symptoms. Otitis externa however, opportunistic may be caused by common pathogens such as Pseudomonas; 40 infections such as Pneumocystis may also be responsible. There are also reports of malignant otitis externa (i.e., skull base osteomyelitis secondary to otitis externa) in 41 of malignant individuals with HIV infection, although some authors note that the incidence 42 otitis externa is not increased in the HIV-infected population as a whole. Children with HIV

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infection often suffer from chronic otitis media. Serous otitis media may result from eustachian tube obstruction secondary to adenoid hypertrophy. Sensorineural hearing loss 43 occurs in 21 to 49 percent of HIV-positive patients and is thought to be multifactorial. Possible causes include secondary infection, central nervous system (CNS) involvement, and 40 44 ototoxicity. Finally, facial palsy is more common in HIV-positive patients.

Immune-Mediated/Connective Tissue Disease There are a number of autoimmune and connective tissue disorders (Chapter 29) that cause otoneurological symptoms, ranging from otitis media to hearing loss or vertigo. Wegener's granulomatosis is characterized by vasculitis of medium and small vessels, as well as by necrotizing granulomas of the upper and lower respiratory tract. Up to 70 percent 45–47 The most common of patients with this disorder experience otological symptoms. otoneurological manifestation of Wegener's granulomatosis 48 is serous otitis media, resulting from inflammatory changes of the nasopharyngeal mucosa. This may cause conductive hearing loss and require treatment with pressure-equalization tubes. The middle ear space can be affected by granulomas, leading to a clinical picture resembling chronic suppurative vasculitis or direct otitis media (Fig. 25-8). Facial palsy can also result, either from45,47,48 Sensorineural hearing involvement of the facial nerve by the granulomatous process. 46 loss occurs in 8 percent of patients and can be rapidly progressive. Vertigo is uncommon. Inflammation of the auricle mimicking relapsing polychondritis may be seen, although this is 46 rare. Wegener's granulomatosis is diagnosed by the presence of c-ANCA antibodies and by the combination of necrotizing granulomas and vasculitis seen on histopathology. Treatment iswith high-dose corticosteroids and immunosuppressive agents such as 45,46 cyclophosphamide.

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FIGURE 25-8 Chronic otitis media in Wegener's granulomatosis.

Granulomatous swelling of the posterior part of the left eardrum viewed through an otomicroscope (arrow). The large white area inferior and to the left of the eardrum is the anterior wall of the external ear canal. (Reproduced with permission from Rasmussen N: Management of the ear, nose, and throat manifestations of Wegener granulomatosis: an otorhinolaryngologist's perspective. Curr Opin Rheumatol 13:3, 2001.) Sarcoidosis is an immune-mediated disease of unknown etiology characterized by hilar adenopathy, pulmonary infiltrates, peripheral lymphadenopathy, and cutaneous and splenic involvement that can affect the CNS (Chapter 51). The characteristic histopathological finding is of noncaseating granulomas. The most common otoneurological manifestation of sarcoidosis is facial palsy, which may be uni- or bilateral and can be associated with parotiditis, fever, and uveitis (uveoparotid fever or Heerfordt's disease). Multiple cranial nerve palsies are common in neurosarcoidosis, which typically involves the meninges of the skull 49,50 Hearing loss base, and occurs in approximately 5 percent of patients with sarcoidosis. and vertigo due to involvement of the eighth cranial nerve are less common. The presentation 49,51 of hearing loss is variable, ranging from mild to severe, and may be unilateral or bilateral. 51 Vestibular testing may be abnormal. Auditory and vestibular symptoms are thought to reflect involvement of the eighth cranial nerve by neurosarcoidosis rather than a direct effect 51 on the inner ear end organs. MRI may show enhancement of the basal leptomeninges 50 following administration of gadolinium; intracranial mass lesions can also be seen. Systemic lupus erythematosus (SLE) may cause sensorineural hearing loss that is uni- or 52–54 The hearing loss bilateral in 8 to 31 percent of patients and can be rapidly progressive. appears to be associated with elevated anticardiolipin antibodies but not with ANA titer and 53,54 54 Vestibular symptoms are less common. frequently improves with treatment. Hearing 52,55 loss is also commonly seen in rheumatoid arthritis, manifesting in 29 to 48 percent of It may be sensorineural, conductive, or mixed in type, and its severity is patients. 55 correlated with disease activity. Conductive hearing loss is thought to be secondary to involvement of the ossicular chain by rheumatoid arthritis, whereas sensorineural hearing loss may be due to immunocomplex deposition, antibodies against inner ear antigens, or 55 of patients with cell-mediated immune processes. Investigations into the vestibular function 56 rheumatoid arthritis have revealed no significant differences from controls. Other immune-mediated diseases causing otologi-cal symptoms include polyarteritis nodosa, Cogan's syndrome, Behçet's syndrome, relapsing polychondritis, Sjögren's syndrome, and Churg–Strauss syndrome. Polyarteritis nodosa, a small-vessel vasculitis, can cause sudden 52 sensorineural hearing loss. Cogan's syndrome is characterized by sudden or rapidly progressive sensorineural hearing loss, vestibular dysfunction, and interstitial keratitis, and it can mimic syphilis or Meniere's disease. Symptoms often respond to treatment with52 52 corti-costeroids. Behçet's syndrome may cause hearing loss, tinnitus, and vertigo. Relapsing polychondritis typically involves the cartilage of the external ear and nose; 52 however, as the disease progresses, hearing loss and vertigo sometimes develop. High-frequency hearing loss may also be seen in 25 percent of patients with Sjögren's 52,57 53 Churg–Strauss syndrome causes hearing loss in rare instances. syndrome. Autoimmune hearing loss also may occur in the absence of systemic illness. It is characterized by fluctuating or rapidly progressive bilateral sensorineural hearing loss that is 52 Antibodies to inner-ear antigens have been responsive to immunosuppressive therapy. 53 detected in some of these patients.

Neurocutaneous Syndromes The most common neurocutaneous syndrome causing otoneurological symptoms is neurofibromatosis type 2 (NF2). This disease is characterized by bilateral vestibular schwannomas, eventually causing bilateral deafness and vestibular dysfunction. Three subtypes have been described. The Wishart type is characterized by onset in the second or third decade and the occurrence of multiple tumors besides vestibular schwannomas. The Gardner type is milder and presents later in life. There is also a subtype called segmental 58 NF2 thought to be caused by somatic mosaicism. Otological manifestations consist of progressive hearing loss that may be unilateral or bilateral, tinnitus, vestibular dysfunction, and facial weakness. Genetic testing is available to detect mutations in the NF2 tumor suppressor gene, although routine screening for children of affected parents is not universally 58 recommended because of its high false-negative rate. Auditory rehabilitation of affected patients is complex owing to the presence of bilateral acoustic neuroma; auditory brainstem

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implants have been used in this population with fair results.


Metabolic and Endocrine Disorders Certain metabolic or endocrine disorders60,61 are known to contribute to hearing loss. Diabetes perhaps secondary to microangiopathy or mellitus has62,63 been linked to hearing loss, A small subset of diabetic patients has been found to have a mitochondrial neuropathy. mutation causing 64 both hearing loss and diabetes, termed maternally inherited diabetes and deafness (MIDD). Diabetic patients frequently suffer from dizziness and imbalance as well. Peripheral 65 neuropathy, autonomic dysfunction, and peripheral vestibular deficits all play a role in etiology. 66

Renal failure in the absence of diabetes is also associated with high-frequency hearing loss. Additionally, Alport's syndrome is associated with congenital hearing loss and renal failure. 29 Neonatal jaundice can cause downward-sloping sensorineural hearing loss. Hyperlipidemia 29 has also been associated with fluctuating hearing loss and vestibular dysfunction.

An association between thyroid disease and otological symptoms also exists. Vertigo and 67 hearing loss have been described in the setting of hypothyroidism. Pendred's syndrome is characterized by congenital hearing loss, reduced vestibular responses, and goiter. In a study of 42 kindreds, resistance68to thyroid hormone was found to be associated with hearing loss in 21 percent of individuals. Certain mucopolysaccharidoses (MPS) are associated with hearing loss, and many forms predispose to otitis media. The Hurler/Scheie and Hunter forms (MPS I and II) cause sensorineural hearing loss. The mechanism of loss is unclear and may involve deposition of 69 glycosaminoglycans in the cochlea.

Diseases of Bone Several disorders of bone lead to otoneurological manifestations, most notably hearing loss. These include osteogenesis imperfecta, Paget's disease, fibrous dysplasia, and osteopetrosis. Osteogenesis imperfecta is an autosomal-dominant disease caused by mutations in the COL1A1 or COL1A2 genes, which code for type 1 collagen. The disorder is characterized by fragility of bones, hearing loss, and blue sclera. Five major types are currently described; hearing loss is most common in types IA and IB. Hearing loss occurs in 22.6 to 58 percent 70 of patients with osteogenesis imperfecta and typically presents in the second or third decade. It typically begins as a conductive loss and progresses to become mixed or largely sensorineural in nature; both ears are eventually affected. Hearing loss may be treated with amplification or stapedectomy, although surgical results are somewhat disappointing compared with those enjoyed by patients with otosclerosis. Tinnitus and vertigo are also common in osteogenesis imperfecta, particularly in those patients with sensorineural hearing loss. Vertigo is typically mild, triggered by head movements or position change, and brief in 71 duration. Abnormalities are frequently seen71on electronystagmography but do not necessarily correlate with subjective vertigo. Paget's disease, first described in 1877, is caused by increased bone absorption and repair, leading to an overall increase in the amount of bone. There is both a monostotic and a polyostotic form. Hearing loss is common in Paget's disease and is usually mixed conductive and sensorineural. Conductive hearing loss may be caused by ossicular fixation or obliteration of the72oval or round window. Bony changes in the cochlea may also contribute to the hearing loss. Furthermore, involvement of the petrous portion of the temporal bone may alter the shape of the internal auditory canal, potentially impairing the function of the eighth cranial nerve. Histologically, Paget's disease is characterized by disordered lamellar bone (Fig. 25-9). CT may reveal demineralization of the temporal bone. Treatment is with bisphosphonates and calcitonin, which may prevent further hearing loss.

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FIGURE 25-9 Histological examples of Paget's disease. A, Hematoxylin and eosin stain of pagetoid bone (original magnification 100×). Note the relatively continuous irregular pattern of bone with vascular channels. B, Hematoxylin and eosin stain of pagetoid bone (original magnification 500×). Note multinuclear osteoblast with lacunar lucency (below) and rimming of bone with osteoblasts (above). (Reproduced with permission from Hullar TE, Lustig LR: Paget's disease and fibrous dysplasia. Otolaryngol Clin North Am 36:707, 2003.)

Fibrous dysplasia, like Paget's disease, also has monostotic and polyostotic forms. It is nonfamilial, but caused by mutations in the GNAS1 gene, which codes for a second messenger G protein. The disease is characterized by expansile bony lesions (Fig. 25-10). Involvement of the temporal bone can cause narrowing of the external auditory canal, resulting in conductive hearing loss. A lesser percentage of 72 patients will manifest sensorineural hearing loss, labyrinthitis, or facial weakness. Treatment is with bisphosphonates or surgical resection.Irradiation increases the risk of malignant transformation and is not indicated.

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FIGURE 25-10 Histology of fibrous dysplasia. Histological examples of fibrous

dysplasia. A, Hematoxylin and eosin stain of fibrous dysplasia (original magnification 100×). Note prominent, disconnected, Chinese-character bone fragments. B, Hematoxylin and eosin stain (original magnification 500×). Note abundant osteoblastic activity surrounding bony fragments. (Reproduced with permission from Hullar TE, Lustig LR: Paget's disease and fibrous dysplasia. Otolaryngol Clin North Am 36:707, 2003.) Osteopetrosis is characterized by decreased osteoclastic activity, leading to constriction of various skull base foramina. Hearing loss, vertigo, and facial palsy or spasm may develop secondary to compression. Furthermore, eustachian tube dysfunction and middle ear 74 73 effusions may be seen. Treatment is with calcitriol, prednisone, and interferon-gamma.

Drug-Induced Disorders There are numerous medications that exert ototoxic effects on the cochlea and labyrinth. The most commonly encountered ototoxic medications are chemotherapeutic agents, antibiotics, and loop diuretics. Cochlear ototoxicity is typically heralded by tinnitus or a sense of fullness in the ear; however, high-frequency hearing loss may also occur without the patient's knowledge. Hearing loss due to certain drugs, most notably salicylate and furosemide, can be reversible, whereas toxicity secondary to cisplatin and aminoglycosides is most often permanent. Vertigo and75disequilibrium may result from vestibular toxicity; bobbing oscillopsia is a common symptom. Conditions contributing to higher risk for ototoxicity include renal insufficiency, hepatic insufficiency, elevated serum medication levels, preexisting hearing loss or vestibular dysfunction, use of multiple ototoxic medications or a previous history of ototoxic medication use, treatment for more than 14 days, prior exposure to noise, hypovolemia, 75,76 bacteremia, fever, and age over 65 years.

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Ototoxicity leads to distinct histological changes within the cochlea and labyrinth. In the cochlea, initial damage occurs in the basal turn to the outer hair cell layer 1 (OHC1). This can be seen in Figure 25-11. Later, degeneration occurs of the outer hair cell layers 2 and 3, followed by damage to inner hair cells. In the labyrinth, type 1 hair cells on the crista ampullaris are the first to degenerate, followed later by macular cells of the utricle and 75 saccule.

FIGURE 25-11 Hair cell loss due to ototoxicity. Three-day-old rat organ of Corti

explants after 72 hours in vitro. Fluorescein isothiocyanate–conjugated phalloidin-stained stereocilia bundles and cuticular plates of whole-mount organotypic cultures viewed with a Zeiss Axiophot epifluorescence microscope. A, The middle turn of a control explant demonstrating orderly rows of inner hair cells (wider arrow) and three rows of outer hair cells (thinner arrow). B, The middle turn of an explant exposed to 10 μg/ml cisplatin. The disrupted pattern of cytoarchitecture and the loss of a significant number of hair cells (arrow) are evident. C, The middle turn of an explant that was pretreated with 10 mmol/L N-acetyl-l-cysteine (L-NAC) before exposure to toxic (10 μg/ml) doses of cisplatin. The cytoarchitecture has been preserved, and hair cell survival is also significantly improved (arrows) when compared with the hair cell survival in the unprotected explants. (Reproduced with permission from Feghali JG, Liu W, Van De Water TR: L-n-acetyl-cysteine protection against cisplatin-induced auditory neuronal and hair cell toxicity. Laryngoscope 111:1147, 2001.) Aminoglycoside antibiotics have been known to be ototoxic since the parenteral use of streptomycin for tuberculosis in the early twentieth century. Symptomatic hearing loss occurs

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in 2.4 to 13.9 percent of patients treated with aminoglycosides ; however, high-frequency 78 (10 to 20 kHz) audiometry reveals the incidence of hearing loss to be as high as 62.3 percent. Certain aminoglycosides, such as streptomycin and gentamicin, cause vestibular toxicity prior to causing cochlear toxicity. It is unclear whether elevated serum levels of antibiotic correlate with increased risk of toxicity. The pathogenesis is thought to involve generation of free 79 radicals leading to apoptosis of hair cells. There is evidence that certain mitochondrial 80 mutations cause increased susceptibility to the ototoxic effects of aminoglycosides. Numerous animal studies are ongoing to evaluate potential protective 76,79 agents such as Other anti-infective antioxidants or iron chelators that may be administered concomitantly. agents reported to cause ototoxicity include vancomycin, macrolides, fluoroquinolones, tetracycline, antivirals, amphotericin, flucytosine, and antimalarials. Cisplatin is the chemotherapy81–83 agent most frequently associated with ototoxicity, with an Hearing loss initially manifests in the high frequencies and incidence of 20 to 65 percent. progressively worsens with continued administration. Tinnitus is a common presenting complaint. Ototoxicity appears related to the cumulative dose. Cisplatin damages the stria 75 vascularis, resulting in hair-cell loss. Ongoing studies are evaluating agents such as amifostine that may protect against cisplatin-induced ototoxicity. Other ototoxic chemotherapeutic agents include carboplatin, oxiliplatin, Vinca alkaloids, bexarotene, and taxane. Loop diuretics can cause hearing loss, tinnitus, and occasionally vertigo, perhaps because disturbances in the sodium and potassium concentrations in endolymph cause edema of the stria vascularis. Hearing loss is typically reversible and is usually seen with parenteral rather 75 than oral administration of the offending medication. Bumetanide may be less ototoxic than furosemide or ethacrynic acid. Salicylates can cause tinnitus and reversible hearing loss, although some cases of permanent hearing impairment have been reported following overdoses. Owing to the high incidence of ototoxicity with aminoglycosides and cisplatin, patient monitoring with high-frequency audiometry and careful attention to symptoms is recommended for early diagnosis and management.

Environmental Disorders Numerous types of environmental injury can result in otoneurological symptoms. Barotrauma may cause otologic injury through multiple mechanisms. The most common otologic injury seen with barotrauma is perforation of the tympanic membrane. Increased pressure in the middle ear may lead to facial palsy if portions of the facial nerve are dehiscent; vertigo and 84 conductive hearing loss may also result. Inner ear barotrauma can manifest as a perilymphatic fistula and can be characterized by hearing loss, vertigo, nausea, and vomiting following exposure to increased atmospheric pressure. Inner ear decompression sickness 85 causes similar symptoms, usually manifesting itself after surfacing from a dive. The prognosis for recovery is good for inner ear barotrauma, but progressive damage to the 86 cochlear and vestibular organs often occurs following inner ear decompression sickness. Lightning strikes have also been documented to have otoneurological sequelae. Lightning 87,88 Hearing loss, may produce injury either through a direct strike or over telephone lines. 89 tinnitus, tympanic membrane perforation, facial palsy, and vertigo have been reported. Hearing loss may have a mixed conductive and sensorineural pattern and appears stable 90 over time. Blast injuries to the ear are also of significance. The tympanic membrane may rupture. Sensorineural hearing loss is also common; it appears to occur via a different mechanism 91 from noise-induced hearing loss, as the audiometric pattern lacks a notch at 4000 Hz. Fortunately, hearing loss tends to recover fairly quickly following injury and any residual 91 hearing loss is often minimal. Vertigo is uncommon. Severe thermal injury to the ear may result from slag burns. Often non-healing perforations of the tympanic membrane are seen. Facial paralysis, sensorineural hearing loss, and vertigo 92 have also been reported. Noise exposure is well known to cause hearing loss, typically with a notched pattern at 4000 Hz on the patient's audiogram. Both occupational and recreational exposure can cause significant loss. Some individuals appear more likely than others to sustain noise-induced 62 loss.

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Nutritional Disease Wernicke's encephalopathy, which results from hypovitaminosis B1 (thiamine), manifests as ataxia, abnormal eye movements, and mental status change. Vestibular laboratory testing of patients with Wernicke's encephalopathy typically indicates bilaterally reduced vestibular 93 responses and abnormal central vestibular processing. Treatment is by replacement of thiamine, which usually corrects the abnormal eye movements and ataxia. Vestibular function remains abnormal.

Neoplastic Disease The temporal bone is affected by primary malignancies as well as metastatic disease. Primary tumors may origi nate in the external ear, middle ear and mastoid, or inner ear structures. Squamous cell carcinoma and basal cell carcinoma can affect the auricle and external auditory canal. Squamous cell carcinoma may either arise primarily in the ear or metastasize from local or regional disease. Pain is a common complaint, although hearing 94 loss and facial weakness may also occur. Rhabdomyosarcoma may originate in the temporal bone in the pediatric population. Endolymphatic sac tumors occur both sporadically 95 and associated with von Hippel–Lindau disease (Fig. 25-12). Symptoms arise from local 95 extension of the tumor and may include pain, hearing loss, and, less commonly, vertigo. Cancer of the breast, 94 kidney, lung, stomach, thyroid gland, and prostate all may metastasize to the temporal bone.

FIGURE 25-12 MRI of endolymphatic sac tumor. Axial contrast-enhanced

T1-weighted MRI demonstrates an irregular, enhancing mass along the posterior border of the petrous apex, at the expected location of the endolymphatic sac (dashed arrow). The mass erodes into the underlying temporal bone (solid arrow). (Courtesy of Barton F. Branstetter, MD, University of Pittsburgh.) NEURO-OTOLOGICAL MANIFESTATIONS OF AGING

Dysequilibrium of Aging Dysequilibrium of aging refers to a loss of balance in association with advanced age in individuals whohave no other known etiology for their balance disturbance. Patients with

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dysequilibrium of aging are generally in their seventies and demonstrate white matter disease on MRI including periventricular and subcortical white matter disease (Fig. 25-13) that may 96 relate to microvascular ischemic changes. Treatment consists of managing risk factors for cerebrovascular disease and balance therapy. Vestibular-suppressant medications should be discontinued.

FIGURE 25-13 MRI of a patient with microvascular disease seen in

dysequilibrium of aging. Axial fluid-attenuated inversion recovery (FLAIR) image through the bodies of the lateral ventricles shows extensive, confluent areas of abnormal signal in a periventricular and subcortical distribution, consistent with white matter microvascular disease. The ventricles are slightly enlarged from associated central volume loss. (Courtesy of Barton F. Branstetter, MD, University of Pittsburgh.)

Presbycusis Sensorineural hearing loss related to aging is termed presbycusis. Approximately one third of persons between the ages of 60 and 70, and up to half of those between 70 and 80, have 62 of presbycusis have been described, relating to different hearing loss. Four subtypes 97 audiometric patterns. The most common type is called sensory presbycusis, manifesting as a symmetric high-frequency downward-sloping sensorineural hearing loss that progressively worsens62with age (Fig. 25-14). Both genetic and environmental factors play a role in speech when there is etiology. Patients typically complain of difficulty in understanding 98 background noise, and they may also suffer from tinnitus.

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FIGURE 25-14 Audiogram of presbycusis. This audiogram shows sensorineural

hearing loss in a downsloping pattern, typical of presbycusis. Previous

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Aminoff: Neurology and General Medicine: Orbital and Ocular Manif...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 26 Orbital and Ocular Manifestations of Neurological Disease KIMBERLY P. COCKERHAM • ANDREA OLMOS •

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ARTERIOLIZED CONJUNCTIVAL VESSELS Cavernous Sinus Fistula Epidemiology Ocular Symptoms Ocular Signs Diagnosis Management Cavernous Sinus Thrombosis Epidemiology Symptoms Ocular Signs Diagnosis Management ORBITAL OR OCULAR PAIN DUE TO INTRACRANIAL PROCESSES Trigeminal Neuralgia Epidemiology Ocular Symptoms and Signs Diagnosis Treatment Cluster Headache Epidemiology Ocular Symptoms and Signs Diagnosis Management Pituitary Apoplexy Epidemiology Symptoms and Signs Diagnosis Management Tolosa–Hunt Syndrome Epidemiology Ocular Symptoms and Signs Diagnosis Management

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CRANIAL NEUROPATHIES INVOLVING THE EYE Cranial Nerve II Papilledema Papillitis and Retrobulbar Neuritis Optic Atrophy Cranial Nerves III, IV, and VI Epidemiology Ocular Symptoms and Signs Diagnosis Management Cranial Nerve V Epidemiology Ocular Symptoms and Signs Diagnosis Management EYELID RETRACTION WITHOUT LAGOPHTHALMOS Guillain–Barré Syndrome Epidemiology Ocular Symptoms and Signs Diagnosis and Management Parinaud's Syndrome Epidemiology Ocular Symptoms and Signs Diagnosis Management

The eye and its surroundings, the orbit and periorbital tissues, are intimately related to pathological processes occurring in the superior orbital fissure, cavernous sinus, parachiasmal region, and anterior cranial fossa. These various processes are discussed with emphasis on their epidemiology and on ocular symptoms and signs, diagnosis, and management. Due to space constraints, the entire subspecialty of neuro-ophthalmology cannot be covered within the context of this chapter; instead, a number of disorders that are of particular importance to neurologists and internists have been selected. The interested reader is directed to more detailed texts providing a1,2comprehensive description of all ophthalmic manifestations of neurological disease. Specifically, disorders of the pupil, ocular motility (Table 26-1 Table 26-2 Table 26-3), and the optic nerve are discussed only briefly in this chapter, the focus being on the most common ocular and orbital manifestations of intracranial processes. Important signs include arterialized vessels (cavernous sinus fistula, thrombosis); orbital or ocular pain (trigeminal neuralgia, cluster headache, pituitary apoplexy, and Tolosa–Hunt syndrome); corneal numbness (intracranial tumors); multiple cranial neuropathies (cavernous sinus fistula or thrombosis, pituitary apoplexy, Tolosa–Hunt syndrome); lid retraction without lagophthalmos (Miller Fisher variant of Guillain–Barré syndrome [GBS] and Parinaud's syndrome); and papilledema (increased intracranial pressure [ICP], which is idiopathic or due to tumor, infection, or inflammation). Click here to view this table.... Click here to view this table.... Click here to view this table.... ARTERIOLIZED CONJUNCTIVAL VESSELS

Cavernous Sinus Fistula Epidemiology Direct or fast-flow carotid-cavernous fistulas (CCFs) type A result from a single tear in the wall of the cavernous segment of the internal carotid artery, thus creating a direct communication between the internal carotid artery and the cavernous sinus. Direct CCFs are usually caused by head trauma, which may be severe enough to require hospitalization, or seemingly trivial, requiring no treatment until symptoms and signs of the fistula develop. Patients are commonly young men. A substantial number of direct CCFs result from a preexisting aneurysm of the cavernous segment of the internal carotid artery. They may also occur after various diagnostic and therapeutic procedures or after maxillofacial surgery. Spontaneously symptomatic direct CCFs may also occur. Patients who develop a direct fistula spontaneously usually have an underlying systemic vasculopathy or connective tissue 1 disorder.

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Dural or slow-flow CCFs result from lesions in one or more meningeal branches of the internal carotid artery, the external carotid artery, or both. Type B fistulas are rare and supplied only by meningeal branches of the internal carotid artery, type C fistulas by branches of the external carotid artery, and type D fistulas by meningeal branches of the internal and 3 external carotid arteries. Dural CCFs are often spontaneous and unrelated to trauma. Pregnancy, systemic hypertension, atherosclerotic vascular disease, connective tissue disease, and minor trauma may cause a predisposition to symptomatic dural CCFs. Spontaneous dural CCFs are more common in elderly women than in men. They usually occur in middle-aged or elderly women, but can produce symptoms at any age in both 1 sexes. Ocular Symptoms Characteristic ocular symptoms include an ache that may be worse on eye movements, double vision, and, rarely, decreased vision. Patients may experience pulsatile tinnitus, and examination may reveal a bruit that is synchronous with the heartbeat and most obvious when patients are recumbent. The eyelids may become moderately or severely swollen in the early stages of a direct CCF. This swelling can lead to progressive changes in the eyelid and its vasculature. Diplopia occurs1 in 60 to 70 percent of patients with direct CCF, and glaucoma in 30 to 50 percent of patients. Fistula size and location within the cavernous4 sinus, rate of flow, and pattern of venous drainage influence symptoms of dural CCFs. With posterior drainage, dural CCFs typically do not produce ocular symptoms, but they may produce a cranial neuropathy, such as trigeminal neuropathy, facial nerve paresis, and an ocular motor nerve paresis. They may also cause brainstem neurological deficits; in rare instances, intracranial hemorrhage 1 occurs. For anteriorly draining dural CCFs, symptoms are similar to, but usually milder, than those of direct CCFs. The mildest cases result in redness of one or, rarely, both eyes due to dilation and arterialization of conjunctival and episcleral veins. More severe cases of dural CCFs 1 show symptoms identical to those of direct CCF. Ocular Signs The conjunctival vessels may become more prominent with irritation, allergies, or inflammatory conditions such as thyroid eye disease, but none of these disorders causes the vessels to become tortuous and engorged right up to the corneal edge or limbus (Fig. 26-1). This characteristic vascular pattern of arterialized conjunctival vessels is seen as a manifestation of the flow alterations created by cavernous sinus fistulas and less commonly by cavernous sinus thrombosis.

FIGURE 26-1 Carotid-cavernous fistula: the characteristic arteriolized

conjunctival vessels are demonstrated. Other characteristic ocular findings in patients with CCF include increased intraocular pressure, chemosis (Fig. 26-2), alterations in eye movement due to passive engorgement or cranial nerve impairment, proptosis, and increased resistance to retropulsion (a firmness to

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the eyeball on palpation).

FIGURE 26-2 Carotid-cavernous fistula: the severe hemorrhagic chemosis

associated with a high-flow fistula can be seen. Diagnosis The diagnosis is based on clinical and imaging findings. Orbital ultrasonography, computed tomography (CT), CT angiography, magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), and conventional angiography are all valuable tools in identifying the enlarged superior ophthalmic vein (Fig. 26-3). Such imaging may also be used to show enlargement of the extraocular muscles, enlargement of the affected cavernous sinus, and abnormal intracranial vessels. Passive enlargement of the extraocular muscles is 1 common, causing a forward movement of the globe resulting in axial proptosis.

FIGURE 26-3 Carotid-cavernous fistula: magnetic resonance imaging (MRI)

shows enlarged superior ophthalmic vein and fullness of the cavernous sinus. Note the convex wall on the involved side. Catheter angiography is still the main diagnostic test for the definitive diagnosis of both direct and dural CCFs. It is the only technique that can accurately define the location of a fistula, its arterial supply, and the venous drainage pathways. However, angiography is invasive and impractical to perform during the follow-up of CCF patients after surgical treatment or embolization. The combined application of transcranial color Doppler imaging and carotid duplex sonography may be used to monitor the flow characteristics of fistulas and obtain accurate estimates of flow velocity and the extent of a CCF and its draining system. By correlating hemodynamic changes with clinical symptoms, this approach provides a noninvasive, reproducible, reliable, and inexpensive way to determine the efficacy of 5 treatment. Carotid duplex sonography alone has also been proposed as a useful instrument for early diagnosis and long-term follow-up of patients with dural CCFs. The resistive index of the external carotid artery of a dural CCF was determined to be the best parameter for

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predicting such fistulas.


6

MRA is another noninvasive technique that can diagnose CCFs by demonstrating the draining veins. However, whereas both MRA and MRI easily7visualize high-flow CCFs, low-flow CCFs are not seen as easily with these techniques. CT angiography is a reliable diagnostic tool for evaluating CCFs in a clinical context and providing a safe, noninvasive, and accurate method for follow-up. Although this technique can distinguish certain draining veins, it rarely shows the exact site of fistulas in direct CCFs or the small feeding branches in dural CCFs. Consequently, CT angiography cannot replace 8 the use of conventional angiography in planning endovascular interventional treatment. Because dural or low-flow CCFs show less specific clinical features and may be difficult to distinguish using CT and MRI, they present diagnostic challenges. However, transcranial Doppler ultrasonography is useful in detecting both dural and direct CCFs and in following the results of treatment, by detecting changes in blood flow within the orbit. It is especially important in the diagnosis and management of dural CCFs, which may exhibit subtle 9 hemodynamic changes. Although traumatic CCFs are rarely diagnosed early, high venous oxygen saturation values that rapidly reach arterial saturation values in the jugular bulb10may reveal the presence of a CCF before the appearance of clinical symptoms and signs. Management Closure of the abnormal arteriovenous communication without obstruction of the internal carotid artery is the optimal treatment of direct CCFs. This may involve direct obliteration of the fistula by surgical repair of the damaged portion of the cavernous internal carotid artery or endovascular closure of direct CCFs by embolization through the transarterial route using platinum coils and detachable balloons. In more than 80 percent of cases, the fistula is successfully closed, and the internal carotid artery remains unobstructed. The most common complications are aggravation of ocular signs, such as proptosis, ophthalmoparesis, and pain, and development of new neurological 1deficits. Severe complications include sepsis, stroke, blindness, and aneurysm formation. When the transarterial endovascular approach fails, the next treatment option is usually transvenous embolization with detachable balloons, standard platinum coils, liquid adhesives, or silk sutures. However, this alternative is not possible when venous routes are inaccessible. Embolization via a transvenous approach through the superior ophthalmic vein or the inferior petrosal sinus may also be used to treat 1 11 CCFs. This option has been more successful in treating low-flow indirect CCFs than high-flow CCFs. Direct CCFs with small fistulous communications have been successfully treated with Guglielmi detachable coils via the transarterial approach. The placement of these coils can be well controlled, and they are easily retrieved, repositioned, and exchanged. Although they are expensive compared to the complex fibered coils typically used for embolization, they offer another approach to treat appropriate fistulas or after transarterial embolization has 12 attempts fail and symptoms persist, a direct failed. When both transarterial and transvenous 11 surgical approach is a remaining option. Treatment options for dural CCFs include conservative treatment, direct surgery, conventional radiation therapy, stereotactic radiosurgery, and intermittent self-compression of the affected internal carotid artery. However, the optimal treatment for lesions producing aggressive symptoms and signs such as visual loss, diplopia, intolerable bruit, severe proptosis, increased intraocular pressure, or cortical venous drainage is endovascular 2 embolization. In most (70% to 95%) cases, dural CCFs are successfully closed by standard particulate or glue embolization. Complications of endovascular treatment include hemorrhage at the catheter site or in the orbit, local infection, sepsis, and temporary and permanent neurological deficits. For the endovascular embolization of dural CCFs, the transvenous route is preferred to the transarterial route. Relative to the transarterial approach, transvenous embolization has a high success rate and a low probability of serious 4 complications. There are various venous routes for executing an endovascular embolization, depending of the type of venous drainage (anterior, posterior, or cortical) and the anatomy. The inferior petrosal sinus is the simplest and shortest route to the cavernous sinus, allowing successful management13in most cases. Other options include the pterygoid plexus and the superior petrosal sinus. Transvenous coil occlusion of the superior and inferior ophthalmic veins and the cavernous sinus of the affected eye is a successful, efficient, and safe 4 treatment for dural CCFs.

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Cavernous Sinus Thrombosis Epidemiology Cavernous sinus thrombosis is usually secondary to paranasal sinus infection, orbital cellulitis, or midface infection. Although most cases occur in14healthy people, this disorder often occurs in immunocompromised and diabetic patients. Pathological changes associated with cerebral venous thrombosis depend on the location and degree of propagation of the clot and on the extent of collateral venous drainage. Symptoms may develop acutely (less than 48 hours), subacutely (48 hours to 30 days), or chronically (more than 30 days). Clinical manifestations also vary, depending on the site of obstruction, the extent and rate of occlusion, the underlying etiology, and the health or fragility 1 of the patient. Three factors are necessary for thrombus to form in the cavernous sinus: damage to the 15 intima of the vessel wall, hypercoagulability of the blood, and vascular stasis. Predisposing infection is usually streptococcal, staphylococcal, or pneumococcal. Anaerobic bacteria may also be responsible. Aseptic cavernous sinus thrombosis is usually secondary to some mechanical phenomenon and is sometimes associated with mechanical obstructive 16 pathology, such as a tumor or aneurysm. The most common pathogenesis is the development of an abscess, cellulitis, or other infected source leading to phlebitis of the veins draining the central portion of the face toward the cavernous sinus. The phlebitis propagates along these veins to the cavernous sinus, resulting in thrombophlebitis of the cavernous sinus. Because of the intercommunicating sinuses, the thrombophlebitis quickly becomes bilateral. Mycotic embolism may also be responsible. In this case, an abscess or infection in the middle third of the face can cause a mycotic embolus that becomes embedded in the cavernous sinus, initiating a thrombophlebitis. A third mechanism is a phlebothrombosis that occurs primarily in the cavernous sinus or one of the veins directly associated with the sinus. Aseptic cavernous sinus thrombosis can arise in this manner after intracranial surgery or other manipulation during which a thrombus with direct continuity to the cavernous sinus is created. Relative to 16 the first two processes, the signs and symptoms are subtler. Septic cavernous sinus thrombosis is commonly preceded by infections of the mid-face or by 15 paranasal (usually sphenoid) sinusitis, otitis media, or dental abscesses. Gram-positive bacteria are typically the pathogens that enter the facial vein and pterygoid plexus in this case. When dental infection is responsible, streptococci, fusobacteria, and Bacterioides species are the most common pathogens. Untreated or incompletely treated bacterial or fungal ear infections may also result in septic cavernous sinus thrombosis, which has a 30 percent mortality rate regardless of therapy. Survivors have neurological deficits, such as diplopia, visual sensory dysfunction, neurotrophic keratrophy, facial numbness, paresthesias, and pain from trigeminal neuropathy. Symptoms Visual symptoms are similar to those in CCF and include an orbital ache and diplopia, but the process is more commonly bilateral. Patients with cavernous sinus thrombosis occurring in conjunction with neurotrophic keratopathy or optic neuropathy may also experience loss of vision. Additionally, patients with septic cavernous sinus thrombosis may experience an altered sensorium and more generalized headache with nausea and vomiting; chills and diaphoresis may also be features, and seizures sometimes occur. Laboratory abnormalities include a pronounced leukocytosis and positive blood cultures. Evidence of meningitis or 1 brain abscess may be present. Complications include blindness, focal seizures, vascular steal syndromes, hemiparesis, and hypopituitarism. Other possible complications are intracranial infection, multiple brain 16,17 abscesses or systemic abscesses, and cerebral edema. Ocular Signs Clinical manifestations depend in part on whether the condition is infectious or aseptic. Pain around the eye is common and associated with several ocular signs, such as proptosis, conjunctival vessel arterialization, chemosis, ptosis, and ophthalmoparesis (Fig. 26-4). When facial, dental, or ethmoidal infection is responsible, eyelid edema is common. Lid swelling may also occur and can conceal neurogenic ptosis. Any or all of the cranial nerves passing

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1

through the cavernous sinus may be affected. Because the abducens nerve passes through the center of the sinus, lateral gaze palsy may be an early sign and can precede the development of complete ophthalmoplegia (i.e., lack of movement in all gazes due to 15 dysfunction of the third, fourth, and sixth cranial nerves). Damage to the first division of the trigeminal nerve in the cavernous sinus leads to corneal anesthesia or hypesthesia. Intraocular pressure is often elevated due to diminished outflow from episceral veins. Other ocular signs include increasing dilation of retinal veins, venous stasis retinopathy (dot-blot hemorrhages throughout the retina) and low-grade optic disc swelling (Fig. 26-5).

FIGURE 26-4 Carotid-cavernous fistula: bilateral chemosis and severe

dysmotility are demonstrated.

FIGURE 26-5 Intracarotid cavernous thrombosis: dilated tortuous retinal vessels

characterize venous stasis retinopathy and dot-blot hemorrhages. Mild disc edema may be present and may mimic papilledema when bilateral. Although superior ophthalmic vein thrombosis is a well-known sign of cavernous sinus 18 thrombosis, it is not always present. Diagnosis Conventional angiography has been replaced by noninvasive neuroimaging as the primary method of diagnosis. CT scanning and MRI can provide information about localization, cause, 1 and severity of the disease. Direct signs of cavernous sinus thrombosis include changes in the density/signal intensity and in the size and contour of the cavernous sinus. Indirect signs are related to associated venous obstruction and include dilatation of the superior ophthalmic vein, exophthalmos, and increased dural enhancement along the lateral border of the 18 cavernous sinus. However, overlap between normal variations and pathological abnormalities of the cavernous sinus makes it difficult to interpret CT and MR studies when performed at an early stage for the evaluation of sus pected septic cavernous sinus thrombosis, the origin of which is being recognized increasingly within the sphenoethmoidal sinus on these studies. CT and MR examinations are also required for early detection of intracranial complications. For example, high-resolution CT and MRI are used to recognize intracavernous carotid arterial wall 18 inflammation as a source of ischemic complications. CT scanning is relatively insensitive for diagnosing cavernous sinus thrombosis, but

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nonenhanced CT scans may show diffuse cerebral swelling, single or multiple hemorrhages, areas of hemorrhagic infarction, and small ventricles. CT with intravenous contrast may show 15 occlusion of the sinus or a dilated superior ophthalmic vein. MRI is the imaging study of choice for diagnosis and follow-up, demonstrating fullness of the cavernous sinus, 15 alternations in the carotid flow void, and the stages of thrombus evolution. It can detect thrombosis in cerebral veins and sinuses, but also distinguishes abnormalities in the brain parenchyma that reflect the pathophysiology of the disease. Advances in diffusion-weighted imaging and other techniques can also provide information about such parenchymal changes. MRI supplemented by a contrast-enhanced spoiled gradient–recalled acquisition in the steady-state sequence may serve as an alternative18to diagnose cavernous sinus thrombosis as well as tributary venosinus thrombosis. Gadolinium-enhanced MRI is also effective in early diagnosis and may reveal low-density areas that probably represent blood 19 clot. The differential diagnosis includes infection, especially fungal; inflammation, such as sarcoidosis; mass lesions (e.g., meningioma); and aneurysm. Management Management depends on the cause of the disorder. Options include antithrombotics in conjunction with corticosteroids if no infection is present. Occasionally surgery is required to obtain a biopsy specimen of the mass. Surgical excision of meningiomas from the cavernous sinus is often complicated by permanent injury to the cranial nerves, and radiation is thus the preferred therapeutic modality. In septic cases, antibiotics or antifungal agents are instituted. The penetration of antibiotics may be limited by thrombus, so that treatment is usually continued for at least 3 weeks with high doses of intravenously administered antibiotics. Empiric therapy should include either nafcillin or oxacillin at maximal doses plus either ceftriaxone or cefepime; if a dental or sinus infection is likely, metronidazole is added. Anticoagulation may be necessary to prevent septic emboli, corticosteroids to reduce edema, and surgery to drain the primary infective 14 source. Delays in diagnosis can result in significant mortality and permanent sequelae. ORBITAL OR OCULAR PAIN DUE TO INTRACRANIAL PROCESSES

Trigeminal Neuralgia Epidemiology 20

Trigeminal neuralgia has an estimated prevalence of 100 to 200 cases per million people. Vascular contact of the trigeminal nerve root at its entry (or exit) zone with a branch of the superior or anterior inferior cerebellar artery results in demyelination of trigeminal sensory fibers within the nerve root or brainstem in 80 to 85 percent of cases; in another 2 percent of cases, a structural anomaly other than neurovascular compression by a normal vessel (e.g., by posterior fossa neoplasm,21cysts, arteriovenous fistulas, cavernous malformations, and arteriovenous malformations ) is responsible. Hypertension is associated with trigeminal 22 in the posterior neuralgia. Multiple sclerosis and compressive space-occupying masses 23 fossa are other causes of trigeminal neuralgia involving demyelination. Ocular Symptoms and Signs 20

The facial pain of trigeminal neuralgia is often associated with photophobia and tearing, but unlike cluster headache, there are no eyelid, conjunctival, or pupillary findings. Nevertheless, complete eye and neurological examination is essential to detect signs of corneal anesthesia (cranial nerve V), involvement of cranial nerves II to VII, or long-tract signs, which would suggest an underlying structural cause for the disorder other than anomalous microvascular compression of trigeminal nerve fibers. Diagnosis CT and angiography can24be used to exclude aneurysm, tumor, or other structural lesions as the cause of symptoms. MRI is the preferred imaging modality, but high-resolution magnetic resonance tomographic angiography (MRTA) is also useful25for visualizing the neurovascular relationships at the trigeminal nerve root entry or exit zone.26 Spoiled gradient–echo (SPGR) MRI, MRA, and three-dimensional imaging are also helpful to demonstrate abnormalities such as tumors, cerebral aneurysms, arteriovenous malformations, and vascular anomalies.

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Treatment Pharmacological treatment options include carbamazepine and phenytoin, but 25 percent of 27 patients do not respond. Surgical procedures are available for medically refractory trigeminal neuralgia. Microvascular decompression is suggested for20otherwise healthy patients with isolated pain in the first ophthalmic trigeminal division. Operative success is more likely in cases in which20,28 the symptoms and signs are typical and severe and have been Gamma knife has also been used with mixed success;27the present for less than a year. most common complications are facial numbness, facial paresthesias, and dysgeusia.

Cluster Headache Epidemiology Cluster headache is a migraine variant characterized by recurring incidents of severe, unilateral orbital or temporal pain associated with cranial autonomic features and usually occurring with circadian periodicity. The prevalence of cluster headache is an estimated 0.1 percent, with a male-to-female ratio of 3.5 to 7:1. Cluster headache can start at any age, but the most common age at onset is 30 to 40 years. Acute attacks are often29provoked by alcohol, nitroglycerin, exercise, and elevated environmental temperature. Chronic cluster 30 headache usually develops from episodic cluster headache, but may also develop de novo. People with episodic cluster headache typically experience one to two attack phases each year, with phase durations ranging from 4 to 16 weeks and remission periods of 6 months to 2 years. Patients with chronic cluster headache experience phase durations exceeding 1 1 year, with remission periods of less than 1 month. The pathophysiology of cluster headache is unknown, although evidence exists indicating that the pain and autonomic symptoms result from activation of both the trigeminal vascular and cranial parasympathetic pathways. There is also evidence that nitric oxide may play a role; it is increased in patients during and between attacks. Hypothalamic dysfunction has been claimed as a potential cause of the rhythmic nature of cluster headache, and altered 1 circadian rhythms of hypophysial hormone systems have been reported in cluster headache. Cluster headache is occasionally associated with trigeminal neuralgia (cluster-tic syndrome). Also, approximately one half to two thirds of patients develop Horner's syndrome (ptosis and miosis) during an attack and may develop a permanent Horner's syndrome after multiple cluster headache attacks. Secondary 30 cluster-like headaches are those with an underlying medical disorder or a structural lesion ; clinical examination may be useful in distinguishing these from primary cluster headaches. Ocular Symptoms and Signs Severe unilateral orbital, supraorbital, or temporal pain occurs, lasting for 15 to 180 minutes. However, any part of the head may be affected and, although the attacks are strictly 29 unilateral, the affected side may alternate. Ipsilateral accompaniments include nasal congestion, rhinorrhea, or both; forehead and facial swelling; and a29sense of restlessness Ocular signs include and agitation. Nausea, vomiting, and photophobia may also occur. 1,30 The conjunctival conjunctival injection, tearing, eyelid edema, and miosis and ptosis. injection is usually diffuse and mild without associated chemosis. The conjunctival vessels are never tortuous (arterialized) as seen with cavernous sinus fistula and thrombosis (Fig. 26-6). Tearing and photophobia are typically present; the eyelids may be erythematous or edematous. Horner's syndrome may be present. The pupil on the involved side is smaller, and this anisocoria is more obvious in the dark.

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FIGURE 26-6 Cluster headache: the diffuse conjunctival injection can be seen.

Note that the vessels are much smaller and less tortuous than those seen in patients with carotid-cavernous fistulas. Diagnosis The diagnosis can be difficult when the attributes of cluster headache are mimicked by other headaches and the patient has an unrelated conjunctival injection due to allergy, infection, or irritation. Differential diagnoses to consider are secondary causes 29 of cluster headache, other trigeminal autonomic cephalgias, migraine, and hypnic headache. MRI can be helpful in distinguishing between cluster headache mimics and primary cluster headache. All patients with a headache should have their optic nerves examined for signs of papilledema (bilateral disc edema, lack of venous pulsations that may be accompanied by venous fullness and retinal hemorrhages), malignant hypertension (discs that are typically hyperemic bilaterally and associated with retinal microinfarcts, so-called cotton wool spots), or optic nerve pallor due to ischemic damage or vasculitis (temporal arteritis). Management Treatment is acute or prophylactic. For acute treatment, inhalation of 100 percent oxygen for 15 minutes may stop an attack. The advantages of oxygen therapy are that it has no established adverse effects, it can be combined with other acute and preventive treatments, 29 and it can be repeated if29necessary. Subcutaneous sumatriptan is the medication of choice to abort a cluster attack. Most oral medications are not absorbed quickly enough to relieve the pain of a cluster headache within a reasonable time. Preventive therapy is required when cluster headache attacks are frequent, severe, and so short that abortive medications are not effective. Medication for preventive therapy is started early in the cluster period and continued until the patient is free from headache for 2 weeks, after which the dose is progressively decreased. Prednisone is the fastest-acting preventive drug; many consider verapamil, a calcium-channel blocker, the best preventive drug; lithium is also effective. Short-term prevention is an option for patients with short bouts or to control attack frequency, but the drugs used for this purpose should not be taken on a long-term 29 basis. They include corticosteroids and nocturnal ergotamine. Patients are advised not to drink alcohol during the cluster bout, warned against prolonged 29 exposure to volatile substances, and advised to avoid afternoon naps.

Pituitary Apoplexy Epidemiology Pituitary apoplexy is an acute life-threatening condition that is typically associated with acute enlargement of a pituitary adenoma resulting from hemorrhage or infarction and occurs in either gender and at31any age. It has been reported in 0.6 to 17 percent of patients with pituitary adenomas. It may be the initial presentation of the tumor (regardless of histological

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32

subtype ) and can be precipitated by trauma, radiation, bromocriptine or estrogen therapy, pregnancy, angiography, anticoagulation, adrenalectomy, cardiac or other recent surgery, dialysis, dynamic pituitary function or stimulation tests, and transient changes in ICP due to 1 coughing, sneezing, or spinal anesthesia. Other predisposing factors including pituitary irradiation, alterations in pressure gradients, diabetes, chronic systemic hypertension, reduction or acute increase in pituitary blood-flow, and abnormal vascularity of pituitary tumors. The clinical 31,32 presentation of pituitary apoplexy is not influenced by the presence of The disorder is probably caused by capillary compression or the associated disease. outstripping of vascular supply as the pituitary tumor expands. Symptoms and Signs The classic triad of pituitary apoplexy is pain, double vision, and bitemporal hemianopia. Pituitary apoplexy causes sudden, severe headache that may be retro-orbital, frontal, or diffuse. Other symptoms include neck pain, photophobia, nausea, vomiting, visual disturbances, autonomic dysfunction, hormonal dysfunction, and alteration of consciousness. However, pituitary apoplexy may also occur with a more gradual onset or with almost no 31,33 symptoms at all. The sudden expansion of the pituitary results in compression of the optic chiasm and ischemia of the optic nerves. Ocular signs include unilateral or bilateral visual loss that is associated with bitemporal hemianopias. The expanded pituitary may also compress cranial nerves III, IV, V, and VI as they course through the cavernous sinus. If all three of the oculomotor cranial nerves are affected, gaze may be absent in all directions. This is often 34,35 referred to as complete ophthalmoplegia or a frozen globe in the ophthalmic literature. Pituitary apoplexy may also occur in association with Horner's syndrome, thought to be the result of disruption of the sympathetic fibers as they course through the cavernous sinus in close proximity to the carotid artery and sixth cranial nerve. Additionally, pituitary apoplexy can produce subarachnoid hemorrhage without aneurysm. Other signs include pyrexia, epistaxis, or cerebrospinal fluid (CSF) rhinorrhea when the mass ruptures 36 or erodes into the sphenoid sinus, and complications of blood or necrotic debris in the CSF. This topic is discussed further in Chapter 23, where its associated endocrine disturbances are also considered. Diagnosis MRI is the main diagnostic tool, being more sensitive than CT, which is usually used in the acute setting to evaluate the sudden severe headache brought on by pituitary apoplexy. Using CT, an apoplectic pituitary tumor shows up as a heterogeneous mass with areas of 33 hyperdensity that correspond to the presence of hemorrhage. CT will sometimes permit recognition of the pituitary adenoma. MRI is superior to CT33in detecting apoplectic changes and also allows the age of a hemorrhage to be estimated. MRI provides a more accurate evaluation of the pituitary fossa contents and can identify areas of hemorrhage and34infarction that might be expected to resolve without invasive surgical intervention (Fig. 26-7).

FIGURE 26-7 Pituitary apoplexy: MRI demonstrates massive enlargement of

the pituitary gland (arrows). The hetero-geneous appearance is due to a mixture of hemorrhage and necrosis. The proximity of the pituitary to the underlying optic chiasm and cavernous sinus results in the classic triad of pain, bitemporal hemianopia, and diplopia. Management

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Management depends on the state of the patient. If the patient is alert and has mild dysmotility, conservative management may be appropriate. On the basis of clinical and tomographic findings, medical treatment with corticosteroids alone, or even no treatment, 37 may be sufficient. Other endocrinological support is sometimes required. If the patient experiences visual loss or persistent cognitive dysfunction, surgical decompression by a 1 transsphenoidal route may be necessary. Studies indicate that early surgery (within 8 days of onset) promotes significantly greater34,35 improvement in visual acuity and visual field deficits Clinical assessment and MRI can help to predict than delayed surgery (after 8 days). 34 which patients should be managed conservatively or surgically.

Tolosa–Hunt Syndrome Epidemiology Tolosa–Hunt syndrome of painful ophthalmoplegia is caused by idiopathic granulomatous inflammation, with epithelioid cells and occasional giant cells, anywhere from the orbit to the 38 superior orbital fissure and cavernous sinus. Rarely, inflammation also spreads intracranially. The syndrome affects people of all ages and either sex; it has been reported in 38 nearly every continent. Ocular Symptoms and Signs The primary symptom is pain, often described as intense, severe, boring, or stabbing. The pain is periorbital and can extend to the retro-orbital, frontal, and temporal regions to become hemicranial. Untreated, it lasts for about 8 weeks. Nausea and vomiting may also occur and 38 probably result from the intense orbital pain. The pain may occur in combination with ipsilateral palsies of the third, fourth, and sixth cranial nerves at the onset of pain or following it within about 2 weeks. The pain may also be accompanied by oculosympathetic paralysis and sensory loss in the distribution of the ophthalmic division of the trigeminal nerve. In contrast to other cavernous sinus processes such as fistula and thrombosis, there is no arterialization of the conjunctival vessels, chemosis, eyelid erythema/edema, or elevation of the intraocular pressure (Fig. 26-8).

FIGURE 26-8 Tolosa–Hunt syndrome: the patient has a complete left

third-nerve palsy. The eyelid has to be held up to examine ocular motility. The patient has been asked to look right, and there is no movement of the eye. In a complete third-nerve palsy, the superior and inferior divisions of the nerve are affected. Optic nerve dysfunction has also been reported; the optic disc can appear swollen, pale, or normal. The resulting degree of visual decline ranges from minimal to blindness. Loss of acuteness varies and can be permanent. Additional cranial nerves outside of the cavernous sinus and the superior orbital fissure may also be affected including the facial nerve and the 38 maxillary and mandibular branch of the trigeminal nerve. Diagnosis

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CT and MRI techniques are used to visualize the cavernous sinus and superior orbital fissure. Contrast-enhanced MRI with multiple views is recommended as the initial diagnostic study. The MRI technique is limited, however, by its lack of specificity. For example, certain signal characteristics used to diagnose Tolosa–Hunt syndrome may also be consistent with other conditions such as meningioma, lymphoma, and sarcoidosis. In response, some authorities suggest additional MRI studies after a systemic course of corticosteroids to support the diagnosis; resolution or reduction in size of the initial imaging abnormalities is 38 supportive, but not diagnostic, of Tolosa–Hunt syndrome. Similar clinical and radiological responses to corticosteroids have been reported in painful ophthalmoplegia caused by sarcoidosis, aneurysm, actinomycosis, lymphoma, plasma cell dyscrasia, and other solid 39 tumors. Although less sensitive than MRI, high-resolution CT may identify changes in soft tissue in the region of the cavernous sinus and superior orbital fissure. Furthermore, CT can be used in addition to MRI to detect bone changes and calcification. Abnormalities in the intracavernous carotid artery38of patients with Tolosa–Hunt syndrome have also been detected using cerebral angiography. Neurosurgical biopsy is rarely used to make the diagnosis. Its use is considered in patients who have progressive neurological deficiencies, do not respond to steroid treatment, or whose neuroimaging studies continue to demonstrate abnormalities 38 associated with Tolosa–Hunt syndrome. 38

The diagnosis of Tolosa–Hunt syndrome can only be made by exclusion, as it 39 is difficult to visualize lesions in the cavernous sinus by classic neuroradiological techniques. Other causes of painful ophthalmoplegia include parasellar syndrome; craniocerebral trauma; vascular lesions, such as intracavernous carotid aneurysm, CCF, and cavernous sinus thrombosis; neoplasm; and other specific inflammatory disorders. Painful ophthalmoplegia may also occur without involvement of the cavernous sinus or the superior orbital fissure, as in various orbital diseases, diabetic ophthalmoplegia, posterior fossa aneurysm, and giant cell 38 arteritis. Specific criteria have been suggested for diagnosing Tolosa–Hunt syndrome. These include (1) steady pain in the ophthalmic division of the trigeminal nerve, (2) dysmotility and pupillary changes due to dysfunction of cranial nerve III, IV, or VI, (3) acute or subacute symptoms that are responsive to corticosteroids, and (4) inflammation limited to the cavernous sinus. Optic nerve involvement is not characteristic and suggests involvement of the orbital apex (i.e., orbital apex syndrome) that may be due to infection, inflammation, or infiltration. Spontaneous remissions and recurring episodes at intervals of months or years have been 36 reported. Management Treatment with systemic corticosteroids usually results in improvement of signs and symptoms within 48 hours. However, spontaneous remissions may occur after days or weeks 40 and recurring attacks can also occur after months or years. If recurrence occurs after taper of the corticosteroids, the diagnosis of lymphoma and sarcoidosis should be considered. In unusual cases, biopsy may be necessary. CRANIAL NEUROPATHIES INVOLVING THE EYE

Cranial Nerve II Papilledema Epidemiology

The epidemiology of papilledema reflects the etiology of increased ICP. Increased ICP may result from brain tumor at any age and in either gender. Intracranial masses that obstruct CSF outflow may be relatively small and still result in markedly increased ICP and papilledema. Pseudotumor cerebri (also known as idiopathic or benign intracranial hypertension) characteristically presents in obese women of child-bearing age. In contrast, infection can result in meningeal infiltration and meningitis at any age and in any gender. Inflammation due to sarcoidosis is more common in African Americans and Scandinavians. Predisposing factors for papilledema include a history of carcinoma or lymphoma and recent viral, bacterial, or tuberculous infection. Risk factors for increased ICP include recent weight

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gain, use of exogenous estrogen or vitamin A, and intake of certain drugs (antibiotics, corticosteroids, isotretinoin). Ocular Symptoms and Signs

Symptoms of increased ICP include headache, transient visual obscurations, intracranial 41–44 noises (humming or ringing), decreased vision, and double vision. The most common presenting ocular symptom of papilledema is transient visual obscurations that are described as graying or blacking out of vision that lasts only for seconds and can be precipitated by moving from a lying to a sitting or standing position. Many patients notice a whooshing sound in one or both ears when lying down. Less frequently, horizontal diplopia that is most prominent at a distance is the first symptom of a sixth nerve palsy associated with the increased ICP. Retro-orbital ache is sometimes present and may be worse with eye movement. Headache is a common presenting symptom; it is typically present upon awakening and associated with nausea and emesis but may be nonspecific in character. Early enlargement of the blind spot is followed by peripheral constriction of the visual fields, especially in the nasal quadrants, which can eventually progress to central visual loss in advanced cases. Early papilledema is associated funduscopically with bilateral, although frequently asymmetric, opacification of the nerve fiber layer, lack of spontaneous venous pulsation, and obliteration of the central cup. Hemorrhages and exudates may also occur. In chronic papilledema, small telangiectatic vessels and white concretions on the disc surface may be present, and afferent function may be abnormal (central visual acuity, color, pupils, and visual 41,42,44,45 With chronic papilledema, choroidal folds (Paton lines) or optic atrophy may fields) result (Fig. 26-9). Rarely, subretinal neovascularization develops due to fracture of Bruch's membrane in the retina and the growth of new vessels through this layer with subsequent leakage of blood and fluid.

FIGURE 26-9 Chronic papilledema is characterized by subtle edema: as the

optic nerve fibers die, they no longer can swell, and become pale. Paton lines are visible adjacent to the disc. Diagnosis

Bilateral disc edema is a clinical diagnosis that is not appropriately termed papilledema until increased ICP is diagnosed. The differential diagnosis of bilateral disc swelling includes malignant hypertension, central retinal vein occlusion, anterior ischemic optic neuropathy, papillitis, or optic nerve involvement by inflammation, infection, or neoplasia (Table 26-4); none of these entities disrupt spontaneous venous pulsations. Occasionally, a patient will present with headaches and atypical-appearing optic nerves. “Pseudopapilledema” may be diagnosed due to optic nerve head drusen, anomalous optic nerves, hyperopic nerves, or tilted discs.

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Click here to view this table.... If there is doubt as to whether disc edema is truly present, several diagnostic testing techniques are available. Ultrasonography (B mode) is used to detect buried drusen. Fluorescein angiography is used to identify early vessel dilatation and leakage. In uncooperative children or adults, fundus photos are invaluable to document the features of the optic nerve heads. Management

Although afferent function may be normal in the early stages of papilledema, formal visual field testing is key to management at all stages. Neuroimaging, preferably MRI, is performed to look for an intracranial mass. In patients with persistent papilledema or who are unusual or unresponsive to medication, magnetic resonance venography should be considered as a diagnostic tool to exclude venous thrombosis. When a lumbar puncture is performed, opening pressure should be documented and the CSF should be analyzed for cells, glucose, 46,47 and protein content. Management is of the underlying disorder and is considered in standard textbooks of neurology. If a tumor is present, surgical intervention is necessary. If pseudotumor cerebri is diagnosed, weight loss should be encouraged and the patient followed very closely with visual field testing. Failure to monitor visual fields can result in permanent visual loss and even blindness. If visual field defects are present, the patient should be placed on a minimum of 1 g acetazolamide. The sustained action capsules are superior to the tablets and result in less gastric disturbance. Corticosteroids are sometimes helpful. If medical therapy fails to relieve the headache or visual loss progresses, surgical options should be discussed. Optic nerve sheath fenestration is indicated if a shunt fails to normalize the visual field or there is catastrophic visual loss with mild or absent headache. Papillitis and Retrobulbar Neuritis Epidemiology

The term papillitis is used for disc edema of uncertain etiology. As such, there are no specifics to the race, gender, or age of those affected. Papillitis may be unilateral or bilateral and, in some cases such as inflammation or neoplasia, occurs recurrently. Bilateral disc edema of uncertain etiology, even if associated with a headache, should be referred to as bilateral papillitis. Ocular Symptoms and Signs

In contrast to disc edema secondary to increased ICP, papillitis is associated with acute onset of visual loss. An afferent pupillary defect, color desaturation, and central visual field defect are present. Papilledema does not typically present with decreased vision, an afferent pupillary defect, color desaturation, or significant visual field defects. The most common visual field defect in papillitis is a central scotoma; by contrast, early papilledema produces only an enlarged blind spot (which may be missed with the new automated fields). Diagnosis

Papillitis may represent an optic neuritis, which is often associated with the development of or coexistent multiple sclerosis (MS). In contrast to the symptoms and signs of papilledema, optic neuritis is typically acute in onset and is associated with retrobulbar pain that is worse with eye movement; it is not accompanied by headache. Transient visual obscurations are not typical. Optic neuritis is commonly retrobulbar (behind the globe) and the optic nerve is entirely normal in appearance. In addition, spontaneous venous pulsations are present, the veins are of normal appearance, and hemorrhages and exudates are absent. If macular edema is present and the exudates form a macular star as it recedes, the diagnosis is more likely infectious (e.g., cat-scratch disease) rather than optic neuritis associated with multiple sclerosis. If microin-farcts (cotton wool spots) are present, the diagnosis is either malignant hypertension or vasculitis such as occurs with systemic lupus erythematosus or temporal arteritis. Papillitis may be idiopathic, infectious, due to ischemia (acute ischemic optic neuropathy or AION), or due to a tumor (optic nerve or sphenoid wing meningioma, glioma, or parasellar process).

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Compressive lesions can also cause cavitation (optic nerve cupping) or shunt vessels on the surface of the disc. Temporal arteritis should be considered in all patients older than 50 years with headaches, especially when visual symptoms are present. In that disorder, transient visual obscurations may precede visual loss; vision may be poor (less than 20/400) unlike in patients with papilledema, in whom vision is typically good unless the papilledema is long-standing. Diplopia due to cranial nerve impairment may also occur. The ocular signs may include optic nerve pallor, swelling, or cavitation. A branch or central retinal artery occlusion may also occur. Occasionally, both optic nerves become swollen in rapid succession and are inappropriately designated papilledema. Management

Management depends on the cause. Oral or intravenous corticosteroids are indicated in inflammatory papillitis, but oral corticosteroids are contraindicated as the initial treatment for optic neuritis. If temporal arteritis is suspected, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complete blood count should be obtained. Elevation of the ESR and CRP along with anemia and thrombocytosis is characteristic. An oral corticosteroid dose of at least 1 mg/kg is initiated and tapered slowly over at least 6 months. Optic Atrophy Epidemiology

Optic atrophy is the nonspecific end-product of all optic neuropathies, so there is no specific age, gender, or race predilection. End-stage glaucoma is associated with optic atrophy and pallor; conversely, cavitation of the optic nerve without pallor can be the only evidence of an intracranial tumor or temporal arteritis. Ocular Symptoms and Signs

Visual loss may be acute, subacute, chronic, or unrecognized. It is not unusual to identify optic atrophy with the associated optic nerve pallor, nerve fiber loss, and visual field defects in patients with multiple sclerosis and no specific memory of an acute event. Chronic compression from Graves' ophthalmopathy, optic nerve tumors, hyperostosis of the optic canal, or other intracranial processes is characteristically slowly progressive and with an onset that is not easily identified by the patient. Diagnosis

Optic atrophy is not a diagnosis; the cause of the pallor or cavitation (cupping) must be sought. Posterior ischemic optic neuropathy is defined as an optic neuropathy without optic disc swelling that evolves into optic nerve pallor over 3 to 4 weeks. Its causes include temporal arteritis, traumatic optic neuropathy, and optic nerve dysfunction related to coma and hypotension. Retrobulbar neuritis is most commonly due to multiple sclerosis. A complete evaluation should include neuroimaging, laboratory studies for temporal arteritis if the patient is at least 50 years old, and studies to exclude such infective processes as syphilis, tuberculosis, and Lyme disease. Rarely, hereditary conditions such as Leber's optic neuropathy, nutritional neglect, and toxic etiologies are present. Management

The management depends on the cause and is discussed in standard comprehensive neuro-ophthalmic texts.

Cranial Nerves III, IV, and VI These three cranial nerves are conveniently discussed as a single group. Disturbances of ocular motility are summarized in Table 26-1 Table 26-2 Table 26-3. Epidemiology

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A combination of cranial nerve III, IV, V, and VI dysfunction may be temporary or permanent as a result of an intracranial process at the level of the superior orbital fissure, cavernous sinus, or brainstem. If the orbital apex is involved, decreased vision due to optic nerve dysfunction is characteristic. Such disorders may affect patients of any age, gender, or race. Ocular Symptoms and Signs The differential diagnosis of involvement of these cranial nerves includes disorders of the orbit, cavernous sinus, and brainstem. Several of the entities already described may cause dysfunction of motility, including orbital infiltration, infection, hemorrhage or mass; cavernous sinus fistula, thrombosis, infection, or mass; and brainstem stroke, infiltration, or compression. Localization of the disorder is based on the associated symptoms or signs. Of note, cavernous sinus fistulas and thrombosis may result in protrusion of the globe anteriorly (prop-tosis or exophthalmos) and increased resistance when an attempt is made to push on the closed eyelid (retropulsion) to feel the firmness of the globe. In contrast, inflammation (Tolosa–Hunt syndrome) or hemorrhage and necrosis (pituitary apoplexy) do not cause proptosis or increased resistance to retropulsion. Classically, processes that infiltrate the orbital apex impair multiple cranial nerves. In these cases, dysmotility due to cranial nerve dysfunction must be distinguished from gaze limitations from muscle dysfunction. Cranial neuropathies are typically associated with slow saccades and no intraocular pressure elevation with eye movement. In contrast, restricted muscles due to infiltration, inflammation, or entrapment are associated with normal saccades, but the intraocular pressure elevates in the gaze that is limited. For example, in Graves' disease, the inferior rectus is often enlarged and can limit upgaze. Intraocular pressure measured in attempted gaze is often 5 to 8 mmHg higher than it is in primary gaze. The speed (fast, normal, or slow) and accuracy (hypometric, normal, or hypermetric) of saccades are normal. The cranial nerves are affected in the region of the superior orbital fissure in the sphenoid bone. Immediately adjacent to the superior and inferior orbital fissures is the optic canal, which transmits the optic nerve, ophthalmic artery, and sympathetic fibers to the orbit. Patients with orbital apex syndromes therefore also have impairment of optic nerve function, including an afferent pupillary defect, whether unilateral or asymmetric; color vision abnormalities; visual field defects; and optic nerve abnormalities. If there is uncertainty about whether a slight afferent pupillary defect is present, testing for red desaturation is useful. The patient is presented with a red test object or item: the better eye is examined first and the patient is then asked whether the color red appears the same on the involved side. If there is optic nerve dysfunction, the patient will describe the red color as “desaturated” to a more brown or orange color. In ophthalmic notation, the patient, for example, then subjectively quantitates the desaturation as 20 percent less red. The visual field defects characteristic of optic nerve involvement include a central or centrocecal scotoma and arcuate or altitudinal defects. The optic nerve is often swollen early in the process. Optic pallor does not develop for at least 3 weeks after injury, so the optic nerve may initially be normal. Chronic compression can result in cavitation (cupping of the optic nerve). Pathological processes in the cavernous sinus are associated with other findings of venous outflow alteration. These include conjunctival injection (discussed earlier), chemosis, elevated intraocular pressure, and proptosis. Finally, other neurological symptoms and signs, as detailed in standard neurological textbooks, accompany disorders of the brainstem such as stroke or infiltration. Diagnosis MRI with gadolinium is the preferred modality to image either the cavernous sinus or brainstem. Further details were provided earlier regarding cavernous sinus fistula, thrombosis, infiltration, and inflammation. Management The reader is referred to standard textbooks of neurology for management of cavernous sinus processes and brainstem syndromes.

Cranial Nerve V

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Epidemiology Diminished corneal sensation may be caused by herpes simplex, ocular surgery, cerebellopontine angle tumors, dysautonomia, and certain congenital disorders. Changes in corneal responsiveness also occur normally with variations in physiological and environmental factors. For example, corneal sensitivity decreases with age, and brown-eyed individuals have corneas that are usually less sensitive than blue-eyed individuals. Ocular surgery and panretinal photocoagulation may denervate parts of the cornea. A permanent reduction in corneal sensitivity occurs in about 10 percent of patients who undergo radial keratotomy for myopia and about 50 percent of patients who also receive transverse incisions 1 for astigmatism. Isolated corneal hypesthesia usually results from acquired local disease of the cornea or sclera. Unilateral corneal hypesthesia can occur with various orbital diseases, Adie's tonic pupil, lower brainstem lesions, and iatrogenic lesions of the trigeminal pathway. Ocular Symptoms and Signs Presenting symptoms include conjunctival injection, tearing, and photophobia in cases of mild corneal breakdown. The surface of the cornea (epithelium) can be disrupted unintentionally by the patient during sleep or with eye rubbing. If the corneal abrasion is not identified early, it may progress to corneal ulceration and infection. In severe cases, the infection can progress posteriorly into the globe and cause endophthalmitis. In neglected cases, loss of vision and the entire globe may occur. In contrast to cavernous sinus fistulas and thrombosis, the conjunctival injection is not tortuous, chemosis is absent, and the intraocular pressure is normal. In contrast to cluster headache, it is not cyclic, but an unrelated headache may be present. Motility is normal and the pupil is not affected. Diagnosis Sensory testing of the cornea can be done without specialized equipment. A cotton tip applicator can be used to touch or brush the inferior aspect of the cornea, and the response evaluated. Corneal sensation may also be assessed by subjective and objective responses (such as involuntary blink reflex and head withdrawal) to eyedrop instillation and quantified using anesthesiometers. Management Topical drops and ointments may be helpful in preventing corneal breakdown in transient or mild cases, but more commonly punctal closure with plugs or cautery is required. Surgical closure of the eyelids (tarsorrhaphy) is sometimes necessary. In severe cases, the conjunctiva can be mobilized as a flap to cover the cornea (Gunderson flap) or the eyelids can be closed permanently. EYELID RETRACTION WITHOUT LAGOPHTHALMOS

Guillain–Barré Syndrome Epidemiology GBS is characterized by an acute onset of a rapidly progressive peripheral demyelinating polyneuropathy. An axonal variant of GBS has also been reported. GBS and its variants are discussed in detail in Chapter 60. The Miller Fisher syndrome is a variant of GBS and is defined as a combination of ophthalmoplegia, ataxia, and areflexia. In the majority of cases, the lesion responsible for the syndrome is in the cranial and peripheral nerves. Although there is usually bilateral involvement of the oculomotor, trochlear, and abducens nerves, partial and asymmetric syndromes also exist. Facial and bulbar weakness are also commonly included as part of the 48 syndrome is much less common than GBS, with a Miller Fisher syndrome. Miller Fisher 49 reported incidence of 0.1 per 100,000. A recent study suggested that cases of isolated abducens nerve palsy associated with antecedent illness, acral paresthesias, hypo- or areflexia, and CSF albuminocytological

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dissociation can be categorized as a regional variant of GBS or as a mild form of Miller Fisher 50 syndrome. Ocular Symptoms and Signs The predominant symptom of GBS is weakness ranging from mild ataxia to total paralysis of any or all muscles supplied by motor and cranial nerves. Full details are provided in Chapter 60. Other symptoms include ophthalmoplegia, absent tendon reflexes, cranial nerve palsies, 51,52 Third-nerve palsy, for instance, was reported to dysautonomia, paresthesias, and pain. 53 occur in 17 percent of GBS cases in one case series. The conjunctival vessels are normal and there is no chemosis. The intraocular pressure is unaffected. The eyelids and globe position are normal. Although uncommon, optic neuritis1 may occur. Papilledema is a rare complication. Light-near dissociation has been reported. Patients with Miller Fisher syndrome have dysmotility due to involvement of cranial nerve III, 1,48 Approximately one third of patients develop IV, or VI, ataxia, and loss of tendon reflexes. facial weakness. Other common symptoms are proprioceptive sensory problems, and areflexia develops after 1 week. The findings on examination of the eyes may mimic an internuclear ophthalmoplegia or a skew deviation. Internuclear ophthalmoplegia is characterized by limitation of adduction (medial gaze) and horizontal gaze-evoked nystagmus on abduction (lateral gaze). Skew deviation is defined as a vertical misalignment of the two eyes associated with vertical diplopia that is usually less than 5 prism diopters, may be torsional, and is not due to a cranial nerve or extraocular muscle problem. Paralysis may be confined to the eye muscles and the face, in which case full recovery is very likely with or without treatment. Extensive paralysis indicates an acute immune axonal polyneuropathy commonly associated with Campylobacter jejuni infection, with a prognosis for recovery that 1 is less favorable. Diagnosis and Management These are discussed in Chapter 60, to which the reader is referred.

Parinaud's Syndrome Epidemiology Parinaud's midbrain syndrome is a form of ophthalmoplegia involving the internal neuromuscular mechanism of the eye, with hypertonicity and paresis of pupillary constriction and accommodation. It typically results from damaged premotor pathways for binocular upward gaze in the dorsal mesencephalon. The most common causes of Parinaud's 54 syndrome are pineal gland tumors and midbrain infarction. Neoplasms, vascular occlusions, trauma, extra-axial and intra-axial arteriovenous malformations, demyelination, giant aneurysms of the posterior fossa, infections, trauma, stereotactic surgery for pain, and 36 hydrocephalus from various causes have also been associated with Parinaud's syndrome. Ocular Symptoms and Signs Ocular signs of Parinaud's syndrome include bilateral eyelid retraction without lagophthalmos and limitation of upgaze (supraduction) (Fig. 26-10). Skew deviation, head tilt, and deviation of the subjective visual vertical have been reported. Light-near dissociation is typical (i.e., the pupils constrict more when the eyes converge than in response to a light stimulus). Vertical voluntary saccades are also affected, and vertical smooth pursuit and vestibular eye movements are sometimes affected, depending on the involvement of the interstitial nucleus of Cajal. Other associated ocular signs include pseudoabducens palsy, convergence-retraction nystagmus, spasm or paresis of convergence, and spasm or paresis 40,55 With obstruction of the aqueduct, internal hydrocephalus develops of accommodation. 36 and papilledema may be found.

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FIGURE 26-10 Parinaud's syndrome: there is the characteristic bilateral eyelid

retraction. The patient has been asked to look up and is unable to do so. Diagnosis Neuroimaging (MRI with gadolinium) is essential to look for hydrocephalus, stroke, tumor, 54 infection, and other structural lesions. Management Most patients with Parinaud's syndrome improve immediately or within a few months of treatment of the hydrocephalus. Those patients who do not show improvement within this time are assumed not to have potential for subsequent progress. A patient's improvement depends on the nature and extent of the damage in addition to the duration between onset of the condition and treatment. If dysmotility persists after treatment of the56underlying cause, surgery on the eye muscles can be performed to achieve single vision. ACKNOWLEDGMENT The authors thank Anthony Liu, BS, for help with preparation of the text and illustrations for this chapter.

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Aminoff: Neurology and General Medicine: Paraneoplastic Syndromes...



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Keyword Index

Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 27 Paraneoplastic Syndromes Involving the Nervous System JEROME B. POSNER •

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GENERAL CONSIDERATIONS Incidence Pathogenesis Diagnosis Treatment SPECIFIC SYNDROMES Cerebellar Degeneration Clinical Findings Laboratory Evaluation Pathology Diagnosis Treatment Subacute Sensory Neuronopathy/Encephalomyelitis Subacute Sensory Neuronopathy Limbic Encephalitis Hypothalamic Dysfunction Cerebellar Degeneration Brainstem Encephalitis Myelitis Autonomic Neuropathy Anti-Hu and Other Paraneoplastic Antibodies Opsoclonus-Myoclonus Anti-Ri Syndrome Visual Loss Retinopathy Optic Neuropathy SPINAL CORD SYNDROMES Stiff-Person Syndrome PERIPHERAL NERVE SYNDROMES NEUROMUSCULAR JUNCTION SYNDROMES NEUROMYOTONIA MUSCLE SYNDROMES

The term paraneoplastic syndrome refers to disorders of an organ or tissue that are caused

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by cancer but are not a direct effect of the primary tumor mass or of a metastasis on the involved organ. Paraneoplastic syndromes can affect many organs (Table 27-1) including the nervous system. Cancer can also indirectly affect the peripheral or central nervous system (CNS) in several ways (Table 27-2), all of which can be considered paraneoplastic 2 1 with cancer (e.g., hypercalcemia, syndromes. Thus, metabolic disorders associated 3 4 5,6 inappropriate antidiuretic hormone secretion, hypoglycemia, cerebrovascular disorders associated with hypercoagulability or hypocoagulability, and opportunistic infections [e.g., 7 progressive multifocal leukoencephalopathy ]) are all paraneoplastic. However, the neurologist usually uses the term paraneoplastic syndrome to refer to a group of neurological disorders that occur with increased frequency in patients with cancer and are not caused by infection, systemic metabolic disorders, vascular disease, or side effects of cancer therapy 8 (Table 27-2). These disorders, also termed remote effects of cancer on the nervous system, encompass a much less common and a clinically and pathologically more restricted group of disorders than other nonmetastatic effects of cancer. It is these remote effects of cancer on the nervous system that are addressed in this chapter. Click here to view this table.... Click here to view this table.... GENERAL CONSIDERATIONS

Incidence Several studies have addressed the frequency of paraneoplastic syndromes. Data from these studies depend on (1) the definition of paraneoplastic syndromes, (2) the rigor used to exclude other causes of neurological dysfunction, (3) the care with which the neurological evaluation was performed, and (4) the referral pattern to specialists. For example, the Lambert–Eaton myasthenic syndrome (LEMS) occurs in 3 percent or less of patients with 9 small-cell lung cancer, but when the symptom of paraneoplastic neuromuscular dysfunction is expanded to include any subjective or objective muscle weakness, the frequency rises to 10 with any type about 50 percent. Croft and Wilkinson found that 7 percent of 1,476 patients 11 of cancer had a neuromyopathy as assessed by physical examination, but Lipton and co-workers 12 found abnormalities of peripheral nerve function by quantitative sensory testing in colleagues found myopathic changes on muscle biopsy in 33 of 44 percent, and Gomm and 13 100 patients with lung cancer. Camerlingo and associates examined and followed 51 patients with peripheral sensory neuropathy of unknown cause; 18 patients (35%) developed 14 cancer within 6 years. With some exceptions, 15 such as myasthenia gravis, which occurs in 10 to 15 percent of 9 patients with thymoma, LEMS occurring in about 3 percent of patients with lung cancer, and paraneoplastic peripheral neuropathy in 10 percent of malignant monoclonal 16 17 gammopathies and 50 percent of patients with osteosclerotic myeloma, most paraneoplastic syndromes listed in Table 27-1 are so uncommon that exact incidence figures cannot be established, but probably occur in less than 1 percent of cancer patients.

Pathogenesis Although the etiology of most neurological paraneoplastic syndromes is unknown (Table 27-3), several potential mechanisms have been proposed. Click here to view this table.... Oppenheim, in 1888, proposed that some neurological disorders associated with cancer resulted from release by the tumor of a toxic substance. That tumors can secrete substances that interfere with the function of the CNS is now well established. Examples include the secretion by tumors of parathormone or adrenocorticotropic hormone (ACTH)–like substances; the former results in hypercalcemia, the latter in Cushing's syndrome. In 1948, Denny-Brown, in describing what were probably the first cases of anti-Hu–positive subacute sensory neuronopathy (see later), noted a similarity between the dorsal root 10 ganglionitis in his patients and that seen in swine deprived of pantothenic acid. He suggested that the malignancy and the nervous system were competing for a vital nutrient. Metastatic carcinoid tumors and large retroperitoneal sarcomas appear to cause neurological symptoms by such a mechanism. However, no evidence indicates that small and occult cancers, such as those usually encountered with paraneoplastic syndromes, are capable of depriving the nervous system of any essential substrate.

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Opportunistic viral infections involving the CNS complicate the clinical course of many patients whose immune systems are suppressed by cancer or its therapy. Progressive multifocal leukoencephalopathy, originally classified as a remote effect, is one such infection. However, most paraneoplastic syndromes affect patients who are not immunosuppressed, making opportunistic infection unlikely unless these patients suffer isolated, currently unknown disorders of immunity. The absence of other opportunistic infections, such as progressive multifocal leukoencephalopathy or herpes zoster, also indicates a lack of significant immunosuppression in most patients with paraneoplastic syndromes. Although individual paraneoplastic syndromes may have different causes and a given paraneoplastic syndrome such as paraneoplastic cerebellar degeneration (PCD) may have more than one cause, an immune mechanism is now the most attractive hypothesis as the cause of most, or perhaps all, paraneoplastic syndromes. The current concept of paraneoplastic syndrome pathogenesis is that the tumor must18–21 ectopically express an antigen (Some of these so-called that normally is expressed exclusively in the nervous system. onconeural antigens are also expressed in the normal testes, an organ that, like the brain, is 22–24 ) Onconeural antigens are present in the tumors of all an immunologically privileged site. patients with antibody-positive paraneoplastic syndromes. In some tumors, such as small-cell lung cancer, onconeural antigens are present in all tumors, even in those patients who do not develop para-neoplastic antibodies or a paraneoplastic syndrome. The onconeural antigen in the tumor cell is probably recognized by the immune system when tumor cells spontaneously undergo apoptosis and the apoptotic bodies containing the antigen are phagocytized by 25–27 Current evidence suggests that the antigens in the tumor are identical in dendritic cells. structure to the neural antigen but, nevertheless, are seen by the immune system as foreign, leading to development of antibodies (paraneoplastic antibodies are discussed in detail in the sections on individual paraneoplastic syndromes) and to an immune attack on both tumor 28 immune attack may control the growth of the tumor and, in and the nervous system. The 29,30 In patients with paraneoplastic syndromes, the tumors, rare instances, obliterate it. although identical in histological type to tumors of patients without paraneoplastic syndromes, are more likely to be heavily infiltrated with inflammatory cells including T cells, B cells, and 31 plasma cells. The immune response also attacks the nervous system either where there is no blood–brain barrier (e.g., myasthenia gravis, LEMS) or where immune cells are able to cross18the blood–brain barrier and react with neurons expressing the onconeural antigens. The T cells found in the nervous system have a limited Vß chain T-cell repertoire, suggesting they are 32 either mono- or oligoclonal and respond to a specific antigen. Both B cells and T cells can be found in the CNS of patients with CNS paraneoplastic syndromes. The B cells generally reside in the perivascular spaces and the T cells in both 33,34 perivascular spaces and in the parenchyma. Paraneoplastic antibodies (anti-Hu immunoglobulin G [IgG]) have been identified in the nervous system and within neurons of some patients who died of paraneoplastic 33,34 This finding has been met with skepticism, but others have found encephalomyelitis. antibodies, particularly to double-stranded DNA, the hallmark of systemic lupus 35,36 erythematosus, that can enter cells and bind to the nucleus, including brain cells. Further evidence of an immune reaction comes from examination of the cerebrospinal fluid (CSF) of patients with paraneoplastic CNS disorders. Early in the course of the disease, there is usually a pleocytosis with a slightly elevated protein level, increased IgG, and oligoclonal 37,38 The bands. Oligoclonal bands in CSF have been identified as paraneoplastic antibodies. relative specific activity of the antibody in spinal fluid (expressed as concentration of antibody against total IgG) is substantially higher than that in the serum indicating that the antibody 39 was synthesized within the CNS rather than simply diffusing across the blood–brain barrier. Furthermore, five plasma exchanges, although effective39in substantially lowering antibody titer in the serum, have no effect on CSF antibody titer. The exact mechanism by which the immune reaction damages neural structures is not established for most paraneoplastic syndromes. The two paraneoplastic syndromes whose immune mechanism has been clearly established to meet the Drachman criteria for an 40 antibody-mediated autoimmune disease (LEMS and myasthenia gravis, see later) are primarily B-cell (i.e., antibody) mediated, but with a T-cell component. Paraneoplastic 41 stiff-person syndrome may be caused by amphiphysin antibodies and perhaps paraneoplastic autonomic neuropathy by antibodies to ganglionic acetylcholine receptor 42 paraneoplastic antibodies. However, increasing evidence, particularly concerning 27,32,43,44 In anti-Yo PCD, CDR2 syndromes of the CNS, suggests a major T-cell component. antigen–specific CD8 T cells can be found in both tumor and brain.

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Tumors express paraneoplastic antigens relatively commonly, raising the question of why more cancer patients do not develop immune responses to their tumors. Activation of the CD8 T cells in the lymph node relies on the presence of CD4 helper cells and the absence of inhibitory factors. Imbalance in these regulatory pathways might underlie the presence or absence of paraneoplastic syndrome antigen–specific CD8 T cells in individual cancer patients.

Diagnosis Paraneoplastic syndromes are encountered in patients not known to have cancer, in patients with active cancer, or in patients in remission after cancer treatment. The first is the most common situation. When they present in pure form, the classic syndromes are not easily confused with other causes of neurological disability. Frequently, however, patients present with one or more atypical features that obscure the diagnosis. In patients with known cancer, other cancer-associated processes need to be excluded before a diagnosis of paraneoplastic syndrome is made. Depending on the part of the nervous system affected, the work-up should include magnetic resonance imaging (MRI) to exclude parenchymal, epidural, and leptomeningeal metastasis; CSF examination to exclude leptomeningeal metastasis; measurement of metabolic and endocrine substances; coagulation studies; and electrophysiological testing. In patients without known cancer, if other causes of nervous system dysfunction have been excluded, a careful evaluation for systemic cancer must be performed. As is detailed later, certain syndromes are associated with particular types of cancer; recognizing these associations helps to focus the search for an underlying neoplasm on a particular organ or organs. Although the clinical presentation varies, several clinical features assist in diagnosis: 1. Most paraneoplastic syndromes develop rapidly, progress over weeks to months, and then stabilize. Syndromes that begin insidiously or are characterized by exacerbations and remissions are less likely to be paraneoplastic. 2. Most paraneoplastic syndromes result in serious neurological disability. 3. Paraneoplastic syndromes affecting the CNS are often associated with an inflammatory CSF, including a pleocytosis, elevated levels of protein, and oligoclonal bands. Leptomeningeal metastases are 45,46 excluded by contrast medium–enhanced MRI and cytological examination of the CSF. 4. Although some patients with paraneoplastic encephalomyelitis have clinical evidence of widespread nervous system dysfunction, and some patients with restricted clinical signs have pathological evidence of diffuse involvement of the neuraxis, many patients present with a clinical and pathological syndrome that predominantly affects one specific portion of the nervous system. 5. Several of the syndromes (e.g., LEMS) are so stereotypical that the correct diagnosis can be strongly suspected even before additional diagnostic testing has excluded alternative diagnoses. In recent years, the diagnosis of at least some of the paraneoplastic syndromes has been aided by the detection of characteristic autoantibodies (discussed with specific syndromes). With the exception of the antibody found in the LEMS, the etiological significance of most of these autoantibodies is unknown. However, their presence helps to confirm the clinical diagnosis of a paraneoplastic syndrome and further focuses the search for an underlying malignancy.

Treatment 47

There have been two general approaches to treatment. The most effective appears to be 48 treatment of the underlying tumor, which often prevents progression of the disease and, in some instances, leads to substantial improvement or complete amelioration of the 49 neurological symptoms. Effective treatment of the tumor should remove the inciting antigen and thus temper the immune response causing the neurological damage. Because paraneoplastic syndromes are believed to be immune mediated, the second approach to treatment is to suppress the immune response. It is important to note that 48 suppression of the immune response does not appear to worsen the outcome of the tumor. Several different forms of immunosuppression, including corticosteroids, plasma exchange, intravenous immunoglobulins, and tacrolimus have been used to treat the paraneoplastic

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43,50–52

syndromes (Table 27-4). In other paraneoplastic syndromes, especially those affecting 48 the CNS, the outcome is less clear. However, the earlier in the course of the neurological syndrome that immunosuppressive treatment or treatment of the cancer is begun, the more 53 likely the patient is to stabilize or improve. The clinical response of each paraneoplastic syndrome is discussed in the appropriate sections that follow. Click here to view this table.... SPECIFIC SYNDROMES Paraneoplastic syndromes that affect the nervous system are classified in Table 27-5. Only some of the more common syndromes are considered in this chapter. More extensive 54–58 reviews are available elsewhere. Click here to view this table....

Cerebellar Degeneration Of the paraneoplastic disorders affecting the brain, paraneoplastic cerebellar degeneration (PCD) is per haps the most easily recognized and best characterized. PCD is characterized pathologically by loss of cerebellar Purkinje cells. It is associated with several different cancers, the disorders differing somewhat in their clinical features and prognosis. Some of the disorders can be separated on the basis of characteristic anti-bodies that react with particular onconeural antigens. Clinical Findings 59

PCD was first described in 1919, but the association between it and cancer was not 60 but the most common recognized until 1938. PCD can be associated with any malignancy, 61 62 ovarian or uterine cancer, and culprits are lung cancer, particularly small-cell lung cancer, 63,64 In most patients, neurological symptoms lymphomas, particularly Hodgkin's disease. prompt medical attention before the cancer itself has been identified. The cancer is usually found within months to a year after the neurological symptoms begin, but occasionally it may elude detection for several years and, in some instances, is found only at autopsy. Typically, the disorder begins with dizziness or vertigo, nausea and vomiting followed rapidly by gait ataxia, evolving rapidly over days to a few months to include incoordination in arms, legs, and trunk; dysarthria; and often nystagmus associated with oscillopsia. Within a few months, the illness usually reaches its peak and then stabilizes. By this time, most patients cannot walk and many cannot sit unsupported, handwriting is impossible, independent eating is difficult, and speech may be difficult to understand. Oscillopsia may prevent reading or even watching television. The neurological signs are always bilateral and usually symmetric, although at times one side may be more affected than the other. In occasional patients, the asymmetry is quite prominent. Diplopia is an early symptom in many patients, although abnormalities of ocular muscles are often not detected by the examiner. Exceptions to the previous statements do occur. The onset may occasionally be abrupt (e.g., overnight) or more gradual, and the disorder itself may be relatively mild so that the patient can walk, write, and be understood, albeit with some difficulty. The signs and symptoms are frequently limited to those of cerebellar or cerebellar pathway dysfunction, but, in as many as 50 percent of patients, other neurological abnormalities, 62,63 including sensorineural hearing loss, usually mild, may be found on careful examination, dysphagia, hyperreflexia with or without extensor plantar responses, extrapyramidal signs, peripheral neuropathy, dementia, and other mental status abnormalities. One study, however, using formal cognitive testing found that dementia was not typical when testing was controlled for impaired motor and speech production, suggesting that perceived clinical changes in 65 intellectual function may be more apparent than real. Laboratory Evaluation Early in the course of this disease, the MRI is usually normal. If patients are followed for months to a few years, diffuse cerebellar atrophy appears. Occasional patients have been reported in whom hyperintensity is found in cerebral and cerebellar white matter on T2-weighted images. Rarely, transient contrast enhancement of cerebellar folia may suggest leptomeningeal tumor and associated edema may cause hydrocephalus. In most patients who are studied early, the CSF contains an increased number of lymphocytes and slightly elevated protein and IgG concentrations. Oligoclonal bands may be

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present as well. The pleocytosis usually resolves with time. Some but not all patients with PCD have autoantibodies in serum and CSF that react with most Purkinje cells of the cerebellum and the causal tumor (Table 27-6). The antibody 66 frequently associated with pure cerebellar degeneration is called anti-Yo, using the first two letters of the last name of the index patient (Table 27-6). The anti-Yo antibody recognizes a major protein antigen termed CDR2, an approximately 62-kDa protein and a minor antigen of 34 kDa that are expressed in Purkinje cells of the cerebellum. All patients with anti-Yo PCD who have ovarian or breast cancer express the Purkinje cell antigens in the tumor cells. About 60 percent of patients with ovarian cancer who do not have PCD also express CDR2 in 67 serum, their tumors. The antibody is found at higher titer in the spinal fluid than in the 39 addition to suggesting intrathecal synthesis from B cells that have crossed into the brain. In26,43 the antibody response, cytotoxic T cells against CDR2 have also been described. Click here to view this table.... A second antibody found in patients with pure PCD is the anti-Tr antibody, named after John 68 Trotter, who, with his colleagues, reported the first such patient in 1976. Anti-Tr antibodies occur in patients with PCD related to Hodgkin's disease. This disorder often begins63,69 after the diagnosis of Hodgkin's disease and sometimes when the patients are in remission. Patients are generally less severely affected than are patients with the anti-Yo or anti-Hu antibody. The prognosis for life and successful treatment of the underlying tumor is good. 70,71

; in other patients, In some patients, cerebellar symptoms outweigh other symptoms sensory neuronopathy is prominent so that it is difficult to discern whether the ataxia is due to sensory loss or cerebellar dysfunction. As with the anti-Yo antibody, symptoms are usually sudden in onset and pathological examination reveals substantial loss of Purkinje cells. More inflammatory infiltrates are found in this disorder than in the anti-Yo syndrome, but that may be because patients only survive for a shorter period of time, although one report seems to 66 suggest otherwise. The anti-Ri antibody (discussed in the section on opsoclonus) is associated with PCD, usually as part of the opsoclonus-myoclonus syndrome. Other less common antibodies include 24 anti-Ma1, an antigen restricted to brain and testis. The paraneoplastic disorder usually is associated with encephalomyelitis, particularly brainstem and hypothalamic dysfunction. The disorder is associated with a variety of tumors including those of breast and colon. Anti-CRMP5 (anti-CV2) antibodies are directed against an antigen in some glial cells and against peripheral nerve antigens. The disorder has been associated with a number of 72 neurological problems including optic neuritis. The most common tumor is thymoma, although some patients have small-cell lung and gynecological cancers. Pathology The CNS may appear grossly normal when examined at autopsy, but usually the cerebellum is atrophic, with abnormally widened sulci and small gyri. Microscopically, the hallmark of PCD is severe, often with complete loss of the Purkinje cells 73 of the cerebellar cortex (Fig. 27-1). Degenerating Purkinje cells may have swellings, called torpedoes, along the course of their axons. Other pathological features may include thinning of the molecular and granular layers of the cerebellar cortex, often without marked cell loss, and proliferation of Bergmann astrocytes. The deep cerebellar nuclei are usually well preserved, although rarefied white matter may surround the nuclei caused by the loss of Purkinje cell axons. Basket cells and tangential fibers are usually intact. Lymphocytic infiltrates, if present in the cerebellum, are usually found in the leptomeninges and in the dentate nucleus and surrounding white matter but not in the Purkinje cell layer.

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FIGURE 27-1 Paraneoplastic cerebellar degeneration (PCD). A, Section of cerebellum from a patient with autoantibody-positive PCD. The molecular and granular cell layers are relatively normal, but Purkinje cells are absent and there is a slight increase in Bergmann's astroglia. There are some inflammatory cells in the leptomeninges. B, Serum from the same patient reacted against human cerebellum by an indirect immunoperoxidase method (anti-Yo antibody). Note the staining of the cytoplasm of Purkinje cells in a granular pattern with sparing of the nucleus. There is also some peroxidase staining of Purkinje cell dendrites. Granule cells and molecular layer cells did not react but are counterstained with hematoxylin.

In many patients, the disorder is noninflammatory, with all pathological changes restricted to the Purkinje cell layer of the cerebellum. However, pathological changes outside the cerebellum do occur and differ from patient to patient. Such abnormalities may include dorsal column and pyramidal tract degeneration in the spinal cord; degeneration of the basal ganglia, specifically the pallidum; loss of peripheral nerve fibers; and inflammatory infiltrates in brainstem, spinal cord, and cerebral cortex. The tumors associated with PCD do not differ histologically from similar tumors unassociated with paraneoplastic symptoms except that the tumors are usually infiltrated with lymphocytes 31 and plasma cells. Furthermore, in many patients, the tumor, when identified, is still localized rather than widely metastatic. Diagnosis The diagnosis depends on recognizing the characteristic clinical syndrome and excluding other cancer-associated causes of late-onset cerebellar dysfunction, such as parenchymal or leptomeningeal metastases, infections, and toxicity of therapy such as cytarabine. Causes unrelated to cancer, such as viral brainstem encephalitis or cerebellitis, demyelinating

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disease, Creutzfeldt–Jakob disease, infarction, hypothyroidism, and alcoholic and hereditary cerebellar degenerations must also be excluded. A disorder clinically identical to PCD may occur without a cancer being identified. How often subacute cerebellar 74 degeneration is nonparaneoplastic is75uncertain. Henson and Urich estimate 50 percent ; others believe the figure is higher. In patients with rapidly developing cerebellar syndromes, the physician should suspect a paraneoplastic disorder, particularly if the CSF contains a lymphocytic pleocytosis. The detection of autoantibodies will identify the neurological disorder as being paraneoplastic and suggest the likely location of the tumor. The tumors may be very small and difficult to identify. If evaluation including total-body 76 fluorodeoxyglucose positron emission tomography (PET) scanning fails to identify a tumor, repeated searches may be necessary. Exploratory laparotomy with salpingo-oophorectomy has been recommended in postmenopausal women who are anti-Yo positive and whose 77 evaluation, including pelvic scans and mammograms, is negative. We have used this approach in several patients, and in all except one instance, we found a tumor in the gynecological tract, sometimes only apparent microscopically. In the one negative patient, breast cancer was identified 4 months later. Treatment Treatment of PCD is usually unsatisfactory. This may in part be due to the fact that death of Purkinje cells is the common pathological finding. Because the disease evolves rapidly, once the Purkinje cells are dead, no amount of treatment is likely to have any effect. However, several reports indicate that treatment of the tumor and immunosuppression either stabilizes 50,66,78 Therapy aimed at reducing CNS or improves PCD associated with different antibodies. 43 T cells has been tried; its efficacy has not been established. In general, however, the anti-Hu and anti-Yo antibodies rarely improve, whereas improvement has been reported in some patients with anti-Tr or anti-CRMP5 antibodies. Symptomatic improvement in the ataxia occurs in a few patients with clonazepam in daily 79 doses varying from 0.5 to 1.5 mg. Buspirone may also give modest relief.

Subacute Sensory Neuronopathy/Encephalomyelitis Henson and co-workers introduced the term encephalomyelitis with carcinoma to describe patients with cancer associated with clinical signs of damage to several areas of the nervous system and with postmortem signs of80inflammation within the brain, brainstem, spinal cord, dorsal root ganglia, and nerve roots. Most of these patients had small-cell lung cancer and most probably had the anti-Hu antibody, although clinically and pathologically similar disorders have been described with a71,81 number of other tumors. At times, the disorder is but in many patients, both clinical and pathological restricted to the dorsal root ganglion, signs of CNS damage are present either with or without evidence of a sensory neuronopathy. Signs may include dementia (limbic encephalitis), cerebellar degeneration, brainstem dysfunction, myelopathy, and autonomic neuropathy. Some patients who suffer from this syndrome, particularly when associated 71 with small-cell cancer of the lung, harbor an antibody in their serum called anti-Hu (Fig. 27-2).

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FIGURE 27-2 Paraneoplastic sensory neuronopathy. A, Dorsal root ganglion

obtained at autopsy from a patient without neurological disease. B, Dorsal root ganglion obtained from a patient with paraneoplastic sensory neuronopathy and an anti-Hu antibody. Note that there are virtually no normal dorsal root ganglion neurons in the entire section. There are a few scattered inflammatory infiltrates. C, Frozen section of a trigeminal ganglion from a patient who died without neurological disease. The ganglion is reacted to the serum of the patient whose dorsal root ganglion is shown in B and who died of paraneoplastic sensory neuronopathy and small-cell lung cancer. The reaction is an indirect immunoperoxidase method and reveals reaction product in the nuclei of trigeminal ganglion neurons with sparing of the nucleolus and cytoplasm. Subacute Sensory Neuronopathy In contrast to axonal or demyelinating sensory neuropathies, sensory neuronopathy, where the dorsal root ganglion is the site of pathology, is a rare syndrome. Sensory neuronopathy can occur in previously healthy individuals or in those with a variety of underlying autoimmune conditions, including Sjögren's syndrome. It can also be caused by heavy metal intoxication, 82 including83the chemotherapeutic agents. The disorder is paraneoplastic in only a minority of patients. At least two thirds of patients with paraneoplastic sensory neuronopathy have small-cell lung cancer as the cause. Symptoms typically begin before the cancer is identified, with dysesthetic pain and numbness in the distal extremities or occasionally in the arms, face, or trunk. The symptoms may be asymmetric at onset, but progress over days to several weeks to involve the limbs, trunk, and sometimes the face, causing a severe sensory ataxia. All sensory modalities are affected, distinguishing this disorder from cisplatin neuropathy in which pinprick and temperature sensation are spared. Deep tendon reflexes are lost, but motor function is preserved. The CSF typically contains 20 to 40 lymphocytes per cubic millimeter, particularly when the sensory changes are associated with encephalomyelitis. Sensory nerve action potentials are diminished or absent, whereas compound muscle action potentials are normal and electromyographic (EMG) evidence of denervation is absent. Pathological changes may be limited to the dorsal root ganglia with neuronal loss and lymphocytic inflammatory infiltrates (Fig. 27-2). The inflammatory process may also advance into the dorsal roots, posterior columns, and peripheral nerves. In about 50 percent of patients, clinically inapparent pathological changes are found in other regions of the nervous system. In most patients, treatment of the underlying tumor or removal of the autoantibody by plasmapheresis or immunosuppressive therapy does not alter the course of the85neurological 84 of responses to immunotherapy. Occasional disease, although there are isolated reports 86 patients have a mild and indolent neuropathy. Limbic Encephalitis

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Limbic encephalitis is a rare complication of small-cell lung or other cancers. A similar clinical syndrome can occur without88a neoplasm but is also associated with antibodies against voltage-gated potassium channels. Typically, subacute personality and mood changes are evident, with severe impairment of recent memory and occasional agitation, confusion, hallucinations, and complex partial seizures. Limbic encephalitis may occur in isolation or in association with encephalomyelitis or sensory neuronopathy. The diagnosis depends on recognizing the clinical syndrome and excluding other causes of encephalopathy. The CSF is typically inflammatory, at least early in the disease. The MRI often shows abnormalities in the medial temporal lobe or lobes, including hyperintensity on T2-weighted images, and, more 89 rarely, contrast enhancement has been reported. A glucose PET scan may show hypermetabolism in the hippocampus. The pathological changes of paraneoplastic limbic encephalitis are usually restricted to limbic and insular cortex, although other deep gray and sometimes white matter structures may be involved. Extensive loss of neurons with reactive gliosis, perivascular lymphocytic cuffing, and microglial proliferation also typify this syndrome. No treatment has been consistently beneficial, although reports relate spontaneous remissions or improvement to treatment of 90,91 the underlying tumor. Hypothalamic Dysfunction Hypothalamic dysfunction includes manifestations such as somnolence, hyperthermia, endocrine abnormalities, and hyperhidrosis. Hypothalamic dysfunction occurs in patients with 92,93 and CRMP5 (CV2)-positive thymomas. Hypothalamic Ma2 positive testicular cancer dysfunction rarely occurs in isolation; it is usually associated with limbic encephalitis or 87 brainstem encephalitis. Cerebellar Degeneration Cerebellar signs identical to those of PCD may occur as the first or only manifestation of encephalomyelitis. The only differences between isolated PCD as described earlier and cerebellar dysfunction associated with encephalomyelitis are that the patient with encephalomyelitis is more likely to have clinical evidence of wide-spread CNS and peripheral nervous system involvement, especially of sensory neuronopathy, and the pathological changes are more likely to be inflammatory. Brainstem Encephalitis Paraneoplastic brainstem encephalitis characterized by the subacute development of bulbar, midbrain, or basal ganglia signs usually occurs as part of the more diffuse syndrome of encephalomyelitis, although it sometimes presents as the dominant or isolated clinical 94,95 Any cranial nerve can be affected. The syndrome usually affects the lower finding. brainstem, causing diplopia, vertigo, oscillopsia, dysarthria, dysphagia, hypoventilation, hearing loss, facial weakness, myokymia, and facial numbness. When the upper part is involved, movement disorders including chorea, dystonia, bradykinesia, myoclonus, 96,97 and there supranuclear eye movement disorders, and typical parkinsonism may occur, may be daytime sleepiness. Myelitis Paraneoplastic non-necrotizing myelitis occurs rarely as an isolated syndrome and more commonly as a part of diffuse encephalomyelitis. Patients present with progressive weakness, sometimes with lower motor neuron signs including fasciculations, in association with sensory loss and autonomic dysfunction (e.g., incontinence and postural hypotension). In at least one instance, the disorder was episodic and primarily involved posterior column function. Early in its evolution, the disorder may clinically resemble motor neuron disease. Often, upper-extremity findings predominate owing to cervical cord involvement, and respiratory failure and death may occur. The differential diagnosis includes compressive or intrinsic spinal cord masses, other inflammatory or infectious myelopathies, and radiation injury in previously treated patients. The CSF is typically inflammatory. Neuroimaging usually shows a normal spinal cord but, occasionally, enlargement or hyperintensity of the spinal cord can be identified on T2-weighted MRI and, rarely, contrast enhancement is present. No treatment is effective. Pathologically, an intense inflammatory reaction with neuronal loss in the anterior and posterior horns is seen, with secondary nerve root degeneration and neurogenic muscle

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atrophy. Inflammation and degeneration of white matter tracts also occur. Autonomic Neuropathy Paraneoplastic98autonomic neuropathy is a rare syndrome that occurs alone or with a sensory may occur with other neuronopathy. Usually associated with small-cell lung cancer, it 99 cancers and may present before or after the cancer is diagnosed. Patients present with the subacute onset of postural hypotension, obstipation, pupillary abnormalities, or a neurogenic bladder. The syndrome is generally progressive but may stabilize or improve with treatment of the underlying tumor. When autonomic neuropathy occurs with lung cancer, it is usually part of the anti-Hu syndrome. Autonomic neuropathy also occurs with an antibody against ganglionic acetylcholine receptor (anti-nAChR). Immunization with the protein produces an 100 autonomic neuropathy and passive transfer of antibodies also causes the neuropathy indicating a B-cell–mediated disease. Anti-Hu and Other Paraneoplastic Antibodies Paraneoplastic sensory neuronopathy/encephalomyelitis may be found in association with a number of paraneoplastic autoantibodies. The same autoantibody may be associated with either a fragment of the syndrome or the entire syndrome. Paraneoplastic encephalomyelitis with the anti-Hu antibody is usually associated with small-cell lung cancer. Other antibodies include CRMP5 (often associated with thymoma), Ma-1 (associated with a variety of tumors), and Ma-2 (associated with testicular cancer). Anti-Hu encephalomyelitis is more likely to be characterized by sensory neuronopathy and anti–Ma-2 by brainstem diencephalic involvement. CRMP5 may be associated with optic neuritis. Paraneoplastic encephalomyelitis is generally poorly responsive to treatment. Ma-2-associated encephalomyelitis is more responsive than the other types, but in all of them, particularly if caught early, improvement may occur.

Opsoclonus-Myoclonus Opsoclonus, a disorder of saccadic stability, consists of involuntary, arrhythmic, multidirectional, high-amplitude conjugate saccades. Opsoclonus is often associated with diffuse or focal myoclonus and truncal titubation, with or without other cerebellar signs. It occurs primarily in children as a self-limited illness and is probably the result of a viral infection in the brainstem. This disorder also occurs as a paraneoplastic syndrome, first 101 recognized by Solomon and Chutorian in 1968. Opsoclonus-myoclonus occurs primarily in children either as a self-limited illness, probably the result of a viral infection in the brainstem, 102 or as a complication of neuroblastoma. In about 40 percent of children, it is paraneoplastic, 103,104 but the incidence of opsoclonus-myoclonus in neuroblastoma is less than 2 percent. However, given the known tendency of neuroblastoma to differentiate and resolve spontaneously, one can question whether at least some patients with opsoclonus-myoclonus without tumor are truly paraneoplastic. The age at peak incidence is 18 months, with more girls than boys affected. Neurological signs precede identification of the tumor at least 50 percent of the time, making recognition of the neurological syndrome an important clue to the presence of neuroblastoma. Ataxia, irritability, vomiting, and dementia may accompany opsoclonus-myoclonus. When a neuroblastoma is associated, there is a higher than expected incidence of intrathoracic tumors and of tumors with a benign histology. The prognosis of the neuroblastoma is better if opsoclonus-myoclonus is present than when the neurological complication is absent. Opsoclonus may respond to treatment with ACTH, plasma exchange, or intravenous immunoglobulins and may improve after chemotherapy of 105 the tumor. Rituximab has been effective in one case. 102However, many patients develop relapses and are left with significant cognitive deficits. The disorder is less common in adults than in children; in about 20 percent of adults, the 106 disorder is paraneoplastic. Lung cancer is the most common cause, but other cancers also cause the syndrome. Neurological symptoms usually precede the diagnosis of tumor and progress over several weeks, although more rapid or slower progression is observed in some instances. Opsoclonus is often associated with truncal ataxia, dysarthria, myoclonus, vertigo, and encephalopathy; some patients appear to have PCD. Ophthalmoplegia has been 107 reported. A mild CSF pleocytosis and a slightly elevated protein level are present in most patients. The results of computed tomography (CT) and MRI are usually normal; in a few patients, an abnormality in the brainstem or cerebellum is detected by MRI. 108 Immunosuppressive agents sometimes seem to be effective, although spontaneous remissions have also been described, making it difficult to interpret results. However, the

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syndrome probably responds less well to immunotherapy unless the tumor is also treated.

109

Anti-Ri Syndrome A number of autoantibodies have been described in neuroblastoma-related opsoclonus, but 104,110 Affected children have a high incidence of antibodies that react with none consistently. CNS antigens, but no particular antibody is characteristic of the syndrome. Recently, an autoantibody that binds the surface of cerebellar granule cells and is cytotoxic to neuroblastoma cell lines has been identified in pediatric patients with opsoclonus-myoclonus, 111,112 Seven of the children had other with or without neuroblastoma, but not in controls. antibodies that also reacted with cerebellar structures. These included two with the anti-Hu 104 antibody. The most commonly associated antibody in adults is the anti-Ri antibody occurring in women 34,113,114 The anti-Ri with breast cancer and gynecological tumors as well as other tumors. 115 antibody identifies a protein called Nova, an RNA-binding protein that regulates messenger RNAs encoding synaptic proteins, including the glycine and GABAA receptors, inhibitory 116–118 transmitter receptors in the brainstem.

Visual Loss Paraneoplastic syndromes can cause visual loss by affecting either the retina or the optic 72,119–121 They can affect photoreceptors, either rods, cones, or both, or can cause a nerve. retinal vasculitis. A paraneoplastic visual disorder can occur either as an isolated phenomenon or as part of a more widespread encephalomyelopathy. Retinopathy Although all paraneoplastic visual disorders are rare, paraneoplastic retinal degeneration, also called cancer-associated retinopathy, is the most common. The disorder usually occurs in association with small-cell lung cancer, melanoma, and gynecological tumors. Typically, the visual symptoms, which include episodic visual obscurations, night blindness, light-induced glare, photosensitivity, and impaired color vision, precede the diagnosis of 120 cancer. The symptoms progress to painless visual loss. They may begin unilaterally but usually become bilateral. Visual testing demonstrates peripheral and ring scotomas and loss of acuity. Funduscopic examination may reveal arteriolar narrowing and abnormal mottling of the retinal pigment epithelium. The electroretinogram is abnormal. The CSF is typically normal, although elevated immunoglobulin levels have been reported. Inflammatory cells are sometimes seen in the vitreous by slit-lamp examination. Pathologically, a loss of photoreceptors and ganglion cells with inflammatory infiltrates and macrophages is usually noted. The other parts of the optic pathway are preserved, although a loss of myelin and lymphocytic infiltration of the optic nerve may occur. Several autoantibodies have been identified in patients with cancer-associated retinopathy, the most common being recoverin. Recoverin is a 23-kDa protein that modulates dark and light adaptation through calcium-dependent regulation of rhodopsin phosphorylation in 123 photoreceptor cells. The antigen is found in lung cancer cell lines. Recoverin antibodies can cross the blood–brain barrier gaining access to photoreceptor cells within the aqueous 124 Several other autoantibodies also occur in patients with paraneoplastic visual humor. 122,125,126 loss.

122

Treatment of cancer-associated retinopathy is usually unsuccessful. Various immunosuppressive treatments have been tried. These include intravenous corticosteroids, plasma exchange, and intravenous immunoglobulins as well as treatment of the underlying 120,127 128 Success using intravenous immunoglobulins has been reported. It is not malignancy. clear whether the presence of the retinopathy or of antiretinal autoantibodies affects the prognosis of the cancer. Optic Neuropathy Paraneoplastic optic neuropathy occurring in the absence of other neurological symptoms is extremely uncommon. Cross and colleagues described 16 patients with optic neuritis (five of whom also had retinitis), all 72 of whom harbored antibodies to CRMP5, a collapsin response–mediator protein. The patients had subacute visual loss. Optic discs were swollen and visual field defects were present. All the patients had a variety of other neurological symptoms including cognitive changes, ataxia, sensory neuropathy, and

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myelopathy. Three patients resembled Devic's disease at onset of symptoms. A variety of tumors were associated with the syndrome, the most common being small-cell lung cancer; 129 one patient had thyroid130 cancer. Other reports have described this disorder in association 120 with multiple myeloma, nasopharyngeal carcinoma, neuroblastoma, and lymphoma. SPINAL CORD SYNDROMES Paraneoplastic disorders may affect the spinal cord, either in an isolated fashion or as part of a more widespread encephalomyelitis. Subacute necrotizing myelopathy is a rare syndrome 131–133 (Fig. 27-3). Antoine and that occurs with lymphoma, leukemia, or lung or other cancers colleagues reported a patient with myasthenia gravis and a thymoma who developed 134 neuromyelitis optica (Devic's disease) 4 months after treatment of the tumor. The onset of the paraneoplastic disorder may precede or follow the diagnosis of cancer. Patients typically present with rapidly ascending flaccid paraplegia; back pain or radicular pain may precede the onset of neurological dysfunction. The disease may ascend the spinal cord, leading to respiratory failure and death. Inflammatory cells are usually present in the CSF. The MRI may be normal or show spinal cord swelling or contrast medium enhancement. The absence of an epidural mass or discrete intramedullary enhancement rules out metastatic myelopathy, which is much more common. Treatment is usually unsuccessful, although one patient is 135 reported to have responded to intrathecal dexamethasone. Pathologically, there is widespread spinal cord necrosis involving all components of the cord, but with some white matter predominance. Inflammatory infiltrates are not typical.

FIGURE 27-3 Subacute necrotic myelopathy in a patient with carcinoma of the

lung. Neurological symptoms of transverse myelopathy had evolved over several days and preceded the diagnosis of the cancer. Note the widespread necrotic changes of both gray and white matter in the cord. As in most instances, vascular changes and inflammatory infiltrates are absent. 136

Motor neuron disease may occasionally occur as a paraneoplastic syndrome. Paraneoplastic motor neuron disease can include amyotrophic lateral sclerosis with both upper and lower motor neuron dysfunction, progressive muscular atrophy, a pure lower motor neuron syndrome that is sometimes reversible and associated with lymphoproliferative disorders, or primary lateral sclerosis, a pure upper motor137 neuron syndrome associated with solid tumors as well as with lymphoproliferative disorders. The clinical and pathological characteristics differ little from nonparaneoplastic motor neuron disease except for the fact that the paraneoplastic disorders are often more rapid in onset and evolution, sometimes reverse spontaneously, and, at autopsy, may be more inflammatory than in the nonparaneoplastic disorder.

Stiff-Person Syndrome Originally called the stiff man syndrome, although it affects more women than men, the 138 syndrome is characterized by muscle stiffness and rigidity that are usually painful. The muscles involved almost always include paraspinal and abdominal muscles and usually those of the lower extremities as well. In some instances, the illness is restricted to a single

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extremity. Sustained muscle contraction results in an abnormal posture such as an exaggerated lumbar lordosis. In addition to the chronic contractions, severe muscle spasms may be precipitated by voluntary movements, unexpected environmental stimuli, and emotional upset. The arms are less commonly involved, and although stiffness of the neck and face can occur, it is rarely severe. On examination, the muscles feel hard and may be difficult to move passively. An unexpected external stimulus or a voluntary movement may precipitate an observable spasm. The EMG is characterized by sustained continuous motor unit activity that disappears during sleep and general anesthesia. The nonparaneoplastic disorder is associated with diabetes and antibodies to glutamic acid decarboxylase. The paraneoplastic disorder is associated with antibodies against 139 (Amphiphysin amphiphysin, a synaptic protein that plays a role in vesicle endocytosis. 139 with the antibodies have also been detected in patients with myelopathy. ) Some patients 140,141 with or paraneoplastic disorder harbor glutamic acid decarboxylase (GAD) antibodies without antiamphiphysin antibodies. Anti-Ri antibodies were reported in one patient with 142 stiff-person syndrome and metastatic adenocarcinoma. A single patient with antibodies to gephyrin, a postsynaptic tubulin-binding protein that binds inhibitory glycine and GABAA 143 receptors, has also been reported. The common tumors include breast cancer, small-cell 144 lung cancer, Hodgkin's disease, and colon cancer. Benzodiazepines and baclofen may relieve symptoms. Treatment of the tumor and immunosuppression with corticosteroids, intravenous immunoglobulin, and other immunosuppressive agents are also effective. PERIPHERAL NERVE SYNDROMES Virtually any of the pathological abnormalities that can affect the peripheral nervous system of 58 patients without cancer can also occur as a paraneoplastic syndrome. The most common is a subacutely developing sensorimotor neuropathy with pathological evidence of axonal damage. The exact incidence of paraneoplastic peripheral neuropathy is unknown. In one series of 422 consecutive patients with peripheral neuropathy referred to a neurological 83 referral center, 26 were believed to have a paraneoplastic peripheral neuropathy. Seven patients had onconeuronal antibodies. The overall incidence of presumed paraneoplastic peripheral neuropathy was 6 to 8 percent, varying with the type of neuropathy. For pure sensory neuronopathy, the incidence was 47 percent. The incidence was 1.7 percent for Guillain–Barré syndrome, 10.5 percent for chronic inflammatory demyelinating polyneuropathy, 10 percent for mononeuritis multiplex, and 10.3 percent for axonal polyneuropathy of otherwise undetermined cause. Subacute sensorimotor neuropathy is predominantly a distal symmetric polyneuropathy, more marked in the lower extremities with weakness, glove-and-stocking sensory impairment to all modalities, and a loss of tendon reflexes. Bulbar involvement is exceptional. Patients with mild sensory or sensorimotor neuropathy that evolves slowly over many months to years are unlikely to have carcinoma as the underlying cause. Patients with subacutely developing severe peripheral neuropathy leading to substantial paralysis and sensory loss are much more likely to be suffering from a paraneoplastic syndrome. A few patients with paraneoplastic sensorimotor neuropathy follow the remitting and relapsing course typical of chronic inflammatory demyelinating polyneuropathy. These patients may respond to corticosteroid therapy. The CSF is typically acellular, with normal or slightly elevated protein concentration. Nerve conduction studies are consistent with an axonal neuropathy, with low-amplitude or absent sensory nerve action potentials and normal or decreased motor nerve conduction velocities. A few patients have marked slowing of motor conduction velocities consistent with a demyelinating process. Pathologically, there is usually axonal degeneration; in a few patients, demyelination is prominent. Spinal root demyelination and lymphocytic infiltrates of peripheral nerves have also been reported. A relatively pure paraneoplastic sensory neuropathy (not neuronopathy) occurs with a variety of malignancies but cannot be distinguished from other causes of sensory neuropathy. In one series, when no cause of the sensory neuropathy was identified, cancer was subsequently identified as a cause in 14 approximately one third of patients. Mean time to cancer diagnosis was more than 2 years. Other neuropathies that had been reported to be paraneoplastic include subacute autonomic neuropathy. In this disorder, nicotinic acetylcholine receptor 99 antibodies may be found. Autonomic neuropathy also occurs as part of the anti-Hu syndrome. Peripheral neuropathy due to microvasculitis is rare as a paraneoplastic syndrome. The disorder is found without obvious antibody involvement in patients with a variety of cancers.

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Vasculitic neuropathy can present either as a diffuse polyneuropathy or as mononeuritis multiplex. It can involve both peripheral and cranial nerves. The importance of making a diagnosis, which may require nerve biopsy, is that the condition may respond to corticosteroid treatment. Peripheral neuropathy may be associated with multiple myeloma and Waldenström's 145–147 With the rare osteosclerotic form of myeloma, peripheral macroglobulinemia. neuropathy is present in about 50 percent of patients. Successful treatment of the myeloma often leads to amelioration of the neurological symptomatology. Amyloidosis associated with myeloma can also cause a peripheral neuropathy that responds poorly to treatment. Rituximab, an anti-CD20 (B-cell145,148 marker) antibody, is effective in treating some neuropathies associated with IgM antibodies. NEUROMUSCULAR JUNCTION SYNDROMES Paraneoplastic disorders of the neuromuscular junction include LEMS and myasthenia gravis. These disorders have a common pathogenetic mechanism (i.e., they are caused by antibodies against ion channels) and, whether paraneoplastic or not, they respond to immunological treatment. Another ion channel disorder included in the following section is neuromyotonia, a disorder not confined to the neuromuscular junction. 149

but, unlike LEMS is characterized by progressive proximal weakness and fatigability, 150,151 Respiratory myasthenia gravis, cranial nerve symptoms are usually not severe. weakness may occur. Power initially increases with effort, so that reported weakness may seem out of proportion to the examiner's findings; however, with continued effort, weakness returns. Deep tendon reflexes, especially those in the legs, are diminished or absent but may reappear after exercise. Cholinergic dysautonomia occurs in more than 50 percent of patients, causing dry mouth and impotence. Characteristic abnormalities are found on electrophysiological testing, including very small compound muscle action potentials (CMAPs) that may increase to normal after brief exercise. Repetitive stimulation causes a decrement of the CMAPs at low rates of stimulation and an increment at high rates of stimulation. About 60 percent of patients with LEMS have small-cell cancer of the lung. A few have other cancers. Some of the 40 percent who do not have cancer may have evidence of other autoimmune diseases. The disorder results from a reduced release of acetylcholine at presynaptic nerve terminals. Anti-bodies that react with the PQ-type voltage-gated calcium channel are found in patients 152 with or without paraneoplastic syndromes. The same PQ-type voltage-gated calcium channels are found in small-cell lung cancers. Interestingly, the richest source of PQ-type voltage-gated calcium channels is the cerebellum, perhaps explaining the occasional relationship of PCD and LEMS. LEMS is a classic autoimmune disease in that the binding of circulating IgG antibodies to the voltage-gated calcium channels reproduces the electrophysiological abnormalities in animals; removal of IgG antibodies from humans with the disorder improves neurological function. Accordingly, LEMS can be treated either by immunosuppression or by treatment of the 153 underlying cancer when present. Patients with small-cell lung cancer associated with LEMS have a better prognosis than patients with small-cell lung cancer who do not develop a 154 paraneoplastic disorder. Myasthenia gravis usually affects ocular, bulbar, and respiratory muscles, often sparing extremity musculature. In contradistinction to LEMS, patients grow weaker with exercise and improve with rest; repetitive stimulation decreases the CMAPs on EMG. Myasthenia gravis is usually not associated with cancer, but about 15 percent of patients suffer from thymoma, and a rare patient develops the syndrome when Hodgkin's disease directly affects the thymus. The disorder is caused by antibodies against the acetylcholine receptor at the postsynaptic myoneural junction. Patients with thymoma-associated myasthenia are more likely to have antibodies against muscle proteins such as ryanodine receptors. Myasthenia gravis usually responds to immunosuppression and thymectomy. However, thymectomy is more effective for the treatment of myasthenia gravis in patients without thymomas than for those with them. NEUROMYOTONIA Several disorders characterized by hyperexcitability of terminal arborizations of peripheral nerves occur in patients with paraneoplastic syndromes.155 These include neuromyotonia, the cramp-fasciculation syndrome, and Morvan's syndrome. Neuromyotonia occurs when single motor unit potentials fire spontaneously at 150 to 300 Hz, leading to chronic contraction of muscles that can be either focal or generalized and sometimes associated with

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pain and hyperhidrosis. The disorder is autoimmune and related to antibodies against 156 the disorder is paraneoplastic, antibodies voltage-gated potassium channels. When 139 against amphiphysin may also be found. In its mildest form it is called myokymia (repetitive and recurrent firing of a motor unit potential at 2 to 60 Hz), clinically seen as undulating muscle twitching. Patients may also demonstrate pseudomyotonia (failure of155 muscles to relax after contraction), and intestinal pseudo-obstruction has also been reported. In some patients, CNS symptoms consisting of memory loss, hallucinations, insomnia, and changes in mood (Morvan's syndrome) also appear to be related to the presence of antibodies against 156 voltage-gated potassium channels. Serum creatine kinase level is elevated in about one half of patients. The diagnosis can be made electrophysiologically when needle EMG reveals spontaneous firing of single or multiple motor units at a rate of 150 to 300 Hz. These units fire at irregular intervals and may persist during sleep, general anesthesia, and even when peripheral nerves are blocked at proximal sites. Symptoms are relieved by blocking the neuromuscular junction, indicating that the action potentials arise from terminal arborizations of the motor nerve. When these disorders are paraneoplastic, thymoma is the most common cause, but they have also been 157 158 reported with small-cell lung cancer and Hodgkin's disease. The pathophysiology of the signs and symptoms of both the CNS and peripheral nervous system involvement is unknown. The fact that symptoms are relieved by plasma exchange suggests that the disorder, or at least the major part of it, is antibody mediated. This view is supported by an experimental study in which IgG voltage-gated potassium-channel antibodies added to an NB-1 cell line reduced potassium currents independent of added complement, suggesting that cross-linking of the channel by antibody (as in LEMS) may159 be an important mechanism of symptom production. F(ab')2 fragments were also effective. Some patients respond well to anticonvulsants, such as phenytoin or carbamazepine, or to muscle relaxants such as diazepam. However, the treatment of choice is immunosuppression with plasma exchange 160 or intravenous immunoglobulins; one report suggests that plasma exchange is superior. MUSCLE SYNDROMES Polymyositis and dermatomyositis and inclusion-body myositis are common inflammatory 161 autoimmune muscle diseases. Only a minority of patients suffering from these disorders have an underlying malignancy as their cause, particularly older patients. Dermatomyositis with typical cutaneous changes is more likely than polymyositis to be paraneoplastic. Females and males are affected in approximately equal numbers. Symptoms of muscle weakness generally precede identification of the cancer. The tumor may be at any site, but breast, lung, ovarian, and gastric malignancies are the most common. Hodgkin's disease and prostate and colon cancer are also reported offenders. The clinical and laboratory findings in dermatomyositis/polymyositis associated with malignancy resemble those in the idiopathic disease, although cancer patients often have more striking abnormalities on muscle biopsy specimens. Patients characteristically present with proximal muscle weakness, elevated levels of serum creatine kinase (CK), and EMG evidence suggesting a myopathic process rather than nerve disease. A muscle biopsy specimen showing inflammatory myopathy confirms the diagnosis. Although laboratory findings do not distinguish paraneoplastic from nonparaneoplastic varieties, the presence of autoantibodies, particularly common in myositis associated with lung disease, is less common in patients with the paraneoplastic disorder. No laboratory test is absolutely diagnostic. Normal serum CK levels are occasionally found even in patients with profound muscle weakness, with or without malignancy; abnormal CK levels indicate a poor prognosis for the muscle disease. Weakness of respiratory and pharyngeal muscles may contribute to death. The prognosis is not as good for the paraneoplastic disorder as it is for the nonparaneoplastic disorder. Corticosteroids, cyclosporine, and other immunosuppressants have been used successfully. Other reports suggest that high-dose intravenous immunoglobulin is useful in patients 161 unresponsive to other forms of immunosuppression. Muscle cramps are a common complication of cancer sometimes related to electrolyte imbalance or induced by chemotherapy. Previous

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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 28 Neurological Complications of Chemotherapy and Radiation Therapy SEAN A. GRIMM • LISA M. DEANGELIS •

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CHEMOTHERAPY Hormonal Agents Adrenocorticosteroids Sex Hormone Agonists and Antagonists Nonhormonal Agents Methotrexate Platinums Vincristine Nitrosoureas 5-Fluorouracil and Capecitabine Cytarabine (Cytosine Arabinoside) Ifosfamide Suramin Paclitaxel and Docetaxel Bortezomib Fludarabine OTHER AGENTS Biological Agents Retinoids RADIATION THERAPY Primary Neurological Damage Brain Spinal Cord Cranial Nerves Peripheral Nerves Secondary Neurological Involvement Radiogenic Tumors Vascular Abnormalities Endocrinopathies

Chemotherapy and radiation therapy are two of the major modalities used to treat cancer (Table 28-1). Their goal is to kill or inactivate enough cancer cells so that the body's own defenses can control the disease; this goal should be accomplished without unacceptable damage to normal tissue. Unfortunately, in most instances, the goal is not fully achieved. The

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reason is that both radiation therapy and chemotherapy are relatively nonspecific and depend on their ability to do more damage to cancer cells than to normal cells. The therapeutic/toxic ratio is often low; even in highly sensitive tumors such as acute lymphoblastic leukemia, Hodgkin's disease, testicular cancer, and choriocarcinoma, for which the cure rate is high, many patients suffer serious side effects of therapy, either immediately or months to years later. Click here to view this table.... One might expect the nervous system to be relatively insensitive to the side effects of cancer therapy. The nervous system is protected from exposure to many chemotherapeutic agents by the blood–brain, blood–cerebrospinal fluid (CSF), and blood–nerve barriers. Furthermore, most neurons do not reproduce, and glia reproduce only slowly, thus affording protection against agents that are directed against dividing cells. Nevertheless, nervous system toxicity is common, second only to myelosuppression as a reason for limiting the dose of chemotherapy and often is dose-limit-ing for radiation therapy as well. The purpose of this chapter is to describe the side effects of these therapeutic modalities on the central and peripheral nervous systems. The emphasis is on chemotherapeutic agents and radiotherapeutic approaches that are widely used in clinical practice. CHEMOTHERAPY Table 28-2 classifies the major chemotherapeutic agents that have been reported to cause central nervous system (CNS) or peripheral nervous system toxicity as well as other commonly used agents that are not neurotoxic. The neurological complications caused by neurotoxic agents1–4 are detailed in the paragraphs that follow. More extensive reviews can be found elsewhere. Click here to view this table....

Hormonal Agents Adrenocorticosteroids The chemotherapeutic agents with which neurologists are most familiar are the glucocorticoids (corticosteroids). These drugs are especially effective in treating clinical symptoms caused by brain tumors and epidural spinal cord compression. Because of their lympholytic activity, corticosteroids are also used to treat tumors of the lymphoid system, including acute lymphoblastic leukemia, Hodgkin's disease, and non-Hodgkin's lymphoma. Common effects of corticosteroids include increased appetite and an improved5,6 sense of Other less well-being, which, in patients being treated for cancer, are considered salutary. 4,7 desirable effects are legion (Table 28-3). Only a few of neurological interest are discussed here. Click here to view this table.... Myopathy

The incidence of corticosteroid myopathy is unknown. The literature suggests that it occurs only after prolonged use of high-dose corticosteroids, particularly the fluorinated compounds, 8 such as dexamethasone. Our experience has been that most patients on conventional doses (e.g., 16 mg of dexamethasone daily) for more than 2 or 3 weeks develop at least mild myopathy. The syndrome is usually characterized by weakness of proximal muscles of the 8 hip girdle with wasting of thigh muscles. Patients complain of difficulty in arising from the toilet seat or from low chairs without using their hands.9 Patients often have trouble with climbing stairs or lifting heavy objects above the head. Bilateral psoas weakness is detected on examination even in early stages. At moderate severity, weakness of neck flexors and the shoulder girdle, particularly the deltoids, can be detected by manual muscle testing. The onset of weakness is usually gradual, but, occasionally, it is acute and painful (myalgia). Distal weakness occurs rarely. In some instances, respiratory function is compromised and is 9 manifested as dyspnea on exertion. Sensation is normal, as are deep tendon reflexes. The differential diagnosis of proximal muscle weakness in a cancer patient being treated with corticosteroids includes metabolic and nutritional myopathies associated with the cancer, leptomeningeal tumor that may occasionally cause predominantly proximal weakness, and polymyositis as a remote effect of cancer. It is particularly important to exclude polymyositis because that disorder may be effectively treated with corticosteroids. Polymyositis is characterized by muscle pain; the typical electromyographic (EMG) changes of increased

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insertional activity, elevated muscle enzyme concentrations in serum, and histological findings of muscle necrosis or inflammation indicate a paraneoplastic disorder. Clinically, the distinction between polymyositis and steroid myopathy is usually clear and rarely requires such extensive testing. The treatment of corticosteroid myopathy is to discontinue the corticosteroids, if possible, after which the myopathy usually resolves over time. Corticosteroid Psychosis

Psychotic changes associated with corticosteroids were common when adrenocorticotropic hormone (ACTH) and naturally occurring glucocorticoids were widely used. With synthetic corticosteroids, the disorder is less common, and with dexamethasone, florid psychosis is 10 rare. A double-blind prospective trial of prednisone, 80 mg daily for 5 days, given to normal volunteers revealed, however, that 11 of1112 patients developed at least a mild psychiatric reaction during treatment or withdrawal. Symptoms included irritability, anxiety, insomnia, difficulty in concentrating, euphoria, and depression. More severe psychiatric reactions are of 12,13 three general types: affective, schizophrenic-like, and delirious. 14 A reversible dementia unassociated with psychotic symptoms has also been reported. Affective disorders, either mania or, less commonly, depression (depression is more common in Cushing's syndrome than with exogenous corticosteroids), cannot be distinguished from psychiatric illness not associated with corticosteroids. Affective disorders usually begin early in the course of therapy, are more likely to affect women, and are dose related. They resolve when the corticosteroids are withdrawn. Neuroleptic drugs are effective in treating these disorders, but tricyclic antidepressant agents may worsen symptoms. The affective disorder may begin during tapering of corticosteroids but almost always resolves once the corticosteroids are entirely discontinued. A persistent bipolar disorder after withdrawal of 15 steroids has been described in one patient. Three patients on alternate-day corticosteroids have been reported to cycle, with mood elevation on the “on days” and depression on the “off 16 that prophylactic use of lithium may prevent affective days.” Several reports suggest 17 predictors to corticosteroid psychosis. However, the literature does not confirm any strong 13 identify individuals at risk, including a history of corticosteroid psychosis. The second form of corticosteroid psychosis resembles acute schizophrenia. The patient may become withdrawn or paranoid and may experience auditory or visual hallucinations. The disorder cannot be distinguished from noniatrogenic psychiatric illness and responds to the withdrawal of corticosteroids or to treatment with neuroleptics. The third form is acute delirium. The patient becomes distractible and unable to attend appropriately to environmental stimuli; confusion and visual hallucinations may also occur. Mild delirium is often not reported to the physician because the patient is neither surprised nor concerned about the hallucinations, correctly attributing them to the drug. Osteoporosis/Aseptic Necrosis

Osteoporosis is a common side effect of prolonged corticosteroid use, and patients on 18 chronic glucocorticoids should be followed with bone densitometry. Maintaining adequate intake of calcium and vitamin D, physical activity, and reducing risk factors such as tobacco smoking can help prevent osteoporosis. A randomized, controlled trial has shown that daily 19 alendronate is superior to alfacalcidol in the prevention of glucocorticoid-induced bone loss. Therefore, patients at high risk should be started on a bisphosphonate. 20

Although not a neurological disorder, aseptic necrosis of the hips (occasionally shoulders, wrist, and clavicle) may be confused with spinal cord compression or peripheral neuropathy in patients with cancer. Patients have usually been on corticosteroids for a long time, although high doses are not required. There are occasional reports of patients developing aseptic 21 necrosis after only a few weeks of treatment. The disorder is characterized by pain in the hip, often radiating down the anterior aspect of the thigh to the knee and resembling, in some respects, a femoral neuropathy or a lumbar radiculopathy. The pain causes difficulty in walking. The diagnosis can be made by reproducing the pain on rotation of the hip. Early during the course of the disorder, radiographs, radionuclide bone scans, and computed tomography (CT) scanning may be normal, but all will eventually reveal the necrosis. 22 Magnetic resonance imaging (MRI) is the most sensitive diagnostic test. Lipomatosis

Corticosteroids cause redistribution of fat, and this sometimes leads to neurological symptoms and signs. Increased fat in the orbits causes proptosis, and increased fat in the

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epidural space can cause spinal cord compression. Fat can easily be distinguished from tumor on CT scan or MRI by its density. Tapering or discontinuation of steroids does not result in sufficiently rapid redistribution of fat to relieve compression causing neurological dysfunction. In a few instances, surgical decompression of the spinal cord has been necessary to relieve neurological symptoms. Visual Changes

Corticosteroids can induce cataracts and increase intraocular pressure, leading to glaucoma, 4 and occasionally may cause exophthalmos from orbital fat deposition. They are also often responsible for changes in visual acuity, leading patients to complain of visual blurring; patients may return to their ophthalmologist several times for a new prescription for glasses, particularly during the course of a prolonged corticosteroid taper. The disorder appears to be due to changes in water content of the lens, leading to a difference in refraction, depending on the dose of the corticosteroids. It usually resolves upon discontinuation of the corticosteroid. Gastrointestinal Symptoms

Gastrointestinal bleeding and bowel perforation are well-recognized complications of 24,25 The most serious complication in neurological patients receiving corticosteroid use. 26 corticosteroids is bowel perforation ; the risk is particularly high in patients treated for spinal cord compression because they often receive high doses of dexamethasone and are prone to developing constipation, a predisposing factor for corticosteroid-induced perforation. Prevention of constipation might avert this serious complication. Many patients on corticosteroids are given a proton pump inhibitor or histamine-blocking agent in the questionable belief that they decrease the incidence of corticosteroid-induced peptic ulceration. The physician should be aware that these drugs occasionally cause encephalopathy and, rarely, coma. Corticosteroid Withdrawal Syndrome

Withdrawal of patients from corticosteroids also causes neurological disability (Table 28-4). The most striking symptom of withdrawal is “pseudorheumatism,” characterized by acute 27 myalgia and arthralgia that may be so severe as to incapacitate the patient. One of our patients was admitted to the hospital with a presumptive diagnosis of spinal cord compression because of severe pain in his legs and an inability to walk. In other patients, the disorder is milder and can be ameliorated by increasing the dose of corticosteroids and tapering more slowly. If very mild, it can be managed with simple analgesics. Click here to view this table.... Another withdrawal syndrome, first described in patients who had no neurological disability, is 28 characterized by headache, lethargy, and sometimes low-grade fever. It also occurs in patients with central nervous system (CNS) disease and may lead the physician to believe that the symptoms are due to recurrent tumor rather than corticosteroid withdrawal. Withdrawal from prolonged corticosteroid treatment has been reported to cause pseudotumor 29 cerebri. Sex Hormone Agonists and Antagonists Androgens and estrogens and their antagonists are not generally associated with neurological side effects. Tamoxifen, however,30,31 has been reported to cause reversible visual All antiestrogens increase the risk of disturbances or, more rarely, encephalopathy. 32 thromboembolic disease and stroke.

Nonhormonal Agents Table 28-2 lists some nonhormonal chemotherapeutic agents. Most do not cause significant neurotoxicity. One reason is that when experimental drugs are discovered to cause major neurotoxicity, they rarely reach the market. However, several chemotherapeutic agents can produce substantial dysfunction of the central or peripheral nervous system, and a few, such as the Vinca alkaloids, methotrexate, and cisplatin, are major offenders. The specific neurotoxicity of these and other commonly used drugs is reviewed in the following paragraphs. Others are noted in Table 28-5. Specific details can be found either in the cited

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references or in recent reviews.


1–4

Click here to view this table.... Methotrexate Methotrexate causes both acute and delayed neurotoxicity. The acute reactions are aseptic meningitis and33transverse myelopathy, both of which are associated with intrathecal administration primarily after administration by lumbar puncture rather than via34ventricular cannula, and a stroke-like syndrome after intravenous high-dose methotrexate. Acute Toxicity

Aseptic meningitis (Table 28-6) begins 2 to 4 hours after the drug is injected and generally lasts for 12 to 72 hours. The symptoms are headache, stiff neck, nausea, vomiting, fever, and lethargy. A CSF pleocytosis is often present and can mimic acute bacterial meningitis, except that it occurs too soon after injection to be caused by bacterial growth. The syndrome is common; in some series, more than 50 percent of patients treated with intrathecal methotrexate are affected. Curiously, a patient can have a florid reaction after one injection but may suffer no reaction after subsequent injections. The symptoms are self-limited, and 35 there is no specific treatment, although some inject hydrocortisone to prevent it. Oral corticosteroids can also reduce the inflammation and have been used prophylactically or as therapy. Rarely,36pulmonary edema (possibly neurogenic) has followed an intrathecal injection 37 of methotrexate ; sudden death has also very rarely followed intraventricular instillation. Click here to view this table.... Transverse myelopathy is a rare complication. Pain in the legs is followed by rapidly developing sensory changes, paraplegia, and neurogenic bladder dysfunction. The symptoms 4,38 after intrathecal treatment but may be delayed as usually begin 30 minutes to 48 hours long as 2 weeks. The pathological changes consist of a necrotic myelopathy without striking inflammation or vascular changes. The pathogenesis is believed to be an idiosyncratic reaction to the drug. A similar complication has been reported following intrathecal cytosine 39 arabinoside or thiotepa. A posterior reversible leukoencephalopathy syndrome has been described following intrathecal methotrexate and cytarabine in a nonhypertensive patient.40MR angiography displayed reversible arterial irregularities consistent with vasospasm. A stroke-like syndrome34affecting adults or children occasionally follows systemic high-dose methotrexate infusion. The disorder usually follows the second or third treatment by 5 or 6 days and is characterized by alternating hemiparesis associated with aphasia and sometimes encephalopathy or coma. Unequivocal seizure activity is rare. The electroencephalogram (EEG) is slow. The MRI displays well-marked T2 areas, and diffusion-weighted imaging displays well-delineated hyperintense areas affecting the deep white matter and not conforming to a vascular territory. Apparent diffusion coefficient maps demonstrate decreased signal intensity, in a corresponding distribution, suggesting restricted diffusion, 41 similar to an acute vascular event. Patients generally recover spontaneously in 48 to 72 hours with complete or partial resolution of the abnormalities on diffusion-weighted images. The T2 hyperintense lesions may persist. Surprisingly, in subsequent treatments, the syndrome usually does not recur, although rare recurrences have been described. The pathogenesis of the disorder is unknown, but Phillips and associates have shown marked changes in brain glucose metabolism following intravenous infusion of high-dose 42 methotrexate in rats. Delayed Toxicity

Leukoencephalopathy is the major and most devastating delayed complication of methotrexate treatment. The disorder generally follows repeated doses of intravenous high-dose methotrexate or intrathecal methotrexate, but it may occur after standard-dose 4,43 (Fig. 28-1). Although the syndrome can be caused by intravenous injection as well methotrexate alone, it is enhanced by brain irradiation and the combination of systemic and intrathecal drug. The sequence of modalities is probably also important. When methotrexate is administered concurrently with or follows cranial radiotherapy, the synergy is particularly toxic.

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FIGURE 28-1 Treatment-induced leukoencephalopathy. Fluid-attenuated

inversion recovery (FLAIR) magnetic resonance imaging (MRI) of the brain demonstrates diffuse periventricular white matter hyperintensity following treatment with methotrexate and whole-brain radiotherapy. Leukoencephalopathy may appear months to years following therapy, beginning insidiously or 44 abruptly with personality changes and learning disability. Children cured of leukemia who have received only intrathecal or high-dose intravenous methotrexate with cranial irradiation 44 show a decreased IQ after therapy. Seizures can occur, usually late in the course. The clinical course varies. Patients may recover slowly over weeks or months, their symptoms may stabilize with a mild to moderate dementia, or there may be relentless pro gression with spastic hemiparesis or quadriparesis, severe dementia, and coma, ending in death. The myelin basic protein concentration may be elevated in the CSF, presumably owing to 45 myelin breakdown. The MRI reveals cerebral atrophy, bilateral and diffuse periventricular white matter hyperintensity (on T2-weighted or FLAIR [fluid-attenuated inversion recovery] sequences), ventricular dilatation, and, sometimes, cortical calcifications; similar 46 findings may occasionally be seen in asymptomatic patients who have received methotrexate. Focal enhancement may be present in the early stages, but does not persist. Calcifications may be better visualized on CT scans. Although scans may be normal, even in patients with diminished intellect, neurological signs are usually preceded by radiographic white matter 47 changes on MRI. These abnormal images should be a warning to the physician that the patient is at risk of clinical leukoencephalopathy. White matter changes on MRI may be seen in patients years after prophylactic treatment with intrathecal or intravenous methotrexate, even in the absence of radiation therapy. 48,49

The most common is Several different pathological abnormalities have been reported. disseminated foci of white matter degeneration characterized by demyelination, axonal swelling, and dystrophic mineralization of axonal debris. These necrotizing changes may occasionally be accompanied by fibrinoid necrosis of small blood vessels. Histologically, leukoencephalopathy from irradiation or methotrexate cannot be distinguished easily, although the presence of axonal swelling is much more characteristic of methotrexate-induced leukoencephalopathy. An unusual toxicity, virtually restricted to children, is mineralizing microangiopathy characterized by noninflammatory fibrosis and calcification of arterial capillaries and venules, particularly in the basal ganglia. This is

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typically identified radiographically, where extensive calcifications are seen in the basal ganglia. It does not necessarily produce neurological dysfunction. The pathophysiology of methotrexate neurotoxicity is poorly understood. Depletion of reduced folates in the brain, inhibition of cerebral protein or glucose metabolism, injury to cerebral vascular endothelium resulting in increased blood–brain barrier permeability, and inhibition of catecholamine neurotransmitter synthesis have all been implicated but not proved to be involved. No effective treatment exists. Administration of intravenous or intrathecal leucovorin, an antidote to methotrexate-induced gastrointestinal or bone marrow toxicity, does not reverse or prevent neurological damage from the drug. Platinums The platinums (cisplatin, oxaliplatin, carboplatin) are drugs with a heavy-metal moiety. Thus, 50 it is not surprising that they, like other heavy metals, cause a peripheral neuropathy (Table 28-7). Click here to view this table.... Cisplatin

The peripheral neuropathy associated with cisplatin is dose dependent and usually follows 2 cumulative doses of greater than 40050mg/m . It is characterized by numbness and tingling in the extremities, occasionally painful. The first symptoms may not appear until cisplatin treatment is completed and then may progress for several months before the neuropathy stabilizes. The disorder affects predominantly the large sensory fibers; the deep tendon reflexes disappear and proprioception is lost, often resulting in ataxia. Pin and temperature sensation are spared, however, and power may be entirely normal. The disorder may be confused with paraneoplastic sensory neuronopathy but differs from that disorder in that paraneoplastic sensory neuronopathy usually affects all sensory modalities equally. Nerve conduction studies reveal decreased amplitude of sensory nerve action potentials and prolonged sensory latencies, compatible with a sensory axonopathy. With discontinuation of the drug, the neuropathy may improve and the patient's condition may even return to normal after many months; however, many patients are left with permanent disability. Because maximal injury is not observed until months after discontinuation of the drug, dose adjustment is not possible to accommodate ongoing neural damage. There is no known treatment. Pretreatment with amifostine, an organic thiophosphate, can reduce the incidence and 51,52 Focal neuropathies may follow arterial infusions in the severity of platinum neurotoxicity. extremities or neck. 53

Pathological examination of nerve roots reveals axonal loss with secondary demyelination. Axonal loss is also found in posterior but not anterior roots, with secondary degeneration of posterior columns. Dorsal root ganglion cells are probably the primary site of pathology, and the predominant pathological abnormality is in the nucleus. A correlation exists between the degree of histological change and the levels of platinum found in dorsal roots and peripheral nerves. 54

Lhermitte's sign appearing during or shortly after treatment with cisplatin suggests a transient demyelinating lesion in the posterior columns of the spinal cord. In some instances, patients may experience paresthesias down the arms when the upper limbs are abducted, suggesting that the brachial plexus may be demyelinated as well. Lhermitte's sign resolves completely and is not associated with any permanent damage. Muscle cramps not related to electrolyte imbalance (see later) are also common but, like 55 Lhermitte's sign, they usually resolve spontaneously. 56

Ototoxicity and vestibulopathy are also caused by cisplatin. Hearing loss results from hair 57 cell damage. The hearing loss is often subclinical and affects primarily the high-frequency range; that is, frequencies greater than 4,000 Hz. Tinnitus may precede hearing loss; rarely, high-dose cisplatin causes58acute deafness. Animal studies suggest that prophylactic vitamin E may reduce this toxicity. Vestibular toxicity is much less common than hearing loss. It is characterized by vertigo, oscillopsia, and ataxia. It may occur either with or without other symptoms of ototoxicity and may be exacerbated by previous use of aminoglycoside antibiotics. Ocular toxicity, which includes retinopathy (usually after intracarotid infusion),

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papilledema,

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and retrobulbar neuritis, is rare. Color perception may be disturbed, probably as the result of retinal cone dysfunction. Cortical visual loss (homonymous hemianopia, cortical blindness) may be part of the encephalopathy sometimes caused by cisplatin. 60

Encephalopathy is rare following intravenous infusion but is more common following intra-arterial infusion. It is characterized by seizures and focal brain dysfunction, particularly cortical blindness, but the symptoms are usually reversible. Encephalopathy due to the drug must be differentiated from the electrolyte disorders that result from its administration. Vigorous hydration precedes cisplatin use and can lead to water intoxication and cerebral 61 herniation. A nephropathy is common following cisplatin, resulting in hypocalcemia and hypomagnesemia, which may rarely cause tetany, encephalopathy, or seizures. Hypozincemia has been reported. Inappropriate antidiuretic hormone secretion (SIADH) with hyponatremia and seizures may also occur. Cisplatin has been implicated in late vascular toxicity, such as Raynaud's phenomenon, cardiac infarction, and cerebral infarction that sometimes follows multiagent chemotherapy. Vascular toxicity can also be subacute and occur within days to weeks of cisplatin administration. Some believe that the toxicity is caused by the cisplatin and is probably related to hypomagnesemia; others believe that bleomycin is the major culprit. However, it has been observed in patients who have received cisplatin as a single agent. Other rare complications of cisplatin include irreversible myelopathy, taste disturbances, and a myasthenic syndrome. Oxaliplatin 62

Oxaliplatin produces two types of peripheral neuropathy. The first occurs during or shortly after infusion and consists of paresthesias and dysesthesias of the hands, feet, and perioral region with jaw tightness. These symptoms are usually transient, may be triggered by cold, and may increase in both duration and severity with repeated drug administration. A pharyngolaryngeal dysesthesia syndrome accompanied by a sensation of shortness of breath without any objective evidence of respiratory distress has been described. Oxaliplatin can also induce a distal peripheral sensory neuropathy similar to that seen with cisplatin. This 2 neurotoxicity generally follows a cumulative dose greater than 540 mg/m and is characterized by sensory ataxia, jaw pain, eye pain, ptosis, leg cramps, visual changes, and voice changes. Although reversible, these clinical findings may persist for several months and require discontinuation of treatment. Less common neurological complications include 63 Lhermitte's phenomenon and urinary retention. Carboplatin

Carboplatin is less neurotoxic than cisplatin or oxaliplatin. Rare cases of peripheral neuropathy have been reported after high doses of carboplatin in patients treated with 64 combinations of other cytotoxic agents. Vincristine Vincristine affects primarily the peripheral nerves but can also be toxic to the CNS, cranial nerves, and autonomic nervous system (Table 28-8). Vinorelbine and vinblastine are much 2 less neurotoxic. A dose-limiting sensorimotor neuropathy appears in virtually all patients. The earliest complaint is tingling and paresthesias of the fingertips and later of the toes. Fine 65 movements of the fingers and toes are often impaired. Loss of the Achilles reflexes is the earliest sign. With continued drug administration, other reflexes disappear as well. Muscle 66 cramps, usually diurnal, affect arms and legs and may be the first symptom of neurotoxicity. They are particularly common in the jaw and tend to occur within 1 day to 2 weeks of drug administration. Objective sensory loss is uncommon, but weakness, especially of the extensors of the feet and hands, is frequent. Foot drop is either unilateral or bilateral. Unilateral foot drop is especially common in patients who have lost weight and habitually sit with crossed legs, thereby causing compression of the peroneal nerve at the head of the fibula. The weakness is usually tolerable, but rarely patients may become bedbound or quadriparetic, particularly if there is a preexisting neuropathy. The sensory symptoms, weakness, and lost reflexes are reversible, although they may require several months after the medication is stopped to improve. Agents used to relieve vincristine neurotoxicity, including gangliosides and glutamic acid, are not very effective. Click here to view this table.... 4

Vincristine occasionally causes focal neuropathies of peripheral or cranial nerves. The most

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common is mild oculomotor nerve involvement with ptosis. Less frequent is ophthalmoplegia with diplopia. The recurrent laryngeal nerve, facial nerve, acoustic nerve, and optic nerve are also affected occasionally. These various neuropathies may be bilateral or unilateral. Night blindness due to retinal damage has also been reported. Autonomic neuropathy, characterized by colicky abdominal pain and constipation, occurs in as many as one third of patients. Rarely, paralytic ileus develops in children and may be fatal. 67 Amelioration of vincristine-induced ileus with metoclopramide has been reported, but prevention of constipation is essential; all patients receiving vincristine should receive a prophylactic bowel regimen of stool softeners and laxatives. Other manifestations of autonomic dysfunction that have been reported include bladder atony, impotence, and postural hypotension. 68

69

CNS toxicity may result from hyponatremia due to SIADH. Encephalopathy and focal or generalized seizures not associated with SIADH have also been reported. Cortical blindness and other focal cerebral signs, including athetosis, ataxia, and parkinsonian-like symptoms, usually reverse after treatment is discontinued. The diagnosis of vincristine neurotoxicity is usually not difficult even when, as is common, the weakness develops a few weeks following therapy and progresses for several additional weeks. Neurophysiological studies are usually unnecessary but, when done, show the typical 4 features of an axonal neuropathy. These findings have been confirmed by nerve biopsy. Nitrosoureas The nitrosoureas rarely cause neurological toxicity when given in conventional doses. However, in patients with brain tumors who have received radiation and are treated with intracarotid or high-dose intravenous carmustine (BCNU), both ocular toxicity and 70 encephalopathy have been reported. After intracarotid treatment, the disorder is sometimes heralded by seizures and followed by slowly progressive neurological dysfunction, the exact signs depending on the region infused. White matter abnormalities are often apparent on CT scan or MRI, sometimes at a site distant from the tumor; with time, the area of white matter signal abnormality may develop calcification. The pathology is that of a necrotizing encephalopathy, giving an appearance similar to that of radiation damage, but strictly confined to the vascular territories perfused by the drug. 5-Fluorouracil and Capecitabine Neurotoxicity is rarely seen with conventional doses of the drug except in patients with a 71 deficiency of the enzyme dihydropyrimidine dehydrogenase. In these patients or others given high doses, a cerebellar syndrome, clinically indistinguishable from paraneoplastic or cytarabine-induced cerebellar disorders, occurs, consisting of truncal and limb ataxia, 71 dysmetria, nystagmus, and slurred speech. The mechanism of this disorder or other neurotoxicity is unknown. The signs usually reverse within a week after the drug is discontinued but may recur with its reintroduction. In animals, the agent damages Purkinje cells, granule cells, and neurons of the inferior olive and vestibular nuclei. Extraocular muscle abnormalities (particularly vergence disturbances), optic neuropathy, and extrapyramidal syndromes have been reported rarely with the administration of 5-fluorouracil. Encephalopathy, with diffuse slowing of the EEG but without cerebellar symptoms, has also been reported. Ocular toxicity includes blepharitis, conjunctivitis, lacrimal duct stenosis, and excessive lacrimation. Cerebral infarcts have been reported to complicate continuous infusion of the drug. Palmar-plantar erythrodysesthesia, a rare complication, may be confused with a peripheral neuropathy because of painful hands and feet. Acute cerebellar ataxia, somnolence, and upper motor neuron signs have been reported following intracarotid arterial infusions. When levamisole is combined with 5-fluorouracil, a few patients developed an inflammatory 72 multifocal leukoencephalopathy. The disorder usually presents with confusion and focal signs, including ataxia or hemiparesis associated with multiple contrast-enhancing lesions on MRI that may be confused with metastases. Capecitabine is an oral prodrug that is converted to 5-fluorouracil. A reversible leukoencephalopathy characterized by nausea, confusion, short-term memory loss, headaches, vertigo, ataxia,73dysarthria, and body shaking or stiffening has been described following treatment with it. Associated MRI abnormalities included nonenhancing diffusion-weighted and T2 hyperintense lesions in the corpus callosum, brachium pontis, and deep periventricular white matter. The symptoms and neuroimaging findings usually resolve

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with discontinuation of the drug. Cytarabine (Cytosine Arabinoside) Aseptic meningitis and rarely myelopathy, both clinically similar to those induced by 74 methotrexate, sometimes follow intrathecal cytosine arabinoside (ara-C). Meningeal irritation causing headache, stiff neck, and pleocytosis has been encountered in approximately 30 percent of patients given the drug, but no direct relationship between this syndrome and the individual or cumulative dose has been established. Aseptic meningitis occurs in virtually all patients who receive intrathecal liposomal ara-C, and oral corticosteroids are recommended for a few days before and after each dose to reduce the inflammation. The myelopathy begins with back pain or radicular leg pain. Weakness, sensory alterations, and bowel or bladder dysfunction occur at any time from a few days to months following treatment. The clinical picture usually evolves rapidly; some patients may recover incompletely, but others may be rendered paraplegic. Examination of the CSF usually reveals an elevated protein concentration and a modest pleocytosis; an elevated myelin basic protein has also been reported. Pathologically, portions of the spinal cord reveal demyelination with associated white matter vacuolization, histologically indistinguishable from methotrexate-induced myelopathy. One patient developed a “locked-in syndrome” (preserved consciousness but inability to move or communicate except by eye movement) 48 hours after a single dose of 100 mg of intrathecal ara-C in conjunction with intravenous ara-C, cisplatin, and doxorubicin. At autopsy, there was extensive brainstem necrosis. Rarely, intrathecal administration of75ara-C has been associated with seizures or an acute or subacute encephalopathy. 2

Intravenous high-dose 76 ara-C (3 g/m per 12 hours for 8 to 12 doses) may cause several neurological disorders. Cerebellar dysfunction occurs most frequently in older patients and 2 in those with preexisting renal dysfunction, usually at a cumulative dose of at least 36 g/m . 2 However, it has been reported after a single dose of 3 g/m . Patients develop dysarthria, nystagmus, and appendicular and gait ataxia. Confusion, lethargy, and somnolence may also be seen. With cessation of the drug, complete resolution of signs and symptoms generally occurs within 2 weeks. Neuropathological changes in patients who succumb to their underlying illness include widespread Purkinje cell loss, most pronounced in the deeper portion of the primary and secondary cerebellar sulci. The rest of the CNS appears largely to be unaffected, although white matter demyelination and filamentous degeneration of neurons in brainstem and spinal cord have been reported. 77

Peripheral neuropathy, axonal or demyelinating or both, is a rare complication of ara-C; in most patients, high-dose ara-C was given along with other potentially neurotoxic agents, including fludarabine. Other reported toxicities include seizures; reversible ocular toxicity, including blurred vision, photophobia, burning eye pain, and blindness; bulbar and pseudobulbar palsy; Horner's syndrome; the “painful legs, moving toes” syndrome; brachial plexopathy; reversible bilateral lateral rectus palsies; and acute aseptic meningitis (after intravenous injection). One patient who received a cumulative dose of 72 g developed a parkinsonian syndrome that resolved within 12 weeks. The mechanism of ara-C toxicity is unknown. Some investigators believe that ara-C kills 78 neurons by interfering with cytidine-dependent neurotrophic signal transduction. There is no treatment for any of the neurotoxic effects of ara-C but, as indicated earlier, many patients recover spontaneously. Ifosfamide High-dose ifosfamide has been associated with 79 a reversible encephalopathy of varying severity, which is a dose-limiting adverse effect. The most common manifestations include confusion, stupor, and mutism, rarely evolving into coma. Other less common features include seizures, hallucinations, personality changes, blurred vision, extrapyramidal symptoms, cerebellar symptoms, and urinary incontinence. EEG abnormalities are found in 80 65 percent of patients, and cases of nonconvulsive status epilepticus have been reported. Although death can occur, the encephalopathy is usually reversible and can be treated with methylene blue. Seizures can be treated with anticonvulsants. Suramin Suramin causes a peripheral neuropathy in 40 percent of patients whose blood levels exceed 350 μg/L. This condition presents like the Guillain–Barré syndrome, with rapid onset81,82 of a predominantly motor neuropathy leading to weakness or paralysis of the extremities and

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sometimes of bulbar and respiratory muscles. Paresthesias in the face and limbs are common before the weakness. The weakness often begins proximally. The disorder probably results from demyelination causing conduction block in peripheral nerves. It reverses after the drug is discontinued and can be prevented by monitoring blood levels carefully. Paclitaxel and Docetaxel 2

Approximately 60 percent of patients receiving paclitaxel (Taxol) at 250 mg/m or less per dose develop paresthesias of the hands and 83 feet that, in most patients, do not progress and may even resolve despite continued therapy. The neuropathy is predominantly sensory and, unlike cisplatin neuropathy, affects all sensory modalities. Examination reveals loss of pain and temperature sensation as well as vibration and position sense. Paclitaxel causes axonal damage, with secondary demyelination, probably reflecting damage to the cell body. A few patients also develop proximal muscle weakness that resolves; it is usually associated with 84 peripheral neuropathy. Acute arthralgia and myalgia of the legs that curtail activity (and are sometimes mistaken for peripheral neuropathy) may occur 2 to 3 days after a course of paclitaxel and can last for 2 to 4 days. Docetaxel causes the same type of sensory neuropathy as paclitaxel but is less neurotoxic. Paclitaxel or docetaxel neuropathy is enhanced by preexisting or subsequent neurotoxic chemotherapy, particularly cisplatin or even vinorelbine. Bortezomib Bortezomib is a novel chemotherapeutic agent that acts as a proteosome inhibitor. It is primarily effective against multiple myeloma. Bortezomib causes a cumulative 85 dose-dependent peripheral neuropathy that is predominantly sensory. Symptoms usually improve, even without stopping treatment, but some patients are left with fixed deficits. Fludarabine Fludarabine (2-fluoroadenosine arabinoside) is an antimetabolite with activity against a variety of lymphoproliferative neoplasms. It is highly immunosuppressive and has been associated with the development of progressive multifocal leukoencephalopathy in some 86 cause delayed neurotoxicity leading to encephalopathy patients. In addition, fludarabine can 87,88 Older patients and those receiving higher doses of and occasionally cortical blindness. the drug are at greater risk. OTHER AGENTS

Biological Agents Several biological approaches may be used either to manipulate the immune system to destroy neoplastic cells (e.g., antibodies, cytokines, vaccines, and lymphocytes), to combat the myelotoxic effects of chemotherapy (e.g., colony-stimulating factors and bone marrow 89 A few of these agents cause transplantation), or to inhibit angiogenesis in growing tumors. 90,91 (Table 28-9). notable nervous system toxicity Click here to view this table.... Bevacizumab is a monoclonal antibody that binds to and inhibits soluble vascular endothelial 89 growth factor (VEGF), a mediator of tumor angiogenesis. An increased incidence of systemic hemorrhages has occurred in patients with colorectal or lung cancer treated with bevacizumab. The risk of CNS hemorrhage in patients with brain metastasis has not been 92 fully assessed because they were excluded from clinical trials. Bevacizumab's most common side effect is hypertension, which may have contributed to a posterior reversible 93 encephalopathy syndrome in several patients. 94

Interleukin-2 causes capillaries, including those in the brain, to leak, leading to increases in 95 brain water content on MRI and to a severe96encephalopathy. Interferons can also cause encephalopathy, which can be irreversible. Nightmares, headache, myalgias, bilateral 97 brachial plexopathy, and oculomotor palsies are also side effects of interferons.

Retinoids The retinoids are a group of compounds consisting of vitamin A and related derivatives. They have been found to exhibit antitumor effects in patients with acute promyelocytic leukemia as

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98

well as other malignancies. Although there is no formal epidemiological evidence from either treatment cohort studies or large population studies, several case reports suggest an 99 increased risk of suicide and depression in patients treated with 13-cis retinoic acid. RADIATION THERAPY Therapeutic ionizing irradiation may affect the nervous system in one of two settings: First, damage to neural structures may occur when structures are included in the radiation portal. This damage can occur whether the cancer undergoing radiation therapy is within or outside the nervous system. Second, nervous system dysfunction can also occur secondarily when therapeutic irradiation damages blood vessels supplying the brain or endocrine organs necessary for appropriate nervous system function (usually the thyroid gland) or when the irradiation causes tumors that compress or destroy nervous system structures. Nervous system dysfunction caused by radiation therapy can occur acutely or may be delayed by weeks, months, or even years following the successful completion of treatment. The likelihood that radiation therapy will damage the nervous system depends on many factors, including the total dose delivered to the nervous system, the dose delivered with each treatment or the dose per fraction, the total volume of nervous system irradiated, the time after completion of radiation therapy, the presence of other systemic diseases that enhance the side effects of irradiation (e.g., diabetes, hypertension), and other unidentifiable host factors. The side effects 4,100 of radiation therapy are detailed here, and more extensive reviews can be found elsewhere.

Primary Neurological Damage Brain Encephalopathy caused by radiation therapy occurs in three forms: acute, early delayed (2 weeks to 4 months), and late delayed (4 months to 24 years) (Table 28-10). Click here to view this table.... Acute Encephalopathy

Acute encephalopathy usually follows large radiation therapy fractions given to patients with increased intracranial pressure from4 primary or metastatic brain tumor, particularly in the absence of corticosteroid coverage. Immediately following treatment, susceptible patients develop headache, nausea, vomiting, somnolence, fever, and worsening of neurological symptoms, rarely severe enough to culminate in cerebral herniation and death. Acute encephalopathy usually follows the first radiation fraction and becomes progressively less severe with each ensuing fraction. Usually, the disorder is mild, with the patient developing headache and nausea in the evening following irradiation. The pathogenesis of the disorder is not certain. Some observers believe it is secondary to a rise in intracranial pressure, with cerebral edema following breakdown of the blood–brain barrier by ionizing irradiation. Experimental evidence indicates that a single dose of 300 cGy delivered experimentally to an animal causes substantial breakdown of the blood–brain barrier, which is still evident 2 hours after radiation; after 24 hours, the barrier has reconstituted itself. Corticosteroids substantially prevent this breakdown of the blood–brain 101 barrier. A few observers4 have noted an increase in intracranial pressure following a single such an increase either in dose of radiation therapy, but others have failed to document 102 humans or in animals even if clinical symptoms develop. For the clinician, there are two implications. First, patients harboring large brain tumors, particularly with signs of increased intracranial pressure, should probably not be treated with large doses per fraction. Doses of 200 cGy per fraction or less appear to be acceptable in such patients. Second, all patients undergoing brain irradiation should be protected with corticosteroids (8 to 16 mg of dexamethasone daily or more if increased intracranial pressure is symptomatic), preferably for at least 24 hours before the start of radiation therapy. Both clinical and experimental evidence indicates that corticosteroids ameliorate the acute complications of irradiation. Early Delayed Encephalopathy

Early delayed encephalopathy usually begins in the second or third month after irradiation but can begin anywhere from 2 weeks to 4 months after treatment. If the patient has a brain 4 tumor, the symptoms of early delayed encephalopathy often simulate tumor progression. For

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example, the patient may develop recurrence of headache, lethargy, and worsening of lateralizing signs. Changes on CT scan or MRI may include an increase in the size of the lesion and sometimes the occurrence of contrast enhancement not present previously. These changes resolve spontaneously if the disorder is due to radiation encephalopathy rather than tumor recurrence, and the resolution can be hastened by the use of corticosteroids. The patient and the scan remain improved after corticosteroids are discontinued, indicating that the disorder was early delayed encephalopathy rather than tumor recurrence. Early delayed encephalopathy also occurs in patients without brain tumors. Early delayed encephalopathy after prophylactic irradiation 103 of the brain of children with leukemia has been called the “radiation somnolence syndrome.” This disorder is characterized by somnolence often associated with headache, nausea, vomiting, and, sometimes, fever. The EEG may be slow, but there are no focal neurological signs. The syndrome is ameliorated by corticosteroids but will also resolve spontaneously. The disorder is sometimes seen in adults following prophylactic radiation therapy for small-cell lung cancer or total body irradiation in preparation for bone marrow transplantation. A rare and serious neurological syndrome is brainstem encephalopathy following irradiation of posterior fossa tumors or when the brainstem has been included in the irradiated field for 104 head and neck cancer. The most frequent symptoms are ataxia, diplopia, dysarthria, and nystagmus. Most patients recover spontaneously within 6 to 8 weeks. Rarely, the symptoms progress to stupor, coma, and death. The pathogenesis of early delayed encephalopathy is believed to be demyelination, resulting from damage to oligodendroglia and subsequent breakdown of myelin sheaths. The best evidence supporting that hypothesis consists of pathological studies in patients with early delayed brainstem encephalopathy in which confluent areas of104 demyelination with varying degrees of axonal loss are found in areas that were irradiated. There is an associated loss of oligodendrocytes and abnormal and often multinucleated giant astrocytes. Furthermore, the latency in the onset and timing of resolution correspond to the cycle of myelin turnover. Late Delayed Radiation Necrosis

Late delayed radiation necrosis usually begins a year or two after the completion of radiation therapy. The symptoms depend on the nature of the primary disease. In patients who are treated for primary or metastatic brain tumors, symptoms generally recapitulate those of the brain tumor, leading the physician to suspect tumor recurrence. In addition, the MRI or CT scan mimics recurrence, with105,106 the appearance of a contrast-enhancing lesion that is (Fig. 28-2). Occasionally, a lesion suggesting a tumor indistinguishable from tumor appears at a distant site. Fluorodeoxyglucose positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) can help distinguish radiation necrosis from 107–109 recurrent tumor. 110 Methionine PET, using an amino acid ligand, may prove superior in this differentiation.

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FIGURE 28-2 Radiation necrosis. T1-weighted, post-contrast MRI 9 months

after stereotactic radiosurgery for a left parietal, dural-based metastasis. The lesion was hypointense on pre-contrast T1-weighted sequences. A second clinical picture has occurred when the patient's brain was included in the radiation portal, but there was no underlying brain tumor. Examples include irradiation of head and 4,107 Because neck tumors, including pituitary tumors, and prophylactic irradiation of the brain. only a portion of the brain has usually been irradiated and there was no previous brain damage, new focal neurological signs are the rule. For example, bilateral medial temporal destruction sometimes follows irradiation for nasopharyngeal or pituitary tumors, and frontal or temporal lobe destruction follows treatment for ocular or maxillary sinus tumors. The clinical features are similar to those of a brain tumor, with signs of increased intracranial pressure and focal signs, depending on the site of brain damage. The MRI usually reveals a mass, occasionally with contrast enhancement. An arteriogram may show vascular beading 4 that suggests a vasculopathy. A definitive diagnosis can only be made pathologically. Histologically, the typical lesion is an area of co-agulative necrosis in the white matter, with relative sparing of the overlying cortex. Microscopically, the most striking abnormalities are found in blood vessels, with hyalinized thickening and fibrinoid necrosis of the walls, often associated with vascular thrombosis, vascular hemorrhages, and accumulation of perivascular fibrinoid material. 107

Radiation necrosis is often treated best with resection. Most patients respond only transiently to corticosteroids, although there111 are occasional reports of prolonged responses after corticosteroid therapy without surgery. Other suggested treatments, such as vitamin E, pentoxifylline, hyperbaric oxygen and anticoagulation, are based on the rationale that the disorder is primarily vascular, but they have not proved useful in all patients. There are three hypotheses concerning the pathogenesis of this disorder. The first is that the vascular changes lead to infarction and necrosis. The second is that radiation therapy directly damages glial cells, both astrocytes and oligodendrocytes, leading to destruction of tissue. The third is that the radiation causes release of brain antigens with subsequent antibody formation and immune destruction of the brain. None of these potential mechanisms are mutually exclusive and all may contribute to the damage. Cerebral Atrophy

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Cerebral atrophy often follows whole-brain irradiation. The atrophy may occur in patients irradiated prophylactically or in those harboring a brain tumor that was eradicated by radiotherapy. It usually begins 6 to 12 months after radiation therapy. The patient may be asymptomatic but, more commonly, suffers memory loss and, in some instances, severe 112 gait abnormalities and urgency incontinence, cognitive dysfunction. Some patients have113 suggesting normal-pressure hydrocephalus. MRI of virtually all patients receiving whole-brain irradiation in excess of 3,000 cGy shows cerebral atrophy with enlarged sulci and ventricles; there may also be symmetric periventricular white matter hyperintense signals on T2-weighted or FLAIR images. Symptomatic patients appear to have greater degrees of cerebral atrophy and ventricular dilatation than asymptomatic patients. In some instances, the ventricular dilatation is out of proportion to the sulcal atrophy; when such patients are symptomatic with dementia, gait apraxia, and incontinence, they may respond to ventriculoperitoneal shunt. Cerebral atrophy also occurs in children receiving prophylactic 114 brain irradiation for acute leukemia. The atrophy is associated with a learning disability. The pathogenesis of the cerebral atrophy is not clear. In some instances, true communicating hydrocephalus, perhaps from radiation-induced arachnoiditis or obliteration of pacchionian granulations, appears to be causal. In other instances, there is simply loss of cerebral substance. Pathology reveals spongiosis of the white matter, but no vascular changes such as those seen with radiation necrosis. Except in patients who respond to shunting, there is no treatment for the cerebral atrophy. Spinal Cord There are no acute effects of radiation on the spinal cord. In the past, it was believed that, as with the brain, high doses of radiation delivered to the spinal cord for the treatment of epidural spinal cord compression might worsen neurological symptoms. Both clinical and 115,116 Therefore, clinical deterioration of experimental evidence have refuted this belief. patients with metastatic spinal cord compression during radiotherapy is usually due to tumor progression. Early Delayed Radiation Myelopathy

Early delayed radiation myelopathy is common after irradiation of the neck (Table 28-10). Several weeks after irradiation, the patient develops Lhermitte's sign that persists for weeks 117 Some investigators have reported delayed or months and then spontaneously disappears. 118 119 sensory evoked potentials, but others have not. Symptoms are believed to result from demyelination of the posterior columns of the spinal cord. Their presence does not predict the development of late delayed radiation spinal cord injury. Late Delayed Radiation Myelopathy

Late delayed radiation myelopathy appears in two forms. The first and most common is characterized by progressive myelopathy, often beginning as a Brown-Séquard116,120 syndrome Usually and progressing over weeks or months to cause paraparesis or quadriparesis. the symptoms progress subacutely, but in some instances they progress over several years and, at times, may stabilize, leaving the patient with only mild or moderate paraparesis. The disorder probably never resolves spontaneously. MRI is usually nonspecific but helps to exclude metastatic spinal cord compression or intramedullary metastasis. Hyperintense changes of the irradiated vertebral bodies due to fat replacing bone marrow may outline the 121 radiation field even if the details of the radiotherapy port are unknown (Fig. 28-3). In the acute stages, spinal cord swelling may be identified, and the area of damage may enhance 122 with contrast material. Spinal cord atrophy develops at a later stage. Pathologically, the lesions are characterized by confluent areas of necrosis with a predilection for the white matter, particularly the deeper parts of the posterior columns and superficial areas of the posterolateral tracts. Vascular changes are similar to those of radiation necrosis in the brain 123 but are usually less striking. There is no good treatment, although corticosteroids sometimes delay progression of the lesion. Other potential therapies include hyperbaric 124,125 oxygen and anticoagulation.

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FIGURE 28-3 Chronic radiation myelopathy. T1-weighted, post-contrast MRI 30

months after 3,750 cGy radiotherapy to the T8 to T12 vertebral levels for bone metastasis. Note the T8 to T12 vertebral hyperintensity and edema/expansion of the spinal cord. A few patients have been described with hemorrhage in the spinal cord developing many 126 years after irradiation. Characteristically, 8 to 30 years after radiation therapy to the spinal cord, a patient without prior neurological symptoms suddenly develops back pain and leg weakness. MRI suggests acute or subacute hemorrhage in the spinal cord. The cord may be slightly atrophic, but no other lesions are found. After several days, the patient typically begins to improve, and the neurological symptoms may resolve entirely. A few patients have had recurrent episodes of spinal cord hemorrhage. The pathogenesis is probably related to telangiectatic vascular changes caused by the radiation therapy. A biopsy sample of the 126 spinal cord from one patient was said to show an arteriovenous malformation. A second form of late delayed radiation myelopathy is a motor127,128 neuron syndrome that but has occurred after characteristically follows pelvic irradiation for testicular tumors 129 or after craniospinal irradiation for lumbosacral irradiation for other tumors 4 medulloblastoma. This disorder occurs 3 months to 23 years following irradiation and is characterized by the subacute onset of flaccid leg weakness affecting both distal and proximal muscles accompanied by atrophy, fasciculations, and areflexia. It is usually bilateral 129 and symmetric but may either begin in or remain restricted to one leg. Sensory changes are absent. Sphincter and sexual functions are normal. The CSF may contain an increased protein concentration. The myelogram is normal. Although electromyography reveals varying degrees of denervation, sensory and motor nerve conduction velocities are normal. The deficit usually stabilizes after several months to a few years; often patients are still able to walk, but some may become paraplegic. The disorder is impossible to differentiate from a pure motor polyneuropathy or isolated motor

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neuron loss. It also resembles the paraneoplastic syndrome of subacute motor neuronopathy. A single report describes a motor neuron syndrome confined to the arms that developed 3 years following cervical irradiation and was associated with a cystic hypodense cavity 130 affecting the spinal cord from C4 to C6. The pathological report of one patient with a motor neuron syndrome in the lower extremities describes randomly distributed demyelination and axonal loss in both sensory and motor roots, with areas of complete demyelination. The roots involved were primarily those of the cauda equina, with some anterior horn cells (motor neurons) in the lumbar cord exhibiting 131 chromatolysis suggestive of secondary damage. Cranial Nerves The clinical features of radiation injury to the cranial and peripheral132nerves and the special senses are shown in Table 28-11. Anosmia may follow irradiation. Taste is affected in almost every patient who undergoes cranial radiotherapy. Visual loss may follow irradiation of the eye or brain. It may be caused by radiation-induced “dry eye syndrome,” glaucoma, or 133,134 The optic cataract; more commonly, it may result from retinopathy or optic neuropathy. neuropathy following irradiation begins 7 to 26 months after the irradiation and is characterized by painless monocular or bilateral blindness. Papilledema and retinal hemorrhages may be present. The likelihood of visual loss is probably increased by the use of concomitant chemotherapy, and visual loss can generally be prevented by shielding the eyes at the time of irradiation. Hearing loss also follows radiation therapy to the brain or 135 ear. Radiation-induced otitis media causes a conductive hearing loss that may require 136 myringotomy for relief. This disorder usually appears during or shortly following radiation therapy. It is different from the sensorineural hearing loss that is a late delayed effect of radiation therapy and has been attributed to an endarteritis producing vascular damage of the 4 nerve, are cochlear or acoustic nerve. The lower cranial nerves, particularly the hypoglossal 137 often involved as a late delayed effect of radiation therapy delivered to the neck. The pathogenesis appears to be radiation fibrosis. Recurrent laryngeal, vagal, and sympathetic fibers (Horner's syndrome) may be involved as well. Click here to view this table.... Peripheral Nerves There are no acute changes in peripheral nerve function following radiation therapy, although Haymaker 138 and Lindgren mentioned that paresthesias may occur when patients are “under the beam.” Early delayed brachial plexus dysfunction is characterized by paresthesias in the hand and forearm, sometimes4,139,140 associated with pain and accompanied by weakness and Nerve conduction studies reveal segmental slowing, atrophy in a C6 to T1 distribution. and the course is characterized by recovery over a few weeks or months. This disorder is particularly common in patients with breast cancer because the brachial plexus is frequently included in the radiotherapy port of the primary cancer. Late delayed radiation plexopathy has 4,141 142,143 been reported after irradiation of either the brachial or lumbosacral plexus, although the former is much more common. The disorder usually occurs a year or more after radiation therapy with doses of 6,000 cGy or greater. Brachial plexopathy is characterized by paresthesias and weakness of the hand or arm. There may be sensory loss, particularly in the fingers and hand, but the numbness and weakness often progress to a pan-plexopathy, rendering the entire arm useless. This disorder is frequently accompanied by lymphedema and by palpable induration in the supraclavicular fossa. Myokymia on electrodiagnostic testing in the territory of 144,145 affected nerves helps to differentiate radiation damage from tumor The radiation-induced disorder is usually painless, which infiltration of the plexus. distinguishes it from tumor plexopathy, which is typically painful. A CT scan or MRI usually reveals a diffuse loss of tissue planes without a mass. Occasionally, radiation damage can produce a marked fibrotic reaction causing a mass of fibrosis that cannot be distinguished 146 from tumor recurrence. In such cases, surgical exploration of the plexus may be necessary to establish the correct diagnosis. There is no treatment for radiation plexopathy, although painful paresthesias may be relieved by amitriptyline or gabapentin. Lumbosacral plexopathy causes weakness of one or both legs. As with143,147 radiation brachial plexopathy, pain is usually absent and, when present, is generally mild. The disorder often affects the foot, and sensory disturbances as well as weakness are present in most cases. EMG frequently reveals myokymic discharges, which help to differentiate the process from tumor recurrence. At times, exploration is necessary to make the diagnosis. Radiation-induced lumbosacral plexopathy is often slowly progressive over many years. The pathogenesis of radiation plexopathy and peripheral nerve disease is believed to be related to

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fibrosis causing damage to Schwann cells, rather than stemming from direct damage to the nerves themselves.

Secondary Neurological Involvement Radiogenic Tumors The manner in which the nervous system may be affected secondarily after radiation therapy is summarized in Table 28-12. Click here to view this table.... 148

Radiation-induced tumors, including meningiomas, sarcomas, and, less frequently, 149 150 gliomas and malignant schwannomas, may appear years to decades after irradiation of nervous system tissue; secondary tumors may develop even after low doses of radiation therapy. An epidemiological study following a group of children who received low-dose scalp irradiation for tinea capitis demonstrated a 9.5-fold increase in the incidence of meningiomas 151 compared with a control group. Malignant or atypical nerve sheath tumors may follow irradiation of the brachial, cervical, or lumbar plexuses. Signs and symptoms of radiogenic tumors are no different from tumors that arise without prior radiation therapy, and their surgical treatment is similar. Some patients may be able to tolerate additional radiation therapy or chemotherapy if the tumor is malignant and cannot be excised totally. Vascular Abnormalities Lesions of large intracranial or extracranial blood vessels may follow radiation therapy by 152 months to years. Patients may develop transient ischemic attacks or cerebral infarcts. Arteriography reveals stenosis or occlusion of the artery within the radiation portal. A particularly vulnerable area is the supraclinoid portion of the internal carotid artery in children who have received brain irradiation. This occlusion is sometimes associated with moyamoya disease. The pathology of radiation-induced vascular occlusion is similar to severe 153 atherosclerosis, although there may be marked periarterial fibrosis as well. This condition can be distinguished from other forms of atherosclerosis by its restriction to the segment of vessel within the radiation field without evidence of widespread atherosclerosis elsewhere, by the younger age of the patients affected, and by the atypical location of153,154 the stenotic carotid If appropriate, segments, which are often situated distal or proximal to the bifurcation. endarterectomy or carotid stenting can be performed successfully on patients with extracranial vascular disease. Endocrinopathies Primary hypothyroidism may appear many years after irradiation for Hodgkin's disease or 155,156 head and neck tumors or, less frequently, after craniospinal irradiation. The patient may not have the typical stigmata of hypothyroidism but instead presents either with central or peripheral nervous system dysfunction, including encephalopathy, ataxia, and peripheral neuropathy. If the CSF protein concentration is elevated, as it often is in hypothyroidism, the patient may undergo an extensive work-up prior to recognition that the neurological disorder is caused by hypothyroidism. Thyroid function should be studied in any patient with neurological symptoms who has undergone prior irradiation to the neck or head. 157

Hypercalcemic hyperparathyroidism has been reported to follow radiation therapy. Hypothalamic-pituitary dysfunction is a frequent delayed complication of irradiation for head and neck or brain tumors, especially in children. In children, the most frequent endocrinopathy is growth hormone deficiency, which is more often symptomatic in patients irradiated for primary brain tumor than after prophylactic irradiation for acute leukemia 158 because of the higher doses used to treat most brain tumors. Growth should be carefully monitored in children irradiated for brain tumor, and treatment given if deficiency is detected. Growth hormone deficiency should be differentiated from growth failure resulting from spinal irradiation. Gonadotropin deficiency and secondary or tertiary hypothyroidism are less frequent endocrinopathies. In adults, hypothalamic pituitary dysfunction is a common sequela of irradiation for head and 155 neck tumors. In a large study, it was found that 5 to 9 years after irradiation, 48 percent of patients had decreased growth hormone, 13 percent had decreased cortisol (two thirds of them requiring cortisol replacement), 40 percent had increased prolactin, and 8 percent had decreased follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Most studies suggest that the hypothalamus is more likely to be damaged by radiation compared with the

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pituitary gland itself. In adults, radiation-induced hypothalamic pituitary dysfunction also occurs in about one third of long-term survivors of primary brain tumors. The most frequent abnormalities are hypothalamic hypogonadism associated with hyperprolactinemia and hypothyroidism. Previous

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Aminoff: Neurology and General Medicine: Connective Tissue Disease...



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Keyword Index

Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 29 Connective Tissue Diseases, Vasculitis, and the Nervous System RICHARD B. ROSENBAUM •

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CONNECTIVE TISSUE DISEASES Systemic Lupus Erythematosus Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Treatment Sjögren's Syndrome Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Treatment Systemic Sclerosis Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Treatment Mixed Connective Tissue Disease Rheumatoid Arthritis Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Myopathies in Connective Tissue Disease VASCULITIS Primary Vasculitis of the Nervous System Primary Angiitis of the Central Nervous System Nonsystemic Vasculitic Neuropathy Systemic Necrotizing Vasculitis Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Treatment Polymyalgia Rheumatica and Temporal Arteritis Systemic Disease Central Nervous System Disease

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Peripheral Nervous System Disease Treatment Takayasu's Arteritis Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Treatment Behçet's Syndrome Systemic Disease Central Nervous System Disease Peripheral Nervous System Disease Treatment DIFFERENTIAL DIAGNOSIS Central Nervous System Syndromes Meningitis Cerebrovascular Disease Relapsing-Remitting Multifocal Disease Headache Movement Disorders Myelopathy Seizures Acute Confusional State Cognitive Dysfunction Affective or Psychotic Disorders Peripheral Nervous System Syndromes Cranial Neuropathy Acute Inflammatory Demyelinating Neuropathy Dysautonomia Mononeuropathy Multiplex Myasthenia Gravis Polyneuropathy THERAPEUTIC CHOICES

The diseases discussed in this chapter are linked by their inflammatory mechanisms and the diversity of their effects on the nervous system. They often present diagnostic challenges. After reviewing each disease, the differential diagnosis of some specific neurological syndromes is explored. CONNECTIVE TISSUE DISEASES

Systemic Lupus Erythematosus Systemic Disease Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease characterized by the presence of a broad spectrum of autoantibodies, including antinuclear antibodies (ANAs). It is protean in its neurological and systemic manifestations. Its severity varies from relatively mild skin problems and arthralgias to life-threatening multiorgan failure. The American College of Rheumatology (ACR) classification criteria are helpful for assessing the possibility of SLE and for understanding its diversity (Table 29-1). However, the criteria must be used cautiously for diagnosis. Since any 4 of the 11 criteria would be sufficient to make the diagnosis, there are 330 distinct initial presentations. Many of the criteria are nonspecific and can be seen in normal individuals or in other diseases. Furthermore, the criteria are insensitive, and some patients have SLE even though they meet fewer than 4 criteria. The prevalence of SLE is 100 per million population; 90 percent of patients are women, and the disease is more prevalent in blacks than in whites. Peak age at onset is 15 to 25 years old. Click here to view this table.... SLE usually causes systemic symptoms such as fatigue and malaise. Some patients are febrile. Perhaps 80 percent of patients have skin manifestations, such as sun sensitivity or the classic malar rash, and arthralgias or nondeforming arthritis. Other systemic manifestations include pericarditis, pleuritis, renal disease (ranging from asymptomatic proteinuria or hematuria to severe glomerulonephritis), anemia (classically autoimmune hemolytic anemia), thrombocytopenia, leukopenia, or lymphopenia. Inflammation can affect nearly any part of the body, including the lungs, gastrointestinal tract, and eyes. Autoantibodies are present universally in patients with SLE. ANAs are present in nearly all

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lupus patients. ANAs also occur in about 10 percent of normal people, usually at a low titer, and in many other inflammatory diseases including rheumatoid arthritis (RA), Sjögren's syndrome, systemic sclerosis, polymyositis, and multiple sclerosis (MS). Patients with SLE often have other antibodies against specific nuclear antigens, such as extractable nuclear antigen (anti-ENA), anti-Ro (SSA), anti-La (SSB), anti-Sm (anti-Smith, not to be confused with anti-SM, which is anti–smooth muscle), and antiribonucleoprotein (anti-RNP). Anti-Ro is often positive in the rare lupus patient who lacks ANA. Anti-Sm is specific but insensitive for SLE. Anti-dsDNA (double-stranded DNA) is also strongly suggestive of SLE. Antibodies to histones are associated with drug-induced lupus. Depressed levels of complement components C3 and C4 are common in patients with lupus, particularly those with immune complex deposition, such as that seen in glomerulonephritis. 1

Many patients with SLE have serum antiphospholipid antibodies ; the most commonly assayed antibody is directed against a phospholipid, cardiolipin. In routine in vitro testing, these antibodies may prolong the partial thromboplastin time. Because of this laboratory property, antibodies to cardiolipin are sometimes called lupus anticoagulants. However, antiphospholipid antibodies rarely cause bleeding; paradoxically, they are frequently associated with thrombosis. Antiphospholipid antibodies may be responsible for false-positive serological test results for syphilis (VDRL and rapid plasma reagin [RPR], but not fluorescent treponemal antibody absorbed [FTA-ABS] test). Antiphospholipid antibodies are associated with thrombosis, especially deep venous thrombosis, pulmonary embolism, nonbacterial thrombotic endocarditis, and stroke. These antibodies may accompany failures of pregnancy, including miscarriage, fetal death, premature birth due to placental insufficiency, preeclampsia, or eclampsia. However, most people with antiphospholipid antibodies do not have lupus or other autoimmune disease. Antiphospholipid antibodies may be present transiently, especially after acute viral infections, and may occur in many other systemic illnesses (Table 29-2). Click here to view this table.... The antiphospholipid antibody syndrome is defined as the persistence of moderate to high titers of antiphospholipid antibodies combined with a clinical episode of thrombosis or of 2,3 pregnancy morbidity. Other phenomena that occur in antiphospholipid antibody syndrome include livedo reticularis, arthralgias, cardiac valve abnormalities, hemolytic anemia, thrombocytopenia, pulmonary hypertension, and Raynaud's phenomenon. The antiphospholipid antibody syndrome may occur in patients with SLE or in isolation, in which case it is called primary antiphospholipid antibody syndrome. Patients with SLE who have 4 antiphospholipid antibodies are more likely to develop neurological manifestations. This applies not only to stroke but also to nonischemic syndromes including headache and less 5,6 common inflammatory syndromes, such as chorea or myelitis. Patients with primary antiphospholipid antibody syndrome may have many of the same neurological problems that 7 occur in patients with SLE. A variety of autoantibodies, including antibodies against endothelium, neurofilament, glial fibrillary acidic protein, neurons, microtubule-associated protein 2, lymphocytes, ribosomal P8 protein, and gangliosides, occur in certain patients with neurological manifestations of lupus. None of these have proven pathogenic action or diagnostic value. Antibodies to ribosomal P protein, probably the most studied of these, occur in about one third of patients with lupus and neurological disease but also occur in other lupus patients and are not useful as a 9 diagnostic test. Central Nervous System Disease The central nervous system (CNS) manifestations of SLE vary tremendously in their symptoms, severity, mechanisms, and treatment. Although at times they are referred to collectively as neuropsychiatric lupus, they are best analyzed as a number of separate syndromes (Table 29-3). Depending on diagnostic criteria used, between 37 and 95 percent of patients with SLE have10–14 one of these during the course of their illness, and many patients Neurological events in patients with lupus may be due to will have more than one. numerous factors (e.g., hypertension, uremia, other metabolic derangements, drug toxicity, opportunistic infections, coincident illnesses) rather than to direct effects of inflammatory disease; in one series, more than two fifths of neurological syndromes in patients with lupus 12 were not directly due to lupus affecting the nervous system. Click here to view this table.... Cognitive dysfunction affects up to 80 percent of patients with SLE at some time during the

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15

illness. The cognitive difficulties can be relatively mild and transient; irreversible deficits or frank dementia are much less common. More than one tenth of16,17 patients with SLE experience a seizure at some time during the These can be one-time events, particularly if related to metabolic course of their illness. derangements, drug toxicity, infections, or other reversible factors. However, SLE may also cause recurrent focal or generalized seizures, particularly in patients who have antiphospholipid or anti-Sm antibodies, strokes, other evidence of focal brain lesions, or psychosis. Patients with SLE are at increased risk of ischemic and hemorrhagic stroke via a variety of mechanisms. Strokes can be caused by cardiogenic emboli (especially in patients with myocardial infarction, atrial fibrillation, or nonbacterial endocarditis), arterial atherosclerosis, arteriolar disease (especially in patients with hypertension), thrombosis associated with antiphospholipid antibodies, and very rarely by vasculitis. Patients with lupus are more than 18 twice as likely as matched controls to develop carotid plaque. All lupus patients need aggressive primary stroke prevention with attention to well-known risk factors such as smoking, hypertension, hyperlipidemia, and diabetes. When a patient does have a stroke, brain imaging is usually supplemented with a thorough evaluation of cardiac sources of emboli, arterial circulation, and antiphospholipid antibodies to clarify the etiology of the stroke and plan secondary stroke prevention. Chorea occurs in perhaps 1 percent of patients with lupus. The movement disorder can be unilateral or bilateral, evolve slowly, and remit spontaneously; it may be the first clinical sign 6 of lupus or appear later in the disease. The chorea is often sensitive to variations in female steroid hormones. Patients with chorea often have increased levels of antiphospholipid antibodies but rarely have evidence of focal cerebral ischemia. Other movement disorders, 19 such as reversible parkinsonism, are rare neurological manifestations of lupus. 20

Acute or subacute transverse myelopathy occurs in 1 to 2 percent of patients with SLE. Patients present with sensory changes, often with a thoracic sensory level, paraparesis, or sphincter dysfunction. Neurological findings in the arms are less frequent. The myelopathy may be the initial clinical manifestation of lupus. Many patients have antiphospholipid antibodies or false-positive VDRL results. Some patients also have a history of optic neuritis, so might be classified as having Devic's syndrome. Magnetic resonance imaging (MRI) of the thoracic spine often shows T2-bright intramedullary signal extending over many spinal segments. Spinal fluid commonly shows a mild pleocytosis and elevated protein concentration and occasionally contains oligoclonal bands. Uncontrolled series suggest that patients treated with corticosteroids, often combined with cyclophosphamide, can make a 20 complete or partial recovery. Acute episodes of aseptic meningitis sometimes occur in patients with SLE; the lifetime prevalence is on the order of 1 percent. The presentation is typical of other forms of meningitis with symptoms such as fever, stiff neck, and headache. In patients with meningitis, spinal fluid studies are necessary to exclude an infectious cause, particularly in immunosuppressed patients who are at risk of opportunistic infections. In patients with aseptic meningitis, spinal fluid usually shows a mononuclear pleocytosis, normal glucose, variable protein levels, and no evidence of a causative organism by culture, polymerase chain reaction (PCR), or serology. Drug-induced meningitis is an important consideration in the 21 differential diagnosis of these patients. The aseptic meningitis of lupus can be self-limited or corticosteroid responsive but is sometimes recurrent. Patients with lupus commonly experience depression, anxiety, and other affective disorders. Perhaps one fifth of patients will experience a major depression during their lives, and many more will have difficulty with mood or anxiety. These disorders do not correlate with brain inflammation and are treated with routine psychiatric drugs, such as selective serotonin reuptake inhibitors (SSRIs) and benzodiazepines, rather than with immunosuppressive therapy. Patients with lupus are at risk of psychosis, delirium, or acute confusional states. When these occur, the differential diagnosis includes a wide variety of causes of encephalopathy, such as CNS inflammation directly from lupus, hypertensive encephalopathy, uremia, other metabolic derangements, drug toxicity, or seizures. Patients with hypertension or those22taking drugs such as cyclosporine can develop posterior reversible leukoencephalopathy. In psychotic patients 23 on steroids, differentiating lupus psychosis from steroid psychosis is key to planning therapy. The focal neurological syndromes of SLE may mimic many clinical features of MS. The ACR classification (Table 29-3) refers to these as demyelinating syndromes, but a more general

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description is multifocal white matter lesions. Like the lesions of MS, these lesions are often associated with relapsing-remitting focal syndromes involving areas such as the optic nerve, brainstem, and spinal cord. In patients with lupus, MRI of the brain often shows T2-bright signals in the cerebral white matter, including periventricular lesions. Occasionally patients with lupus have cerebrospinal fluid (CSF) oligoclonal bands or increased intrathecal immunoglobulin G (IgG) synthesis. Some patients with MS have systemic autoantibodies such as ANAs or antiphospholipid antibodies. Peripheral Nervous System Disease The peripheral nervous system is also affected in diverse ways in SLE (Table 29-4). Carpal tunnel syndrome is 24 probably the most common manifestation, occurring in up to 30 percent of patients with lupus. Patients occasionally have other compression neuropathies. Perhaps one fifth of patients have distal symmetric axonal sensory or sensorimotor peripheral 25 neuropathy, which is usually relatively mild. Patients with mild neuropathy rarely need nerve biopsy or aggressive immunosuppression, even though the nerve, if biopsied, might show some epineurial vasculitis. Findings of autonomic neuropathy, such as abnormal pupillary responses, impaired sweating, loss of cardiovascular reflexes, and impaired gastrointestinal mobility also26,27 occur in many lupus patients, regardless of whether they have sensory neuropathy. Click here to view this table.... Acute demyelinating polyneuropathy, clinical and electrodiagnostically similar to Guillain–Barré syndrome, affects perhaps 1 percent of patients with lupus, a higher incidence than that in the general population. The differential diagnosis of acute motor neuropathy in patients with lupus includes vasculitic neuropathy, particularly if the presentation is in the asymmetric pattern of mononeuritis multiplex; however, this is uncommon. Patients with lupus can also develop other inflammatory neuromuscular syndromes such as chronic inflammatory demyelinating polyneuropathy (CIPD), myasthenia gravis, or neuralgic amyotrophy. Less than 1 percent of patients with lupus develop cranial mononeuropathies, most often of 28 the facial nerve. Treatment Treatment of SLE, with or without neurological involvement, must be individualized based on the organ systems involved and the severity of involvement. Thus, mild arthralgias might be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), whereas severe renal disease often justifies treatment with cyclophosphamide. Many of the neurological manifestations of SLE can be treated symptomatically. Examples include recurrent headache, mood and anxiety disorders, carpal tunnel syndrome, and length-dependent peripheral neuropathy. Cognitive dysfunction usually29requires no specific therapy; behavioral approaches to cognitive therapy deserve exploration. All patients with SLE should attend to factors for primary stroke prevention. Those who have had a stroke associated with a cardiac source of emboli are often treated with warfarin. The appropriate anticoagulation for patients with stroke and antiphospholipid antibodies is 2,30,31 A retrospective study found that patients with antiphospholipid antibodies and debated. an episode of venous or arterial thrombosis were less likely to have recurrent thromboses if treated with warfarin, keeping the international normalized ratio (INR) to 3.0 or more, when 32 compared to patients treated with aspirin or with less aggressive warfarin doses ; however, a study of stroke patients, most of whom did not have lupus, found that in patients with stroke who had antiphospholipid antibodies, either low-dose aspirin or warfarin with a target INR of 33 1.4 to 2.8 was equally effective in preventing recurrent stroke. Patients with lupus psychosis can be managed with antipsychotic drugs, and, once corticosteroid-induced psychosis has been excluded, with steroids. Patients with Guillain–Barré syndrome or myasthenia can be treated with intravenous immunoglobulin (IVIg) or plasmapheresis; however, some patients do not respond to these but appear responsive to corticosteroids combined with cyclophosphamide. Patients with focal CNS inflammatory syndromes such as myelopathy, optic neuritis, or focal cerebral white matter lesions are sometimes treated with corticosteroids alone, but prognosis is better if this is 34 combined with immunosuppressives such as cyclophosphamide.

Sjögren's Syndrome

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Systemic Disease Sjögren's syndrome is a chronic autoimmune disorder that causes inflammation in many organs but particularly in the exocrine glands, primarily salivary and lacrimal glands causing dry mouth (xerostomia) and dry eyes (xerophthalmia), which can be severe enough to 35 damage conjunctiva or cornea (keratoconjunctivitis sicca). The salivary glands may be enlarged. In most cases, Sjögren's syndrome is associated with other rheumatic diseases such as rheumatoid arthritis, SLE, or systemic sclerosis. Sjögren's syndrome occurring without another connective tissue disease is known as primary Sjögren's syndrome, which is the focus in the following discussion of neurological manifestations. Most (90%) patients with Sjögren's syndrome are women, usually middle-aged. The prevalence in the United States exceeds 1,000 cases per million population, so an estimated 500,000 to 2 million Americans have Sjögren's syndrome. Varied diagnostic criteria have been proposed. The European classification criteria (Table 29-5) are valid and reliable. Click here to view this table.... In addition to dry eyes and dry mouth, Sjögren's syndrome can cause dysfunction of other exocrine glands, resulting in dry skin, vagina, or upper respiratory tract. Patients commonly have systemic symptoms such as arthralgias, myalgias, or fatigue, and less often weight loss or fever. Patients can have palpable purpura due to small-vessel vasculitis, but inflammation of larger arteries is uncommon. Sjögren's syndrome can also cause renal (interstitial nephritis, renal tubular acidosis), thyroid (thyroiditis or hypothyroidism), gastrointestinal (atrophic gastritis, dysphagia), pulmonary (interstitial pneumonitis), and liver (biliary cirrhosis or sclerosing cholangitis) disease. Liver, spleen, or lymph nodes may be enlarged. Patients with Sjögren's syndrome have an increased risk of developing lymphoma. Dry eyes or dry mouth are common symptoms and have ubiquitous causes including drugs, aging, or the local effects of contact lenses. In patients with sicca, parotid enlargement, systemic symptoms, and neurological findings, sarcoidosis is often prominent in the differential diagnosis. The pathogenesis of Sjögren's syndrome is unknown. The pathological changes in exocrine glands are lymphocytic infiltrates. Patients with Sjögren's syndrome commonly have serological evidence of autoimmunity including ANAs (present in perhaps three fourths of patients). The anti-Ro (SSA) and anti-La (SSB) antibodies are more specific to Sjögren's syndrome but are also sometimes present in patients with SLE and other autoimmune disease and have limited sensitivity, occurring in between one fourth and three fourths of patients. Blood studies can also show rheumatoid factor, anemia, lymphopenia, and hypergammaglobulinemia; monoclonal gammopathy occurs less frequently. Central Nervous System Disease The prevalence of CNS disease in patients with Sjögren's syndrome is debated; estimates 36 range from 0 to 100 percent. Part of this discrepancy is because the most common CNS problem is subtle cognitive change, particularly of memory or frontal lobe function, which can 37 be hard to detect without detailed psychometric testing. Sjögren's syndrome may cause focal brain lesions, which present abruptly, as for a stroke, or more gradually. Either cerebral hemisphere or the brainstem can be affected; white matter syndromes are more common than gray matter syndromes. These clinical presentations correlate with the neuropathology of the focal brain lesions, which shows38mononuclear infiltrates of veins, venules, and less commonly small arteries or arterioles. The lesions favor the periventricular or subcortical white matter and less commonly affect the gray matter. The surrounding brain tissue can show focal infarcts, which are usually microscopic. Meningeal vessels are often involved. Syndromes clinically associated with gray matter disease, such as seizures, can occur. Even though the CNS pathology in patients with Sjögren's syndrome often includes the meninges, clinical meningitis is not common; however, instances of aseptic meningitis do occur and at times become chronic or recurrent. The CSF typically shows mild mononuclear pleocytosis, occasional elevation of protein level, and, less frequently, oligoclonal bands or 39 evidence of increase intrathecal IgG synthesis. Similar CSF findings can accompany the focal neurological syndromes, such as myelopathy. The CNS lesions of Sjögren's syndrome can evolve with a relapsing-remitting course that approximates that of MS. When Sjögren's syndrome causes optic neuritis, focal paresthesias, brainstem syndromes such as internuclear ophthalmoplegia, or myelopathy, the distinction from MS is important. Surveys from MS clinics suggest that Sjögren's 40–42 syndrome is rarely misdiagnosed as MS.

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Lesions localized to the spinal cord are one of the most common focal CNS findings in Sjögren's syndrome. The myelopathy can evolve slowly or rapidly, be generalized or localized, with presentations as varied as transverse myelopathy or Brown-Séquard 43 syndrome. Some patients also have episodes of optic neuritis, so can be classified as having Devic's syndrome. In most cases, spinal MRI shows T2-bright intramedullary lesions spanning multiple spinal segments. Sometimes the cord appears swollen, and some lesions enhance with gadolinium. Peripheral Nervous System Disease In patients with Sjögren's syndrome, peripheral nervous disease is more common than CNS disease. The peripheral neuropathy is often the presenting manifestation of the Sjögren's 44 syndrome. The peripheral manifestations of Sjögren's syndrome can be separated into a number of clinical syndromes, but many patients have features overlapping more than one of these (Table 29-6). Click here to view this table.... Distal sensory or sensorimotor neuropathy is the most common peripheral neuropathy in patients with Sjögren's syndrome. Clinical examination shows this pattern in up to one fifth of patients with Sjögren's syndrome, and other patients will have asymptomatic neuropathy detectable by nerve conduction studies. The typical presentation is a chronic distal axonal neuropathy including small and sometimes larger sensory fibers. Distal motor involvement is less common. Nerve biopsy specimen usually shows nonspecific axonal loss rather than vasculitis. Some patients with otherwise idiopathic axonal neuropathy will meet diagnostic 45 criteria for Sjögren's syndrome. However, if neuropathy patients have dry eyes or dry mouth but no other objective supportive findings, they are unlikely later to develop systemic 46 manifestations of Sjögren's syndrome. Sensory neuronopathy presents acutely or indolently as asymmetric dysfunction of large and small sensory fibers. Patients often have impaired distal or proximal cutaneous touch, pain, temperature, and joint position senses.44,47 They may have pseudoathetosis and sensory ataxia. Many patients also have elements of trigeminal or They have depressed tendon reflexes. autonomic neuropathy. On electrodiagnostic studies, most patients have some low-amplitude or unobtainable sensory nerve action potentials and somatosensory evoked responses. 44,48 Sural nerve biopsy Spinal cord MRI often shows T2-bright signal in the posterior columns. shows axonal loss of large and small myelinated fibers and of unmyelinated fibers, but few biopsy specimens show vasculitic changes or lymphocytic infiltrates. Pathology of the dorsal root ganglia can include neuronal destruction and lymphocytic infiltration. In addition to dry eyes and dry mouth, these patients often fully meet diagnostic criteria for Sjögren's syndrome, including objective evidence of xerophthalmia and xerostomia and abnormal lip biopsy samples; however, they usually do not have other systemic manifestations of Sjögren's syndrome. Trigeminal neuropathy impairs sensation, usually in the mandibular or maxillary divisions, but not motor trigeminal function, unilaterally or bilaterally, with acute or subacute evolution. Electrodiagnostic studies suggest abnormality of the gasserian ganglion with impaired blink 49 reflexes but normal masseteric reflexes. Mild autonomic neuropathy, with manifestations such as Adie's pupil, orthostatic hypotension, impaired sweating, constipation or diarrhea, and abnormal cardiac reflexes, often accompanies the other neuropathies of Sjögren's syndrome. In an occasional patient, more 44 severe autonomic dysfunction is the predominant neurological problem. Mononeuritis multiplex or multiple cranial neuropathies may occur in patients with Sjögren's syndrome. In contrast to trigeminal sensory neuropathy, the multiple cranial neuropathies also affect motor function and can include nerves III, V, VI, VII,44IX, X, and XII. Biopsy of an involved peripheral nerve is likely to show epineurial vasculitis. Other neuropathic presentations occasionally found in patients with Sjögren's syndrome include painful asymmetric sensory neuropathy, proximal radiculoneuropathy, Guillain–Barré 50 syndrome, and lower motor neuronopathy. Predominantly motor neuropathy is less common in patients with Sjögren's syndrome; motor neuron disease is linked to Sjögren's 50 syndrome 51–53 by case reports. Carpal tunnel syndrome occurs in some patients with Sjögren's syndrome. Treatment

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Treatment of Sjögren's syndrome varies greatly depending on the organs involved and the severity of disease. Dry eyes may be treated with artificial tears or topical approaches; arthralgias may be controlled35with nonsteroidal anti-inflammatory drugs or with antimalarials such as hydroxychloroquine. There is no specific cure for some neurological syndromes, 54 such as mild cognitive impairment, trigeminal neuropathy, or distal sensory neuropathy. Myelopathy or symptomatic focal brain lesions are often treated with corticosteroids, sometimes in conjunction with cyclophosphamide; in one series, more than5490 percent of patients with myelopathy improved after treatment with cyclophosphamide. Mononeuritis multiplex or multiple cranial neuropathies also appear responsive to corticosteroids, sometimes with cyclophosphamide added. A minority of patients with sensory neuronopathy 44,54,55 improve after treatment with corticosteroids, IVIg, or other immunosuppressants.

Systemic Sclerosis Systemic sclerosis causes a relatively noninflammatory vasculopathy and fibrosis in multiple organs. The pathogenesis is unknown, but the combination of microvascular ischemia and fibrosis causes the bulk of clinical manifestations of systemic sclerosis. Strictly speaking, scleroderma refers to the typical skin thickening of systemic sclerosis; patients may have cutaneous scleroderma alone without having systemic sclerosis, and localized cutaneous scleroderma is not associated with the neurological complications discussed later. Estimated prevalence in the United States is between 100 and 300 cases per million population, with an annual incidence about one tenth of the prevalence; the disease affects women more than 56 men and blacks more than whites. Systemic Disease In addition to scleroderma, patients with systemic sclerosis typically have CREST: subcutaneous calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly (tight digital skin), and telangiectasia. The esophageal disease often causes dysphagia. Some patients have only CREST and no other systemic disease; however, systemic sclerosis can also cause pulmonary fibrosis or hypertension, renal or cardiac involvement, especially with hypertension, hypothyroidism, sicca syndrome, arthralgias, and tenosynovitis. Almost all patients with systemic sclerosis have some serological evidence of ANAs. These can include antibodies against antigens such as centromeres, topoisomerase, U1-RNP, RNA polymerase 57 III, U3-RNP, and Th/To. These antibodies have some prognostic value: for example, patients with anticentromere antibodies usually have the CREST syndrome, are at risk of pulmonary hypertension, but usually do not develop more diffuse systemic disease. Perhaps 58 those with anti-U1-RNP or anti-Scl-70 are more prone to neurological complications. Central Nervous System Disease CNS disease is not particularly common in patients with systemic sclerosis, so whether reported cases represent true pathogenic associations is often problematic. For example, nearly one third of patients with systemic sclerosis have migraine, but a pathological 59,60 A number of case reports link systemic sclerosis to association has not been proven. intracerebral vasculopathy, presenting with transient ischemic attacks (TIAs), ischemic strokes, or intracranial hemorrhages. Although systemic sclerosis can lead to hypertensive 61–66 In a few emergencies, cerebral vasculopathies can also occur in normotensive patients. 67 link systemic instances, patients have both MS and systemic sclerosis. Other case reports 68,69 sclerosis and optic neuropathy, memory impairment, or affective disorders. About one third of patients with systemic sclerosis, compared to less then one tenth of control 70 patients, have basal ganglia calcification visible by computed tomography (CT) scan. 71 Patients with SLE may also have an increased prevalence of basal ganglia calcification. Peripheral Nervous System Disease Carpal tunnel syndrome occurs in about one fourth of those with systemic sclerosis; one series found a higher incidence (43%) among those with anti-Pol3 antibodies, which are also associated with more diffuse disease and renal crisis. Trigeminal sensory neuropathy, clinically resembling that described in Sjögren's syndrome, affects 1 percent or more of 72,73 Distal symmetric axonal neuropathy, plexopathies, and patients with systemic sclerosis. 72–74 mononeuritis multiplex occur infrequently in patients with systemic sclerosis. Many forms of autonomic dysfunction affect patients with systemic sclerosis, including abnormal sympathetic skin responses, even in nonsclerodermatous skin, abnormal

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cardiovascular reflexes, impaired urodynamics, impotence, and abnormal pupillary responses 75 to sympathetic or parasympathetic stimuli. With the exception of impotence, these autonomic changes are usually asymptomatic. Treatment Data on the treatment of neurological disease in patients with systemic sclerosis are scant. Trigeminal neuropathy or mild distal neuropathy is usually not specifically treated. Case reports suggest possible benefit of cyclosporine in patients with systemic sclerosis and 61 cerebral vasculopathy.

Mixed Connective Tissue Disease Mixed connective tissue disease (MCTD) is one example of the many overlap syndromes in which a patient has features of more than one inflammatory disease. Patients with MCTD typically have some features of SLE and some features of systemic sclerosis, particularly 76 Raynaud's phenomenon and digital sclerotic skin changes. The serological hallmark of MCTD is high titers of autoantibodies to ribonucleoprotein (RNP or more specifically U1-RNP) and absence of anti-Sm and anti-DNA antibodies. These patients have a high incidence of pulmonary hypertension. Inflammatory muscle disease,77histologically resembling dermatomyositis, is another common aspect of MCTD. Perhaps 10 percent of patients with MCTD have CNS disease; their neurological complications are like those of SLE; in addition, similar to patients with systemic sclerosis, they probably are at increased risk of trigeminal 78–80 sensory neuropathy.

Rheumatoid Arthritis Rheumatoid arthritis is a chronic disease characterized by symmetric joint inflammation, particularly of the small distal joints such as the metacarpophalangeal, proximal interphalangeal, wrist, and metatarsophalangeal joints. Rheumatoid arthritis has a prevalence between 10,000 and 20,000 cases per million population, affecting women more often than men. More than four fifths of those with rheumatoid arthritis have autoimmune serological changes, particularly the presence of rheumatoid factor, but rheumatoid factor is nonspecific, being present in many other inflammatory conditions and in a small percentage of the healthy population. Autoantibodies to cyclic citrullinated peptide (anti-CCP) are more specific than rheumatoid factor for the diagnosis of rheumatoid arthritis. Systemic Disease Patients with rheumatoid arthritis can develop systemic manifestations such as subcutaneous rheumatoid nodules, sicca syndrome, Felty's syndrome of hypersplenism, amyloidosis, scleritis or episcleritis, lung or heart involvement, anemia of chronic disease, eosinophilia, and thrombocytosis. A rare but serious complication is widespread rheumatoid vasculitis, with neurological complications such as those of other medium-vessel vasculitides (discussed later). A community-based survey of rheumatoid arthritis in Olmstead County, Minnesota, found extra-articular manifestation in nearly one half of patients over 30 years of follow-up; important neurological manifestations were cervical myelopathy in 2 percent, neuropathy in 2 81 percent, and major organ vasculitis in less than 1 percent. Central Nervous System Disease Patients with rheumatoid arthritis are probably at increased risk of headache and neck ache but rarely develop serious or focal cerebral disease. Strokes due to rheumatoid vasculitis or 82,83 Pachymeningitis caused by to compression of a vertebral artery are quite infrequent. rheumatoid nodules or pannus is a rare complication of chronic rheumatoid arthritis. The lesions are84visible by contrast-enhanced MRI, which can demonstrate focal or irregular dural thickening. Clinical manifestations can be absent, focal (e.g., optic neuropathy, spinal cord compression), or nonfocal (e.g., headache, mental status changes). Cervical myelopathy caused by atlantoaxial subluxation and by soft-tissue pannus is a feared late complication of rheumatoid arthritis. The subluxation is due to laxity of inflamed ligaments. Subluxation is usually anterior but can be in any direction. It is rare in the first years of rheumatoid arthritis but85develops in more than one fourth of those who have had the disease for more than 15 years. The subluxation is usually asymptomatic; however, the risk of cord compression increases as subluxation increases, particularly in those with smaller spinal canals. Signs of myelopathy (quadriparesis, spasticity, sensory loss, sphincter

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disturbance) can evolve slowly or worsen suddenly. Patients with high cervical instability are at particular risk of spinal cord injury during intubation or anesthesia. Vertical atlantoaxial subluxation can lead to brainstem compression; possible symptoms, in addition to those of cervical myelopathy, include bulbar palsy, trigeminal or high cervical sensory loss, ophthalmoparesis, nystagmus, drop attacks, hydrocephalus, and sleep apnea. A rare presentation is vertebral arterial stroke due to the subluxed neck. Cervical collars can decrease neck ache or headache due to atlantoaxial subluxation; however, a halo and cervical traction are needed if neck stabilization is required due to neurological deterioration. Surgical stabilization in patients with myelopathy or brainstem compression can stabilize the spine and prevent further neurological loss but often does not 86 improve existing neurological deficits. Peripheral Nervous System Disease Carpal tunnel syndrome is the most common neurological manifestation of rheumatoid arthritis. Estimates of its prevalence vary; careful questioning of patients with87rheumatoid arthritis can reveal median-distribution sensory symptoms in more than half. Patients with rheumatoid arthritis are more likely than age-matched controls to develop carpal tunnel syndrome and88,89 are more likely to develop carpal tunnel syndrome when they have hand flexor The carpal tunnel syndrome can improve with successful treatment of the tenosynovitis. arthritis or after carpal tunnel surgery, occasionally supplemented by tenosynovectomy. Ulnar nerve compression at the ulnar groove, radial or posterior interosseus nerve compression, compression of the peroneal or posterior tibial nerves by a Baker's cyst in the popliteal region, tarsal tunnel syndrome, and digital neuropathies may affect patients with rheumatoid arthritis. Mild length-dependent symmetric sensory neuropathy is a potential late effect of rheumatoid arthritis, especially in those with more severe disease. If a nerve biopsy is performed, the specimen may show vasculitic changes, but this is not indicative of systemic vasculitis and is not an indication for immunosuppressive treatment. Patients may also have autonomic neuropathy with impaired sweating or abnormal postural and cardiovascular reflexes, even in the absence of sensory neuropathy. Patients who develop rheumatoid vasculitis are at risk of mononeuritis multiplex.

Myopathies in Connective Tissue Disease The inflammatory myopathies 90 are dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). Both DM and PM cause subacute, predominantly proximal, weakness, sparing the face and eyes. Serum creatine kinase (CK) is elevated up to 50 times normal. Electromyography (EMG) shows brief, low-amplitude, easily recruited motor unit potentials, often accompanied by fibrillation potentials or positive sharp waves. Antisynthetase autoantibodies are present in up to one fourth of patients with DM or PM; anti-Jo is the most common of these. Despite these similarities, DM and PM differ in their pathology, immunopathogenesis, and relation to other connective tissue diseases. DM can affect either children or adults. It is usually accompanied by characteristic skin changes: heliotrope upper eyelid discoloration with swelling and an erythematous rash on the face, neck, anterior chest, back and shoulders, and extensor surfaces of extremity joints. On the fingers, a papular, reddish purple keratotic rash can involve the knuckles but spare the phalanges (Grottron rash). Fingernails may show dilated capillaries under the bases and distorted cuticles. In DM inflammatory changes concentrate around blood vessels and in the perifasicular connective tissue. Perifasicular atrophy of myocytes is characteristic. The + inflammatory cells are predominantly CD4 . DM affects about one eighth of patients with 77 systemic sclerosis and probably occurs in more than one half of patients with MCTD. PM rarely occurs before the age of 18 years. Weakness develops insidiously and is not associated with rash. Muscle biopsy sample shows inflammatory infiltrates, predominantly + CD8 lymphocytes, invading muscle fibers. PM occurs in 5 to 8 percent of patients with SLE and has a lower prevalence in patients with rheumatoid arthritis or Sjögren's syndrome. Given the vagaries of diagnostic definition and the multiplicity of overlaps among the connective tissue diseases, the division among diseases associated with DM or PM can hardly be absolute. For example, muscle biopsy samples of some patients with myositis and MCTD + + 91 endomysial CD8 cells. Furthermore, have a combination of perivascular CD4 cells and 92 DM and Sjögren's syndrome may occur together.

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Sporadic IBM usually begins after age 50, particularly in men, and is the most common progressive muscle disease in older adults. It causes a distinct pattern of weakness, favoring the quadriceps, gluteus maximus, and forearm flexors and extensors. Biceps and triceps weakness and foot drop are often present. A muscle biopsy specimen shows vacuoles in multiple muscle fibers, mononuclear cell inflammation,93intracellular amyloid deposits, and intracellular inclusions containing phosphorylated 94–97 tau. IBM is linked to the autoimmune connective tissue diseases by a few case reports. More details on the inflammatory myopathies are available in Chapter 60. Myositis is not the only form of muscle dysfunction seen in those with rheumatic diseases. Patients with advanced rheumatoid arthritis often have diffuse weakness. EMG and serum CK are normal. Muscle biopsy shows type II atrophy, the same pattern that can be seen with disuse. Similarly, patients with Sjögren's syndrome may have mild weakness with normal serum CK levels. Severe hypokalemia due to distal renal tubular acidosis is a rare cause of 98 weakness in patients with Sjögren's syndrome. Most patients with systemic sclerosis have some proximal weakness. These patients have normal or slightly elevated serum CK, sometimes mildly decreased duration or increased polyphasia of motor unit potentials99–101 by EMG, and nonspecific changes, such as type II atrophy, on muscle biopsy specimen. Drug toxicity is another cause of muscle disease in patients being treated for connective tissue diseases. Corticosteroid myopathy is a common 102,103 cause of proximal weakness, especially in patients on high doses or chronic therapy.104,105 Treatment with cyclosporine or Penicillamine can cause chloroquine may rarely cause myalgias and weakness. 106 myositis. VASCULITIS The vasculitides are a diverse group of illnesses characterized by inflamed blood vessels. They can be subdivided based on the size and type of blood vessels that are inflamed, details of pathology, and areas of the body involved. Most vasculitis is systemic, with involvement of multiple organ systems. However, there are two classic forms of vasculitis in which the principal manifestations are neurological: primary angiitis of the CNS and nonsystemic vasculitic neuropathy.

Primary Vasculitis of the Nervous System Primary Angiitis of the Central Nervous System Primary angiitis of the CNS (PACNS) is a clinical challenge: a rare disease that causes common syndromes such as headache, encephalopathy, or stroke, is potentially fatal but potentially treatable, and is difficult to diagnose, even with cerebral angiography and brain biopsy. Synonyms include cerebral granulomatous angiitis, giant cell granulomatous angiitis of the CNS, and isolated angiitis of the CNS. PACNS is pathologically defined by transmural, predominantly monocytic, infiltrates of small to medium (100 bpm), ataxia, and polyneuropathy on 26–28 admission. The major threat to life is from associated illnesses or injuries, hyperthermia,

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Aminoff: Neurology and General Medicine: Alcohol and the Nervous S...


dehydration, and hypotension. Although initial studies reported mortality rates as high as 15 26 percent, with current treatment rates have fallen to 1 percent or less. A variety of sedatives, anticonvulsants, sympatholytics, and neuroleptics have been administered to patients with 20,26 Several double-blind studies alcohol withdrawal delirium, usually in uncontrolled trials. have suggested that benzodiazepines are effective in controlling the symptoms of alcohol 27,28 A recent meta-analysis found sedative-hypnotics (diazepam, withdrawal. chlordiazepoxide, pentobarbital, paraldehyde, and barbital) better than neuroleptics in reducing mortality from alcohol withdrawal delirium, with a relative risk of 6.6 (95% CI, 26 1.2–34.7). The dose of medication required to control symptoms can vary greatly among different patients and over time in the same patient. A typical regimen is to administer 5 to 10 mg of diazepam intravenously every 5 to 10 minutes until the patient is lightly somnolent, followed 26 by 5 to 20 mg every few hours as needed to control delirium and agitation. Shorter acting benzodiazepines such as oxazepam or lorazepam may be safer in patients with liver 29 disease. Although there are not measurable differences in efficacy between individual sedative-hypnotic drugs, patients refractory to benzodiazepines may respond to addition of a different class of sedative-hypnotic (e.g., propofol or pentobarbital). Neuroleptics, such as haloperidol, may be used for severe agitation but should only be administered as adjunctive therapy with sedative-hypnotics. Fluid and electrolyte abnormalities can be severe and require prompt therapy. Dehydration accompanying delirium tremens may lead to circulatory collapse, requiring replacement of up to 4 to 10 L of fluid during the first 24 hours. Hypomagnesemia is common and should be treated with magnesium sulfate (1 g intravenously every 6 hours during the first day in patients with adequate renal function). Potassium should be included in intravenous solutions because hypokalemia may be exacerbated by glucose administration and cause cardiac arrhythmias. DEMENTIA Several disorders may cause dementia in alcoholic patients. With these conditions, cognitive function is impaired in a diffuse and nonspecific fashion.

Pellagra Pellegra, which results from deficiency of nicotinic acid (niacin) or its amino acid precursor, 30 tryptophan, may produce dementia in alcoholics. The disorder is uncommon in developed countries30,31 because of fortification of processed foods with niacin. Neuropathological involve mainly the large neurons of the motor cortex, although changes are also changes seen elsewhere in the cortex, in large neurons of the basal ganglia, in cranial motor and deep cerebellar nuclei, and in anterior horn cells. Affected neurons appear swollen and rounded, with eccentric nuclei and loss of Nissl substance. Axonal damage is too minor to account for 31 the chromatolysis, which is more likely related to metabolic effects on nerve cell bodies. Systemic manifestations of pellagra include diarrhea, glossitis, anemia, and erythematous cutaneous lesions that appear in sun-exposed areas. Early mental symptoms of irritability, depression, fatigue, insomnia, and inability to concentrate are nonspecific and suggest a psychiatric disorder. However, the later development of confusion, hallucinosis, or paranoid ideation confirms the presence of an encephalopathy, and is usually accompanied by spastic weakness and Babinski signs. Tremor, rigidity, polyneuropathy, optic neuritis, and deafness may also be present. Pellagra responds readily to administration of niacin, although cerebral symptoms may not be completely reversible. Further details are given in Chapter 17.

Marchiafava–Bignami Disease Marchiafava–Bignami disease was first described in 1903 in wine-drinking Italian men but has since been observed among people of many nationalities and with consumption of all 30,32 In this rare disorder, there is destruction of myelin mainly in types of alcoholic beverages. the corpus callosum and anterior commissure. Exceptionally, lesions extend laterally to involve the centrum semiovale, and in some instances the middle cerebellar peduncles are demyelinated. Neurons in layer 3 of the cerebral cortex may be replaced by gliosis, possibly owing to disruption of callosal fibers. The disorder is usually diagnosed postmortem because the clinical signs are nonspecific, though magnetic resonance imaging (MRI) has made the diagnosis more feasible during life. Most patients are alcoholics of long standing and many have associated malnutrition or liver disease, although the disease has appeared in a few nondrinkers. The etiology is not known. Symptoms may present acutely with seizures and coma often accompanied by signs of upper motor neuron dysfunction, or may follow a subacute course with gait disturbance, dysarthria, hyperreflexia, cognitive impairment,

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neuropsychiatric symptoms, and signs of interhemispheric disconnection. Patients may show minimal impairment of consciousness or may progress to stupor or coma. MRI shows T2-hyperintense swelling of the corpus callosum followed later in the course by callosal 33,34 T1-weighted images may show atrophy, as well as cortical and subcortical atrophy. hypointense necrotic lesions of the corpus callosum. Motor deficits, such as pyramidal tract signs and gait disturbance, tend to recover with abstinence from alcohol and improved nutrition, but many patients show residual cognitive impairment and a disconnection 30,33 Patients who develop coma carry the greatest risk of serious disability or syndrome. death, whereas those with little impairment in consciousness may recover with only mild 33 disability.

Acquired Hepatocerebral Degeneration Alcoholic liver disease may be accompanied by acquired hepatocerebral degeneration, a disorder associated with liver failure due to many causes, and with neuropathological lesions 35,36 Brains of affected individuals show diffuse, patchy necrosis similar to Wilson's diease. with microcavitation at the junction of cerebral gray and white matter, and a loss of neurons and myelinated fibers in the basal ganglia and cerebellum. Protoplasmic type II (Alzheimer) astrocytes are increased in number, and Opalski cells may be present. Patients are often demented and show reduced attentiveness and diminished ability to concentrate on problems, retain new facts, and sustain mental activity. Motor signs always accompany the dementia and include cerebellar ataxia, dysarthria, tremor, dystonia, myoclonus, and choreoathetosis. Mild corticospinal tract deficits may also be present, and occasional patients show signs of a myelopathy. A mild form of the disorder may occur with parkinsonian features 36 that include rigidity, bradykinesia, and impaired gait and posture, but normal cognition. In some cases, the neurological findings precede recognition of liver disease by several years. The deficits are irreversible, the rate of progression is variable, and the course is often punctuated by superimposed episodes of reversible hepatic encephalopathy. Death usually occurs as a complication of advanced liver disease or intercurrent infection rather than from the neurological disorder.

Alcoholic Dementia Dementia unrelated to the foregoing disorders has been recognized in alcoholics for several years. Numerous psychometric studies have shown cognitive impairment to be common in 37 alcoholics. Parker and colleagues found performance on tests of abstraction ability also to be impaired in social drinkers, and the degree of impairment was 30,39 correlated with the amount 38 have argued that of alcohol consumed per drinking occasion. Some investigators unrecognized Korsakoff's syndrome (see later)40,41 accounts for most cases of cognitive claim that alcohol is directly toxic to the impairment among alcoholics, whereas others brain and induces structural nervous system abnormalities that account for dementia. In rodents, chronic alcohol consumption can lead to learning41,42 deficits, altered dendritic Postmortem studies have morphology, decreased synaptic density, and neuronal loss. attempted to document the existence of alcohol-induced dementia by quantifying changes in brain weight and size, and the number of cortical neurons in alcoholics. Torvik and associates compared the brain weights of 545 male alcoholics and 586 age-matched control subjects 40 and found that the brains of alcoholics weighed an average of 31 g less. Skullerud found a 70- to 90-g reduction in brain43weight in alcoholics that was independent of the presence of liver disease or malnutrition. Harper and Kril compared brains from 25 alcoholics and 44 control patients and found that there was a statistically significant loss of brain tissue in chronic alcoholics, which was worse in patients with associated thiamine deficiency or liver 44 the number of neurons in the frontal cortex disease. Harper and associates also found that 45 was significantly reduced in chronic alcoholics. Computed46–54 tomography (CT) and MRI studies have shown decreased brain size in In the CT studies, the incidence of atrophy ranged from 7 to 100 percent alcoholics. 50 among alcoholics and48–52 heavy social drinkers, and atrophy tended to be greater in alcoholics MRI studies show widespread volume loss affecting cortical than55,56 in nonalcoholics. 46 and white matter. In addition, MRI studies show deficits in several subcortical gray 57 structures, including the corpus callosum, pons, cerebellar hemispheres and vermis. These regions are less affected in patients with uncomplicated alcoholism free of alcohol-associated electrolyte and nutritional disturbances when compared with patients with clinically defined syndromes such as Marchiafava–Bignami disease, alcoholic cerebellar degeneration, and 57 may be observed with greater central pontine myelinolysis. White matter abnormalities 58 sensitivity and detail using diffusion tensor imaging.

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Neuropsychiatric abnormalities correlate poorly with structural abnormalities on MRI49,51,53 or CT 49,51,52 Neither variable correlates well with the duration or pattern of drinking.51,54,57 scans. Imaging and neuropsychiatric abnormalities are partly reversible during abstinence. However, Carlen and colleagues found that54improving CT parameters correlated poorly with changes in psychometric test performance. Mechanisms that account for volume loss and recovery during abstinence have been postulated to reflect changes in brain water, but recent longitudinal studies using MR spectroscopy have shown increases in N-acetyl aspartate and in phospholipids in59,60 certain brain regions, suggesting recovery of neurons and white matter during abstinence. Several biochemical and physiological abnormalities require many weeks to resolve after alcohol withdrawal. In chronic alcoholics, CSF acidosis may persist for weeks after62the last 61 drink, and evoked response abnormalities may require up to 3 weeks to recover. In longitudinal studies, Parsons has found 37 that neurocognitive deficits in recovering alcoholics remit slowly over 4 years of abstinence. Thus, it appears that although alcohol can be toxic to the brain, several radiological and neuropsychiatric abnormalities observed in alcoholics are partially reversible. WERNICKE'S ENCEPHALOPATHY Wernicke's encephalopathy is an acute disorder manifested by ophthalmoplegia, gait ataxia, 63–65 Neuropathological findings include demyelination, glial and and a confusional state. vascular proliferation, hemorrhage, and necrosis, which particularly affect gray matter regions of the thalamus, hypothalamus, brainstem, and cerebellum. An underlying disorder that predisposes to malnutrition appears to be common to all cases. Alcoholism is the most frequent predisposing factor, but persistent vomiting due to a variety of causes, starvation, and malignancy or other chronic systemic diseases have also been implicated. A detailed account of its clinical features is provided in Chapter 17. The link between malnutrition and Wernicke's encephalopathy is a deficiency of vitamin B1 (thiamine). With chronic alcoholism, decreased dietary intake of thiamine may be compounded by alcohol-induced defects in intestinal absorption, metabolism, and hepatic storage of thiamine. However, the manner in which thiamine depletion produces neurological dysfunction is unknown. Thiamine pyrophosphate is a required cofactor for at least four enzymes involved in intermediary metabolism: pyruvate dehydrogenase, α-ketoglutarate dehydrogenase, transketolase, and branched-chain α-ketoacid dehydrogenase. Several investigators have reported heterogeneity of transketolase affinity for thiamine or variant 66–69 which could provide a basis for preferential vulnerability of certain forms of transketolase, alcoholic patients to thiamine deficiency. Thiamine phosphates have also been suggested to have a role in axonal conduction or synaptic transmission. Experimental thiamine deficiency 70–73 is characterized by widespread depression of glucose metabolism in gray matter regions, 72 which may be accompanied by enhanced metabolism in white matter tracts ; 73 a later phase of gray matter hypermetabolism may precede the onset of histological lesions. 63

Ocular abnormalities in Wernicke's encephalopathy may take a variety of forms. The most common is nystagmus, which almost always exhibits a horizontal component; vertical nystagmus is less common, and rotatory nystagmus is rare. Ocular palsies are also frequent, particularly lateral rectus palsy, which is usually bilateral. Horizontal or horizontal and vertical gaze palsies are often seen. Ptosis and internuclear ophthalmoplegias are rare, and loss of pupillary reactivity does not occur. Ataxia results from disease in the superior cerebellar vermis and vestibular nuclei. Consequently, the gait is most severely affected. Only a few patients exhibit limb ataxia, such as is revealed by finger-to-nose or heel-knee-shin testing; dysarthria is unusual. The acute confusional state is nonspecific. As with other metabolic encephalopathies, there is typically sedation, disorientation, and inattention, and the level of consciousness may fluctuate. The ability to incorporate new memories is severely impaired. Most patients with Wernicke's encephalopathy have an associated polyneuropathy at the time of presentation. Hypothalamic involvement occasionally leads to hypothermia or hypotension. Coma may occur. The diagnosis of Wernicke's encephalopathy is established by the clinical findings and the response to thiamine74,75 (discussed later). However, acute, reversible MRI abnormalities have and may be helpful for diagnosing mild cases or those with atypical also been described clinical features. In patients who present with ophthalmoplegia, ataxia, and confusion, the differential diagnosis includes sedative drug intoxication and structural lesions in the posterior fossa.

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Wernicke's encephalopathy is, at least in theory, a preventable disorder. One widely 76 discussed approach is the fortification of alcoholic beverages with thiamine. Although thiamine hydrochloride is stable in alcoholic beverages, it is poorly absorbed by alcoholic patients; thiamine propyldisulfide, which is well absorbed, is unstable. Thus, new analogues combining the desirable properties of these two compounds will have to be developed before this approach is technically feasible. Prevention of iatrogenically induced Wernicke's encephalopathy is more easily achievable. Iatrogenic conditions associated with Wernicke's 77 78 79 kidney dialysis, and the administration disease include persistent vomiting, malnutrition, 80 of large amounts of oral hypoglycemic agents. Such patients at risk for nutritional deficiency should receive thiamine regardless of whether clinical signs of Wernicke's encephalopathy are present. Treatment of Wernicke's encephalopathy is by repletion of thiamine. Patients should be hospitalized and receive 100 mg of thiamine intravenously daily for several days. Outpatient therapy with 50 mg of oral thiamine per day should follow, although in alcoholic patients absorption of the vitamin is likely to be impaired. The prognosis of Wernicke's encephalopathy depends on the prompt institution of appropriate treatment. The overall mortality rate is high, with figures in the range of 10 to 20 percent commonly cited. After the institution of treatment, ocular and gaze palsies begin to improve within hours to days, and nystagmus, gait ataxia, and confusion within days to weeks. Long-term sequelae include residual nystagmus or gait ataxia (alcoholic cerebellar degeneration; see later) in approximately 60 percent of patients and a chronic memory disorder (Korsakoff's amnestic syndrome; see next section) in more than 80 percent. KORSAKOFF'S AMNESTIC SYNDROME Korsakoff's syndrome is a selective disorder of memory (amnestic syndrome) that typically arises in chronic alcoholics in the wake of one or more episodes of Wernicke's encephalopathy. The63distribution of histopathological lesions is identical to that seen in acute considerable progress has been made toward understanding Wernicke's disease. Although81–83 it is not known how a disorder of memory is produced in the biological basis of memory, Korsakoff's syndrome. Some authors have proposed that memory impairment in Korsakoff's syndrome is due to selective damage to ascending noradrenergic pathways by brainstem and 84 diencephalic lesions, whereas others have postulated that an increase in NMDA receptor function permits excitotoxicity leading to thalamic and hypothalamic lesions and memory 85 impairment. A causal relationship between (acute) Wernicke's encephalopathy due to thiamine deficiency and (chron-ic) Korsakoff's syndrome is generally assumed. However, this issue is not 86 resolved. For example, Korsakoff's syndrome was rarely a consequence of Wernicke's disease in malnourished prisoners of war in the Pacific theater during World War II. A review of cases of nonalcoholic Wernicke's encephalopathy found that patients who developed subsequent amnestic syndromes showed a substantial improvement in memory over time 86 compared with alcoholics with Wernicke's encephalopathy. This may be because the duration of malnutrition is briefer in nonalcoholics than is usually the case in chronic alcoholics or because alcohol itself contributes to development of the syndrome. The latter is supported by the finding that alcoholics who develop Wernicke's encephalopathy after a period of vomiting perform better on tests of memory than those without vomiting, possibly 87 because emesis helps to clear alcohol from the body. The disability afflicting patients with Korsakoff's syndrome is one of the most striking in clinical neurology. There is both impaired retrieval of previously established, especially recent, memories (retrograde amnesia) and inability to incorporate new memories (anterograde amnesia). Immediate recall, tested by having patients immediately repeat what is said to them, is intact. Patients are typically disoriented to time and place. Hospitalized patients are characteristically unaware of their room numbers or hospital floor, how long they have been in the hospital, what they had for their last meal, or who visited them. At the same time, very distant memories may be preserved in detail. Some patients appear to be stuck in time, insisting that the year is one from decades past. Patients with Korsakoff's syndrome appear to be unaware of their deficit and commonly attempt to reassure the examiner that nothing is seriously wrong. Confabulation, the invention of material to fill in gaps in memory, is often but not invariably seen. Other aspects of cognitive function may exhibit subtle 63 impairment, but alertness and language are intact. Patients with Korsakoff's syndrome may show evidence of other alcohol-related neurological disorders. Nystagmus and gait ataxia related to past bouts of Wernicke's disease are common, as are signs of a peripheral neuropathy.

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Korsakoff's amnestic syndrome is a clinical diagnosis. This relatively selective memory disorder must be distinguished from the more global cognitive impairment that occurs in dementia due to a variety of causes. The differential diagnosis of a chronic amnestic syndrome resembling Korsakoff's syndrome includes pancerebral hypoxia or ischemia, bilateral posterior cerebral artery strokes, herpes simplex virus encephalitis, paraneoplastic limbic encephalitis, and brain tumors in the vicinity of the third ventricle. Although acute Wernicke's disease should always be treated with thiamine, the effectiveness of thiamine88in preventing the subsequent development of the chronic amnestic syndrome is uncertain. Similarly, thiamine has not been shown to be effective for the treatment of established Korsakoff's syndrome, although patients with this disorder may improve 86 spontaneously. ALCOHOLIC CEREBELLAR DEGENERATION In some alcoholic patients, a chronic cerebellar syndrome develops that, like Korsakoff's63 amnestic syndrome, may represent a long-term sequela of Wernicke's encephalopathy. In common with Wernicke's and Korsakoff's syndromes, alcoholic cerebellar degeneration is 89 usually attributed to nutritional deficiency and specifically to depletion of thiamine. However, it has also been suggested that the disorder may result from a direct toxic effect of alcohol on 90 the cerebellum or from electrolyte abnormalities associated with alcoholism. The neuropathological basis of alcoholic cerebellar degeneration consists of loss of cerebellar cortical neurons, especially Purkinje cells, with particular predilection for the anterior and superior vermis; the anterior and superior cerebellar hemispheres are affected 89 pathological process is strikingly similar to that less often. The distribution of this cerebellar 63 seen in Wernicke's encephalopathy, providing an important clue that the two disorders may be pathophysiologically linked. The natural history of alcoholic cerebellar degeneration is variable. The syndrome usually occurs in the setting of chronic alcoholism of 10 years' or more duration. The most frequent mode of onset is with cerebellar ataxia that progresses steadily for weeks to months. A more gradually progressive disorder that evolves over years is also common. Less often, a mild and stable deficit that has been present for years may become suddenly worse. Although gait ataxia is the most prominent manifestation of both alcoholic cerebellar 63 degeneration and Wernicke's encephalopathy, the pattern of involvement in the two disorders may otherwise differ. Limb ataxia, which is absent in most patients with Wernicke's syndrome, is usually detectable in alcoholic cerebellar degeneration. Examination of such patients typically discloses severe involvement of the legs, with milder involvement of the arms. Dysarthria, which is usually mild, is also more frequent in alcoholic cerebellar degeneration. In contrast, nystagmus is present far less often than in Wernicke's encephalopathy. Uncommon manifestations of alcoholic cerebellar degeneration include hypotonia, ocular dysmetria, and postural tremor. Patients with alcoholic cerebellar degeneration may also exhibit signs of a polyneuropathy (see later). Alcoholic cerebellar ataxia is a clinical diagnosis. The CT scan or MRI may show cerebellar cortical atrophy, but laboratory findings usually are helpful only for excluding other causes of ataxia. Conditions that must be considered in the differential diagnosis of subacute or chronic cerebellar ataxia in middle life include multiple sclerosis, hypothyroidism, paraneoplastic cerebellar degeneration, idiopathic cerebellar or olivo-pontocerebellar atrophies, Creutzfeldt–Jakob disease, and posterior fossa tumors. Like alcoholic cerebellar degeneration, many of these disorders can produce ataxia preferentially affecting the gait. Ataxia due to alcoholic cerebellar degeneration often stabilizes or improves with cessation of 91 drinking and improved nutritional status, although the relative importance of these two factors is uncertain. Patients with this condition should receive parenteral thiamine. CENTRAL PONTINE MYELINOLYSIS Central pontine myelinolysis is manifested by rapidly evolving paraparesis or quadriparesis, pseudobulbar palsy, and impaired consciousness. Certain aspects of the disorder92are discussed in Chapter 19. It was first described by Adams and associates in 1959, although a German-language report of pontine demyelination in a patient with Wilson's disease 27 93 years earlier has recently been 93 confirmed. A history of alcoholism is common and found in of 39 percent of affected patients. Recent liver transplantation accounts for 17 percent 93 cases and as many as 7 percent of patients with burns may develop the disorder. Less

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often it develops after prolonged use of diuretics, psychogenic polydipsia, pituitary surgery, or 94 urological surgery. Central pontine myelinolysis is mainly an iatrogenic disorder, and its appearance coincided with the widespread use of intravenous therapy for correction of fluid and electrolyte 93,94 Hyponatremia frequently precedes central pontine myelinolysis, and disorders. 93–95 Norenberg aggressive correction of hyponatremia appears to be the precipitating factor. and colleagues retrospectively studied the records of 12 patients with autopsy-proven central pontine myelinolysis and provided the most convincing evidence for a link between 96 hyponatremia and the disorder. All of these patients had been hyponatremic, and their serum sodium levels had been raised by more than 20 mEq/L over 1 to 3 days. Eleven patients became hypernatremic (serum sodium level >147 mEq/L) during treatment. Signs of central pontine myelinolysis developed 3 to 10 days after correction of the serum sodium. In a control group of nine hyponatremic patients without pontine myelinolysis at autopsy, the serum sodium level had increased more slowly or to lower maximal levels. A causal relationship between rapid correction of hyponatremia and central99pontine myelinolysis was 97 98 established in the 1980s by studies in rats, rabbits, and dogs. Well-documented rapid correction of hyponatremia has now been identified in approximately 22 percent of human 93 of central pontine myelin-olysis in cases. However, the existence of well-documented cases93,100,101 indicates that rapid patients with hypernatremia or normal serum sodium levels correction of hyponatremia is not the only cause of this neurological disorder in humans. The characteristic pathological lesion in central93pontine myelinolysis is bilaterally symmetric, focal destruction of myelin in the ventral pons. Gocht and Colmant reviewed 58 cases and found that in approximately 50 percent characteristic lesions were present outside the basis 102 pontis, and in half of these cases extrapontine lesions were found without pontine lesions. Extrapontine myelinolysis has been observed in the cerebellum, thalamus (especially the lateral geniculate body), external and extreme capsules, basal ganglia, deep layers of cerebral cortex and adjacent white matter, and rarely in the fornix, anterior commissure, 93 subthalamic nucleus, amygdala, optic tract, and spinal cord. Histologically, there is severe loss of myelin, and oligodendroglia are reduced in number. Neurons and axons are relatively spared, although axonal swelling and neuronal shrinkage may occur, particularly in the center of lesions. There is no inflammation, and blood vessels appear normal. Coexistent illnesses often influence the clinical manifestations of central pontine myelinolysis, making it difficult to diagnose this disorder. Furthermore, small lesions detected postmortem 93 can be asymptomatic, and the disorder is therefore often not recognized before death. 95 Nevertheless, certain clinical features are typical of reported cases. Central pontine myelinolysis often evolves over several days to weeks in a severely ill patient, and mental confusion is a prominent feature in almost all cases. Demyelination of pontine corticobulbar fibers leads to early dysarthria or mutism. Spastic quadriparesis and pseudobulbar palsy are common, occurring in more than 90 percent of symptomatic cases. If lesions extend into the midbrain, medulla, or pontine tegmentum, there may be papillary and oculomotor signs, depressed consciousness or coma, and dysfunction of cranial nerves. Progressive demyelination of corticospinal and corticobulbar tracts in the basis pontis may produce a locked-in syndrome. Extrapontine lesions can cause ataxia, parkinsonism, choreoathetosis, 94,95 Cognitive and behavioral symptoms have also been reported and include and dystonia. restlessness,93emotional lability, apathy, agitation, insomnia, paranoia, delusions, rage, and disinhibition. 103

The CSF is normal in up to 72 percent of patients. Elevated CSF pressure, increased protein concentration, and mononuclear pleocytosis occur in a few. Immunoglobulins are 104 CT brain scans may be normal or may normal, but myelin basic protein may be elevated. 105–107 105 and extrapontine lucencies. Clinical recovery can show nonenhancing pontine 107 precede resolution of CT findings by as much as 18 months. MRI scans may be normal during the first 2 weeks of illness, but eventually affected regions appear hyperintense on T2-weighted images and hypointense on corresponding T1-weighted images, and usually do 95 visualization not enhance with gadolinium. Because MRI is more sensitive and allows better 94 of the brainstem, it is preferable to CT for imaging central pontine myelinolysis. Although the disorder had historically been considered to carry a93poor prognosis, recent addition, several autopsy series have shown that many cases are asymptomatic. In104,107,108 Menger and Jorg symptomatic patients have shown improvement after 1 to 4 weeks. found in a group of 44 patients that 32 survived and 11 recovered completely, and outcome did not correlate with the severity108 of neurological deficits during the acute phase of illness or with the degree of hyponatremia. Therefore, all patients with suspected central pontine myelinolysis should be supported aggressively because substantial improvement may occur after several weeks.

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Over the past 20 years there has developed a consensus on the treatment of hyponatremia to minimize the risk of myelinolysis. Severe hyponatremia (500 mg/dl and increasing); and intracerebral tuberculoma when edema is out of proportion to the mass effect and there are any clinical signs. It is recommended that either dexamethasone or prednisone is administered according to the following dose schedules. For dexamethasone, the dose is 8 mg daily for children weighing less than 25 kg, 12 mg/day for adults and children weighing more than 25 kg, given for 3 weeks and then tapered off gradually over the following 3 to 4 weeks. For prednisone, the dose is 2 to 4 mg/kg daily for children and 60 mg/day for adults, given for 3 weeks and then tapered gradually over the following 3 to 4 weeks. The decision to use corticosteroids should rest on a strong presumptive or positive diagnosis. Caution is advisable in the face of diagnostic uncertainty, especially in cases in which fungal CNS infection is considered a strong possibility The expected benefit from corticosteroids must be weighed carefully against the potential for adverse consequences, bearing in mind that initial improvement in clinical signs may be nonspecific. In select cases, the addition of systemic antifungal therapy is advisable until a specific etiological diagnosis is reached. Surgery Hydrocephalus is a common complication of tuberculous meningitis, with the propensity for sustained increased intracranial pressure leading to permanent neurological damage. The combination of corticosteroid therapy and serial lumbar puncture and diuretics may suffice 73 while awaiting the early response to chemotherapy, as assessed by serial imaging studies. However, surgical decompression of the ventricular system should not be delayed in the very ill and in those74,75 with progressive neurological impairment in spite of conservative management.

Paradoxical Worsening on Therapy In a widely quoted article, Teoh and co-workers reported 10 patients and collected 12 more from the literature in whom symptomatic new tuberculomas developed, with neurological 48 deterioration, during the course of effective drug therapy for tuberculous meningitis. The latent period between the initiation of treatment and onset of neurological deterioration ranged from 2 weeks to 18 months. Watson and associates reported 5 more cases76of paradoxical tuberculoma development in a series of 22 cases of CNS tuberculosis.

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Aminoff: Neurology and General Medicine: Tuberculosis of the Centra...


Although several of the patients reported had initially been treated with corticosteroids, it is not possible from the details to determine whether these complications had developed on the full dose or after discontinuation of corticosteroid therapy. Most patients improved with continued conservative management including reinstitution or increase in the dose of corticosteroid therapy.

Prognosis and Outcome The clinical outcome in any individual case is greatly influenced by age, duration of illness, clinical stage at the initiation of therapy, and the extent and character of optochiasmic arachnoiditis and vascular complications. The influence of the stage of disease on outcome is illustrated in Table 42-3. In general, when specific antituberculous treatment is started before patients progress 17 beyond stage 1 or early stage 2 disease, cure rates of 85 to 90 percent may be achieved. Age younger than 5 years and older than 50 years is associated with a poor prognosis. The observed mortality rate exceeds 50 percent in patients older than 50 16,77 The incidence of residual neurological deficits years and in those with stupor and coma after recovery from tuberculous meningitis varies from 10 to 30 percent in recent series. Late sequelae include cranial nerve deficits, gait disturbance, hemiplegia, blindness, deafness, learning disability, dementia, and various syndromes of hypothalamic or pituitary 17,78 dysfunction. Click here to view this table.... CONCLUDING COMMENT Tuberculosis of the CNS is uncommon in the West, potentially devastating, but an eminently treatable disorder. Current drugs are highly effective when therapy is initiated early, before the onset of altered mentation or focal neurological deficits. Prompt recognition and consideration of empirical therapy are therefore of paramount importance. Patients with subacute meningitis syndrome and CSF findings of low glucose concentration, elevated protein, and mononuclear pleocytosis should be treated immediately if there is evidence of tuberculosis elsewhere in the body or if prompt evaluation fails to establish an alternative diagnosis. Serial examination of the CSF is the best diagnostic approach; smear and culture for acid-fast bacilli yield positive results for days after antituberculous drugs have been administered. In a patient with compatible clinical features, CT or MRI evidence of basilar meningeal enhancement combined with any degree of hydrocephalus is strongly suggestive of tuberculous meningitis. Serial CT or MRI is useful for following the course of hydrocephalus and tuberculoma, particularly in reference to the need for, and response to, adjunctive therapy with corticosteroids and surgery. The recommended chemotherapy regimen for known or presumed drug-sensitive infection is isoniazid and rifampin in all patients, together with pyrazinamide and ethambutol for the first 2 months. Adjunctive corticosteroid therapy is effective in managing a variety of complications and reduces mortality in patients with stage 2 and 3 disease. Surgical shunting should be considered early in the patient with hydrocephalus and symptoms of increased intracranial pressure. Tuberculomas are best treated medically.

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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 43 Neurological Complications of Leprosy THOMAS D. SABIN • THOMAS R. SWIFT •

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GENERAL MANIFESTATIONS NEUROPATHOLOGY LEPROUS NEURITIS LEPROMATOUS LEPROSY TUBERCULOID LEPROSY BORDERLINE LEPROSY TREATMENT

The acid-fast organism Mycobacterium leprae, the cause of leprosy, was the first pathogen conclusively linked to a human disease, a discovery made by Dr. G. Armauer Hansen in 1 “reductive 1874. The genome of the organism was recently elucidated and showed dramatic 2 evolution” with loss of the metabolic machinery that other mycobacteria retain. The organism must live within human cells. Single nucleotide polymorphisms indicate that leprosy originated in East Africa3 and passed on to Europe and Asia before explorers brought the disease to West Africa. The genome has also been found in ancient remains of the Near East from biblical times. The number of active cases in the world has recently fallen dramatically from 10 to 20 million in 1970 to 286,063 in 2005 because 4patients are now rapidly classified as “cured” with brief courses of multidrug therapy (MDT). The long-term validity of this optimistic trend, however, relies on the assumption that the relapse rate will be very low. No corresponding drop in incidence has yet occurred, but the hope of the World Health Organization program is to 5 eliminate leprosy by effecting a critical decrease in infectious bacteria within the population. The leprosy bacillus is unique in two important ways. First, it is the only bacterial pathogen that regularly invades peripheral nerves. Recent studies have provided details regarding the molecular biology underlying this neurotropism of M. leprae, which is unique among bacteria. An α-dystroglycan in the G domain of the α2 chain of laminin in the basal lamina of the 6 Schwann cell–axon unit is a specific binding target for M. leprae. After entering the Schwann cell, the organism commandeers the kinase kinase 7MEK kinase cascade, causing proliferation of more potential victim Schwann cells. Macrophages are the other major target cell. Second, M. leprae multiplies at temperatures that are 7° to 10°C lower than the core body

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temperature of 37°C. These two factors account for several important clinical features of the disease. All patients with leprosy have some degree of nerve involvement, making leprous neuritis a significant cause of treatable neuropathy in the world. Visible deformities from involvement of facial structures, eyes, nerves, bones, and skin result in stigmatization and 9 social ostracism. The diagnosis of leprosy is often missed by physicians, leading to a delay in treatment during which progressive neuropathy, visual loss, and deformity may occur. GENERAL MANIFESTATIONS Leprosy may be spread by aerosol or rarely 5by skin-to-skin contact; fortunately, more than 95 percent of individuals are naturally immune. Animal reservoirs have10been found in chimpanzee, sooty mangaby, cynomolgus macaque, and armadillo. In susceptible patients, the organisms rapidly gain access to cooler dermal tissues, primarily cutaneous and subcutaneous nerves and nerve networks, skin appendages, sweat glands, and erector pili 11 muscles. Leprosy occurs in three major forms: tuberculoid, borderline, and lepromatous. The type of leprosy that develops depends on the degree of host resistance rather than on the bacterium. these do not play a role in There are some intraspecific genetic variations in M. leprae, but 12 the severity of the disease, which is the same for all three types. In patients with high resistance, the leprosy that develops is called tuberculoid (or TT) or paucibacillary. A single patch of skin is involved by a granulomatous infiltrate, often with enlargement of underlying nerve trunks, but systemic dissemination does not occur, bacterial organisms are few, and self-healing is the rule. The skin lesions have raised edges and may have one or more satellite lesions (Fig. 43-1). Within these lesions, nerves are destroyed in an epithelioid granulomatous reaction. Often, a superimposed inflammatory response, known as a reversal reaction, occurs within the lesion either spontaneously or in response to drug treatment. Such a reaction reflects altered immunological responsiveness by the host to the organism and often results in bacteriological clearing of the lesions.

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FIGURE 43-1 Tuberculoid (TT) leprosy. There is complete anesthesia within

this lesion, which has a raised erythematous border and a pale, dry center. (Courtesy of Gillis W. Long Hansen's Disease Center, Carville, Louisiana.) In contrast, patients with multibacillary leprosy (called lepromatous or LL) have little or no resistance, and bacilli are disseminated throughout the body through a continuous 13 bacteremia, multiplying to extremely high numbers. There is little histological evidence of host resistance; histiocytes are literally packed with huge numbers of organisms that proliferate in cool areas of the body: the skin, upper respiratory tract, anterior one third of the 14 eye, superficial nerves, testes, and other tissues. Beading of corneal nerves may be seen. While bacilli may be deposited passively in the deeper, and therefore warmer, vital organs, such as the lungs, heart, liver, kidneys, and brain, there is little evidence of bacterial proliferation or pathological tissue reaction at those sites. Clinically, patients present with skin infiltration, particularly prominent in the cool areas, such as facial promontories, ears, dorsal forearms, legs, nasal mucosa, and scrotum (Fig. 43-2). Biopsy sample examination and skin scrapings of such tissues reveal innumerable acid-fast organisms. Without treatment, lepromatous leprosy continues to progress, eventually leading to severe deformities in most cases. At times spontaneously, but more often in response to antibacterial treatment, a reaction known as erythema nodosum leprosum occurs. Clinically, this is a very severe form of erythema nodosum and is a result of the deposition of antigen-antibody complexes in the walls of small arteries. Erythema nodosum leprosum occurs in areas where large amounts of mycobacterial antigen are present. The resulting inflammatory lesions can be devastating to the cornea and anterior eye, peripheral nerves, testes, and skin, producing multiple painful erythematous nodules (Fig. 43-3), leading to frank ulceration in some cases. During the course of erythema nodosum leprosum, iritis, neuritis, and orchitis occur and may be more damaging than the underlying leprosy itself. Erythema nodosum leprosum is a complex immunological reaction occurring with the production of cytokines such as tumor necrosis

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15–17

factor α (TNF-α). It is ironic that the circulating antibodies to mycobacterial antigen, constituting the host's only immunological responsiveness to the offending organism, appear not to benefit the host, but paradoxically to result in additional tissue damage.

FIGURE 43-2 Lepromatous (LL) leprosy. There is infiltration of the cooler facial

promontories, such as the ears, upper lip, chin, and supraorbital and malar areas. (Courtesy of Gillis W. Long Hansen's Disease Center, Carville, Louisiana.)

FIGURE 43-3 Erythema nodosum leprosum. Painful subcutaneous nodules

cover the face and trunk (not shown) and the extremities. (Courtesy of Gillis W. Long Hansen's Disease Center, Carville, Louisiana.) In the third type of leprosy, called borderline leprosy (or BB), a variable spectrum of disease occurs, depending on the degree of host resistance. In patients having low resistance, the disease resembles lepromatous disease (BL), whereas in those with higher resistance it resembles tuberculoid disease (BT). Patients with borderline leprosy have less skin involvement than those with lepromatous disease and may have more circumscribed skin

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lesions, but they have more skin lesions than patients with tuberculoid disease (Fig. 43-4). A 18,19 Increasingly in leprosy form of “pure neuritic” leprosy occurs without visible skin lesions. work, the terms paucibacillary and multibacillary are used in an attempt to simplify disease classifications and treatment decisions.

FIGURE 43-4 Borderline (BB) leprosy. The widespread symmetric skin lesions

are hypesthetic. (Courtesy of Gillis W. Long Hansen's Disease Center, Carville, Louisiana.) In the spectrum of borderline leprosy, immunity may change, with patients worsening, their disease becoming more like lepromatous (BL) disease (downgrading reaction), or evolving more toward the tuberculoid (BT) form (reversal reaction). Such shifts in the spectrum of disease may occur spontaneously or in response to drug treatment or intercurrent medical conditions, such as underlying neoplasms or secondary infections. Considering the extent of infection with human immunodeficiency virus (HIV) in leprosy-endemic areas, it is fortunate that no increase in leprosy has been associated with acquired immunodeficiency syndrome (AIDS), which may, however, precipitate reversal or downgrading reactions in leprosy 20 patients. NEUROPATHOLOGY In tuberculoid leprosy, the few organisms present in peripheral nerves evoke a strong granulomatous response with early and severe nerve damage, fortunately limited to the few nerves involved. In lepromatous leprosy, the overwhelming majority of organisms are present neuropathological and electrophysiological data show in Schwann cells (Fig. 43-5), but 21 substantial axonal destruction,22 and some of the demyelinating lesions themselves may be secondary to axonal changes. The complex immunological parasite–host interactions are

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gradually emerging as the basis for nerve damage.


11,12

FIGURE 43-5 Sural nerve biopsy, lepromatous leprosy (LL). Acid-fast stain

reveals numerous organisms in endoneurial vacuoles. (Courtesy of Gillis W. Long Hansen's Disease Center, Carville, Louisiana.) In addition to the damage to nerves caused by the invasion of M. leprae, there are several types of leprosy reactions in which there is a sudden and often sustained increase in immune response to bacilli or products released by dead bacilli. Erythema nodosum leprosum occurs only in multibacillary leprosy and appears to be a clinical example of the Arthus phenomenon, 23 with consumption of complement and an intense vasculitis. The vasculitis is most severe in the regions of greatest bacterial density and therefore may result in a devastating acute 24 neuritis. There is a high amount of TNF-α in the blood with debilitating systemic symptoms. Although the nerve lesions of leprosy tend to be permanent, prompt treatment of reactions 21,25 It is also unclear to what extent or by what may improve neurological deficits. mechanisms erythema nodosum leprosum produces nerve damage, but it is likely that cytokines released by immunocompetent cells are important. Exogenous interferon-gamma (IFN-γ) used in an attempt to treat leprosy has caused erythema nodosum leprosum in 15,17 patients, who then have increased release of15,16 TNF. Thalidomide, which controls erythema Thalidomide also reduces elevated numbers nodosum leprosum, reduces TNF secretion. + 26 of CD4 lymphocytes in the blood of patients with erythema nodosum leprosum. During erythema nodosum leprosum, 26 there is a loss of suppressor cell function and an increase in leprosum and interleukin-2 (IL-2) production. Cyclosporine suppresses erythema nodosum 27,28 A recent report restores suppressor cell activity, possibly by its effect on macrophages. describes the effectiveness of infliximab, a monoclonal antibody that inhibits the production of TNF-α, in suppressing erythema nodosum leprosum in a single patient in whom corticosteroid and thalidomide therapy had failed. Presumably it would be effective in reactive 29 states in other varieties of leprosy in which TNF production is increased. In the higher-resistance tuberculoid and border-line cases, reactions are related to increase in tissue-mediated immune factors. There is infiltration of the lesions with IFN-γ and CD4 lymphocytes producing TNF-α, which causes local30redness, swelling, and rapid loss of function in any nerve coursing through the lesion. LEPROUS NEURITIS A meticulous neurological examination yields definitive diagnostic information of this treatable neuropathy. The diagnosis is based on the recognition of two interplaying themes that, although they produce limitless combinations in individual cases, capture the unique nature of this neuropathy once they are discerned. Both of these themes rest on the fact that M. leprae is the only bacterium that consistently invades peripheral nerves. The first of the two diagnostic themes is based on another biological feature of M. leprae: it 8,31,32 has a highly thermosensitive growth rate that is optimal at 27° to 30°C. The organism does not reproduce at all at core body temperature. This feature limits leprosy to involvement of only superficial nerves. The distinction between the “superficial” neuropathy of leprosy and a distal polyneuropathy is vital for correct diagnosis. This has been a source of confusion

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because long nerves tend to innervate cooler parts of the body. In leprosy, nerve damage is limited to intracutaneous nerve endings and networks and to the named nerves of gross anatomy at certain segments along their length where they course closest to the cooler 33 surface of the body. Since M. leprae cannot proliferate at core body temperature, peripheral nerves that are situated in deep tissues under or close to muscles, nerve roots, and the central nervous system (CNS) are not actively involved. The second diagnostic theme relates to host factors that determine the immune resistance to the invasion and proliferation of bacilli. This host resistance has resulted in the classification of leprosy into the three subtypes mentioned earlier and is the other major determinant of the clinical features including nerve damage. LEPROMATOUS LEPROSY There is very little evidence of tissue-mediated immune responses to M. leprae in lepromatous leprosy, and lepromin skin testing is negative. The organism proliferates most rapidly in the coolest tissues, and there is a constant blood-stream dissemination of 13 organisms. In untreated cases, this type of leprosy becomes widespread and symmetric within superficial tissues and may involve large areas of the skin, the anterior chamber of the eye, the upper respiratory tract, and the testes, as well as superficial nerves. Sensory loss is largely due to destruction of intracutaneous nerve endings and first appears in cool areas, such as the dorsal surfaces of the hands, dorsomedial surfaces of the forearms, dorsal surfaces of the feet, and ventrolateral aspects of the legs, as well as in the pinnae of the ears, 34,35 (Fig. 43-6). The tip of the nose, malar areas, and especially the helices and earlobes buttocks are often the next to show intracutaneous sensory loss (Fig. 43-7). There is a stage with sparing of the soles of the feet and palms of the hands, which may be due in part to the insulating effect of the thickened corium in these areas. If the patient is examined at the right stage, a distinct change in sensation at the cuticular border can sometimes be found in the hands or feet. When the intracutaneous pattern has evolved to this point, nerve trunk deficits supervene. Involvement of a 10- to 15-cm segment of the ulnar nerve proximal to the olecranon groove is most common, but the segment just proximal to the wrist may also be affected. Further paralysis is seen with damage to (1) the median nerve in the segment where it assumes a superficial position just proximal to the transverse carpal ligament (Fig. 43-8), (2) the peroneal nerve where it courses around the fibular head, (3) the branch of the peroneal nerve to the extensor digitorum brevis, and (4) the posterior tibial nerve at the level 33 of the ankle. There is also a unique patchy paralysis of the most superficial facial nerve twigs, causing lagophthalmos and paralysis of some segments of the orbicularis oris and of 36 the medial aspects of the corrugators of the forehead.

FIGURE 43-6 Lepromatous leprosy (LL). Sensation is diminished in cool zones

of the face, trunk, and extremities.

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FIGURE 43-7 Lepromatous leprosy (LL). Sensation is preserved in warm areas:

axillae, palms, antecubital fossae, inguinal region, gluteal cleft, and center of back and chest.

FIGURE 43-8 Lepromatous leprosy (LL). Enlargement of the median nerve

proximal to the carpal tunnel is shown. (Courtesy of Dr. Paul Brand and Gillis W. Long Hansen's Disease Center, Carville, Louisiana.) With progression of the intracutaneous sensory loss, this pattern is more easily recognized by the areas of sparing that include the intergluteal fold, the perineum, the anterior neck, under the scalp hair, the posterior creases at the attachment of the ears to the head, the axillae, the sternal area, and the center of the back where skin overlies the “warm” paraspinal muscles and the concavity overlying the spinous processes where cross-radiation of heat occurs. Sparing may be found in the webs of the toes or fingers and the antecubital and popliteal fossae (Fig. 43-9). A careful search may reveal unique features, such as sparing under constantly worn items of clothing (e.g., under a watchband or at a belt line) and even in small 37 cutaneous vascular malformations. A patient with chronic hemiplegia developed 38 lepromatous leprosy with skin lesions limited to the cooler hemiplegic side. Sensory examination of the distal extremities alone may result in confusion with a distal sensory polyneuropathy; therefore, the search must include the ears, nose, and malar areas in order to detect the pattern of temperature-linked sensory loss. This differential diagnosis is also suggested by the preservation of muscle stretch reflexes. Even total destruction of the mixed sensorimotor nerves at the sites outlined earlier would fail to disrupt the arcs for the usually elicited tendon reflexes. Despite the appearance of an extensive sensorimotor neuropathy with clawed toes, footdrop, and clawed hands, preserved tendon reflexes are the rule. Rarely, radial nerve involvement affects the segment that emerges from under the triceps, 4 to 6 cm proximal to the elbow. There are paralysis and atrophy in the wrist and finger extensors, whereas the triceps, brachioradialis, and anconeus muscles tend to be spared. The differential diagnosis of leprous neuritis is summarized in Table 43-1. Click here to view this table....

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FIGURE 43-9 Lepromatous leprosy (LL). There is sensory sparing of the scalp,

in the axillae and the groin, in the center of the back and the chest, and in the antecubital fossae. A variety of cutaneous lesions are associated with lepromatous leprosy, and they are most abundant and prominent in the areas where bacilli are most common in the cooler tissues. There is no precise linkage between those skin lesions and the intracutaneous sensory loss. Because the tissue immune response to the bacilli in lepromatous leprosy is very indolent, the neuropathy evolves over many years. Nerves that are grossly enlarged and infiltrated with abundant bacilli may still function well. These enlarged nerves are more liable to recurrent trauma, and measures must occasionally be taken to prevent the addition of mechanical damage to these already vulnerable nerves. TUBERCULOID LEPROSY At the other end of the spectrum of host response to infection with M. leprae is tuberculoid leprosy. There is a vigorous tissue-mediated immune response to the invasion of bacilli that 5 greatly limits the spread and proliferation of M. leprae. Only rare organisms are found in the resulting epithelioid granuloma, and nerve damage occurs as the lesion develops. The 39 lesions contain abundant activated CD4 T cells that produce IFN-γ. This means that the neurological picture is generally one of a clearly demarcated patch of sensory loss and absent sweating corresponding with a visible skin lesion that is usually hypopigmented, with an elevated border (Fig. 43-1). Bacteria have often been cleared from the center of these lesions but are still detectable in biopsy samples at the perimeter. Results of lepromin skin testing are positive in this form of the disease. Temperature has only a “permissive” role, in the sense that the lesions must occur in a region where the bacilli can reproduce; tissue temperature does not otherwise determine the precise nature of the neuropathy, as it does in lepromatous disease. Local bacillary invasion of nerves and the immediate immune tissue response are the two factors that result in focal, limited, and asymmetric disease. There is a tendency for self-healing in this type of leprosy. A named mixed, motor, or sensory nerve near a solitary tuberculoid patch may also be affected. These observations have suggested that M. leprae can travel from the intracutaneous endings back to the major nerve supplying the area of anesthetic skin. The major mixed nerves that are most commonly affected are the ulnar, median, peroneal, and facial. Subcutaneous sensory nerves near the tuberculoid patch are most likely to be enlarged, but one should also palpate for enlargement of distant nerves, such as the superficial cutaneous radial, digital, sural, and posterior auricular nerves. The tissue response within nerves may be so intense that there is necrosis and formation40of a “cold” abscess. Intense local pain results, requiring surgical drainage of the abscess. Calcification resulting in radiographically detectable linear streaks within nerves may also41 occur, and enlarged nerves may be demonstrable on computed tomography (CT) scans. Anhidrosis is always present within tuberculoid lesions; injections or iontophoresis of

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cholinergic agents into the area may be helpful in establishing the diagnosis. BORDERLINE LEPROSY

Many patients have clinical and pathological features that fall between polar tuberculoid and 5 lepromatous leprosy, and their conditions are thus classified as borderline leprosy. Such patients demonstrate unending permutations in the roles of tissue temperatures and host resistance in the pathogenesis of their nerve dysfunction. The immunological reactivity in these patents is unstable, and a drift toward one of the polar patterns occurs over time. The neurologist experienced in leprosy can place patients along a spectrum paralleling a pathological classification by the pattern of cutaneous sensory loss. Cases of pure neural leprosy with no skin lesions are usually of the borderline type; they are revealed by a good neurological examination and can be confirmed with nerve biopsy or polymerase chain 30 reaction (PCR) testing. Patients with borderline features that are nearer to tuberculoid disease have several skin lesions that tend to be larger and less distinctly demarcated than those in the pure tuberculoid cases. As one moves away from the tuberculoid end of the spectrum, there is less overlap of the sensory deficit with the visible skin lesion. In the midrange of borderline leprosy, lesions may be quite large and begin to coalesce with insensitivity covering a large area of the body, but they retain geographical borders that do not closely reflect tissue temperature gradients beyond a general tendency to spare the warmest parts of the body (Fig. 43-10). Sensory maps in such cases may show extensive intracutaneous loss that does not conform to the disruption of named peripheral nerves, nerve roots, or any known neuropathy. Further movement toward lepromatous disease is revealed by symmetry of neural deficits and the loss of linkage between the perimeters of skin lesions and areas of sensory loss. A definite tendency toward temperature-linked patterns of sensory loss emerges, but these are not as perfectly symmetric and graduated as in pure lepromatous disease.

FIGURE 43-10 Borderline leprosy (BB). Sensory loss occurs in the skin lesions.

Skin lesions tend to affect cooler areas. TREATMENT The treatment of leprosy is threefold: (1) drug treatment aimed at the eradication of M. leprae, (2) drug treatment of leprosy reactions, and (3) rehabilitation, cosmetic and restorative procedures, and prevention of further deformity consequent to loss of sensation. The drug treatment of leprosy is changing. Since 1940, sulfones have been the mainstay of treatment, replacing chaulmoogra oil, which had only limited antimycobacterial action. However, with sulfone treatment, many patients developed recurrent disease after periods during which they were apparently free from bacteria. The organisms found at recurrence 43 were shown to be sulfone resistant using the mouse footpad test.

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In addition, sulfones themselves may produce peripheral neuropathy and other idiopathic and 44 dose- related side effects, such as hemolysis and, rarely, agran-ulocytosis. Another useful drug is clofazimine (Lam-prene, B663), a rimino phenazine dye, and this drug may be helpful 5 in suppressing erythema nodosum leprosum. However, it discolors the skin and is therefore unacceptable to many patients, and its hepatotoxicity is a major side effect. In patients with tuberculoid or single skin lesions, current guidelines of the World Health Organization suggest45a single-dose combination of rifamycin 600 mg, ofloxacin 400 mg, and minocycline 100 mg. In paucibacillary intermediate disease, rifamycin 600 mg monthly and dapsone 100 mg daily are both given for 6 months. With low-resistance disease (low-resistance borderline and lepromatous leprosy), triple therapy with dapsone, rifamycin, and clofazimine is advocated. Rifamycin 600 mg monthly, clofazimine 300 mg monthly, 45 clofazimine 50 mg daily, and dapsone 100 mg daily are given for 12 to 14 months. For the most recent treatment recommendations, biopsy interpretation, patient referrals, or suggestions for management, the reader should contact the Gillis W. Long Hansen's Disease Center in Carville, Louisiana. The treatment of leprosy reactions is important because of the threat that such reactions pose to the patient. Leprosy reactions are of three types. Erythema nodosum leprosum is treated with high-dose corticosteroids (prednisone 60 to 80 mg or more daily), particularly if accompanied by neuritis, or with thalidomide 300 to 400 mg daily. Thalidomide is available in the United States at no charge through arrangements with the Gillis W. Long Hansen's Disease Center. (Female patients receiving thalidomide must take absolute precautions to prevent pregnancy because the drug 15,16 induces phocomelia in offspring.) Thalidomide +reduces + the secretion 26 of TNF-α by monocytes and causes a decrease in the ratio of CD4 to CD8 lymphocytes. When erythema nodosum leprosum is controlled, the dose of thalidomide is tapered to 100 mg daily. Long-term thalidomide treatment may also cause or worsen 46,47 A recent report describes the use of infliximab in resistant peripheral neuropathy. 29 erythema nodosum leprosum in a single patient. Reversal reactions, which may be very intense, are treated with high-dose corticosteroids as necessary. Clofazimine in a dose of 200 to 300 mg daily is also of value in treating reactions, in addition to being antibacterial. After the reaction is controlled, the dose can be tapered to 100 mg daily. It is important to note that thalidomide or high doses of corticosteroids are required to treat erythema nodosum leprosum. In tuberculoid and high-resistance borderline leprosy, a reversal reaction consists of a sudden increase in tissue-mediated immunity, with flaring of the skin lesions and acute neuritis. Corticosteroids (but not thalidomide) are effective in these reactions. Rehabilitation of leprosy patients is difficult because the associated stigma makes patients reluctant to come forward for treatment. Many such patients who have cosmetic and crippling deformities involving the face, eyes, eyelids, eyebrows, ears, nose, hands, and feet may benefit from surgical restorative procedures. The attendant peripheral neuropathy, with loss of temperature and pain sensation and of sweating but with preservation of motor function, creates the risk of progressive damage to hands and feet from painless injury followed by ulceration, infection, osteomyelitis, and eventually bone resorption. Such patients must be instructed in the care of the hands, feet, and eyes to prevent secondary disability resulting from the neuropathy, in a manner similar to patients with other neurological conditions in which pain sensation is lost but power is retained, such as syringomyelia, hereditary sensory and autonomic neuropathies, amyloid neuropathy, certain cases of diabetic neuropathy involving small fibers, and other conditions. In fact, patients with these neurological conditions can often be found in leprosariums, where they are mistakenly believed to have leprosy because the mutilating deformities are so similar. Previous

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Aminoff: Neurology and General Medicine: Nervous System Complica...



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Keyword Index

Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 44 Nervous System Complications of Systemic Viral Infections LARRY E. DAVIS •

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VIRAL MENINGITIS Enteroviruses Mumps Virus Herpes Simplex Virus Type 2 Human Immunodeficiency Virus Treatment of Viral Meningitis VIRAL ENCEPHALITIS Diagnosis of Encephalitis Herpes Simplex Encephalitis West Nile Neuroinvasive Disease Treatment of Viral Encephalitis PARALYTIC POLIOMYELITIS Postpolio Syndrome PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY HERPES ZOSTER (SHINGLES) POSTVIRAL ENCEPHALOMYELITIS (ACUTE DISSEMINATED ENCEPHALOMYELITIS) Measles Chickenpox Management of Postviral Encephalomyelitis TRANSVERSE MYELITIS AND MYELOPATHY OPTIC NEURITIS DEAFNESS AND VERTIGO GUILLAIN–BARRÉ SYNDROME CREUTZFELDT–JAKOB DISEASE

Evolution has protected the brain from infections in ways different from those of other organs. One would expect the brain to be an easy target for viral infections because it is an immunoprivileged organ. The brain lacks a lymphatic system, and it has few immunological cells migrating through the brain parenchyma. Normal cerebrospinal fluid (CSF) has fewer than five lymphocytes per cubic millimeter and has only about 0.5 percent of the amount of 1 antibody that is present in serum. As a consequence, many viruses replicate in the central nervous system (CNS) when they are directly inoculated into the brain. The resulting brain infection can be severe, whereas the same viral infection of other organs may be mild. For example, herpes simplex virus (HSV) infection in labial skin causes a localized small blister,

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but infection in brain causes a severe encephalitis. Despite the potential vulnerability of the brain, most systemic viral infections do not cause CNS disease because they do not reach the CNS. To reach the CNS, viruses must overcome several major protective systems. First, viruses entering the body do not have the opportunity to infect nerves directly. To reach the CNS, all viruses must first establish a primary site of replication. Viruses that enter the gastrointestinal tract (e.g., enterovirus) 2 establish a primary site of replication in the oral pharynx and gastrointestinal tract. Viruses that enter via the respiratory system (e.g., mumps3 virus) establish local replication in the upper respiratory tract and regional lymph nodes. Viruses that enter the body via inoculation (e.g., ARthropod BOrne viruses, or arboviruses) establish local replication in vascular 4,5 endothelium and regional lymph nodes. During the primary viral infection, the host's normal defense system comes into play to counteract the local infection. The few viruses that do successfully reach the CNS do so by two major routes: blood and peripheral nerves. Hematogenous spread is the most common. Following primary viral replication, a viremia often develops and this allows secondary tissues to become infected and results in a systemic illness. Despite the viremia, most viruses still do not reach the CNS because of several factors. Virus particles, like other colloidal particles in the blood, are efficiently cleared by the reticuloendothelial system. For example, the reticuloendothelial system can clear more 6 than 90 percent of an arbovirus viremia within 1 hour. Within days, the host humoral immune system–immunoglobulin M (IgM) antibodies against the virus and cellular immune systems (macrophages and lymphocytes) actively participate in clearing the virus from infected tissues and blood. The blood–brain barrier also prevents viruses from entering the CNS. The morphological blood–brain barrier consists of cerebral capillaries that have tight junctions between cells to 7 prevent egress of plasma and white blood cells (WBCs). These tight junctions prevent viral particles from escaping the capillary lumen. In addition, cerebral blood vessels are surrounded by tight astrocytic footplates. The occasional viral infection that does bridge the blood–brain barrier appears to do so by either infecting and replicating within capillary endothelial cells, with release of progeny virions into the brain, or by infecting choroid plexus 2 epithelial cells. Capillaries in the choroid plexus have fenestrations, but the adjacent choroid epithelial cells have tight junctions. Thus, viruses such as mumps appear to reach the CSF by infecting choroid plexus epithelial cells, with subsequent release of progeny virions into the 8 CSF. The efficiency with which these defense systems prevent viruses from infecting the CNS is remarkable. Less than9 1 percent of nonimmune children infected with wild-type poliovirus develop poliomyelitis, and less 4than 1 percent of individuals infected with West Nile virus develop neuroinvasive disease. A few viruses are transported to the CNS via peripheral nerves. With rabies, there is local virus replication in muscle following inoculation from the animal bite. As the muscle infection spreads,10virus eventually reaches synapses at the neuromuscular junction or muscle spindle. After viral attachment to presynaptic membranes, the virus is transported via retrograde axoplasmic flow to the brainstem, spinal cord, or dorsal root ganglion, and from there, it spreads throughout the CNS. There is some evidence that herpes simplex encephalitis (HSE) may be the result of exacerbation of latent virus in the trigeminal ganglion 11 and spread to the brain via branches of the trigeminal nerve. Poliovirus appears to reach the spinal cord both from a viremia and via retrograde axoplasmic flow within the axon of an 12 anterior horn cell following virus entry at the neuromuscular junction. In animals and possibly humans, viral infections of epithelial cells of the upper respiratory system occasionally reach the brain via peripheral infection of olfactory or trigeminal nerves and retrograde axonal advance to the brain. The human immunodeficiency virus (HIV) may reach the brain inside an infected macrophage that passes into the brain. These unusual neural routes circumvent the reticuloendothelial system and blood–brain barrier. When a virus infects the CNS, the cellular immune system and the humoral immune system appear to have important roles in clearance of the virus, depending on the virus. With experimental viral meningitis, the meningeal infection elicits an inflammatory response that 13 14 contains mainly T lymphocytes that are specifically immune mediated. Similarly, with experimental viral encephalitis, the inflammatory response includes specifically 15 immune-mediated lymphocytes. The cellular immune system is critical in eliminating many viruses from the brain. However, for arboviruses, such as West Nile virus, specific antibody 16 appears more important than immune lymphocytes to clear the virus from brain. The brain is not a homogeneous organ, such as the liver. Viral infections directed toward different brain locations or cell types in the CNS result in differing symptoms and signs.

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Viruses that infect leptomeningeal cells 17 cause a meningitis, whereas viruses that infect neurons and glia cause an encephalitis. Even subtypes of neurons (e.g., those of the motor system) can be preferentially infected by viruses, such as poliovirus, giving rise to an illness in which muscle weakness predominates. The time course of spread of the viral infection varies from virus to virus. Some viruses, such as echovirus, give rise to a brief (about 118 week) infection of the leptomeninges and are cleared promptly by the immune system. Other viruses, such as measles (rubeola virus), occasionally cause a chronic infection, 19 subacute sclerosing panencephalitis, that slowly progresses over months to years. Some viruses, such as varicella-zoster virus, can escape immune surveillance20by becoming latent in dorsal root ganglion neurons following the primary chickenpox infection. Decades later, they can reactivate and cause shingles, an acute neuritis involving a dermatome. In summary, most viruses that cause systemic illnesses in humans do not reach the CNS. When they occasionally do so, they cause a variety of diseases with differing symptoms and signs and varying time courses. The focus of this chapter is on the common and important nervous system syndromes that occur with or following systemic viral infections. Table 44-1 lists the major viruses that infect humans and estimates the frequency (per 100,000 systemic viral infections) of a variety of nervous system syndromes that can develop. Click here to view this table.... VIRAL MENINGITIS Viral meningitis, the most common viral infection of the CNS, is due to a viral infection of leptomeningeal cells. Viral meningitis is often discussed together with aseptic meningitis. Aseptic meningitis includes viral meningitis plus transient meningeal inflammation from other causes, such as bacteria that do not grow in routine cultures (Leptospira icterohaemorrhagiae, Treponema pallidum, Mycoplasma pneumoniae), parasites (Toxo-plasma gondii), Rickettsia (human monocytic ehrlichiosis), and parameningeal 17 infections. In addition, a number of drugs, such as trimethoprim-sulfamethoxazole, ibuprofen, carbamazepine, intravenous immunoglobulin, and the murine monoclonal 21 Lyme meningitis from anti-body OKT3, have caused an acute aseptic meningitis syndrome. 22 Borrelia burg-dorferi and meningitis from two Ehrlichia organisms that cause human monocytic ehrlichiosis and human granulocytic ehrlichiosis are becoming increasingly 23,24 It is important to recognize these three infections, common in parts of the United States. as treatment with doxycycline eliminates the infection. However, most cases of aseptic meningitis are due to a variety of viruses (Table 44-2). Click here to view this table.... Each year more than 8,000 cases of aseptic meningitis are35reported to the Centers for incidence of aseptic Disease Control and Prevention (CDC) in Atlanta, Georgia. The annual 36,37 Most cases occur in meningitis has varied from 11 to 27 cases per 100,000 individuals. children and young adults during summer and early fall. The etiology of the viral meningitis varies by geographic region, age of patient, year, and season. For adults in developed countries, a rough distribution is enteroviruses (30%), HSV type 2 (20%), varicella-zoster 38,39 virus (10%), arboviruses (3%), HIV (1%), HSV type 1 (1%) and unknown (35%). 25,26

Regardless of the viral etiology, the symptoms and clinical signs are similar. The illness is characterized by the abrupt onset of fever, headache, nuchal rigidity, and, occasionally, nausea, vomiting, and photophobia (Table 44-3). Patients may experience lethargy and irritability, but obtundation and coma should not occur. The headache is particularly intense and usually is the most dramatic feature. However, in young children and infants and individuals with immunosuppression, it may be less prominent. Click here to view this table.... The peripheral WBC count may be normal or elevated. A lumbar CSF sample may have a normal or mildly elevated opening pressure. The CSF always contains a pleocytosis, usually 3 the ranging from 50 to 2,000 WBCs/mm. On the first day that the patient has symptoms, 38,40 The CSF may contain mainly neutrophils, but lymphocytes rapidly come to predominate. CSF glucose level is usually normal, but mildly depressed levels have occasionally been reported in patients with mumps,17varicella-zoster, HSV type 2, and lymphocytic choriomeningitis (LCM) viruses. If the CSF glucose level is below 25 mg/dl, bacterial or fungal causes should be seriously considered. In patients with viral meningitis, cultures of the CSF should not grow bacteria or fungi, which should also not be seen on Gram's stain of the CSF sediment; bacterial or fungal antigens should not be detected in CSF. The

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electroencephalogram (EEG) is usually normal but occasionally shows mild background slowing. Marked asymmetries or seizure foci should not be seen. Computed tomography (CT) scans and magnetic resonance imaging (MRI) of the brain are typically normal. The clinical diagnosis of aseptic meningitis is thus based on the presence of typical clinical and laboratory features that may occur in association with a mild systemic illness (rashes, parotitis, orchitis, diarrhea, myalgia, herpangina, or pharyngitis). To determine the etiology of the viral meningitis, the specific virus must be identified by virus isolation, polymerase chain reaction (PCR) assay for viral nucleic acid, or serological studies. Samples of CSF obtained 37,41 The virus early, preferably during the first day of illness, often contain a recoverable virus. may also be recovered from other body sites. Enteroviruses and mumps virus can be isolated from throat swabs or stool, HSV type 2 from a genital herpetic lesion, and LCM virus from urine. It is often possible to isolate these viruses from non-CSF sites during the first week of illness. The ability to amplify small amounts of viral nucleic acid from CSF using the PCR technique has revolutionized the diagnosis of viral CNS infections. CSF PCR is rapid, inexpensive, and only minimally invasive. False-positive CSF PCR results are rare when tests are performed according to strict standards in experienced laboratories with rigorous attention to procedures designed to avoid specimen contamination and to verify the specificity of amplification products. The sensitivity of CSF PCR varies with different viruses, and can be dramatically influenced by the timing of specimen collection in relation to onset of illness. 42 43 Nevertheless, PCR assays for enteroviruses and HSV type 2 are considerably more sensitive in detecting these viruses than conventional viral isolation methods. Clinicians are still faced with the daunting task of ordering individual PCR tests for each virus of potential interest. Recently, ‘‘multiplex” CSF PCR assays have been developed that use multiple primers simultaneously in a single reaction mixture to amplify nucleic acid from a group of viruses. Although this is a powerful technique, it is becoming apparent that caution must be used in the interpretation of some results. In one study, more than one virus was 44 detected in CSF in 10 percent of 88 samples. When the nucleic acid of two infectious 45 agents are found, usually only one infectious agent is the cause of the illness. Detection of nucleic acid from multiple infectious agents increases when the patient is immunocompromised. Although all the reasons are still unclear, some dual infections stem from detection of latent lymphotrophic viruses, such as Epstein–Barr virus (EBV), in CSF inflammatory cells or from reactivation of latent viruses in the CNS. In addition, PCR detection of infectious agents is occasionally found in44CSF when the clinical suspicion of a viral infection is deemed low and the CSF is normal. Thus, clinical judgment must be used both in determining when to order diagnostic PCR assays of the CSF and in interpreting the findings. Serological studies of acute and convalescent serum (obtained 3 to 6 weeks after the acute serum sample) may be useful in establishing meningitis due to mumps, arbovirus, HIV, and LCM viruses. Serological studies for diagnosing enterovirus infections are seldom performed because of technical difficulties requiring the use of neutralization tests. As a group, patients with viral meningitis generally make a complete recovery within 1 to 2 weeks. However, there have been occasional reports of permanent sequelae in small children, 25 including mental retardation, deafness, cranial nerve palsies, and aqueductal stenosis.

Enteroviruses In the United States, enteroviruses account for as many as 80 percent of cases of viral 46 picornavirus family and are small (30 nm meningitis in children. Enteroviruses belong to the 47 in diameter, the size of a ribosome) RNA viruses. Initially, enteroviruses were subdivided into echoviruses and coxsackieviruses. Newly isolated enteroviruses are now assigned numbers as enteroviruses (e.g., enterovirus 71 or EV 71). Enteroviruses have a worldwide distribution and often cause epidemics, primarily during the summer and early fall. The enterovirus subgroup is stable at room temperature, stable at acidic pH as low as 3.0, and resistant to lipid solvents because it lacks a lipid envelope. These viruses are thus well suited for survival in water and sewage and are transmitted by the fecal-oral or hand-to-mouth routes. 47

Enteroviruses initially replicate in the gastrointestinal tract. This replication is asymptomatic or causes a mild gastroenteritis or pharyngitis. A secondary viremia then develops, with subsequent tissue infections that may involve regional lymph nodes, skeletal muscle, myocardium, pericardium, brown fat, skin, lung, pancreas, and leptomeninges. Patients with enterovirus infections may develop rashes, pericarditis, myocarditis, myalgia, orchitis, herpangina, arthritis, polymyositis, hemolytic-uremic syndrome, nephritis, insulin-dependent

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diabetes mellitus, respiratory symptoms, and conjunctivitis. When enteroviruses invade the CNS, most patients develop meningitis. The fever, headache, and stiff neck typically last 1 to 3 weeks in older children and adults but can persist for prolonged periods in patients with hypogammaglobulinemia. Enterovirus can be isolated from the CSF during the first 1 or 2 days of meningitis, from throat for several days, and from stool for a few weeks. Because asymptomatic enterovirus infections are common in summer, enterovirus isolation from throat or stool does not make a definitive diagnosis of enterovirus meningitis. Today the most sensitive and fastest method of identification of enterovirus RNA from CSF uses a reverse transcriptase–PCR assay. This method identifies all strains of enteroviruses but does not distinguish between the strains. Virus isolation and neutralization typing are necessary to determine the specific strain. Occasional strains of enteroviruses have been reported to cause a poliomyelitis syndrome, meningoencephalitis, cerebellar ataxia, transverse myelitis, and Guillain–Barré syndrome. For example, enterovirus 71 has caused numerous cases of meningoencephalitis with acute 48 flaccid paralysis and neurogenic pulmonary edema. Children with X-linked hypogammaglobulinemia may develop a chronic meningitis and have difficulty in eradicating the enterovirus infection from CSF and stool and develop a chronic persistent infection.

Mumps Virus 49

Worldwide, mumps virus is the most common cause of viral meningitis. In developed countries, the incidence of mumps meningitis is low because of the widespread administration of mumps vaccine to children. However, minor outbreaks of mumps in older children and young adults have occurred in the United Kingdom and United States in the past few years. Most cases have occurred in individuals who were never vaccinated or received only one dose of the mumps vaccine in childhood. Mumps virus is a large (100 to 600 nm in diameter), roughly spherical RNA paramyxovirus that spreads primarily via respiratory 3 droplets. Initial replication is within the upper respiratory tract and regional lymph nodes. A viremia disseminates the virus to parotid glands and occasionally to submaxillary glands, testes, ovaries, mammary glands, and the leptomeninges. The parotitis usually occurs 16 to 18 days after exposure to27the virus. About one half of all individuals with mumps parotitis develop CSF pleocytosis. In some, the meningeal infection is asymptomatic, whereas in others, a typical viral meningitis develops. The meningitis usually occurs 2 to 10 days after 28 the onset of the parotitis, but it may rarely precede the parotitis or even occur without it. In most patients, the meningitis spontaneously resolves within 2 weeks, and full47,50 recovery cerebellar occurs.51Occasionally, individuals develop complications, including deafness, 52 53 ataxia, cortical blindness, and aqueductal stenosis with obstructive hydrocephalus. 28 Among patients with a CNS mumps infection, 1 to 5 percent develop meningoencephalitis. Available pathological studies suggest that the meningoencephalitis may result from direct55 54 viral invasion of the brain or from a postviral encephalitis with perivenous demyelination. Although most of these individuals recover completely, occasional patients are left with permanent sequelae.

Herpes Simplex Virus Type 2 In young, sexually active adults with viral meningitis, HSV type 2 should be considered. This virus accounts for 0.5 to 5.0 percent of viral meningitis in all ages but up to 20 percent in adults. At the time of the first attack of genital herpes, about 36 percent of women and 11 percent of men29have signs and symptoms of meningitis, including fever, headache, and of these individuals subsequently develop nuchal rigidity. Approximately 20 percent 56 recurrent attacks of aseptic meningitis. HSV type 2 is the most common cause of recurrent aseptic meningitis. Many affected individuals have never had a history of genital herpes and lack genital lesions at the time of 43 Although virus can often be isolated from CSF during the the second attack of meningitis. 30 56 first attack of HSV meningitis, it is seldom isolated from CSF in recurrent43attacks. However, the viral DNA can frequently be detected in CSF by PCR assay.

Human Immunodeficiency Virus Primary HIV meningitis should be considered in young adults with meningitis, particularly if they are homosexual males or have a history of intravenous drug abuse and have a coexistent mononucleosis-like syndrome (see Chapter 45). It is of importance that these individuals usually do not have antibodies to HIV during the acute meningitis but develop 32 antibody 1 to 3 months later during convalescence. In the acute stage, the diagnosis can be made by PCR detection of HIV viral RNA in acute serum.

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Treatment of Viral Meningitis Treatment of most cases of viral meningitis is symptomatic. Analgesics may be required for individuals with severe headaches, and antiemetics for those with considerable nausea and 18 vomiting. Hospitalization is seldom required except when the vomiting is severe enough to cause dehydration or when bacterial meningitis cannot be completely excluded. If an acutely ill patient has CSF containing low glucose levels or a pleocytosis in which neutrophils predominate, it may not be possible initially to rule out bacterial meningitis. In these cases, it is often prudent to hospitalize the patient and treat the individual with antibiotics over the first day. By the second day, the patient usually feels better, the initial CSF bacterial cultures are sterile, and a 40 repeat lumbar puncture shows that the CSF pleocytosis now contains mainly lymphocytes. For mild to moderately severe HSV meningitis, the treatment is usually symptomatic. In more severe cases, treatment with acyclovir, 15 to 30 mg/kg divided into three doses per day, may 57 be given slowly intravenously over 1 hour for 5 to 10 days. This treatment should be given early in the illness to have maximal benefit. Oral acyclovir, 200 mg five times daily, is sufficient to treat genital herpes. It is difficult, however, to achieve high enough CSF concentrations of the drug when given orally to be beneficial in HSV meningitis. An oral prodrug of acyclovir, valacyclovir, has better oral bioavailability than acyclovir and may lead to better CSF acyclovir levels. In patients with recurrent HSV meningitis, it may be useful to give the patient oral acyclovir or valacyclovir to keep at home and take with the onset of symptoms of aseptic meningitis. Pleconaril, an antiviral drug designed to block enteroviruses from attacking and entering host 58 cells, may be of benefit in severe enteroviral infections in immunosuppressed individuals. Unfortunately, studies suggest limited value in the treatment of typical enterovirus 59 meningitis and no value in the treatment of acute poliomyelitis. The drug has not received U.S. Food and Drug Administration (FDA) approval. Therefore, treatment remains symptomatic. Because enterovirus meningitis can rapidly be diagnosed using a PCR assay of CSF for enteroviral RNA, hospitalization may not be required unless the patient is dehydrated from fever and vomiting or it is necessary to exclude a more serious form of meningitis. One study reported that use of the enterovirus PCR assay in the emergency department in children with aseptic meningitis resulted 60 in significantly less antibiotic use, shorter length of hospitalization, and lower hospital costs. VIRAL ENCEPHALITIS Viral encephalitis is due to a viral infection of the brain parenchyma. The viral infection causes widespread death of neurons and glia, with accompanying inflammation and edema. Each year in the United States, between 1,000 and 5,000 61 cases are reported to the CDC. Most of the cases occur during the summer and early fall. Viral encephalitis occurs worldwide, with a particularly high incidence in the tropics. Table 44-4 outlines the major viruses that cause encephalitis in the United States and lists some of their distinguishing characteristics. However, studies of encephalitis from Europe and the United States using comprehensive diagnostic methods report identifying an etiology in only about 50 percent of 85–87 cases. Click here to view this table.... The hallmark of encephalitis is the abrupt onset of deterioration of mental status, low-grade headache, and fever (Table 44-5). Encephalitis differs from meningitis in that18the patients have prominent mental symptoms and minimal signs of meningeal irritation. The mental changes may include confusion, delirium, or lethargy that fluctuates and can progress to 27,66,74 On stupor and even coma. Seizures often occur and may be generalized or focal. physical examination, patients may demonstrate hyperreflexia, mild spasticity, and Babinski signs. Papilledema is occasionally present. Some patients develop focal neurological signs, including hemiparesis, cranial nerve palsies, aphasia, ataxia, tremor, dysarthria, and cortical 66 blindness. Depending on a variety of factors, including patient age (the very young and the elderly do worst) and particular strain of the virus, the encephalitis may be mild or severe. Click here to view this table.... Many patients have a prodromal illness several days before the onset of the encephalitis. The prodrome may include parotitis (mumps) or fever, malaise, and myalgias (arboviruses). However, no prodromal illness develops in HSV encephalitis. 88

Laboratory findings in viral encephalitis vary. The leukocyte count is often elevated in the blood. Blood urea nitrogen, creatine kinase, and transaminase levels may be elevated

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(particularly with arbovirus encephalitis). Hyponatremia may occur from inappropriate 66 secretion of antidiuretic hormone. A lumbar puncture shows a normal or elevated opening pressure. The CSF usually contains five to several hundred WBCs per cubic millimeter, 75 which are mainly lymphocytes. In occasional cases, the CSF is acellular or hemorrhagic. The CSF glucose is usually normal, whereas the protein level is elevated in the 89 range of 50 to 200 mg/dl. Bacterial cultures are sterile. Viruses are seldom isolated from CSF. The EEG is always abnormal and typically shows diffuse background slowing with occasional epileptiform or electrographic seizure activity. If 2-Hz, high-voltage periodic complexes develop in the temporal lobe area, the possibility of HSV encephalitis is increased. Early in the illness, MRI studies may show areas of increased signal on T2-weighted and diffusion-weighted images, 90 which can be multifocal or mainly in the frontal or temporal lobes. The CT scan is often normal early in the illness,75but later it shows areas of increased vascular permeability, necrosis, or hemorrhage.

Diagnosis of Encephalitis During an epidemic, the diagnosis of a classic case of encephalitis is not difficult. However, sporadic cases may be difficult to distinguish from cases of metabolic encephalopathy. The presence of fever, headaches, fluctuating mental changes, focal neurological signs, or 18 seizures (particularly if focal) favor encephalitis over encephalopathy. Similarly, the presence of a blood leukocytosis, CSF pleocytosis, and focally abnormal areas on the EEG, brain scan, or MRI favor encephalitis over encephalopathy. In years past, all cases of encephalitis were treated symptomatically, and the diagnosis was 70 made during convalescence with the use of serological tests. With the advent of specific antiviral drugs, such as acyclovir for treating HSV encephalitis, there is now a need to determine rapidly the etiology of the encephalitis. Several factors may help to narrow the list of possible viruses. In the United States, arbovirus encephalitis occurs predominantly during the summer and fall, when the vector (mosquito or tick) is present. Similarly, cases of arbovirus encephalitis usually cluster and may develop into epidemics. Occasionally, the prodromal illness is of help. The presence of parotitis suggests mumps meningoencephalitis. Rashes may accompany Colorado tick fever, varicella-zoster (dermatomal rash), or Rocky Mountain spotted fever (Rickettsia) infections. Thrombocytopenia may develop from Rocky Mountain spotted fever, lymphocytic choriomeningitis, and Colorado tick fever infections. Many serological tests for encephalitis require acute and convalescent sera and therefore are 89 not helpful early in the illness. Recently, an immunoglobulin (Ig) M antibody capture enzyme-linked immunosorbent assay71(MAC ELISA) has been developed for detecting early antibody to arboviruses, but not HSV. Currently West Nile neuroinvasive disease is diagnosed in a patient with acute 62 encephalitis or myelitis by detection of IgM antibodies to West Nile virus in serum or CSF. Detection of viral nucleic acid in CSF or other tissues using PCR is becoming a rapid, sensitive, and specific method for the early detection of many viruses that cause encephalitis. 88 It is now the standard method for diagnosis of herpes simplex and enterovirus encephalitis but has not become standard for arbovirus encephalitis.

Herpes Simplex Encephalitis Encephalitis from HSV type 1 is the most common cause of sporadic encephalitis. Unfortunately, HSE has no characteristics that easily distinguish it from other types of 75,76 HSE occurs worldwide, during all seasons and at all ages. However, one encephalitis. third of cases occur in individuals younger than 20 years and 50 percent occur in those older than 50 years. HSE75has no characteristic prodromal illness and no specific serum or CSF laboratory findings. Isolation of the virus from the mouth is not helpful, as it commonly occurs in any individual with an acute febrile illness. MRI has been helpful in suggesting the diagnosis. It frequently demonstrates edema or necrosis in one or both medial temporal lobes 91 in the first few days of illness. When early MRI abnormalities are seen in the temporal lobe, the possibility of HSE increases, but this90abnormality is not diagnostic. Cranial CT often does not become abnormal for several days. Attempts to develop early antibody serological tests for HSE have been difficult. Most individuals have previously been infected with HSV during childhood, and therefore most older children and adults have serum IgG antibodies to HSV. IgM antibody in HSE seldom develops. Intrathecal HSV antibody synthesis and low ratios of CSF/serum HSV antibody titers do develop76,77 in patients with HSE but take one or more weeks and thus are not helpful for early diagnosis.

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In the past, brain biopsy with isolation of HSV from the brain tissue was the standard method 76,89 At present, use of the PCR assay of CSF for the presence of making a definite diagnosis. of HSV DNA fragments has become the standard and is widely available. In the first 4 days of encephalitis, the PCR test of CSF is positive in 92 more than 95 percent of cases, and HSV DNA can be detected in about 80 percent at 1 week. A few patients with proven HSE may have a PCR assay of the CSF that is negative initially but becomes positive for HSV on a second CSF examination. Patients of all ages with sporadic encephalitis of unknown cause should be considered as having possible HSE. It is now being recognized that atypical clinical 93 pictures occur in about 15 percent of patients with positive PCR assays of the CSF for HSV. In general, these patients present with milder encephalitis that progresses more slowly and has a better prognosis, even if acyclovir treatment is delayed. However, MRI frequently shows abnormalities in the temporal lobe.

West Nile Neuroinvasive Disease In recent years, West Nile neuroinvasive disease has become the most common cause of 62 encephalitis in the United States and has occurred in almost every one of the contiguous states. More than 4,000 cases have been reported to the CDC since 1999 when West Nile virus, an arbovirus, appeared in the United States. In nature, the virus cycles between many 63 types of birds and many strains of mosquitoes. Human infections occur when a mosquito carrying the virus bites a human. Since the virus is mosquito borne, cases of West Nile neuroinvasive disease develop mainly in the summer and fall and often in clusters. Unusual infections also occur following transfusions of blood infected with West Nile virus, after 62,94 infected organ transplants, or by transplacental spread. About 80 percent of West Nile virus infections are asymptomatic, 20 percent result in mild febrile illness called West Nile fever, and 1 to 2 percent develop West Nile neuroinvasive disease. The risk of developing this disease increases in the elderly and those who are immunosuppressed, such as in patients who are transplant recipients; it is quite uncommon in children. The majority of patients with West Nile neuroinvasive disease develop typical 62,95 About 10 percent of encephalitis that is mild to moderate in severity, but death may occur. patients also 96 develop flaccid paralysis of one or more limbs that resembles paralytic poliomyelitis. In the CNS, the virus predominantly infects neurons, particularly in the brainstem. When the virus invades the spinal cord, anterior horn neurons are mainly infected. 3 The CSF typically shows a pleocytosis of 50 to 200 lymphocytes/mm , normal glucose concentration, and mildly elevated protein level. As noted previously, detection of IgM antibody to West Nile virus in CSF or serum is the usual method of establishing the diagnosis.

Treatment of Viral Encephalitis 70

Treatment of all types of viral encephalitis requires excellent symptomatic care. Patients should be placed in an intensive care unit early in the illness because the encephalitis may progress rapidly. If seizures develop, anticonvulsant drugs such as phenytoin should be given. Increased intracranial pressure often develops as a consequence of vascular engorgement and cerebral edema, but placement of an intracranial pressure monitor is seldom necessary. Treatment of increased intracranial pressure consists of nasotracheal intubation with hyperventilation from a mechanical ventilator. Arterial partial pressure of carbon dioxide (Pco2) should be maintained between 25 and 30 mmHg. Mannitol, at a dose of 0.25 to 0.50 g/kg, may be given intermittently as an intravenous bolus to control pressure. Serum osmolality should be monitored to ensure that it is maintained below 320 mOsm/L. Use of corticosteroids is controversial, as much of the cerebral edema appears to be cytotoxic, which usually does not respond to corticosteroids. All patients should receive excellent nursing care to prevent decubitus ulcers, corneal abrasions, and contractures. Optimal oxygenation of the patient should be maintained. During convalescence, patients may require physical therapy and speech therapy. Neuropsychological testing is often needed to assess intellectual damage. The length of convalescence varies with the severity of the illness, but several months may be required. There is now an effective antiviral treatment for HSE. Acyclovir has been found to inhibit HSV thymidine kinase and effectively interferes with both type 1 and 2 HSV replication. Acyclovir has considerably less potency against other members of the herpesvirus family. The earlier in 74,76 Patients the course of encephalitis that the acyclovir is given, the better is the outcome. who are lethargic at the start of therapy do better than those who are comatose. Acyclovir not only increases the number of patients who survive but also improves the quality of survival. The acyclovir should be given as 30 mg/kg per day divided into three doses. It is given intravenously and slowly (over at least 1 hour) because rapid administration can cause acute

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renal toxicity, particularly in a dehydrated patient. In patients receiving acyclovir, the urine output should exceed 100 ml/hr. Acyclovir should be given for 14 to 21 days. A longer treatment period may be necessary if the patient is immunosuppressed or taking corticosteroids since relapses after a shorter course occur occasionally. Because acyclovir is most effective when given early, the drug is often administered when the diagnosis if first suspected and continued until the result of the PCR assay of CSF for HSV is known. If another diagnosis is established or the CSF PCR assay is negative and MRI does not demonstrate typical temporal lobe involvement, administration of acyclovir usually may be discontinued. Currently, there are no antiviral medications for arbovirus infections, so treatment is symptomatic. The acute illness generally lasts 1 to 3 weeks. Convalescence is slow, taking months for recovery of cognition. 4,66,70

Rabies encephalitis The prognosis of viral encephalitis depends on the etiological agent. is usually fatal. Eastern equine, Japanese B, Murray Valley, and Russian spring-summer encephalitides are usually severe, with mortality rates as high as 20 to 40 percent; permanent neurological sequelae are seen in as many as 50 percent of survivors. These neurological sequelae include dementia, seizures, and focal neurological deficits such as hemiparesis, aphasia, cranial nerve palsies, and ataxia. West Nile neuroinvasive disease, Western equine encephalitis, St. Louis encephalitis, California encephalitis, and mumps encephalitis are moderately severe, with a 2 to 10 percent mortality rate; 5 to 10 percent of patients are left with permanent sequelae. Venezuelan equine encephalitis and Colorado tick fever viruses cause mild encephalitis from which full recovery occurs. PARALYTIC POLIOMYELITIS Poliovirus does not infect glia or all neurons but selectively infects specific neuronal 97 populations, mainly of the motor system. Instead of developing encephalitis, patients develop an illness characterized by weakness and atrophy of skeletal muscles. Although most cases of paralytic poliomyelitis are due to infection with poliovirus, occasional cases have been reported due to enterovirus or arbovirus. In the United States, paralytic poliomyelitis from wild virus currently does not occur. From 1960 to 2000, poliomyelitis occasionally developed as a complication of administration of the live oral polio vaccine 9 (Sabin vaccine). However, in developing countries, such as Africa and Asia, that do not widely administer the vaccine, poliomyelitis from wild virus still occurs. Although most poliovirus infections result in asymptomatic illness, approximately 1 in 1,000 young children 9 who are infected develop paralysis. In adults, the risk may be as high as 1 in 100 infections. In patients who develop paralysis, the incubation period is 4 to 10 days. The illness begins 9,28 Some with malaise, headaches, and fever followed 1 day later by neck and back stiffness. 2 to 5 days later, the weakness begins. Patients often complain of stiff, sensitive, painful muscles. A progressive asymmetric flaccid weakness develops, typically with greater involvement of the proximal than distal muscles. Legs are more often affected than arms. Atrophy begins in involved muscles about 5 to 7 days after the onset of weakness and progresses over several weeks. The muscles of the thorax and trunk occasionally are severely involved. About 10 to 15 percent of patients develop pharyngeal and laryngeal muscular weakness, along with a facial diplegia. In rare patients, there is involvement of the reticular formation, thalamus, and hypothalamus, with lethargy, respiratory difficulties, and 97 3 20 to 500 WBCs/mm , mildly elevated autonomic instability. The CSF typically contains 9 in the protein concentration, and normal glucose level. Initially, neutrophils predominate 98 CSF, but the fluid soon converts to contain predominantly lymphocytes. Other routine laboratory tests are usually normal. Poliomyelitis should be suspected in any patient with rapidly progressive, asymmetric weakness and CSF with a lymphocytic pleocytosis. The diagnosis can be confirmed by 9 isolating the poliovirus from the throat or stool specimens or from the spinal cord at autopsy. Poliovirus is rarely isolated from CSF. All poliovirus isolates from patients should be sent to reference laboratories to determine whether the virus is wild type or vaccine-like. Since 2000, only the inactivated poliovirus vaccine (Salk) is administered in the United States, but many countries including Mexico continue to use the live oral poliovirus vaccine. There is no specific antiviral treatment for poliomyelitis. Patients should be hospitalized and 98 watched carefully for respiratory complications. If the vital capacity decreases to less than 30 to 50 percent of predicted volume, if respirations become irregular or labored, or if arterial oxygen tension decreases, the patient should be placed on assisted ventilation. Patients with severe paralysis often experience rapid resorption of bone with increased serum and urinary calcium that can result in nephrolithiasis or bladder calculi. Adequate hydration and

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acidification of the urine should be ensured to prevent the formation of urinary stones. Patients with severe muscle weakness usually require extensive physical therapy during convalescence. Death occurs in about 8 percent of patients, usually from bulbar involvement. In survivors, strength begins to increase a few weeks after the acute illness ends. By 6 months, 80 percent of young patients have made a good or full recovery. The prognosis is somewhat poorer for older children and adults. Poliomyelitis can be effectively prevented through immunization with either killed (Salk) 99 100 trivalent poliovirus vaccine or live (Sabin) trivalent poliovirus vaccine. However, use of the killed vaccine requires repeated boosters of the vaccine throughout life to maintain effective immunity. Live poliovirus vaccine, on the other hand, should not be given to individuals with a possible immunodeficiency because they are at increased risk of developing paralytic 100–103 poliomyelitis.

Postpolio Syndrome It is now recognized that individuals with a history of poliomyelitis years earlier are at risk of 104,105 The clinical features of the postpolio syndrome include developing late complications. progressive weakness, fatigue that does not correlate with the weakness, and muscle and joint pains. Joint problems include arthritis, tendinitis, bursitis, and ligament strain from incorrect posture and use of the joints. The neurological signs may include new muscle weakness, fasciculations, cramps, respiratory insufficiency, sleep apnea, dysarthria, and dysphagia. Individuals at particular risk are those who were older at the onset of the acute poliomyelitis, had severe disease, and were very active after their recovery. Currently, the diagnosis of postpolio syndrome requires a credible history of poliomyelitis, partial recovery, a minimum of 10 years of stability, and progressive weakness that cannot be explained otherwise. Numerous studies have failed to find any evidence of poliovirus persistence as the cause of the progressive weakness. Current hypotheses include loss of the branching axons of anterior horn cell neurons that sprouted to reinnervate skeletal muscle fibers whose axons were lost during the acute poliomyelitis or death of the enlarged motor neurons that sprouted and subsequently died due to excessive metabolic demand. At present, there is no specific treatment for the syndrome, but careful physical therapy with exercise to strengthen weak muscles does not seem to accelerate disease progression. At times, splints and other orthopedic appliances may be of benefit. PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY Progressive multifocal leukoencephalopathy is a rare progressive demyelinating disease of the CNS white matter that usually develops in adults with impaired immune responses, such 106,107 However, recently a few cases have as acquired immunodeficiency syndrome (AIDS). developed in adults receiving immunosuppressive therapy for multiple sclerosis and Crohn's disease with natalizumab, a humanized neutralizing monoclonal antibody directed against 108 alpha 4 integrin expressed by leukocytes. The disease appears to result from recrudescence of a previous childhood infection with a papovavirus (JC strain), and 109 antibodies to the JC strain are found in most normal adults. The initial signs and symptoms usually indicate multifocal lesions in the cerebral hemispheres, but often the signs from one hemisphere predominate. The onset is insidious, often with a slowly progressive hemiplegia, dysarthria, personality change, or homonymous hemianopia. Fever, headache, and meningismus are not present. The disease steadily progresses to death over 6 months to several years. The CSF is normal, and the EEG usually shows nonspecific slowing. Cranial MRI and CT show multifocal areas of discrete white matter damage (Fig. 44-1). No laboratory 110 or serological test is diagnostic. A clinical diagnosis can now be made in an immunosuppressed patient with a characteristic clinical history, MRI with white111matter lesions, and CSF that contains DNA fragments of the JC virus by PCR assay. It should be noted that occasional patients with AIDS have had CSF that was positive for JC virus by PCR assay in the absence of clinical signs or typical MRI changes. The diagnosis can also be made by brain biopsy, with electron microscopic identification of intranuclear inclusions within oligodendrocytes or of papovavirus virions within oligodendrocytes. Virus can be isolated 106,107 No from brain biopsy sample by inoculation onto human fetal glial tissue culture cells. effective antiviral treatment is available, but improving the patient's immune status may slow the rate of disease progression.

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FIGURE 44-1 Sagittal T1-weighted (A) and axial T2-weighted (B) magnetic resonance imaging (MRI) at the level of the occipital lobes, showing multifocal areas of discrete white matter change in a patient with progressive multifocal leukoencephalopathy.

HERPES ZOSTER (SHINGLES) Varicella-zoster virus, a member of the herpes family of viruses, causes herpes zoster (shingles). Herpes zoster typically develops in patients who, decades earlier, had a primary infection with varicella-zoster virus as chickenpox. 112 Following the primary infection, the virus The incidence of herpes zoster ranges becomes latent within neurons of sensory ganglia. 113,114 Most cases are seen in patients older from 1.3 to 4.8 cases per 100,000 person-years. than 50 years. The precipitating cause of herpes zoster is unknown in many cases. However, systemic cancer, irradiation of the vertebrae, immunodeficiency, spinal trauma, and old age are recognized as precipitants. The patient usually experiences a sharp, burning discomfort in a dermatomal distribution for 2 to 5 days before the onset of the rash. A localized redness with red macules that become 114 vesicles develops in the same dermatomal pattern. New vesicles usually appear over the first 2 days, but occasionally continue to appear over the first week. The vesicles evolve to pustules and form crusts in 2 weeks. Often, the regional lymph nodes become swollen. The distribution of herpes zoster is usually unilateral and involves a single dermatome. The rash appears on the trunk in 50 percent, on the head in 20 percent, on the arms in 15 percent, and on the legs in 15 percent of cases. Over the next month, the dermatomal pain slowly disappears, leaving a residual hypalgesia or hyperalgesia. Treatment of acute herpes zoster depends on the severity and location of the dermatomal

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rash and immunocompetence of the individual. Individuals with a mild rash may require only 115 symptomatic treatment with non-narcotic analgesics. Individuals with severe zoster rash, especially 115 involving the face, or who are suspected of being immunodeficient require antiviral 116 orally three times daily for 10 to 14 days, treatment. Treatment with famciclovir 500 mg 117 acyclovir 800 mg orally 5 times daily for 10 days, or acyclovir 7.5 mg/kg given slowly 118 intravenously over 1 hour 3 times per day for a total of 7 days has been shown to shorten the period of acute dermatomal pain, to accelerate cutaneous healing of the rash, and to prevent virus dissemination. However, these drugs have not been shown to reduce the incidence or severity of postherpetic neuralgia. The use of zoster immunoglobulin has not been shown to be beneficial. The use of prednisone 40 to 60 mg daily for 10 days plus an antiviral drug during the acute rash may lessen the pain of acute shingles when given with an 119 antiviral drug, but it does not prevent postherpetic neuralgia. It is now possible to prevent shingles in the elderly by immunizing the person with a live attenuated varicella-zoster, Oka strain, virus vaccine (Zostavax) that was approved by the FDA in 2006. A major study demonstrated that elderly healthy individuals who received the varicella vaccine had a 61 percent reduction in the incidence of shingles and a 67 percent reduction120 in the incidence of postherpetic neuralgia compared to those receiving a placebo. Complications from acute herpes zoster develop from spread of the virus to the eye (herpes 121 122 roots or motor nerves, spinal cord (myelitis), brain zoster ophthalmicus), the anterior 80 123 (small- or large-vessel vasculitis), and the entire body (disseminated zoster). Herpes zoster auricularis or Ramsay Hunt syndrome, in which there is involvement of motor fibers of the facial nerve, is characterized by marked peripheral facial weakness, with pain 124 and vesicles appearing over the skin of the external pinna and external auditory canal. Varicella-zoster virus occasionally causes a progressive white matter viral infection involving a small-vessel vasculitis with small ischemic infarctions and demyelination from infection of 125 oligodendrocytes. The CNS infection usually occurs in immunocompromised patients who experienced shingles in the previous month. A large-vessel vasculitis of the internal carotid or large cerebral arteries also can occur, producing a sudden contralateral hemiplegia or 126 ipsilateral central retinal artery occlusion. Most patients will have had shingles, usually involving the face, 1 to 2 months earlier. Diagnosis usually can be made by a cerebral arteriogram demonstrating arteritis and a CSF PCR assay positive for varicella-zoster DNA fragments. Limited anecdotal cases suggest that patients respond to treatment with acyclovir administered intravenously in a dose of 15 to 30 mg/kg for 10 to 14 days. Postherpetic neuralgia, pain in the distribution of the rash that persisted longer than 3 months, is a dreaded complication of shingles and occurs in 9 to 14 percent of patients with 127,128 In one third of these individuals, the pain persists for a year or more. The herpes zoster. incidence of postherpetic neuralgia increases with age. About 10 to 20 percent of patients older than 60 years develop postherpetic neuralgia. Three types of pain occur. Burning pain is a steady, burning, boring, or tearing aching pain, whereas lancinating pain is paroxysmal, jabbing, and ticlike; allodynia is severe discomfort brought on by touching or lightly rubbing the involved skin with clothing. The pathogenesis of postherpetic neuralgia is unknown, and the pain is difficult to treat. Several drugs help to reduce but do not eliminate the pain of postherpetic neuralgia.129The most commonly used drugs are nortriptyline up to 100 to 150 mg 130 up to 900 mg daily in divided doses, gabapentin daily in divided doses, oxcarbazepine 131 up to 2,400 mg daily in132 divided doses, and divalproex sodium up to a dose of 1,000 mg daily in divided doses. Lidocaine patches or capsaicin cream to the rash area are only occasionally helpful. POSTVIRAL ENCEPHALOMYELITIS (ACUTE DISSEMINATED ENCEPHALOMYELITIS) It is apparent that some viruses appear capable of damaging the nervous system by mechanisms other than conventional viral replication (viral encephalitis) (Table 44-6). Acute disseminated encephalomyelitis (ADEM) is the abrupt development of multiple neurological 207 signs related to a monophasic, inflammatory, demyelinating disorder of the CNS. ADEM occurs most commonly in children, but adult cases are recognized. In solitary case reports, 207 many different viruses have been associated with ADEM (reviewed elsewhere ). Vaccination with live virus vaccines (measles, rubella, vaccinia) or killed virus vaccines (influenza, rabies) also occasionally has been reported to cause a similar postvaccinal encephalopathy or encephalomyelitis. Although associated with a variety of viruses, postviral encephalomyelitis has several features in common. The neurological symptoms typically begin during the late stages of the primary illness, the neurological illness is monophasic, and the clinical disease207,208 is characterized by depressed levels of consciousness and multifocal Fever develops in half and seizures in one fourth. The pathology is neurological signs.

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one of inflammatory perivascular infiltrates, localized edema, and demyelination. Lesions that are seen best on T2-weighted MRI are usually multiple, bilateral, asymmetric, and localized mainly in the subcortical white matter, thalamus, and basal ganglia. Click here to view this table.... Measles is thought to have the highest rate of postviral encephalomyelitis (100 cases per 124,209 Varicella-zoster virus has an incidence of about 10 cases 100,000 primary infections). per 100,000 primary infections, but many are a localized cerebellar ataxia. Rubella has an incidence of about 5 cases per 100,000 primary infections. Neurological complications 210 following influenza virus often present as an encephalopathy (normal MRI and CSF) but ADEM is recognized.

Measles Uncomplicated measles frequently has neurological manifestations. Many children complain of headache, myalgia, lethargy, and photophobia. An abnormal EEG, demonstrating 209 pathological slowing of the background activity, occurs in about 50 percent of individuals. In 10 percent, lumbar puncture demonstrates a CSF pleocytosis. Behavioral disturbances are thought by some to occur211,212 more frequently during the months immediately following However, other studies have shown no significant increase in uncomplicated measles. 213,214 The etiology of the mental retardation or minor neurological signs following measles. acute neurological manifestations of measles is unknown, and rubeola virus has not been isolated from CSF or brain. About 1 per 1,000 individuals develop encephalomyelitis associated with measles. This neurological illness begins 2 to 7 days after the onset 133–138 of rash, usually when the rash is fading Older children and adults are and the child is recovering from the primary measles. disproportionately affected. The common clinical signs include depressed levels of consciousness, seizures, and focal neurological signs, including hemiparesis, paraparesis, and ataxia. Less common signs include cranial nerve palsies, choreoathetosis, and myoclonus. The EEG is abnormal, showing diffuse slow activity. The CSF typically shows a mononuclear cell pleocytosis with protein elevation. However, the CSF is normal in approximately one third of patients. Contrast-enhanced CT scans are usually normal, whereas MRI may demonstrate focal areas of increased signal intensity, primarily in cerebral white matter and the brainstem. Pathological studies have shown multiple focal areas of perivenous mononuclear cell cuffing 136 and demyelination. In more severe cases, perivenous hemorrhage, edema, and adjacent nerve cell damage may occur. Viruses have only rarely been isolated from CSF or brain in 215 was not found in the brains of 10 patients who died with these patients, and viral antigen 216 Intrathecal synthesis of rubeola virus antibody rarely postmeasles encephalomyelitis. 134 occurs. Thus, the pathology, virology, and immunology of postmeasles encephalomyelitis differ considerably from the findings in more conventional viral encephalitis and from two other CNS complications of measles, subacute sclerosing panencephalitis and progressive measles encephalitis.

Chickenpox Varicella-zoster virus causes uncomplicated chickenpox in most children. Occasional children, however, develop CNS symptoms as they are recovering from chickenpox, most 133,137,138,145 Limb and gait ataxia appear an average of commonly an acute cerebellar ataxia. 21 days after the onset of the rash. The CSF may contain a mononuclear pleocytosis and increased protein concentration. The pathology of this acute cerebellar ataxia is unknown.

Management of Postviral Encephalomyelitis Patients with severe postviral encephalomyelitis should be hospitalized in an intensive care unit. There is no proven specific treatment. High-dose corticosteroids, such as dexamethasone (1 mg/kg per day intravenously), methylprednisolone (10 to 30 mg/kg per day intravenously) or prednisone (40208 to 60 mg daily orally in adults) are often administered for 5 to 10 days during the acute illness. Other investigative treatments include plasmapheresis and intravenous γ-globulin. Symptomatic treatment for controlling body temperature, seizures, and intracranial pressure should be undertaken. The use of intracranial pressure monitoring may be worthwhile. If intracranial pressure is increased, the use of hyperventilation and intravenous mannitol, 0.25 to 0.5 g/kg, in boluses may be helpful.

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The prognosis of patients with mild ADEM or acute cerebellar ataxia is good, with recovery 133,137,138 Individuals with severe encephalomyelitis, typically occurring over several months. particularly from measles, carry a worse prognosis with a mortality rate of 25 percent, and many survivors have permanent neurological sequelae that include mental retardation, 137 behavioral problems, spasticity, ataxia, hemiparesis, and paraparesis. Up to one third of older children and adults initially diagnosed with ADEM have subsequent episodes and are 207,208 diagnosed as having multiple sclerosis. TRANSVERSE MYELITIS AND MYELOPATHY 146,158,160

Transverse myelitis is a clinically recognized entity that follows viral infections. The disease affects persons of158,160 all ages, but the incidence appears somewhat increased during Transverse myelitis has been reported to occur following the second decade of life. several viral infections and vaccines (Table 44-6), but in the majority of instances, an antecedent infection cannot be recognized. The initial symptoms usually include fever, pain in the back and legs, muscle weakness, sensory disturbances, and sphincter dysfunction. The tendon reflexes are usually decreased or absent during the acute stage, and the affected limbs have diminished muscle tone. The extent of leg weakness ranges from difficulty in walking to paralysis. Over the next several weeks, most patients develop hyperactive reflexes, spasticity, and extensor plantar responses. The interval between the first symptom and maximal neurological deficit ranges from hours to 1 to 2 weeks. Usually, a sensory level is identified in the patient, most often in 167 the thoracic segments but occasionally in the cervical or lumbar segments. Most patients present with a CSF pleocytosis and elevated protein concentration. The pleocytosis may have a predominance of either neutrophils or lymphocytes. The CSF protein levels may be as high as 500 mg/dl. However, about one fourth of patients present with normal CSF. Myelography is normal, but MRI of the spinal cord often demonstrates focal areas of increased signal within the cord that range over several vertebral segments. Since patients rarely die during the acute illness, there are limited pathological studies that 217 show focal areas of necrosis, inflammation, or perivenous demyelination. The criteria for the diagnosis usually include the following: (1) an acutely developing paraparesis, with motor, sensory, and sphincter disturbances; (2) spinal segmental levels of sensory disturbances; (3) a stable, nonprogressive clinical course after the acute phase; (4) no evidence of spinal cord compression; and (5) the absence of other known neurological diseases that affect the spinal cord, such as syphilis, severe back trauma, encephalitis, and 160 malignant disease with spinal metastases. Patients should be hospitalized, usually in the intensive care unit. Catheterization of the 218 bladder is often necessary. High-dose corticosteroids are often given, but their efficacy is not proven in randomized trials. Additional empirical treatments include plasmapheresis, intravenous γ-globulin, and even immunosuppressive drugs. About one third of158,160 patients make a good recovery, one third make a moderate recovery, and one third do poorly. Occasionally, in adults, the acute transverse myelitis is the first episode of multiple sclerosis 219 or, rarely, neuromyelitis optica. OPTIC NEURITIS Several viral infections have been associated with optic neuritis (Table 44-6), but most cases 220 are idiopathic. The incidence is about 3 per 100,000 people per year. As the primary viral infection is subsiding, the patient develops a subacute progressive loss of central vision with 164 decreased visual acuity. The visual loss is unilateral in about 75 percent of patients. Patients may complain of drabness or desaturation of colored objects, especially red objects, and decreased appreciation of brightness in the involved eye such that a swinging light from the normal eye to the eye with optic neuritis induces dilation of the pupil (Marcus Gunn phenomenon). Retrobulbar pain, exacerbated by eye movement, is usually present. The retina and optic disc appear normal (retrobulbar optic neuritis) in two thirds of patients or show evidence of papillitis. With papillitis, the disc is edematous with blurred margins, and the retina is edematous, often with flame hemorrhages. Visual evoked potentials may be unobtainable, attenuated, or prolonged in latency. CT scan and skull radiographs are usually normal but T2-weighted MRI may demonstrate increased signal within the optic nerve. The CSF is usually normal. Spontaneous recovery of vision usually occurs in 4 to 12 weeks. Intravenous methylprednisolone hastens recovery of visual function but does not affect 164 that oral prednisone alone may increase long-term visual outcome. There is some concern 221 the risk of subsequent attacks of optic neuritis. Most patients make a good recovery, but some individuals are left with a relative central visual defect or a pericentral visual defect and slightly decreased color vision. Visual acuity usually returns to better than 20/40, and most

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patients maintain good to excellent visual function for over 10 years. About 40 percent of 219,223 adult patients subsequently develop multiple sclerosis or, rarely, neuromyelitis optica. The risk of multiple sclerosis is increased to 56 percent in patients in whom brain164,220 MRI demonstrated one or more white matter lesions suggestive of multiple sclerosis. DEAFNESS AND VERTIGO Mumps, measles, varicella-zoster, influenza, and HSV infections have been those most often 224 associated with acquired deafness and vertigo. During the primary infection or as it is subsiding, patients experience the abrupt onset of unilateral sensorineural hearing loss, vertigo, or both. Patients may complain of tinnitus, nausea, and vomiting, which may be severe. Otitic pain is uncommon. On examination, the patient usually exhibits deafness or a high-frequency sensorineural hearing loss, often with hypoactive caloric responses on the involved side. The vertigo typically resolves over weeks, but the hearing loss may be permanent. The inner ear damage may result from direct viral invasion of the inner ear or possibly from an immune-mediated process. Rubella and cytomegalovirus can cause 186,189 With the congenital hearing loss, which may suddenly worsen 5 to 20 years later. advent of sensitive assays, such as PCR, to detect viral nucleic acid, herpes sim plex, cytomegalovirus, and varicella-zoster viral DNA has been detected within endolymphatic or 225,226 227 or auditory or vestibular ganglia in both normal patients and perilymphatic fluid patients with sudden hearing loss, vestibular neuritis, and Meniere's disease. This may suggest that latent herpes viruses are involved in these illnesses. However, their exact role, if any, in the pathogenesis of these illnesses remains uncertain. GUILLAIN–BARRÉ SYNDROME Guillain–Barré syndrome (GBS) 228,229 has been divided into four types, with acute idiopathic 230 and acute motor axonal neuropathy (AMAN) being inflammatory neuropathy (AIDP) the most common types. In North America and Europe, AIDP accounts for more than 90 percent of cases, whereas in Asia and Central and South America, AMAN accounts for one 231 231 third of cases. The clinical features are similar, but the pathology is different. In AIDP, there is multifocal mononuclear cell infiltration of peripheral nerves that corresponds to the clinical deficit. The macrophage immune attack is primarily directed against myelin. Focal areas of segmental demyelination are usually seen throughout the peripheral nerves as the disease progresses. In AMAN, macrophages invade the nodes of Ranvier where they insert between the axon and the surrounding Schwann cell membrane, leaving the myelin sheath intact. In severe cases of AMAN, the involved axon degenerates. During the past decade, studies have strongly implicated bacterial and viral infections inducing antibodies that cross-react with neural antigens leading to Guillain–Barré syndrome. infections as a likely cause Attention has primarily focused 167–169 on Campylobacter jejuni bacterial 169,170 of AMAN and cytomegalovirus, Epstein–Barr virus, and nonspecific upper 232 respiratory illnesses as likely causes of AIDP. Case reports also have associated other viruses and vaccines (Table 44-6). Viruses have not been successfully isolated from involved peripheral nerves, but cytomegalovirus DNA has been identified by PCR in the CSF of 31 231 percent of cytomegalovirus-seropositive patients with Guillain–Barré syndrome. Guillain–Barré syndrome occurs during all seasons, affects both children and adults, and 231–234 Patients characteristically complain of involves males slightly more often than females. leg and foot paresthesias and weakness at the onset of the232–234 illness. Over the next 7 to 10 In most patients, the days, the patient develops a progressive flaccid weakness. weakness begins in the legs and ascends proximally. Initially, tendon reflexes are somewhat depressed, and they typically disappear as the illness progresses. Objective sensory loss is usually minor, involving vibration and position sense in the feet. Mentation is normal. In about 25 percent of patients, the weakness may progress, and respiration is sufficiently impaired that assisted ventilation is required. As discussed in Chapter 8, autonomic disturbances are common and may be life threatening, particularly cardiac arrhythmias and marked 235,236 Fever, lymphadenopathy, and splenomegaly are usually fluctuations in blood pressure. absent. The CSF is under normal pressure and is acellular, usually with an elevated protein 232 concentration. Infectious agents are not isolated from the CSF. Initially, motor nerve conduction231,237 velocities may be normal or depressed only slightly, but F and H waves are often Over the next several weeks, motor nerve conduction velocities become abnormal. markedly slowed. Most patients with this clinical picture have Guillain–Barré syndrome. However, diphtheria polyneuropathy, poliomyelitis, vasculitis, chronic inflammatory demyelinating polyneuropathy, tick paralysis, porphyria, and acute toxic neuropathies must be considered in the differential

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diagnosis. The pathogenesis of Guillain–Barré syndrome is unknown, but current evidence suggests both AIDP and AMAN result from abnormal immune responses. AIDP resembles experimental autoimmune neuritis, which is predominantly caused by T cells directed against peptides from231 the myelin proteins P0, P2, and PMP22 plus involvement of antibodies and complement. In AMAN, there is even stronger evidence that the weakness is triggered by antibodies to gangliosides on the axolemma that target macrophages to invade the axon at 231 the node of Ranvier. As noted previously, specific bacteria and viruses are thought to trigger the autoimmune event. It should be noted, however, that Guillain–Barré syndrome can 238 occur in individuals who are partially immunosuppressed. Patients with Guillain–Barré syndrome should be hospitalized, usually in an intensive care unit. Because the weakness may progress rapidly to involve the respiratory muscles, the patient's respiratory status must be assessed frequently. Respiratory assistance should be instituted at the first signs of dyspnea, usually when the vital capacity decreases to less than 800 ml or a decrease in blood oxygen saturation occurs. Nasotracheal intubation should be the first step, but prolonged respiratory failure may require a tracheostomy. Cardiac monitoring should be undertaken, as life-threatening cardiac arrhythmias may occur, 235,236 particularly during nasotracheal suction or when the patient is moved about in bed. Early treatment with plasma exchange or intravenous immunoglobulin (IVIg) is equally effective in reducing the time on a ventilator, shortening the time to ambulation, and 231 volumes of plasma improving return of full strength by 1 year. Patients usually receive five 231 exchange over 1 to 2 weeks or IVIg at a daily dose of 0.4 g/kg for 5 days. Since plasma exchange carries a somewhat higher complication rate, IVIg has become more popular. The 239 use of corticosteroids is not beneficial. 231,232

Prognosis is generally good, but 5 to 10 percent of patients still die. Excellent recovery occurs in more than 75 percent of survivors, but 20 percent of patients are left with some residual weakness. Recovery begins after a plateau phase of several weeks and may continue for up to 24 months. Persistent fatigue is a common residual in adults. Children tend to make a faster and better recovery than older adults. Histological studies have shown that remyelination of involved peripheral nerves occurs during recovery. Recurrences of Guillain–Barré syndrome are rare. CREUTZFELDT–JAKOB DISEASE It is now recognized that Creutzfeldt–Jakob disease (CJD) results from a special class of infectious agents, called unconventional agents or proteinaceous infectious particles 240–243 This class of infectious agents causes CJD, variant CJD, 244–246 kuru, (prions). In animals, Gerstmann–Straussler syndrome, and fatal familial insomnia in humans. scrapie, bovine spongiform encephalopathy, and chronic wasting disease of deer and elk are the most common. CJD is the most common prion disease in humans and has a worldwide distribution, with an 244 incidence of 1 to 2 cases per million population per year. The average age at onset is 60 years. Most cases are sporadic, but 12 percent cluster in families. Both sexes are equally involved. 247,248

The onset is insidious, with the The clinical features fall broadly into three phases. development of mental deterioration. The patient typically becomes forgetful and nervous, with a decline in work performance. A relentless, slowly progressive dementia then develops. Progressive memory loss, parietal lobe dysfunction, and dysphasia often develop. Behavioral disturbances include the appearance of personality change, apathy, irritability, depression, and paranoia. Systemic signs, such as fever, meningismus, adenopathy, and splenomegaly, do not develop. Headaches are rare. In the second phase, more than 85 percent of patients develop myoclonic jerks—involuntary, repetitive muscular contractions that are quick, shocklike, and of sufficient severity to cause visible displacement of limbs. They may be stimulus sensitive. Some patients develop spasticity with Babinski signs, whereas others develop cortical blindness, severe ataxia, or amyotrophy. In the third phase, the patient develops severe dementia, wasting, and spasticity. The clinical course to death usually ranges from 6 months to 2 years. The CSF is acellular, with a normal protein content. CSF and serum immunoglobulin levels are normal. The EEG is distinctly abnormal in 75 percent of cases, usually in the later stages of the illness. The tracing is characterized by repetitive, periodic, stereotyped, bilaterally 249 synchronous sharp waves, usually occurring at a frequency of 1 to 2 per second. They are often associated with myoclonic jerks. On cranial MRI, diffusion-weighted and

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fluid-attenuated inversion recovery imaging often demonstrate multifocal subtle foci of 250 hyperintensity in the putamen, caudate, thalamus, and gray matter of the cerebral cortex. Later in the illness, diffuse brain atrophy is seen on CT and MRI. The clinical diagnosis of CJD is usually made on the basis of a rapidly progressive dementia and development of myoclonic jerks coupled with laboratory tests demonstrating a characteristic EEG, 14-3-3 protein on CSF electrophoresis, and hyperintensities seen on 244 MRI. However, to date, there is no simple diagnostic test that is specific for CJD. Confirmed diagnosis requires characteristic brain histopathology and staining with specific prion antibody or demonstration of prions from homogenized brain by immunodiagnostic procedures. The conformation-dependent immunoassay245 appears to be the most sensitive and specific for brain tissue but is not sensitive for CSF. 246

The pathology appears to be confined to the nervous system. There is diffuse atrophy of the brain. Histologically, there are extensive loss of neurons, prominent astrocytic gliosis, conspicuous absence of inflammatory changes, and a characteristic spongiform change. This spongiform appearance is due to vacuoles located in the cytoplasm of neurons and astrocytes. Electron microscopy does not identify infectious particles in the brain. Technically, prions are not viruses but are included in this chapter because they are infectious particles. The characteristics of 240,241 this unique infectious sialoglycoprotein, called a It is of low molecular weight, hydrophobic, prion protein (PrP), are becoming clearer. 247,248 and tightly bound to membranes. The particle appears to amplify within the cytoplasm 243 and lacks a nucleic acid. The infectious agent appears not to stimulate a humoral or cellular immune response. Infectivity of the agent is not destroyed by common virucidal agents, such as ultraviolet light, formalin, β-propiolactone, and 100°C heat. However, it is 2 destroyed by autoclaving for 1 hour at 125°C at 20 lb/in or by soaking infected tissues for at least 1 hour in 2 M sodium hydroxide. More is becoming known about the pathogenesis of these unique infectious and inherited diseases. Current evidence strongly suggests that the nucleic acid for the prion lies cwithin a 240,246 The gene normally produces a cellular protein called PrP that is host's chromosome. found mainlyc in neuronal membranes. Under conditions that are not well characterized, the normal PRP can alter its three-dimensional structure to become the infectious prion or cjd PrP . Thus, the abnormal protein has the same amino acid sequence as that of the normal protein but is folded in a manner that alters its function and ability to be degraded. Somehow, c the abnormal protein can also induce normal PrP to refold into the abnormal configuration. Accumulation of prions in neurons leads to death of the neuron and to clinical disease. The presence of specific mutations in the PrP gene increases the likelihood of production of abnormal PrP. Furthermore, it appears that there are several three-dimensional configurations that the PrP protein can adopt, each producing a different clinical illness. Thus, CJD may develop because of a specific mutation in the host's PrP gene or by inoculation of infectious prions into an individual. Iatrogenic spread of CJD has been documented via infected244,248 corneal grafts, dural grafts, and growth hormone prepared from human pituitary Accordingly, patients who die from unexplained dementia should not be organ glands. donors. The infectious agent does not appear to be in saliva, urine, or stool. Therefore, spouses or individuals who are caring for the patient are not at increased risk of contracting the disease. The patient does not require isolation, but needles, blood, and CSF should be 251 considered infectious and should be autoclaved before being discarded. In general, animal prion diseases, such as scrapie, have not been thought to transmit to humans. However, there is considerable evidence that bovine spongiform encephalopathy 245 (mad cow disease) may rarely transmit to humans and cause a fatal illness. More than 150 cases of variant CJD, mainly from the United Kingdom, are thought to have resulted from consumption of infected beef containing prions. Such cases are primarily in younger individuals and present with psychiatric signs before the more classic features of CJD 244 disease develop. At present, no effective treatment exists for any prion disease. The mean time to death from clinical onset of sporadic CJD is 5 months, and 90 percent die within 1 244 year. ACKNOWLEDGMENTS The author is supported by the Neurology and Research Services, Veterans Administration Medical Center, and the Departments of Neurology, Neuroscience and Microbiology, University of New Mexico School of Medicine, Albuquerque, New Mexico. Previous

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Aminoff: Neurology and General Medicine: AIDS and the Nervous Sy...



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Keyword Index

Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 45 AIDS and the Nervous System JOSEPH R. BERGER •

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MENINGITIS Viral Meningitis HIV Meningitis Bacterial Meningitis Mycobacterial Infections Treponemal Infection Listerial Infection Other Bacterial Meningitides Fungal Meningitis Cryptococcal Meningitis Other Fungal Meningitides Parasitic Meningitis Lymphomatous Meningitis GLOBAL ENCEPHALOPATHY Viral Encephalopathy HIV Encephalopathy (AIDS Dementia Complex) Cytomegalovirus Encephalitis FOCAL NEUROLOGICAL DYSFUNCTION OF CENTRAL ORIGIN Brain Disease With Mass Effect Toxoplasma gondii Infection Other Infectious Diseases Primary CNS Lymphomas Cerebrovascular Disease Brain Disease Without Mass Effect Progressive Multifocal Leukoencephalopathy SPINAL CORD DISEASE HIV-Associated Myelopathy HTLV-I–Associated Myelopathy PERIPHERAL NEUROPATHY MYOPATHY

Clinically apparent and frequently debilitating neurological disease is common with infection by human immunodeficiency virus type 1 (HIV), the etiological agent of the acquired immunodeficiency syndrome (AIDS). In the era before highly active antiretroviral therapy

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(HAART), in excess of 50 percent of persons infected with HIV developed symptomatic neurological disease. Early studies1,2 detected an incidence of neurological complications with AIDS of approximately 40 percent, but these studies were retrospective in nature and performed at a time in the course of this pandemic when life expectancies were considerably shorter and many of the neurological illnesses associated with the infection were unrecognized. Subsequent studies demonstrated significantly higher rates of neurological 3 disease. In 1996, HAART became the standard of care. The effect of this therapy on the incidence of neurological disease remains uncertain. Some studies have suggested both a change in 4,5 the spectrum and a decline in the frequency of many HIV-associated neurological of neurological disorders that disorders, whereas others report an incidence and spectrum 6 essentially parallels that observed in the pre-HAART era. The frequency with which neurological disease is observed at autopsy is substantially higher than in clinical studies, and in some series, neuropathological7,8 abnormalities have been demonstrated in more than 90 percent of patients dying of AIDS. Not surprisingly, careful neurological examination, even in the absence of specific complaints by the HIV-infected patient, frequently reveals evidence of central nervous system (CNS) or peripheral nervous system dysfunction. A novel clinical disorder that followed the introduction 9of HAART has been referred to as the immune reconstitution inflammatory syndrome (IRIS). IRIS is characterized by new or worsening symptoms of AIDS-associated opportunistic infections, malignancies, or other noninfectious complications due to an increased inflammatory reaction that paradoxically occurs as HIV viral loads decline and CD4 lymphocyte counts recover. Neurological disease consequent to IRIS has been well described. Initiating HAART before the CD4 lymphocyte count decreases to less than 100 cells/ml has been recommended to avoid this 10 complication. Neurological disease typically occurs with advanced disease and profound immunosuppression; however, it may also be the harbinger of AIDS. The frequency with which neurological disease heralded AIDS in the pre-HAART era ranged from 10 to 20 3,11 Whether that is also true with earlier diagnosis and more effective treatment is percent. unknown. It is estimated that there are approximately 1.2 million persons with HIV infection in 12 and one fourth are unaware of their the United States, roughly 1 in every 250 persons, 12 infection. Annually, 40,000 persons become infected with HIV in the United States. These numbers indicate that the burden of neurological disease associated with HIV/AIDS remains high. Not only is the spectrum of neurological disorders that complicate HIV infection extremely broad (Table 45-1), but also any part of the neuraxis may be affected. In general, the illnesses affecting the nervous system can be classified into those that are believed to be the direct result of HIV and those that result from other identifiable etiologies. Among the disorders in the former category are encephalopathy, myelopathy, peripheral neuropathy, and inflammatory myopathy. Their relative frequencies are depicted in Table 45-2. The illnesses in the latter category are chiefly a consequence of the severe abnormalities of cellular immunity accompanying AIDS. Infectious complications, particularly, cerebral toxoplasmosis and cryptococcal meningitis, are among the most common complications (Table 45-3). As a rule, these opportunistic neurological infections are the consequence of a dissemination or recrudescence of a latent or persistent infection rather than a recently acquired one. Often these infections relapse after initially successful therapy. Therefore, secondary antibiotic prophylaxis is warranted in certain infections, such as Toxoplasma encephalitis and cryptococcal meningitis. Other causes of neurological disease seen in association with the immunosuppression of HIV infection include primary and metastatic neoplasms, metabolic-nutritional disorders, and cerebrovascular complications. Click here to view this table.... Click here to view this table.... Click here to view this table.... In evaluating and treating HIV-infected patients with neurological disease, the physician must remain aware of the fact that the severely immunocompromised patient with AIDS often has two or more different illnesses responsible for neurological impairment. Furthermore, the neurological problems of HIV-infected persons may be the consequence of common neurological problems, such as migraine and herniated intervertebral disc with associated radiculopathy rather than related to HIV/AIDS. A high degree of vigilance is warranted, but these ordinary problems should not be overlooked. MENINGITIS

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Headache, signs of meningeal irritation, cranial nerve palsies, and other neurological symptoms and signs with or without fever generally herald more ominous disorders resulting from a broad array of microbial pathogens or from lymphomatous infiltration of the meninges. Radiographically, meningitis may be suspected by contrast enhancement of the subarachnoid space on computed tomography (CT) or magnetic resonance imaging (MRI). This enhancement of the subarachnoid cisterns can be either diffuse or focal, but its absence does not preclude the diagnosis. Other radiographic features seen in association with meningitis include communicating hydrocephalus, arterial or venous infarctions due to vasculitis, sinus thrombosis, and brain abscesses. The diagnosis of meningitis necessitates cerebrospinal fluid (CSF) examination. In HIV-infected patients with suspected meningitis, the CSF examination is incomplete without thorough microbiological studies including fungal and mycobacterial cultures and stains, India ink and cryptococcal antigen studies, and the Venereal Disease Research Laboratory (VDRL) test. Viral cultures, particularly for cytomegalovirus (CMV), should also be considered. Polymerase chain reaction (PCR) for Mycobacterium tuberculosis, herpes simplex viruses 1 and 2, CMV, and varicella-zoster virus 13 are also helpful in establishing the diagnosis. Cytological investigation is also essential in light of the relative frequency of lymphomatous meningitis.

Viral Meningitis HIV Meningitis The frequency of clinically apparent HIV meningitis is substantially lower than is suggested by the observation of an otherwise unexplained CSF pleocytosis or the findings of meningeal inflammation at the time of autopsy. In a minority of individuals, acute meningitis may accompany primary infection with HIV. This acute viral illness, indistinguishable from many other viral illnesses, is characterized by fever, generalized lymphadenopathy, pharyngeal injection, splenomegaly and splenic tenderness, maculopapular rash, and urticaria. It typically 14,15 before seroconversion to HIV, an14,16 event that develops within 3 to 6 weeks of infection, or averages 8 to 12 weeks after exposure. With this acute infection, a meningitis 17 meningoencephalitis may supervene, with headache, meningismus, photophobia, generalized seizures, and altered mental state. CSF examination reveals an increased protein concentration (more than 100 mg/dl), mononuclear pleocytosis (more than 200 3 16 cells/mm ), and normal glucose content. HIV may be isolated from the blood and CSF, but viral cultures are notoriously insensitive. The presence of HIV can be more reliably demonstrated by finding p24 antigen in the CSF or by amplifying HIV RNA by PCR. Routine examination of the CSF in asymptomatic individuals infected with HIV commonly reveals abnormal CSF parameters, including a sterile pleocytosis. A study of HIV-infected U.S. Air Force personnel (80% entirely asymptomatic clinically) revealed some CSF 18 abnormality in 63 percent. Among the CSF abnormalities frequently detected were mononuclear pleocytosis, increased protein concentration, increased immunoglobulin G 18 (IgG), and the presence of oligoclonal bands. The presence of myelin basic protein is unexpected. The CSF abnormalities do not appear to be predictive of the subsequent 18 development of neurological disease, and their interpretation requires caution.

Bacterial Meningitis Mycobacterial Infections Infection with M. tuberculosis, Mycobacterium avium-intracellulare, and, rarely, other atypical 19 mycobacteria occurs frequently in AIDS and is often extrapulmonary. The frequency of CNS involvement varies with the organism and the population studied. Haitians, American blacks, 20 and intravenous drug abusers appear to be the risk groups that have the highest incidences of mycobacterial infection. In Miami, 2.4 percent of HIV-infected patients with CNS disease 3 had CNS tuberculosis. In underdeveloped countries, the frequency with which CNS tuberculosis complicates HIV infection greatly exceeds its prevalence in the United States. In addition to meningitis, the clinical spectrum of CNS tuberculosis associated with HIV 21 22 infection includes cerebral abscesses and tuberculomas and spinal cord abscess. The most common clinical manifestations of tuberculous meningitis in AIDS include seizures, 21 altered mental status, fever, and meningismus. Although HIV infection increases the risk of meningitis with M. tuberculosis, it may not alter the clinical manifestations or response to 14 therapy. In contrast to M. tuberculosis, which most often presents as meningitis, M. avium-intracellulare typically causes single or multiple mass lesions. Ring-enhancing lesions 21 and hypodense areas are seen on CT scan. The CSF may, on occasion, be normal or

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Aminoff: Neurology and General Medicine: AIDS and the Nervous Sy... 14

acellular, patients.


emphasizing the value of brain biopsy in establishing the diagnosis in some

All HIV-seropositive patients should be skin-tested for tuberculosis and, if positive, should be treated. In those with active tuberculosis, a regimen involving three or more drugs is required for a minimum of 9 months. Recent descriptions of multidrug-resistant M. tuberculosis raise concerns about the adequacy of this treatment regimen, and drug sensitivity testing should be performed in all cases. In regions where multidrug-resistant organisms have been isolated, a more extensive regimen is probably required. Atypical mycobacterial infection requires a 23 and may necessitate experimental antimicrobials, such as rifabutyn and four-drug regimen 24 clofazimine. Treponemal Infection Neurosyphilis must always be considered in patients with HIV infection, even in the absence of neurological disease. In some populations, between 1 to 6 percent of all18,25–27 HIV-infected ; this is patients have neurosyphilis as defined by a positive VDRL test in the CSF probably an underestimate of the true incidence of neurosyphilis in AIDS because of the 28 relative insensitivity of this test. An acute, symptomatic, syphilitic meningitis during the course of secondary syphilis is not uncommon. A decrease in the latent period for the development of certain neurosyphilitic manifestations, such as meningovascular syphilis and general paresis, has been suggested. Johns and colleagues noted the development of meningovascular syphilis within 4 months of primary infection despite the administration of 29 accepted penicillin regimens. Relapse of neurosyphilis in HIV-infected individuals after 30 appropriate doses of benzathine penicillin for secondary syphilis has also been noted. Other unusual manifestations of 31 syphilis that have been reported in association with HIV infection 32 Bell's palsy and severe include unexplained fever, bilateral33optic neuritis with blindness, 34 syphilitic meningomyelitis, syphilitic bilateral sensorineural hearing loss, 35 36 polyradiculopathy, and syphilitic cerebral gumma presenting as a mass lesion. Although still controversial, concomitant HIV infection appears to alter the natural course of 37–39 syphilis. Treatment of syphilis requires the administration of intravenous, high-dose aqueous penicillin G (12 million U/day or more) for 10 to 14 days. Successful therapy of neurosyphilis with 33 doxycycline 100 mg twice daily for 21 days in an HIV-infected person has been reported. CSF examinations following treatment should be repeated at 6-month intervals over the succeeding 2 years. Ideally, the CSF cell count should be normal and the protein concentration lower, but the presence of concomitant HIV infection may alter the expected CSF resolution in successfully treated patients. The CSF VDRL titer should decline, but the CSF VDRL may remain reactive in low titer. Listerial Infection Despite a profound impairment of cellular immunity, the incidence of Listeria monocytogenes infection appears to be less with AIDS than with other causes of impaired cell-mediated 40 41 immunity. Listeria infection may result in meningitis or brain abscess and appears to have a predilection for the brainstem. In any case of meningitis of unknown cause occurring in a patient with AIDS, the antibiotic regimen should include agents effective against L. 42 monocytogenes, such as ampicillin, high-dose penicillin, or trimethoprim-sulfamethoxazole. Other Bacterial Meningitides Both infections that are typically associated with cellular immunodeficiency, such as Salmonella, and those more commonly seen with humoral immunodeficiency, such as43 Streptococcus pneumoniae, are seen with increased frequency in patients with AIDS. Pneumococcal meningitis is particularly common among HIV-infected children in 44 underdeveloped regions of the world. These and other less common causes of meningitis must be considered in any AIDS patient presenting with meningitis.

Fungal Meningitis Cryptococcal Meningitis 45

The estimated incidence of cryptococcosis in patients with AIDS varies between 1.9 and 11 2 percent. Blacks and intravenous drug abusers appear to have higher rates of this illness than other people. Cryptococcal meningitis, the chief clinical consequence of cryptococcal

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infection in patients with AIDS,3,46,47 may be the heralding illness or may occur simultaneously with In some communities, cryptococcal meningitis is more other opportunistic infections. common 40 than toxoplasmosis as the presenting neurological illness associated with HIV infection. Symptomatically, headache is almost universally noted in patients with cryptococcal meningitis. Other frequently observed clinical features include nausea and vomiting, photophobia, blurred vision, fever, mental status changes, and meningismus. Cranial nerve palsies, hemiparesis, language disturbances, seizures, cerebellar findings, and psychosis occur with lesser frequencies. In one series of 25 patients with AIDS and cryptococcal meningitis, headache was present in 88 percent, fever in 84 percent, meningeal signs in 36 percent, mental status changes in 12 percent, and other neurological findings 40 Though unusual, (cranial nerve palsies, papilledema, ataxia, and seizures) in 10 percent.1,48,49 focal neurological findings may be observed with cryptococcal disease. Cryptococcal meningitis is among the most common of the neurological disorders associated 50 51 with IRIS. The illness generally starts within 3.5 months of initiation of HAART and typically exhibits higher CSF opening pressures, glucose levels, and white blood52cell counts than patients with typical HIV-associated Cryptococcus neoformans meningitis. Pathological examination reveals a basilar, chronic meningitis that is typically neither particularly thick nor exudative. Diffuse or focal opacifications of the leptomeninges and brain edema may be noted by gross examination. Small (2- to 3-mm) nodules may be observed studding the meninges, particularly in the interpeduncular fossa and in the sulci. Cystic lesions composed of clusters of budding yeast and displaying little surrounding inflammation or reactive gliosis may be seen throughout the brain, chiefly in the superficial layers of the cerebral cortex. When macroscopic in size, they are referred to as cryptococcomas. Lumbar puncture typically reveals an increased opening pressure, mononuclear pleocytosis, increased protein content, and depressed glucose level. However, two or three of the standard CSF parameters (protein, glucose, cell count) may be normal in48,53 up to 50 percent of 40 and the these individuals. An India ink study is positive in more than 70 percent positivity rate of CSF48cryptococcal antigen, CSF culture, and serum cryptococcal antigen exceeds 90 percent. When cryptococcal meningitis is suspected, blood should be cultured and serum assayed for the presence of cryptococcal antigen. Cultures of other extraneural 53 sites, such as bronchoalveolar lavage fluid, may also be positive. Radiographic imaging is typically unremarkable. More often than not, a brain CT scan does not reveal evidence of the 54–57 In one series, mass lesions (cryptococcomas) and hydrocephalus pathological process. were each observed in approximately 10 percent of patients and diffuse cerebral edema in 58 another 3 percent. 48

The mortality of cryptococcal meningitis is about 30 percent. Many of the factors that predict a poor prognosis (positive India ink test, a low CSF leukocyte count, a positive blood culture, the presence of C. neoformans at extraneural sites, high CSF cryptococcal antigen titers, 54 CSF hypoglycorrhachia, and an increased CSF opening pressure) are present in AIDS. One study found that the most important predictor of poor outcome was an abnormal mental 59 controversy, however, status at the time of diagnosis. There remains considerable 53 regarding the importance of these predictors of survival. The standard treatment of cryptococcal meningitis consists of intravenous amphotericin B (0.6 to 1 mg/kg per day) for a minimum of 6 weeks. However, a comparative study of amphotericin B (0.4 mg/kg) intravenously with or without flucytosine to 59 oral fluconazole 200 No benefit of mg/day showed similar rates of treatment success (40% versus 34%). 59 flucytosine was detected. Although oral fluconazole appears to be the equivalent of 59 intravenous amphotericin B in the treatment of uncomplicated cryptococcal meningitis, there remains considerable debate regarding the use of fluconazole as initial therapy. The current recommendation regarding treatment of cryptococcal meningitis is to use amphotericin B (0.7 mg/kg per day) with or without flucytosine (100 to 150 mg/kg per day). At the completion of 2 or more weeks, this therapy may be supplanted by oral fluconazole at 400 mg/day for 8 to 10 weeks. If at the end of this time, the CSF culture is negative for C. neoformans, the fluconazole dose may be reduced to 200 mg/day and continued indefinitely as secondary prophylaxis to prevent relapse. Half of the patients who are48not treated with maintenance therapy following completion of their initial therapy relapse. The prostate has been suggested as the site for redissemination of infection because at least 20 to 30 percent of AIDS patients who have completed successful treatment for cryptococcal meningitis have positive urine cultures for C. 60 neoformans. Oral fluconazole or itraconazole appears to be equally effective in reducing recurrent cryptococcal meningitis; however, prophylactic therapy with antifungal agents 61 appears to have no effect on overall survival.

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Other Fungal Meningitides Other fungal infections, including Candida, may also result in meningitis in AIDS patients. Although more than 50 percent of AIDS patients develop oropharyngeal or esophageal candidiasis, it is rarely observed in the brain at autopsy. Meningitis secondary to 62,63 in the absence mucormycosis has been observed in parenteral drug abusers with AIDS of the classic triad of ophthalmoplegia, necrotic nares, and diabetes insipidus. Large intracerebral lesions with associated vascular involvement are hallmarks of this typically fatal 49 disease. Similarly, CNS Aspergillus fumigatus has been seen in AIDS, but brain abscesses requiring surgical excision are a more common form of presentation than meningitis. Other 40 fungal meningitides64rarely observed with AIDS include histoplasmosis, coccidiomycosis, and blastomycosis.

Parasitic Meningitis Toxoplasmosis may, on rare occasions, cause a ventriculomeningitis in the absence of mass 65 lesions. This clinical picture can be very confusing, and the diagnosis is rendered even more problematic by the difficulty in isolating the organism from CSF. PCR for T. gondii may 66,67 In addition to T. gondii, other CNS parasitic infections have been reported in be helpful. 68,69 association with HIV infection, including Chagas' disease (Trypanosoma cruzi) and 70 paracoccidiomycosis.

Lymphomatous Meningitis Among patients with AIDS, 5 percent ultimately develop71systemic lymphoma; approximately one third of the latter have a neurological presentation. The most common form of neurological illness occurring in association with AIDS-related systemic lymphoma is lymphomatous leptomeningitis, which may be either asymptomatic or symptomatic. The frequency of unsuspected lymphomatous meningitis occurring in AIDS-related lymphoma 71 approaches 20 percent. Accordingly, lumbar puncture is mandated in all AIDS patients with systemic lymphoma. Of these patients, 5 to7210 percent will also have cranial or peripheral nerve involvement and paraspinal masses. The clinical features of symptomatic lymphomatous leptomeningitis include headache, altered mental status, seizures, cranial neuropathies, and radiculopathies. Cranial neuropathies are not infrequent in association with HIV infection, but the potential etiologies of cranial neuropathy occurring with AIDS are extremely diverse (Table 45-4). Click here to view this table.... The most likely mode of entry73of the lymphomatous cells into the CNS is direct spread from contiguous extraneural sites. The high frequency of lymphomatous bone marrow infiltration argues for dissemination from the medullary cavity through the dura and into the 73 subarachnoid space. The neurological manifestations of AIDS-associated lymphomatous meningitis, particularly cranial neuropathy, may be exquisitely responsive to the administration of corticosteroids. Appropriate treatment requires intrathecal chemotherapy. GLOBAL ENCEPHALOPATHY Both an alteration in cognitive abilities and a decline in level of consciousness may occur in the setting of HIV infection. The former, currently attributed to a direct effect of HIV infection, is usually insidious in nature but on occasion may present in precipitous fashion. Alterations in level of consciousness are often associated with focal neurological abnormalities and typically result from mass lesions of the brain, usually opportunistic infections or lymphoma. The evaluation of a global encephalopathy complicating HIV infection requires a thorough physical and neurological examination; laboratory studies that assess electrolytes and renal, liver, and thyroid function; syphilis serologies; vitamin B12 and folate levels; cranial MRI, preferably with gadolinium or, alternatively, CT with a double dose of contrast and delayed scanning; and CSF analysis (unless contraindicated) with recording of opening pressure, measurement of total cell and differential counts, determination of protein and glucose levels, detailed microbiological studies, and cytology.

Viral Encephalopathy HIV Encephalopathy (AIDS Dementia Complex) Several appellations have been attached to the unique, progressive, dementing illness

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2,74

recognized shortly after the initial description of AIDS, including subacute encephalitis, AIDS dementia complex,75HIV encephalopathy, and, more recently, HIV-associated major cognitive/motor disorder. The exact incidence of this encephalopathy in HIV-infected individuals is unknown. Of 144,184 persons with AIDS reported to the Centers for Disease Control (CDC) between September 1, 1987, and August 31, 1991, there were 10,553 (7.3%) reported to have HIV encephalopathy: in 2.8 percent of the adult patients with AIDS and 5.3 75 percent of children with AIDS, HIV encephalopathy was the initial manifestation of the disease. In 2,3 other studies, HIV encephalopathy was the initial AIDS-defining illness in 0.8 to patients, and it has been detected in 4.0 percent of patients at the 2.2 percent of adult AIDS 76 The annual incidence in AIDS patients has been reported to be time of diagnosis of AIDS. 76,77 By the time of death, approximately one third of AIDS patients between 7 and 14 percent. 75 although estimates in excess of 50 percent have been will exhibit this dementia, 78 of this disorder has been suggested to be suggested. An apparent decline in the incidence 77,79 Since the introduction of HAART, the the result of the widespread use of zidovudine. incidence of this disorder appears to be decreasing. The incidence of pathological features concordant with HIV encephalopathy that have been observed at autopsy has varied in different series but in general is substantially higher than the estimates based on clinical 7,80–85 data. Considerable controversy has surrounded the issue of whether lesser degrees of cognitive impairment accompany HIV infection in its earlier stages. In general, large prospective longitudinal studies that have employed limited screening batteries have suggested that the occurrence of these abnormalities is no more frequent than in a suitably matched control population without HIV infection. However, smaller studies that have employed more extensive neuropsychological screening measures and electrophysiological tests suggest an increased prevalence over the control population. Whether the presence of these cognitive abnormalities predicts the development of AIDS dementia complex remains uncertain. There clearly appears to be a group of individuals with minor cognitive problems who do not progress over long periods of follow-up; however, the same observation has been made for 86 individuals meeting the criteria for significant cognitive disturbance. Brain atrophy characterized by sulcal widening and ventricular dilatation is commonly observed at autopsy in patients with HIV encephalopathy. Meningeal fibrosis may also be present. Histologically, the most common and distinctive feature of this illness is pallor of the white matter, chiefly seen in a paravascular distribution and often accompanied by an 87 astrocytic reaction. The favored location for this demyelination is the periventricular and central white matter. Multinucleate giant cells, the pathological hallmark of the disease, 78 probably result from direct virus-induced cell fusion. Other microscopic features include microglial nodules, diffuse88astrocytosis, and perivascular mononuclear inflammation. Thinning of the neocortex and neuronal loss on quantitative assessment in specific brain 89 regions have also been noted. In general, the pathological features correlate poorly with the clinical symptoms. The presence of diffuse myelin pallor and multinucleate giant cells seem 76 to correlate best. HIV encephalopathy typically78,90–95 occurs in the context of advanced immunosuppression and but it may be the presenting or even sole manifestation of coexistent systemic disease, HIV infection before96–98 the infected individual exhibits any other illnesses characteristic of The encephalopathy is characterized by an insidious onset of impaired immunity. disturbed intellect. Fatigue and malaise, headaches, increasing social isolation, and loss of sexual drive are noted. On rare occasion, the disorder begins abruptly and progresses rapidly. Symptoms include forgetfulness, difficulty in concentrating and reading, and a slowness in thinking, with an accompanying decline in job performance. Depression is 78 Sleep disturbance is not frequently considered, but dysphoria is typically absent. 99 100–102 uncommon, and both focal and generalized seizures have been described. The hallmarks of advanced AIDS, namely, wasting, alopecia, seborrheic dermatitis, and generalized lymphadenopathy, are typically apparent. The mental status examination reveals a slowing of mental processing (bradyphrenia) and other features consistent with a subcortical dementia. Abnormalities of both saccadic and pursuit eye movements are 103–107 Facial expression is diminished, and the voice is often hypophonic and 108 common. monotonous. Coordination is impaired, consistent with involvement of the basal ganglia. Fine movements are performed slowly and imprecisely. Bradykinesia, postural instability, slow and clumsy gait, and altered muscle tone are noted. In many respects, this disorder shares many features characteristic of Parkinson's disease, and some investigators maintain 109 that it is chiefly a disorder affecting the basal ganglia and forebrain. CSF studies show a mononuclear pleocytosis in one fifth of individuals, with counts usually 3 96 less than 50 cells/mm . An increased protein concentration, but usually less than 200 mg/dl,

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110

is observed in two thirds. Intrathecal synthesis of HIV-specific antibody and oligoclonal 112 111 bands are frequently present but are not predictive of the development of CNS disease. Potential surrogate markers in the CSF for HIV encephalopathy include an elevated HIV p24 113,114 and elevated levels of β2-microglobulin, neopterin, and quinolinic acid. The antigen 115 isolation of HIV from CSF is not a useful marker for HIV-related neurological disease. 116,117 However, quantitative HIV RNA PCR appears to correlate with disease severity. The latter is not regarded as a diagnostic marker, but may be helpful in explaining whether advancing dementia in the face of systemic viral suppression by antiretrovirals is the consequence of “CNS viral escape” (J. McArthur, personal communication). The most important aspect of radiographic imaging of the brain118 in patients with suspected The most commonly HIV encephalopathy is to exclude other neurological disorders. 1,108,119,120 MRI may show reported abnormality on CT scan of the brain is cerebral atrophy widespread involvement of large areas of white matter or smaller “patchy'' or “punctate'' 121 lesions as well as atrophy (Fig. 45-1). Neither the electroen-cephalogram (EEG) nor other electrophysiological studies are particularly useful diagnostic tools in HIV-infected individuals with HIV encephalopathy, despite assertions to the contrary. Detailed neuropsychological batteries, however, are often invaluable in determining whether there is an associated depression and in gauging the extent of the impairment and the response to therapy.

FIGURE 45-1 A, T1-weighted magnetic resonance image (MRI) of patient with AIDS dementia showing marked cerebral and cortical atrophy. B, T2-weighted MRI of the same patient showing extensive hyperintense signal abnormalities in the white matter. 122,123

Anecdotal clinical reports suggesting improvement in HIV encephalopathy with 90,124 and in zidovudine administration have been confirmed in controlled trials in adults 125 The response appears to require higher doses of zidovudine than are routinely children. 126 claim that HAART has a substantial salutary effect on HIV used. Some investigators 127–129 A longer duration of HAART therapy (more than 18 months) correlated encephalopathy. 128,129 Others have failed to find a robust response of HIV with better cognition. 130,131 The pattern of neurocognitive deficits may be different with encephalopathy to HAART. HAART, and some have suggested that some neuropsychological functions improve while others deteriorate, perhaps reflective of “burnt out” damage rather an active intracerebral 132 process. Cytomegalovirus Encephalitis CMV not infrequently results in retinitis, pneumonitis, gastroenteritis, hepatitis, and 133 encephalitis in persons with advanced immunosuppression due to AIDS. Pathological evidence of its presence in the brains of AIDS patients with neurological disease was found in 2 36 percent of patients in one study. Evidence of this involvement included neuropathological findings (i.e., microglial nodules, cytomegaly, and typical CMV inclusions), disseminated CMV infection, or serological evidence of previous CMV infection. Despite histopathological and virological evidence implicating CMV in the etiology of an HIV-associated encephalitis, the clinical features of CMV encephalitis in the AIDS population remain poorly characterized and clinical recognition is difficult. Indeed, CMV may localize to 134,135 Although imaging studies and analysis CNS tissues without significant clinical sequelae. of CSF may reveal abnormalities in many patients, none has been specific enough to allow a definitive diagnosis of CMV encephalitis. Kalayjian and colleagues argue that CMV

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ventriculoencephalitis in AIDS has sufficiently distinct clinical and pathological features to 136 allow identification. These features include previous or concomitant CMV retinitis or other serious CMV infection; altered mental status; nystagmus; cranial neuropathies; ventriculomegaly on neuroimaging; periventricular enhancement on CT scan; increased 3 periventricular signal intensity on T2-weighted MRI; CSF pleocytosis (up to 18,666 cells/mm , often with substantial numbers of polymorphonuclear cells); increased CSF protein (exceeding 50 mg/dl) and hypoglycorrhachia (less than 40 mg/dl). A multifocal CNS 137 138 disorder and isolated brainstem dysfunction have been observed with CMV encephalitis. Other clinical syndromes associated with CMV in AIDS are polyradiculoneuropathy,136 vasculitic neuropathy, myelopathy, and adrenal insufficiency with concomitant hyponatremia. Typically these illnesses occur after the onset of other AIDS-defining illnesses and in the 136 presence of low CD4 lymphocyte counts. Anecdotal reports support the use of ganciclovir, a selective guanosine analogue, and foscarnet for CMV encephalitis. FOCAL NEUROLOGICAL DYSFUNCTION OF CENTRAL ORIGIN Focal neurological disturbances, such as hemianopia, hemiparesis, and hemianesthesia, occurring with HIV infection may result from a variety of lesions affecting the cerebrum. These lesions can be broadly classified in their order of frequency as opportunistic infections, tumors, and cerebrovascular disease. The most common opportunistic infections in this category are Toxoplasma encephalitis and progressive multifocal leukoencephalopathy. With rare exception, brain tumors occurring with AIDS are primary CNS lymphomas, although other primary CNS tumors and metastatic tumors have been reported. It is not unlikely that the latter malignancies are more common than in the general population as a consequence of impaired tumor immunosurveillance in AIDS. In the HIV-infected patient with focal neurological signs, either a cranial MRI with gadolinium or a double-dose, delayed brain CT scan is mandated. The presence or absence of mass effect on radiographic imaging is extremely helpful in determining the etiology of the lesions.

Brain Disease With Mass Effect Toxoplasma encephalitis is the most common cause of focal intracranial mass lesion in HIV infection, followed in frequency by lymphoma. An approach to the management of intracranial mass lesions occurring with HIV infection is found in the algorithm shown in Figure 45-2. Less common causes of intracranial lesions with mass effect are pyogenic abscess, syphilitic gumma, Candida abscess, Nocardia abscess, cryptococcoma and cryptococcal pseudocysts, other fungal and parasitic diseases, and vascular-occlusive lesions.

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FIGURE 45-2 Algorithm for the management of intracranial mass lesions

occurring with human immunodeficiency virus (HIV) infection. CT, computed tomography; PET, positron emission tomography; SPECT, single-photon emission computed tomography. (Based on preliminary recommendations of a working group of the American Academy of Neurology on Mass Lesions in AIDS. From Berger JR: Quality Standards Subcommittee of the AAN: evaluation and management of intracranial mass lesions in AIDS. Neurology 50:21, 1998, with permission.) Toxoplasma gondii Infection Approximately 20 to 30 percent of AIDS patients in the United States will develop Toxoplasma encephalitis, although these numbers may be decreasing due to primary prophylaxis in HIV-infected persons with positive toxoplasmosis serology and profound immunosuppression. Usually, these patients present with focal neurological symptoms and signs often superimposed on a global encephalopathy. A prodrome of fever and malaise may occur for several days to weeks before the onset of the neurological illness. Mild hemiparesis 139 is the most common focal139 finding. Confusion, lethargy, brainstem and cerebellar disorders, of chorea in AIDS patients is believed to be and seizures are not rare. The appearance 140 virtually pathognomonic of toxoplasmosis. CT scan of the brain (Fig. 45-3) usually reveals multiple nodular or ring-enhancing lesions 139,141,142 Occasionally the CT scan is normal or reveals only a with edema and mass effect. hypodense lesion that fails to enhance with contrast. Most lesions occur in the basal 142,143 139 and the cerebral hemispheres, particularly the frontoparietal lobes. MRI ganglia 144 reveals discrete areas of increased signal intensity on T2-weighted images. The CT scan is probably the best radiographic method to judge the response to therapy. Although generally abnormal, the CSF findings in these patients are nonspecific. An elevation of CSF

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protein concentration (50 to 200 mg/dl) is seen in the majority,3and one third show a mononuclear 3pleocytosis (usually not exceeding 100 cells/mm ). Cells counts in excess of of another disease. Serological studies for 100 cells/mm suggest the presence145 146,147 A presumptive toxoplasmosis are typically elevated, but this is not invariable. diagnosis is made on the basis of the response to antitoxoplasmosis therapy, but brain biopsy is the only unequivocal means to establish the diagnosis. Excisional biopsies usually 148 show tachyzoites on routine histology, particularly in the periphery of the necrotic lesion.

FIGURE 45-3 A 33-year-old HIV-positive man presented with a seizure and

right hemiparesis. A, Contrast-enhanced CT scan shows edema in the basal ganglia bilaterally, with abnormal central enhancement, more marked on the left than on the right. The ventricles and sulci are excessively prominent for a patient of this age, consistent with the global parenchymal volume loss of HIV encephalopathy. B, A more superior image shows a ring-enhancing lesion with surrounding vasogenic edema in the left frontal lobe. The patient's anti-Toxoplasma titer was positive, and he responded well to a course of toxoplasmosis-specific therapy, supporting the diagnosis of toxoplasmosis. (Courtesy of Nancy Fischbein, MD, University of California, San Francisco.) A trial of therapy for toxoplasmosis of 2 to 3 weeks' duration in those patients with suspected Toxoplasma encephalitis is recommended. These patients should be carefully monitored clinically and radiographically for resolution of their lesions. If the therapy fails to effect clinical and radiographic improvement, brain biopsy should be performed. The use of corticosteroids may confuse the interpretation of this therapeutic trial, and their use should be avoided in this context. The current recommended therapy for Toxoplasma encephalitis is combination therapy of sulfadiazine and pyrimethamine, a dihydrofolate reductase inhibitor. The pyrimethamine is administered orally in an initial loading dose of 200 mg, followed by 50 to 75 mg daily, and the 149 sulfadiazine is administered as 4 to 6 g daily divided into four equal doses. Folinic acid, 5 to 10 mg daily, is needed to diminish bone marrow suppression. Side effects of these 150 medications are common, occurring in as many as 60 percent of patients. If sulfadiazine is unavailable, an alternative preparation is sulfisoxazole. In patients not tolerating sulfa medications, clindamycin 2.4 g daily can be substituted. The risk of relapsing Toxoplasma encephalitis is high, warranting the use of secondary prophylaxis. Agents employed for prophylaxis of Pneumocystis carinii pneumonia, namely trimethoprim-sulfamethoxazole and pyrimethamine-sulfadoxine, significantly reduce the risk of developing Toxoplasma 151 encephalitis. Other Infectious Diseases Infection with Nocardia asteroides, a gram-positive, weakly acid-fast bacillus, may occasionally result in brain abscess in AIDS patients. Treatment is often unsuccessful. Other causes of cerebral mass lesions of infectious origin seen in AIDS include mass lesions associated with brain abscesses due to mixed bacterial flora, Aspergillus, and the agents responsible for mucormycosis; tuberculous abscesses and tuberculomas due to M. tuberculosis or M. avium-intracellulare; cryptococcomas and cryptococcal pseudocysts; and syphilitic gummas.

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Primary CNS Lymphomas In the setting of HIV infection, the incidence of primary CNS lymphomas increases dramatically. As many as 0.6 percent of patients will present with these tumors concurrent 152 Estimates with the diagnosis of AIDS, and ultimately 2 percent develop the disease. 153 suggest that its incidence currently exceeds that of low-grade astrocytomas. These tumors are mostly of B-cell origin and both large-cell immunoblastic and small noncleaved 154 lymphomas are seen. Of potential etiological significance is the observation that Epstein–Barr virus (EBV) expression can be demonstrated in virtually all cases of 155 AIDS-related primary CNS lymphomas. Primary CNS lymphoma typically presents with confusion, lethargy, memory loss, hemiparesis, speech and language disorders, seizures, and cranial nerve palsies, in 91 descending order of frequency. The lesions are often multiple, and involvement of the meninges is frequently demonstrated by cytological examination or at the time of postmortem examination. On CT scan, most lymphomas are either hyperdense or isodense, round or oval 156 CSF masses with homogeneous contrast enhancement and variable surrounding edema. 13 analysis by PCR for EBV is diagnostically helpful. Distinguishing primary CNS lymphoma from toxoplasmosis and other infectious brain mass lesions is often difficult. An algorithm (Fig. 45-2) has been suggested by a working group of the American Academy of Neurology for evaluating brain mass lesions in AIDS. These tumors respond both clinically and radiographically to whole-brain irradiation. A regimen of 4,000 rads administered over 3 153 and regimens employing chemotherapy have weeks has been successfully employed, 157 157 been reported. The average survival is less than 4 months, with death often due to concurrent illnesses related to the immunodeficiency. Cerebrovascular Disease The spectrum of cerebrovascular disease that has been reported in association with AIDS is hemorrhagic disorders. In autopsy series, broad (Table 45-5) and includes both ischemic and 158 159 rates as high as 19 percent have been reported. In a case-control autopsy series, cerebrovascular disease was detected at autopsy in 8 percent of HIV-infected individuals but did not appear to occur significantly more frequently in HIV-infected persons than in age- and sex-matched controls with other terminal illnesses. Concomitant heart disease, particularly nonbacterial thrombotic (marantic) endocarditis, was frequent in both groups. Infectious vasculitis, especially meningovascular syphilis, must always be considered in the differential 160 diagnosis of these disorders. Vasculitis secondary to HIV infection has been reported. Click here to view this table....

Brain Disease Without Mass Effect The most common causes of intracranial lesions without mass effect in HIV-infected patients are progressive multifocal leukoencephalopathy, HIV encephalopathy, and CMV encephalitis. Of these disorders, only progressive multifocal leukoencephalopathy typically presents with focal neurological disturbances. MRI is the imaging study of choice, owing to its superior contrast resolution and marked sensitivity in detecting lesions that affect the white matter. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy is the result of infection of the brain with JC virus, a papovavirus. Before the AIDS pandemic, it was a rare disease, almost invariably occurring in association with the immunosuppression associated with lymphoproliferative disorders. Current estimates suggest that 2 to 5 percent of all patients with AIDS will develop 8,158 it. In approximately one fourth of AIDS patients with progressive multifocal leukoencephalopathy, the illness is the presenting manifestation of their immunosuppression. Limb weakness is the most common initial manifestation, followed in frequency by cognitive dysfunction, visual loss, gait161 disturbance, limb incoordination, speech or language disturbance, and headache. CT scan of the brain typically, although not invariably, reveals nonenhancing, hypodense white matter lesions without mass effect. These white matter lesions without mass effect are chiefly located in the centrum semiovale, predominantly in the 158 T2-weighted spin-echo MRI is highly sensitive parieto-occipital region and the cerebellum. 162 8 to 9 percent of the lesions in AIDS in detecting these lesions (Fig. 45-4). Approximately 161,162 The CSF is usually normal, although a show faint contrast enhancement by CT or MRI. mild increase in protein concentration, the presence of myelin basic protein, an increase in

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Aminoff: Neurology and General Medicine: AIDS and the Nervous Sy... 3


IgG, and a pleocytosis (9 to 25 mononuclear cells/mm ) have all been reported. The presence of an increased opening pressure or significant CSF pleocytosis should raise serious concerns about the diagnosis. Diagnostic confirmation requires either brain biopsy or 163 a positive CSF PCR for JC virus coupled with the appropriate clinical and radiographic findings. The disorder is characterized pathologically by demyelination; giant astrocytes with pleomorphic, hyperchromatic nuclei; and altered oligodendrocytes containing enlarged nuclei that stain abnormally densely with hematoxylin and harbor ill-defined inclusion bodies. JC virus can be directly demonstrated by electron microscopy or by in situ hybridization. The mean survival of patients with progressive multifocal leukoencephalopathy in AIDS is 3 to 6 158,161 Long-term161survival with nearly complete neurological recovery is observed in 7 months. 164 to 9 percent of patients. Low CSF titers of JC virus by quantitative PCR and the constellation of progressive multifocal leukoencephalopathy as the heralding manifestation of AIDS, contrast enhancement on radiographic imaging, and a high CD4 count are predictors 165 of prolonged survival. HAART improves the survival of HIV-associated progressive multifocal leukoencephalopathy, particularly in previously drug-naive patients. A significant improvement in survival in HAART-treated patients 166 with AIDS-associated progressive but has not been observed multifocal leukoencephalopathy has been reported, 167 universally. Antiretroviral therapy affects survival by restoring the immune system and not by a primary effect on JC virus. However, worsening symptoms and new lesions on MRI associated sometimes with mass effect and contrast enhancement may occur with IRIS complicating progressive multifocal leukoencephalopathy and 171 displays a significant 168–170 172 Survival is unaffected by cytosine arabinoside, interferon-alpha, or mortality.173 174 cidofovir. The apparent importance of the serotonin receptor 5HT2A for JC virus entry into cells suggest the possibility that serotonin-blocking agents may be of value.

FIGURE 45-4 T2-weighted MRI of brain of patient with progressive multifocal

leukoencephalopathy, showing extensive hyperintense signal abnormalities in the posterior regions of both hemispheres. SPINAL CORD DISEASE Spinal cord disease is frequent in HIV infection. A unique HIV-associated vacuolar myelopathy is the chief cause of myelopathy. The diagnosis of this disorder, like that of HIV encephalopathy, is one of exclusion. A number of other myelopathies may also occur with

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HIV infection including infectious myelopathies (due to CMV, herpes simplex type 2, herpes zoster, human T-lymphotropic virus type I [HTLV-I], mycobacteria, Treponema pallidum, and epidural abscesses), vascular myelopathies, epidural and intramedullary tumors, and a demyelinating myelopathy (Table 45-6). Click here to view this table.... For diagnostic and therapeutic purposes, it is useful to categorize spinal diseases occurring with HIV infection into two major groups, those that are the result of a mass lesion and those occurring in the absence of a mass lesion. The most common mass lesion affecting the spinal cord is lymphoma. Spinal lymphoma may present as (1) an intramedullary lesion, (2) meningeal lymphomatosis, (3) an epidural mass lesion, (4) bony metastases, and (5) some combination of these presentations. Other causes of mass lesions affecting the spinal cord are epidural and intramedullary nonlymphomatous tumors, intramedullary infections, and epidural abscesses. Epidural abscesses are most often seen in parenteral drug abusers and the most common organism isolated is Staphylococcus aureus.

HIV-Associated Myelopathy This unique degeneration of the spinal cord is seen at autopsy in more than 20 percent of 104 patients dying of AIDS. Usually, it begins insidiously and is characterized by leg weakness, gait impairment, paresthesias and vague leg discomfort, and bladder and bowel incontinence. Like HIV encephalopathy, HIV-associ-ated myelopathy generally occurs with advanced immunosuppression. Casual recording of the patient's symptoms often results in their being attributed to intercurrent illnesses and associated debilitation. However, neurological examination reveals spastic paraparesis, lower-extremity hyperreflexia (except when diminished as a result of concomitant peripheral neuropathy), gait ataxia, and impaired sensation, with vibratory and position sense being disproportionately affected. Lower-extremity involvement may be asymmetric. A discrete sensory level is distinctly unusual. HIV-related vacuolar myelopathy is seldom associated with abnormalities on MRI but, on rare occasion, spinal cord atrophy and hyperintense signals on T2-weighted images may be observed. Although gross examination of the spinal cord in this disorder is normal, histological examination reveals loss of myelin and spongy degeneration with 175,176 relative axonal Microglial nodules preservation, particularly affecting the dorsal and lateral columns. and HIV-laden multinucleate giant cells can be detected, but the correlation between the presence and degree of HIV infection and the spinal177pathology is poor. A metabolic disorder akin to vitamin B12 deficiency has been suggested. No treatment has demonstrated unequivocal value in178 HIV-related vacuolar myelopathy. Trials with high-dose l-methionine showed no efficacy. Other spinal cord disorders attributed to HIV include179an acute 175 and a myelopathy occurring at the time of primary infection, spinal myoclonus, 180,181 relapsing-remitting myelopathy that may accompany optic neuritis.

HTLV-I–Associated Myelopathy HTLV-I is recognized with increasing frequency in the HIV-infected population. It is transmitted in the same fashion 182–184 as HIV. Co-infection has been associated with an HTLV-I–associated myelopathy. 185 A similar myelopathy has been observed in a person co-infected with HIV and HTLV-II. HTLV-I–associated myelopathy is discussed further in Chapter 47. It is clinically indistinguishable from HIV-associated myelopathy. PERIPHERAL NEUROPATHY HIV infection is associated with a diverse group of peripheral neuropathies (Table 45-7). The exact role of HIV in the etiopathogenesis of these neuropathies remains obscure, and other factors such as concomitant infections, nutritional deficiencies, metabolic disorders, and side effects of drugs may be responsible for some of them. Prospective neurological evaluation may reveal evidence of peripheral neuropathy in up to 50 percent of patients with advanced HIV infection. Click here to view this table.... Although other types of peripheral neuropathy may be observed, the peripheral neuropathies associated with HIV infection can be divided into three major groups: a distal, symmetric peripheral neuropathy; an inflammatory demyelinating peripheral neuropathy; and a mononeuritis multiplex. The most common is a distal, symmetric sensorimotor neuropathy that typically develops in the late stages of the disease. Patients complain of often

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debilitating, painful dysesthesias and numbness of the feet. When present, distal weakness is generally mild; muscle stretch reflexes are depressed or absent. The sensory loss is greatest for vibratory perception, but other sensory modalities may be affected. Nerve conduction velocities are usually slightly decreased and sensory action potentials are either absent or of low amplitude, suggesting an axonal neuropathy, although features of demyelination may also be seen. Nerve biopsy may reveal epineural and endoneural perivascular inflammation 186 with axonal degeneration or demyelination. Symptomatic therapy with carbamazepine, phenytoin, tricyclic antidepressants, mexiletine, and topical capsaicin are of variable benefit. HAART,187,188 lamotrigine, and recombinant nerve growth factor have been demonstrated to be of benefit. Both acute Guillain–Barré syndrome and 143,189 a chronic, relapsing polyradiculoneuropathy may Nerve conduction studies are compatible with occur as a consequence of HIV infection. a demyelinating neuropathy. CSF examination reveals a normal to increased protein concentration (but usually 3less than 200 mg/dl) with a mild mononuclear pleocytosis (usually no more than 50 cells/mm ) or, more rarely, a normal cell count. Therefore, in contradistinction to typical Guillain–Barré syndrome, a CSF albuminocytological dissociation occurs in only a minority of affected individuals. Plasmapheresis may be beneficial in those 143 patients with chronic relapsing polyradiculoneuropathy, and high-dose intravenous immunoglobulin may be associated with striking improvement. On rare occasion, mononeuritis multiplex may be observed with HIV infection. Cranial, 189 peripheral, or spinal nerves may be affected. The disorder has been attributed to immune complex deposition resulting in a necrotizing vasculitis. Other causes of mononeuropathy, such as herpes zoster, CMV, and lymphomatous nerve root infiltration, must be excluded. 156,190

presents a striking picture. Progressive polyradiculomyelopathy that occurs due to CMV This illness is characterized at onset by lower extremity and sacral paresthesias. Progressive paraparesis ensues rapidly, with concomitant areflexia, ascending sensory loss, and 191 sphincter dysfunction. Although reported rarely as an early manifestation of HIV infection, it generally occurs with advanced immunodeficiency. An important clue to the presence of this potentially treatable illness is a polymorphonuclear pleocytosis in the CSF. CMV190 can be Rarely, detected in the CSF by culture, immunohistochemistry, and in situ hybridization. 190 cytomegalic cells may be seen in the CSF. A painful neuropathy has been attributed to a CMV-associated dorsal root ganglionitis, and CMV may also result in a disorder like 192 Guillain–Barré syndrome. Ganciclovir and foscarnet are the treatment modalities for these CMV-related conditions, but favorable reports have been anecdotal. MYOPATHY Skeletal muscle disease associated with HIV infection can be classified in four groups: (1) HIV-associated myopathies, (2) muscle complications of antiretroviral and other therapies, (3) 193 opportunistic infections and tumor infiltrations, and (4) rhabdomyolysis. Since the 193 introduction of HAART, the prevalence of these disorders appears to have decreased. Several forms of myopathy have been recognized in association with HIV infection. Among the most common is a polymyositis, which is clinically indistinguishable from idiopathic polymyositis. This disorder is characterized by proximal muscle weakness, myalgias, 194,195 Weight loss and excessive fatigability, and an increase in serum creatine kinase level. wasting, particularly of gluteal muscles, are often evident. Electromyographic features mirror those seen with idiopathic polymyositis. Muscle biopsy reveals fibrous tissue proliferation, necrosis,195 and phagocytosis of muscle fiber accompanied by an intense inflammatory infiltrate. The treatment of HIV-associated polymyositis parallels that of polymyositis in the non–HIV-infected person and includes the use of corticosteroids and other 196 immunosuppressive agents. Inclusion-body myositis, nemaline myopathy, and diffuse infiltrative lymphocytosis syndrome are among the other myopathic disorders observed with 193 HIV infection. Another form of myopathy has been attributed to zidovudine therapy. This illness is chiefly characterized by muscle wasting and proximal weakness and tends to occur 197 in individuals who have been treated with high doses of the drug for more than 6 months. It typically occurs in individuals who have received high cumulative doses of zidovudine and is 198 consistently associated with depletion of mitochondrial DNA (mtDNA), presumably as a consequence of the drug's ability to inhibit γDNA polymerase, an enzyme involved in mtDNA replication. Some investigators have suggested that HIV polymyositis predisposes to the 194 Other drugs used in treating HIV or200 its development of zidovudine-related myopathy. 199 complications, such as the statins, tenofovir, and trimethoprim-sulfamethoxazole, have also been associated with muscle disease, including rhabdomyolysis. A disorder referred to as the HIV-associated neuromuscular weakness syndrome that is

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characterized by weakness and elevated lactic acid levels has been reported with 201 antiretroviral therapy, particularly d4T (stavudine). This illness is characterized by hepatic steatosis, pancreatitis, and lactic acidosis and displays electrophysiological and pathological features of both peripheral nerve and muscle disease. Muscle biopsy in these patients has 201 revealed both inflammation and mitochondrial changes. 193Lipid accumulation in muscle resembling that of Reye's syndrome has been observed. The syndrome has been attributed to depletion of mtDNA and impaired oxidative phosphorylation due to selective 202 inhibition of DNA polymerase-γ by nucleoside analogues. In the largest series of this entity 201 to date, death occurred in 20 percent of patients with follow-up. The absence of prospective studies precludes any meaningful comments regarding the best therapeutic approach, although the offending antiretroviral medications should be discontinued and the acidosis aggressively treated. Previous

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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 46 Neurological Complications of Organ Transplantation and Immunosuppressive Agents ROY A. PATCHELL •

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NEUROLOGICAL COMPLICATIONS COMMON TO ALL TRANSPLANTATION TYPES Long-Term Effects of Immunosuppressants Direct Neurological Side Effects Neurological Infections Lymphoproliferative Disorders Seizures NEUROLOGICAL COMPLICATIONS ASSOCIATED WITH SPECIFIC TRANSPLANTATION TYPES Renal Transplantation Bone Marrow Transplantation Cardiac Transplantation Pulmonary Transplantation Hepatic Transplantation Pancreatic Transplantation

Organ transplantation, which began in the early 1950s with renal transplantation, has developed into one of the great advances in modern medicine. Over the past 50 years, transplantation has become the treatment of choice for many otherwise fatal diseases. Advances in tissue matching, improvements in surgical technique, and new immunosuppressive agents have increased both the number and type of transplantations performed. Kidney, bone marrow, heart, lung, liver, and pancreas transplants are now used regularly in the treatment of end-stage disease. Three types of transplants exist: syngeneic (identical twins), allogeneic (different genetic origins), and autologous (patient's own tissue). Of these, allogeneic transplants are the most common, although autologous transplants of bone marrow have become common in conjunction with chemotherapy. When a new organ is implanted in the same anatomical site as the old one (e.g., liver transplantation), the transplant is said to be orthotopic. When the organ is transplanted into a site that was not the original location of the organ being replaced, the transplant is heterotopic. Advances in immunology and transplant technique have allowed longer survival for transplant recipients, but this has resulted in the emergence of a number of neurological problems in

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these patients. Depending on the type of organ transplanted, 30 to 60 percent of transplant 1–4 recipients develop neurological problems. The neurological complications of organ transplantation can be divided into two major categories: (1) those common to all allogeneic transplants, due primarily to the effect of long-term immunosuppression, and (2) those specific to particular transplant types, due either to the underlying disease, which led to the need for a transplant, or some phenomenon that is peculiar to the transplantation technique. NEUROLOGICAL COMPLICATIONS COMMON TO ALL TRANSPLANTATION TYPES

Long-Term Effects of Immunosuppressants Syngeneic and autologous transplants do not require immunosuppression; however, most transplants are allogenic, and, therefore, most transplant recipients require some degree of chronic, lifelong immunosuppressive therapy to prevent rejection of the transplanted organ. Immunosuppressive agents and the resulting immunosuppression may affect the nervous system either directly or indirectly. The major neurological complications of immunosuppression are direct neurotoxic side effects of immunosuppressive drugs, infections, and the development of de novo malignancies. Direct Neurological Side Effects Cyclosporine

Cyclosporine is one of the most commonly used agents to prevent rejection and is employed for both chronic maintenance immunosuppression and for the treatment of acute organ 3 selectively inhibits helper and cytotoxic T cells by rejection. The drug binds to calcineurin and 5,6 blocking antigen-induced T-cell activation. There is also an inhibition of lymphokine production and release. Renal and hepatic toxicity and hypertension are the most serious systemic complications of the drug. Cyclosporine toxicity is one of the most common causes of neurological problems after organ transplantation, with 15 to 40 percent of patients experiencing some type of neurological side 5–8 effect. Although higher blood levels of cyclosporine are generally associated with side effects, there is no simple correlation between blood level and the development of any specific neurological complication. Other factors in combination with cyclosporine increase the risk of developing neurological problems; these risk factors include cranial radiation, hypocholesterolemia, hypomagnesemia, β-lactam antibiotic therapy, high-dose 5–10 corticosteroids, hypertension, and uremia. Tremor is the most common neurological complication of cyclosporine and is present in up to 7–9 within days of the start of 40 percent of patients. The tremor is usually mild and develops 11 cyclosporine. It is usually caused by sympathetic activation, but patients with cyclosporine-induced encephalopathy or leukoencephalopathy may also experience tremor. In addition, tremor may be a part of a syndrome of generalized cerebellar dysfunction. Most of the serious neurological toxicity of cyclosporine is due to its tendency to produce 5–8 hypertension. The hypertension that nearly always complicates cyclosporine use is due in part to renal toxicity, but, to a larger extent, it is due to the tendency of cyclosporine to stimulate the sympathetic nervous system by an unknown mechanism. The encephalopathy of cyclosporine toxicity is roughly correlated with blood levels, but it is 7,8 better correlated with the rate of change in blood pressure from the patient's baseline level. Cyclosporine neurotoxicity may be thought of as a forme fruste of hypertensive encephalopathy. It is characterized by tremor, abnormalities in mental states ranging from mild inattention to coma, seizures, and various visual syndromes characteristic of dysautoregulation in distal arterial 7,8 territories of the posterior circulation. These include visual hallucinations, visual field deficits, visual agnosia, Balint's syndrome (the triad of simultanagnosia, abnormalities in visually directed reaching, and difficulties with voluntary eye movements), and cortical 7–9 blindness with denial of deficit (Anton's syndrome). Magnetic resonance imaging shows increased signal on T2-weighted images in the occipital white matter, a finding that may be quite evanescent and does not represent stroke. Flow studies such as single-photon emission computed tomography demonstrate that this is due to 6–8 increased flow with extravasation of water. These findings are identical to those found in patients with hypertensive encephalopathy, including the syndrome of toxemia of pregnancy. It should be emphasized that the patient's blood pressure need not be very high (i.e., need not be in the range of malignant hypertension) for this syndrome to occur. The pathogenesis appears to be related to the rate of change of blood pressure combined with loss of cerebral

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autoregulation rather than the absolute level of blood pressure. Lowering of blood pressure by any means, including but not limited to lowering the blood level of cyclosporine, will result in resolution of the clinical syndrome and the imaging abnormalities. 12

Cyclosporine is epileptogenic and causes seizures in 2 to 6 percent of patients receiving 6,8,9 The seizures may be focal or generalized and are usually (but not invariably) associated it. with high serum levels of the drug. Hypertension, hypomagnesemia, hypocholesterolemia, aluminum overload, and the concomitant administration of high-dose corticosteroids have 5,8,9 been identified as aggravating or precipitating factors. Neuralgia and neuropathy are less common complications of cyclosporine. Sensory disturbances consisting of paresthesias, dysesthesias, and hyperesthesias of the distal extremities (especially hands) are more common than weakness. Nerve conduction and electromyographic abnormalities are rarely present, although evidence of combined 8,13 demyelination and axonal damage has been reported. The treatment for all the direct neurotoxic side effects of cyclosporine is either to decrease the dose or to eliminate the drug entirely, if possible. Fortunately, nearly all the direct side effects (including the most severe encephalopathies and motor syndromes) are usually completely reversible after stopping the drug. Tacrolimus

Tacrolimus (previously known as FK506) is an immunosuppressive agent that is used for 14 long-term immunosuppression. The drug is used with a frequency equal to that of cyclosporine and has a mechanism of action similar to that of cyclosporine, with similar 15 neurological and systemic side effects. Neurological side effects are somewhat less common but resemble those of cyclosporine and consist of tremor, anxiety, restlessness, 7,15,16 Approximately one third of patients who insomnia, nightmares, and paresthesias. receive parenteral tacrolimus develop headache; oral administration is only rarely associated with headaches. As with cyclosporine, most neurotoxic side effects of tacrolimus reverse completely after the drug is withdrawn. Corticosteroids

Corticosteroids were the first immunosuppressive agents used in transplantation and continue to be used for long-term immunosuppression and to treat acute rejection. Corticosteroids affect both cellular and humoral immunity and expose patients to a greater risk of opportunistic infection than do the newer immunosuppressive agents that are relatively T-cell specific. The systemic side effects of corticosteroids are many and are not reviewed here. The most common neurological side effects of corticosteroids are myopathy, steroid psychosis, and problems resulting from corticosteroid withdrawal. The exact frequency of corticosteroid myopathy is unknown, but many patients on moderate-dose corticosteroids 9,17 The syndrome is develop some signs of myopathy 2 to 3 weeks after the start of therapy. 18 characterized by proximal muscle weakness that is most severe in the hip girdle. Treatment is to discontinue the corticosteroids (if possible) or to change to a nonfluorinated corticosteroid and decrease the dose. The myopathy usually resolves completely in 2 to 8 9,19 months after corticosteroid therapy is stopped. Psychiatric complications occur frequently in patients taking corticosteroids; many patients develop mild psychiatric symptoms, which may include anxiety, 20 insomnia, irritability, More severe acute difficulties with concentration and memory, and mood changes. 21 psychiatric syndromes occur in about 3 percent of patients. The phrase steroid psychosis refers to several psychiatric syndromes that are associated with corticosteroids. Severe psychiatric reactions usually take the form of affective disorders, schizophrenia-like 20 syndromes, or delirium. The treatment of steroid psychosis involves stopping the drug (if possible) or changing over to dexamethasone (the corticosteroid least likely to cause steroid psychosis) and reducing the dose. In addition, affective syndromes may respond to lithium, and schizophrenia-like syndromes are treatable with major tranquilizers. Withdrawal from corticosteroids also may cause neurological complications, including myalgias and arthralgias 22 consisting of headache, lethargy, and (steroid pseudorheumatism), and a syndrome 23 nausea, with or without a low-grade fever. Spinal cord or cauda equina compression from epidural lipomatosis caused by 24,25 This rare complication usually corticosteroids has been reported in transplant recipients. 24 does not occur in patients taking less than the equivalent of 30 mg/day of prednisone.

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Clinical manifestations include back pain, myelopathy, and radiculopathy. The usual treatment is surgical decompression,25although simply stopping the corticosteroid therapy has been reported to improve symptoms. OKT3 Monoclonal Antibody (Muromonab-CD3) +

26,27

OKT3 is a monoclonal antibody directed against CD3 lymphocytes. Its major neurological side effect is aseptic meningitis, which occurs in about 5 percent of patients during the first 3 days of exposure to the drug. Cerebrospinal fluid analysis shows a lymphocytic pleocytosis with normal glucose and normal or slightly elevated protein concentrations. The syndrome is self-limited and benign. Lumbar puncture and culture of the cerebrospinal fluid should be performed to exclude a bacterial or fungal meningitis before OKT3-induced aseptic meningitis is diagnosed. The mechanism of the meningeal inflammation is probably part of a cytokine release syndrome or an allergic process similar to that occurring in some patients placed on nonsteroidal28anti-inflammatory drugs such as ibuprofen or treated with intravenous immunoglobulin. A more severe syndrome with variable degrees of mental status derangement, including seizures, may occur even more 29 rarely. It is associated with neuroimaging evidence of cerebral edema, but it is also self-limited and benign, even if the OKT3 is continued. OKT3 use also predisposes patients to develop lymphoproliferative processes (including lymphoma), a side effect that appears to be dose related. Antithymocyte and Antilymphoblast Globulins

Antithymocyte globulin (ATG) and antilymphoblast globulin (ALG) are antisera directed against thymocytes or lymphocytes. Rarely, patients develop an aseptic meningitis similar to 7,9 that seen with OKT3, which is also self-limited and benign. Azathioprine

Azathioprine is an antimetabolite that suppresses both cell-mediated and humoral immunity. Although used less frequently now that more specific immunosuppressants are available, the drug is still used for long-term immunosuppression. The main systemic side effects are 7,9 myelosuppression and hepatotoxicity. There are no direct neurotoxic side effects, although the nervous system may be affected secondary to infection or liver failure. Neurological Infections Patients who receive long-term immunosuppression are at increased risk of developing infections. Neurological infections occur in 5 to 15 percent of all transplant recipients but are more important clinically than that number implies because about half of the central 30,31 nervous system (CNS) infections that occur in immunocompromised patients result in death. Nearly every conceivable organism has been reported to infect transplant recipients, but about 75 percent of the cases are due to infection with Listeria monocytogenes, 31 Cryptococcus neoformans, or Aspergillus fumigatus. Transplant recipients are at increased risk of infection for several reasons, the most important of which is the immunosuppression necessary to prevent rejection of the allograft. However, factors other than exogenous immunosuppressive agents also contribute to the risk of infection. After transplantation, patients often have indwelling catheters, endotracheal tubes, and other portals of entry for infection. The patients' underlying diseases and their complications (especially hyperglycemia and uremia) contribute to the net state of immunosuppression. In addition, certain infections (especially viruses) also cause 30,31 The single most important risk factor for developing suppression of the immune system. post-transplantation CNS infection is the magnitude and length of time of immunosuppression. CNS infections in immunocompromised hosts may be difficult to recognize, as the usual signs of infection, such as fever and meningismus, may be subtle or absent in such patients, as these signs depend on a vigorous immune response to the infection. Because the usual 32 signs of CNS infection may be absent and because nearly any organism—bacterium, fungus, parasite, or virus—may be responsible, the clinician should have a high suspicion index for infectious causes of neurological deterioration in any transplant recipient. A few clues may be of help in determining the likely organism. An infection outside the nervous system should alert the clinician to a possible neurological

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infection. Skin lesions may be found to harbor Cryptococcus, and lung infection suggests Aspergillus, Nocardia, or Cryptococcus. Acute meningitis is often due to L. monocytogenes, whereas chronic meningitis, often with cranial nerve palsies, suggests tuberculosis or fungal organisms. A progressive multifocal syndrome with hemiparesis, visual symptoms, ataxia, dysarthria, and dementia should raise the specter of progressive multifocal leukoencephalopathy caused by the JC polyomavirus. A localized mass lesion (e.g., a brain abscess) is often due to multiple organisms, including anaerobes, but the predominant organism in the immunocompromised patient is usually Aspergillus, Nocardia, or Toxoplasma. 30–32

Another clue to the causative organism is the time period after transplantation. In the early period (up to 1 month after transplantation), CNS infections are rare. When infections are present, they usually were present before the transplantation, acquired from the donor organ, or related to surgical complications of the transplantation procedure or the presence of indwelling catheters. These infections are usually due to common pathogens that are found in the general (nonimmunosuppressed) population. If opportunistic infections occur during the first month after transplantation, there is usually some problem with the transplant recipients' environment (e.g., Aspergillus in the air supply). In the intermediate period (between 1 and 6 months after transplantation), the net state of immunosuppression is usually at its peak because of prolonged immunosuppressive therapy and the immunomodulating effect of common viral infections. During this period, the risk of CNS infection is greatest. Two types of infections predominate—viruses and opportunistic organisms. Viruses (especially cytomegalovirus [CMV] and Epstein–Barr virus [EBV]) are themselves immunosuppressive, and infections with these agents predispose patients to develop infections with opportunistic organisms, including L. monocytogenes, A. fumigatus, 30,31 and Nocardia asteroides. Most late infections (more than 6 months after transplantation) fall into three categories: the lingering effects of an infection acquired earlier, opportunistic infections related to long-term immunosuppression, or the return to a pattern of infection similar to that seen in nonimmunosuppressed individuals. Most lingering infections are caused by viruses. Examples of lingering CNS infections are progressive chorioretinitis from cytomegalovirus 30,31 and B-cell lymphoproliferative disease in the form of EBV-associated CNS lymphomas. Opportunistic infections that develop more than 6 months after transplantation tend to occur in patients with chronic allograft rejection who have been maintained on higher-than-usual doses of long-term immunosuppressive agents (cyclosporine, corticosteroids) and have received additional antirejection therapy (usually with OKT3, ATG, or ALG). These patients are at the greatest risk of developing opportunistic CNS infections. C. neoformans, L. monocytogenes, and N. asteroides are the most common organisms causing opportunistic CNS infections in this group of patients. Most instances of cryptococcal meningitis that occur 30 in transplant recipients are found in these patients. Not all patients who survive for longer than 6 months after transplantation are at a substantially increased risk of developing opportunistic infections. Patients who are maintained on minimal long-term immunosuppression and whose post-transplantation courses have been free of chronic viral infections or the need for excessive antirejection therapy have only a slightly increased risk of infection. In these patients, the organisms causing CNS infections are usually the same as those present in the nonimmunosuppressed population. Lymphoproliferative Disorders Lymphoproliferative syndromes occur after prolonged immunosuppression. Early reports identified an increase in 33,34 non-Hodgkin's lymphomas in transplant recipients, especially but many of these apparently malignant lymphomas lacked the primary CNS lymphomas, histological and genotypic characteristics of true lymphomas. Currently, post-transplantation lymphoproliferative disorder is a description used to cover the wide spectrum of abnormal proliferations of B lymphocytes ranging from “benign” diffuse polyclonal lymphoid hyperplasia 35,36 CNS involvement occurs in 15 to 25 percent of to malignant monoclonal lymphoma. 34,37 The38CNS is the only site of patients with post-transplantation lymphoproliferative disorder. detectable disease in about 85 percent of cases that involve the CNS. Post-transplantation lymphoproliferative syndromes are strongly associated with EBV infection (even though primary CNS lymphomas in immunocompetent people are not 33 necessarily associated with this virus). These B-cell lymphomas arise deep in the brain with

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a propensity for the perivascular spaces. CNS lymphoma is distinguished from progressive multifocal leukoencephalopathy by the fact that the former produces mass effect and is enhanced with gadolinium on magnetic resonance imaging. Therapy for CNS involvement by post-transplantation lymphoproliferative disorder consists of reduction in immunosuppression, antiviral therapy, conventional cytotoxic chemotherapy, radiotherapy, and33,34,39,40 other experimental therapies (e.g., anti–B-cell antibodies and Treatment of CNS involvement begins with reduction of interferon-alpha). immunosuppression. Antiviral therapy may be tried, but standard radiotherapy and 36,40 The result of treatment of CNS chemotherapy are often the only practical treatments. disease is difficult to assess because no large series have been reported, but there is no 40 doubt that CNS involvement makes the prognosis extremely poor. The overall survival rate of patients who develop post-transplantation lymphoproliferative disorder is only about 30 34,37 percent.

Seizures Seizures are a common neurological complication after organ transplantation and occur in 6 1,41 The most common causes of seizures are drugs (especially to 36 percent of patients. cyclosporine and OKT3), metabolic derangements, and hypoxic-ischemic injury (usually producing seizures in the first weeks after heart, lung, or liver transplantation). Infections, infarcts, and tumors are less frequent causes. Often, the seizure disorder is transient and requires no treatment other than reduction in the dose of cyclosporine, correction of any responsible metabolic problem, or treatment of any underlying infection. Long-term treatment with chronic antiepileptic drugs is undesirable in transplant recipients because many of the older major anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine) interfere with the metabolism of the most commonly used immunosuppressive agents because of induction of the hepatic cytochrome oxygenase 42 P-450 system. Adding an anticonvulsant may cause a variable decrease in cyclosporine levels, and the dose of cyclosporine sometimes has to be increased when older anticonvulsants are started. Patients who have had only a single seizure should not be started on long-term anticonvulsants. For short-term acute management of status epilepticus, the benzodiazepines are the least likely to interfere with cyclosporine metabolism (although 41 benzodiazepines do cause some increased degradation). These drugs have an advantage in that they can be given either orally or intravenously. In patients who require long-term treatment with anticonvulsants, the choice of agent to use has become easier with the introduction of newer anticonvulsants that have oral and intravenous formulations and do not induce hepatic enzymes, such as valproate, gabapentin, and levetiracetam. However, valproate should be avoided in patients with liver transplants because of potential hepatotoxicity. In general, phenytoin should be avoided because of its interference with cyclosporine levels and adverse effect on engraftment. NEUROLOGICAL COMPLICATIONS ASSOCIATED WITH SPECIFIC TRANSPLANTATION TYPES

Renal Transplantation The first successful human renal transplantation occurred in 1954 when Murray and 43 associates transplanted a kidney from one identical twin to another. Renal transplantation has now developed into the best therapy for most patients with end-stage renal disease, and the kidney is the most frequently transplanted organ. For kidney transplantations, there is virtually a 100 percent 1-year patient survival rate and an approximately 90 percent graft survival rate. The 5-year survival rate for nondiabetic renal transplant recipients is more than 44 30 percent of renal transplant recipients develop neurological 90 percent. Approximately 45–52 (Table 46-1). complications Click here to view this table.... Renal transplantation is most often performed in patients with glomerulonephritis (membranous or membranoproliferative), diabetes mellitus, and hypertensive renal disease. Other underlying diseases include polycystic kidney disease, lupus erythematosus, amyloidosis, analgesic nephropathy, and obstructive nephropathy. The toxic effects of pretransplantation uremia can cause subclinical neurological impairment and leave the 47,53 In addition, uremia nervous system vulnerable to subsequent injury after transplantation.

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may recur after transplantation. Many of the underlying diseases, especially diabetes and hypertension, are associated with accelerated atherosclerosis and predispose patients to 53 develop cerebrovascular complications before and after transplantation. Most of the neurological complications of renal transplantation are due to the underlying 53 disease for which the transplantation was performed. For example, polycystic kidney disease may be associated with multiple cerebral berry aneurysms, hypertension with ischemic and hemorrhagic stroke, lupus erythematosus with antineuronal antibodies and mental state changes, and uremic encephalopathy with hepatorenal syndrome. Rapid correction of hyponatremia may lead to central pontine myelinolysis, a syndrome that can range in severity from mild quadriparesis to deep coma or even death and can now be easily demonstrated in the pons or in extrapontine sites by magnetic resonance imaging. The renal transplantation procedure itself is relatively benign. Neurological complications, other than those caused by anesthesia or intraoperative hypotension, consist of arterial and 53 peripheral nerve venous thromboses and peripheral nerve injuries. The most common 54–56 The usual cause is injuries involve the femoral and lateral femoral cutaneous nerves. intraoperative compressive injury due to pressure from self-retaining retractors. In a few patients, the caudal spinal cord is supplied by branches of the internal iliac arteries rather than by intercostal arteries; in these patients, 55 when the iliac artery is used to supply blood to the allograft, spinal cord ischemia may result. Several characteristics of renal transplant recipients make their overall complication rate different from that of other organ transplant recipients. Many renal transplant recipients have some degree of vascular compromise either as a result of their underlying disease (hypertension,53diabetes) or because of emboli associated with underlying atherosclerosis or heart disease. The most common post-transplantation neurological complications in this patient population are cerebrovascular events; these occur in approximately 9 percent of all 46,47,50,51 renal transplant recipients. 57

Acute rejection of the renal allograft can produce an encephalopathic syndrome. Neurological manifestations consist of a nonfocal encephalopathy with headache, altered mental status, and seizures. Systemic manifestations are fever, weight gain, renal failure, and swelling and tenderness of the graft. This syndrome has been described only in renal transplantations, and the mechanism has not been identified; it is likely, however, that the syndrome is caused by soluble neuroactive immune factors (e.g., cytokines) released during the rejection process. A similar syndrome occurs as a side effect of OKT3.

Bone Marrow Transplantation 58

Bone marrow transplantations became a viable treatment option in the late 1960s. With improvements in tissue matching, immunosuppression, and supportive care, bone marrow transplantation has developed into an important method of treatment for aplastic anemia, certain inborn errors of metabolism, and a variety of hematological, lymphoreticular, and solid malignancies. Today, bone marrow transplantation is the second most common type of organ transplantation. Most of the associated neurological complications59occur in allogeneic transplants, which usually require long-term immunosuppression. Neurological complications occur in 60 to 70 percent of allogeneic bone marrow recipients (Table 46-2) 50,51,59–69 and are the cause of death in 5 to 10 percent. Click here to view this table.... The underlying diseases for which allogeneic bone marrow transplantations are performed may be the cause of neurological problems. Leukemias recur in the CNS in up to 1559,60,63,70 percent of patients undergoing bone marrow transplantation for acute lymphocytic leukemia and produce neoplastic meningitis. In addition, patients with malignancies have sometimes received prior radiation and chemotherapy that may result in neurological damage. The procedure for bone marrow transplantation is the most benign of all transplantation procedures. No anesthesia or incisions are required. The donor's bone marrow is infused intravenously, and there are usually no immediate complications. In the past, toxic 60,70 myelolethal preparatory regimens often caused neurological complications. Modern preparatory regimens consisting of alkylating agents (usually cyclophosphamide) with or without small doses (90%) and specific (>90%) if proper controls are used. Although cases occasionally are difficult to diagnose, with the proper use of CSF culture, India ink studies, and polysaccharide antigen test, the only limiting factor is usually failure to perform a lumbar puncture because the diagnosis was not considered. COCCIDIOIDES IMMITIS C. immitis is a dimorphic fungus with a natural habitat in semiarid soil, which explains its geographical distribution in the southwestern United States and in parts of Mexico and South America. Because many tourists travel through these areas and may become infected, clinicians outside the organism's natural habitat occasionally encounter coccidioidomycosis. This fungal infection begins as a primary pulmonary infection after inhalation of the organism. Most patients remain asymp-tomatic, and less than 0.2 percent of primary infections disseminate. Occasionally, this fungus may reach the meninges, either by hematogenous spread or by direct extension from osteomyelitis of the skull or vertebrae. 44,45

There are cases in which brain Symptoms of chronic meningitis are most common. 46,47 Spinal involvement occurs without meningitis, but this presentation is unusual. arachnoiditis with obstructive hydrocephalus and cerebral vasculitis with infarcts have been 48–50 Finally, it appears that patients with coccidioidomycosis involving the facial skin reported. 51 are at higher risk of meningitis than those with skin involvement at more distant body sites. Diagnosis may be confirmed by culture of the fungus from the CSF, but in many patients in endemic areas, it is diagnosed on the basis of a CSF pleocytosis (which shows eosinophilia in up to 70% of cases) and evidence of complement-fixing antibodies (CFAs) in the CSF. CFA titers are positive in 70 percent of patients at initial diagnosis, and in almost all patients as meningitis progresses. It is likely that genetic susceptibility plays a subtle but important role as a risk factor for meningitis. Meningitis appears to develop at a greater rate in African Americans and certain Asian populations than in whites. Most patients who contract CNS infection with C. immitis have no underlying disease, but immunosuppressed patients are at increased risk. However, corticosteroid treatment has been associated with more severe manifestations of primary infection, as well as with

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reactivation of latent disease and dissemination to the CNS. There have been many cases of 52 CNS infection with C. immitis in patients with AIDS. The fact that several areas of high prevalence of HIV infection are also areas of endemicity for this fungus has tremendous implications for the health care system because it is likely that the number of CNS infections due to C. immitis will parallel the numbers of patients with AIDS. Interestingly, the natural history of coccidioidal meningitis shows that patients whose only extrapulmonary site of53 infection was the CNS lived significantly longer than patients with more diffuse disease. It has also been shown that the white cell count in the CSF decreases during the course of untreated infection. However, lifelong triazole therapy for meningitis is required because of 54 the high rate of relapse. HISTOPLASMA CAPSULATUM H. capsulatum is a dimorphic fungus endemic in certain areas in the Ohio and central Mississippi valleys and Latin America. It can be found in bird and bat guano and in soil contaminated with guano. Many outbreaks of the disease have been attributed to disturbing contaminated soil, thus allowing the conidia to become airborne. Most infections develop after inhalation of the conidial form of the fungus, and infection in endemic areas is very common. Skin test data indicate that in one endemic area, up to 69 percent of the population 55 showed evidence of previous infection with this fungus. Most of the people infected have minimal symptoms, and dissemination occurs only rarely. When dissemination does occur, it has been estimated that between one tenth and one fourth of patients have CNS involvement. Although granulomas and other brain parenchymal lesions have been described, most patients with CNS lesions present with meningitis. Although Histoplasma meningitis can occur in apparently normal hosts, it has been shown to occur in immunocompromised hosts at a higher rate. Patients with AIDS are at high risk of development of disseminated disease, usually due to reactivation of latent infection. In the era before HAART, involvement of the CNS during disseminated infection was particularly 56 common in patients with AIDS. Because CSF cultures may be positive in only 10 to 30 percent of cases, even when large volumes of CSF are incubated for weeks, it is important to check CSF serologies for both antibodies and antigen. There are occasional cross-reactions 57,58 The Histoplasma CSF with other fungi, which can cause diagnostic confusion. polysaccharide antigen has been found to be positive in 40 percent of patients with histoplasma meningitis. BLASTOMYCES DERMATITIDIS B. dermatitidis is a dimorphic fungus endemic in Africa and in certain parts of the lower Mississippi valley, North Central states, and mid-Atlantic states in the continental United States. It is presumed to be inhaled from a source in soil, but its natural location in the environment has not been defined. Most people with infection have subclinical disease, and dissemination occurs rarely. Disseminated blastomycosis is characterized by granulomatous or suppurating lesions (or both) of the lung, bone, and skin. In some series, blastomycosis has been reported to involve the brain in 6 to 33 percent of disseminated cases. Although patients with CNS blastomycosis usually present with evidence of infection at other sites, 59,60 occasionally meningitis is the initial presentation, without evidence of extraneural disease. Although CSF cultures are rarely positive, chronic neutrophilic pleocytosis is a common 61 an finding in blastomycotic meningitis. CNS involvement is not limited to meningitis; 62,63 occasional patient has a mass lesion (blastomycoma) in the brain parenchyma. Immunocompromised patients are at increased risk of infection with B. dermatitidis. A review of 24 cases of infection with B. dermatitidis in a heterogeneous population of immunocompromised patients showed 6 cases of disseminated disease, including 4 with 64 CNS involvement. PARACOCCIDIOIDES BRASILIENSIS P. brasiliensis is a dimorphic fungus endemic to subtropical areas of Mexico and Central and South America. The lung is the primary location for initial infection; a few patients have widely disseminated disease that involves the CNS, but rarely has the infection been reported to involve only the CNS. Meningitis is an 65 unusual manifestation of infection with P. brasiliensis but occurs occasionally in normal hosts. The host response against this microorganism remains poorly understood. SPOROTHRIX SCHENCKII S. schenckii is a worldwide saprophyte of vegetation, notably sphagnum moss. Sporotrichosis

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presents as a chronic infection of skin and subcutaneous lymphatics, developing after a primary inoculation such as a rose thorn puncture. Pulmonary disease from inhalation of spores is uncommon. Dissemination beyond the skin, lung, and joints is rare; only 66–68 Most of the approximately a dozen cases of Sporothrix meningitis have been reported. patients with meningitis did not have overt extraneural disease at presentation. Diagnosis of this infection can be extremely slow and difficult using traditional culture methods; to reduce delays of up to 6 to 7 months, a test for Sporothrix antibodies in the CSF should be done in any undiagnosed case of chronic meningitis. Although meningitis with S. schenckii is so uncommon that risk factors cannot be defined accurately, certain patients may be predisposed to dissemination from a local infection, including patients with myelodysplastic syndromes, ethanol abusers, or patients on 66 corticosteroids. Disseminated sporotrichosis has also been described in patients with AIDS. PENICILLIUM MARNEFFEI This dimorphic fungus is found in the geographical range of bamboo rats and has become a common cause of opportunistic infection in HIV-infected patients in parts of Southeast Asia. Pathophysiologically, the infection appears similar to histoplasmosis, but it has a unique predisposition for producing skin lesions. In one series, 3 of 20 CSF samples were positive for this fungus during disseminated disease. Remarkably, 10 percent of patients in one series 22 with disseminated penicilliosis also had concomitant cryptococcal meningitis. CANDIDA SPECIES Candida species form part of the normal human microbial flora and rarely cause invasive disease unless host defenses have been impaired. This yeast can gain access to the blood stream and then the CNS via contaminated intravenous catheters or through illicit 69 70,71 2 Neonates, neutropenic subjects, and patients recovering from intravenous drug use. 72,73 are particularly susceptible to invasive candidiasis, including CNS major surgery are the most common fungi to involvement. Based on autopsy studies, Candida species 74,75 76 77 invade the CNS. Candida may cause meningitis, ventriculitis, or parenchymal lesions such as abscesses or granulomas. C. albicans is the species implicated in most81–83 CNS 78–80 infections, but other species such as Candida tropicalis, Candida lusitaniae, and 84 Candida parapsilosis, occasionally produce CNS infection. In the normal host, Candida rarely causes deep-seated infections. However, there are multiple factors that can encourage spread of Candida from mucosal surfaces to deeper tissues, including the subarachnoid space. These factors include prematurity, broad-spectrum antibacterial therapy, hyperalimentation, malignancies, indwelling catheters, treatment with corticosteroids, neutropenia, abdominal surgery, diabetes mellitus, burns, and intravenous drug use. Candida invades brain tissue more commonly than the subarachnoid space. Candida species are susceptible to the oxidative and nonoxidative antimicrobial mechanisms of professional phagocytes, cells that are undoubtedly important for control of infections with Candida. The importance of the host response has been further emphasized by reports of Candida meningitis in both congenital and acquired immunodeficiency syndromes. Patients with chronic granulomatous disease of childhood and myeloperoxidase 85,86 may present with Candida meningitis. Several cases of Candida meningitis deficiency have been reported in patients with the global immune defects caused by severe combined 87 immunodeficiency (SCID). Therefore, a specific underlying immunodeficiency should be considered in any case of spontaneously occurring Candida meningitis, especially in children. Patients with AIDS frequently have mucocutaneous forms of candidiasis such as thrush and esophagitis, but involvement of the CNS has been reported only rarely in these patients. Although neutropenia is a risk factor for Candida infection of the CNS, most patients with candidemia with or without neutropenia do not commonly have seeding of the CNS. However, candidemia in neonates may be more likely to seed the subarachnoid space and produce a as a superinfection of the CSF in CNS infection. Candida meningitis has been described 88 patients recovering from bacterial meningitis. Candida infection can involve the brain and subarachnoid space by direct extension through trauma, ventriculostomy placement, or ventricular shunts, particularly in the presence of antibacterial use. Candida can also invade 89 from adjacent sinuses or bone. Finally, the infection can produce intracranial extension 88 through an arteritis and even lead to subarachnoid hemorrhage. The CSF in Candida meningitis can show a predominance of either mononuclear or 90 neutrophilic phagocytes. Unfortunately, only approximately half of routine CSF cultures yield the fungus, despite the fact that Candida organisms are easy to grow in the laboratory. A large CSF volume is needed to optimize culture, and better methods are needed to detect fungal products or antigens. The clinical significance of a positive culture for Candida

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organisms from CSF obtained through an indwelling device like a ventriculostomy tube is 91 are normal, another CSF unclear. If a positive culture is found and CSF parameters 91 specimen should be obtained from a lumbar puncture. In the absence of symptoms or an abnormal CSF profile, and with a negative follow-up culture, further treatment is probably 71,91 but the device should be removed and, if necessary, replaced. unnecessary, ASPERGILLUS SPECIES Aspergillus species are ubiquitous in the environment and can be found in the air of most buildings, including hospitals. Both neutrophils and macrophages provide important host defense mechanisms directed against the spores and hyphae of Aspergillus. CNS infection with Aspergillus species can develop by direct extension from the paranasal sinuses; by direct inoculation after head trauma, surgery, or lumbar puncture; or by hematogenous spread in immunocompromised hosts, particularly those with prolonged neutropenia. This 75 fungus accounts for approximately 5 percent of CNS fungal infections. A clinically important characteristic of Aspergillus infections is their predilection to invade arteries, causing thromboses. Therefore, cerebral infarction or mycotic aneurysm due to invasion along cerebral arteries is a common presentation of Aspergillus infection in the CNS. Meningitis and 92,93 meningoencephalitis19,94–97 can also occur, and rhinocerebral disease similar to mucormycosis has been described. Most intracranial infections with Aspergillus have occurred in neutropenic patients. The risk of disseminated aspergillosis with subsequent brain parenchymal involvement or meningitis 98 increases with the duration of neutropenia or high-dose corticosteroid therapy for graft-versus-host disease. Most infections manifest as parenchymal lesions, but meningitis 99 and spinal cord lesions have been seen. Occasionally, Aspergillus infection involves the vertebrae and eventually the subarachnoid space. Patients with chronic granulomatous disease of childhood are particularly susceptible to this type of infection. The pulmonary alveolar macrophage may be most important in initial control of this ubiquitous fungus in the lungs, but polymorphonuclear leukocytes are probably crucial in defense against CNS invasion. Diagnosis can be delayed because of insensitivity of cultures. Thus, both CSF polymerase 100 chain reaction and galactomannan antigen tests are being studied to help in diagnosis. ZYGOMYCOSIS Fungi of the class Zygomycetes are widespread in the environment. Infection is usually due to inhalation of spores. The genus Rhizopus is responsible for most infections caused by this group. CNS infection in compromised hosts can occur by direct extension from the paranasal sinuses through hematogenous spread such as illicit intravenous drug use or even by spread 101 species, commonly invade up nerve roots into the CNS. Zygomycetes, like Aspergillus 102,103 Zygomycetes occasionally arteries and cause thromboses with resulting infarction. invade the subarachnoid space; however, disease limited to the meninges is unusual. Patients with diabetes mellitus (with or without ketoacidosis) or malignancy or those receiving immunosuppressive or voriconazole therapy for a severe underlying disease are at risk of disseminated infection. There have been reports of disseminated zygomycosis, including 18 brain involvement, in patients on dialysis receiving desferroxamine. This iron-chelating agent may interfere with the antifungal activity of transferrin, thus allowing dissemination of Zygomycetes. PSEUDALLESCHERIA BOYDII P. boydii has worldwide distribution in soil and contaminated water. This fungus is also known as Monosporium apiospermum or Scedosporium apiospermum when it is in the asexual state. Although rare, infection can result in brain abscesses or chronic neutrophilic 104 with aspiration of contaminated water during meningitis. CNS infection is associated 104,105 Presumably, this fungus penetrates through the trauma or near-drowning in fresh water. cribriform plate during water immersion or establishes a pulmonary focus with later dissemination to the CNS, producing meningitis or brain abscesses. Other risk factors include 106 steroid immunosuppression and diabetes. PHAEOHYPHOMYCOSIS The dematiaceous fungi are a group of common environmental molds that have brown pigment in their walls; thus, diverse genera are linked by their ability to produce melanin. This group of fungi has occasionally caused CNS infection, and for certain species, it appears that there is some neurotropism. Cladosporium trichoides, also known as Xylohypha bantiana and

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renamed as Cladophialophora bantianum, is the most common isolate of this class of fungi found in CNS infections; the infection usually manifests as a brain abscess, although 107–110 Meningitis caused by other species of these “black meningitis has been described. molds” is also reported occasionally, and it111–114 has even been caused by contaminated corticosteroid injections around the spine. Most patients diagnosed with brain abscesses due to one of the dematiaceous fungi have no apparent underlying immune defect, but immunosuppressed patients can be at risk. The portal of entry for these fungi in most cases is not known, but because of a predilection for abscess formation in the frontal and parietal lobes, it can be hypothesized that at least some of these infections result from direct extension through the sinuses. HYALOHYPHOMYCOSIS These nonpigmented, hyaline filamentous molds cause occasional infections of the CNS. For 115 Acremonium and example, meningitis and cerebritis have been reported with 14 Paecilomyces species. In severely neutropenic patients, the soil saprophytes, Fusarium species, can produce CNS lesions. Because of similar histopathological features, Fusarium infection can be confused with aspergillosis unless cultures are performed. Finally, in the growing immunosuppressed population, Trichosporon infection, which usually involves only superficial skin or hair shafts, can disseminate to the brain. CNS infections with both T. 10,116,117 9 beigelii, and Blastoschizomyces capitatus (Geotrichum capitatum) have been reported. DIAGNOSIS The diagnosis of CNS fungal infections can be very difficult, even when involvement of the CNS occurs in the setting of disseminated fungal infection. This is due to many factors, including unusual clinical presentations of patients with CNS fungal infection, difficulty in culturing the organism, and the lack of sensitive serological tests for most of the fungi. In cases of cerebral mass lesions due to fungi, most patients present with nonfocal neurological complaints and physical findings. For instance, many patients present only with altered sensorium or seizures, despite having extensive focal CNS infection revealed by radiographic testing. Patients with fungal meningitis usually present with chronic signs and symptoms. Some combination of fever, headache, lethargy, confusion, nausea, vomiting, stiff neck, and neurological deficits usually is present. However, these markers of CNS infection may not always be present when the patient is first observed. In fact, the characteristic markers of CNS infection, fever and headache, both may be absent, and patients may present only with a subacute dementia. Furthermore, cases of cryptococcal, coccidioidal, and Histoplasma meningitis may be indolent, with symptoms persisting for months to years if 118–122 untreated ; thus, timing of symptoms is not always an accurate guide to diagnosis. However, patients with fungal meningitis usually present with subacute symptoms; some cases of cryptococcal meningitis present acutely after only several days of symptoms. Immunocompromised patients, especially those receiving high doses of corticosteroids or with an underlying HIV infection, can manifest symptoms or signs over just a few days. Fungal infection is a primary consideration in the differential diagnosis of any case of chronic meningitis. Ellner and Bennett have defined this group of patients as those with CNS 123 abnormalities that either progress or fail to improve during at least 4 weeks of observation. The differential diagnosis of chronic meningitis includes both infectious and noninfectious causes (Table 48-2), but fungal infection should be high in the differential diagnosis. It may be particularly difficult to distinguish infection due to fungi from that caused by certain other subacute or chronic pathogens such as mycobacteria. Click here to view this table.... The CSF findings in fungal meningitis have been well described. Most cases3have a in mononuclear pleocytosis, with counts ranging between 20 and 500 cells/mm . However, 124 some cases of fungal meningitis, there is a predominance of polymorphonuclear cells. Eosinophilic pleocytosis of the CSF has been described in cases of coccidioidal meningitis 125 and, rarely, in cases of cryptococcal meningitis. If there are eosinophils in the CSF, Coccidioides should be strongly considered because approximately 70 percent of cases have 126 3 CSF eosinophilia. Very low CSF leukocyte counts (2,500/ml) before drug treatment in order to limit the risk of complications during therapy.

Trematodes

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Schistosomiasis Schistosoma organisms are trematode parasites transmitted to humans in contact with fresh water. The infectious larvae (cercariae) are released by parasitized snails, which serve as 201 intermediate hosts. There are three major species: Schistosoma mansoni is common to Africa and Brazil; Schistosoma haematobium is found in Egypt, in the Middle East, and throughout tropical Africa; and Schistosoma japonicum is found in Asia, Indonesia, and the Philippines. After cercariae penetrate the skin, developing worms migrate to the mesenteric blood vessels (S. mansoni and S. japonicum) or to the venous system surrounding the ureters and bladder (S. haematobium). Host morbidity results from release of parasite eggs into surrounding host tissues, with resultant granulomatous inflammation and scar formation. CNS disease is relatively rare in schistosomiasis and appears to result from aberrant deposition of eggs within nervous tissues, either by migration of adults into the CNS or by transport of eggs into the CNS circulation via collateral veins. The syndrome of cerebral schistosomiasis is most common in S. japonicum infection, 201 affecting up to 2 to 4 percent of patients. It is characterized by focal motor and sensory deficits, seizures (jacksonian or generalized) with electroencephalographic abnormalities, focal abnormalities on MRI, and hyperdense, multinodular enhancing lesions on CT scans, 202–204 In uncontrolled trials, treatment with praziquantel (60 mg/kg) with surrounding edema. has been associated with improvement or cure of seizures and resolution of CT 203 abnormalities. By contrast, cerebral schistosomiasis is rarely seen with infections due to other schistosome 201 species. With S. mansoni infection, cerebral involvement often appears with acute infection, manifesting as a febrile meningoencephalitic reaction that may be associated with a 205 206 Chronic CNS disease may show evidence of vasculitis or cutaneous allergic reaction. 207 mass lesions. Spinal cord syndromes 208–212 appear to be more common in patients with S. mansoni or S. Presentation may be acute or subacute and may be associated haematobium infection. 213,214 with cutaneous deposition of eggs at the level of spinal cord involvement. Presenting 208–212 syndromes include low back pain, paraparesis, sensory loss, and bladder dysfunction. 212 Acute vascular compromise may result in myelonecrosis, or expanding granulomatous inflammation may lead to cord compression with evidence of CSF blockage 212 on MRI, 208 deterioration to one of myelography, or CT. The course may vary from one of rapid 207,215 gradual improvement and resolution after antiparasitic therapy. 201

Diagnosis should include parasitological or serological evidence of schistosome exposure 216 and must exclude other causes of myelitis found in areas endemic for schistosomiasis. Because developing areas also pose significant hazards in terms of chemical and venomous toxins as well as endemic polio and coxsackievirus infection, it may not be possible to determine 216 with certainty the etiology of a patient's CNS disease without biopsy or autopsy diagnosis. Therapy 201 with praziquantel will provide eradication of infection in more than 80 percent of or both, patients. Symptomatic treatment with corticosteroids or surgical decompression, 207,215 may be necessary to control acute CNS symptoms and prevent tissue injury. Paragonimiasis and Fascioliasis Tissue trematodes (flukes) infect217 humans who consume larval metacercariae in undercooked Paragonimus species are endemic in areas of Asia and crustaceans or raw water plants. 217,218 but paragonimiasis has also been transmitted within the South and Central America, 219 United States. Fascioliasis is cosmopolitan in its distribution and is common to many sheep- and cattle-raising areas. Disease occurs as maturing larvae migrate through host tissues from the gastrointestinal tract to the lungs (paragonimiasis) or liver (fascioliasis). CNS disease is frequent in paragonimiasis but rare in fascioliasis, occurring when ectopic parasite 217,218 Presenting CNS syndromes may localization takes place within the brain or spinal cord. include acute and chronic meningitis, mass lesions, hemorrhage, infarction, or ocular abnormalities (papilledema, hemianopia, nystagmus,217and optic atrophy). Frequent symptoms include seizures, headache, and visual disturbance. Intellectual deterioration and vomiting may also be noted. Diagnosis depends on a positive exposure history, along with parasitological, serological, or 217 biopsy evidence of infection. Sputum examination for ova is appropriate for identification of

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Aminoff: Neurology and General Medicine: Parasitic Infections of the...


the lung fluke Paragonimus westermani, the most common cause of paragonimiasis in Asia, whereas stool examination for ova is appropriate for identification of the liver fluke Fasciola hepatica. Radiographic examination of the lungs may show typical lesions of concurrent Paragonimus infection; retrograde cholangiography and bile duct aspiration may confirm exposure to or infection with liver flukes. Skull radiographs may show localized punctate or 220 nodular calcification. Neuroimaging studies may reveal ventricular dilatation and multiple lesions within brain tissues. In the CSF, examination often shows lymphocytic pleocytosis and elevated protein concentration, but eosinophils are found in less than 10 percent of CSF 221 samples examined. Effective therapies for CNS paragonimiasis or CNS fascioliasis are not established. A combination of 218,221 surgical removal of the parasite and praziquantel therapy has been Symptomatic therapy with corticosteroids, anticonvulsants, or ventricular recommended. shunting may be necessary. Previous

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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 50 Neurological Complications of Vaccination ALEX C. TSELIS •

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Previous HISTORY OF VACCINES TYPES OF VACCINES COMPLICATIONS OF VACCINATION DETECTION OF VACCINE ADVERSE EVENTS Smallpox Measles, Mumps, and Rubella Measles Mumps Rubella Diphtheria, Pertussis, and Tetanus Diphtheria Pertussis Tetanus Influenza Hepatitis B Poliomyelitis

Yet it was with those who had recovered from the disease that the sick and the dying found most compassion. These knew what it was from experience, and had now no fear for themselves; for the same man was never attacked twice—never at least fatally. Thucydides, The Peloponnesian War: Plague of Athens, 430 bc Moreover, I have known certain persons who were regularly immune, though surrounded by the plague-stricken, and I shall have something to say about this in its place, and shall inquire whether it is impossible for us to immunize ourselves against pestilential fevers. Fracastoro, On Contagion, 1546 Infectious diseases have historically been the major cause of human morbidity and mortality. Vaccinations have added immeasurably to human health by preventing such diseases. The benefits of vaccinations have not come without some costs, however, and rare adverse

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effects of vaccines occur. Many important adverse events are neurological, and these are discussed in this chapter. In addition, the U.S. Centers for Disease Control and Prevention 1 (CDC) regularly update and publish useful summaries of vaccine recommendations. Table 50-1 shows a schedule for the routine immunization of healthy children and adolescents. Click here to view this table.... HISTORY OF VACCINES The idea of vaccination came from the observation that a survivor of “the plague” was unlikely to fall ill from that disease again. It had long been known that matter from smallpox lesions, when inoculated into the skin of a naive recipient, often caused a mild form of the disease and protected against the full disease. Lady Mary Wortley Montague, the wife of the British ambassador to Turkey, introduced this method, called variolation, to Europe in 1721. Variolation was not always safe and occasionally resulted in fully virulent smallpox. In 1798, Jenner used cowpox inoculation to protect against smallpox, which eliminated the possibility of transmitting fully virulent smallpox with variolation. The basic strategy of vaccination further developed with Louis Pasteur's first successful rabies vaccine, Max Theiler's yellow fever vaccine, and Jonas Salk's and Albert Sabin's polio vaccines. Other important vaccines include those against influenza, whooping cough (pertussis), diphtheria, tetanus, hepatitis B, measles, mumps, rubella, Haemophilus influenzae B, meningococcus, and varicella-zoster. Vaccines are available in Asia to prevent Japanese encephalitis and in Central Europe to prevent tick-borne encephalitis. TYPES OF VACCINES Vaccines are made up of relevant antigens presented to the immune system in a way that generates protective immunity against the fully virulent pathogen without causing disease. There are several types of vaccines with different mechanisms of action. These include inactivated, attenuated, subunit, recombinant, component, DNA, and vector vaccines. Inactivated vaccines consist of pathogens that have been treated by chemical or physical methods so that they are nonviable. These treatments generally modify viral proteins essential to some critical function, such as attachment of the virus to the cell. Nevertheless, in successful vaccines, these inactivated organisms have sufficient antigenicity that protective immunity is achieved. Examples of inactivated vaccines include influenza vaccine, the Salk polio vaccine, rabies vaccine, and the whole-cell pertussis vaccine. Attenuated vaccines use a virus (or other pathogen) that has been adapted to replicating in a different host system, such as tissue culture, or in chicken eggs. This is achieved by serially passaging the virulent (or wild-type) pathogen in an alternative host system. The pathogen is now “adapted” to the alternative host system and humans are an “unnatural host.” The agent is unable to express its full virulence and so causes a mild infection but still stimulates full immunity. An example of an attenuated vaccine is the combined measles, mumps, and rubella (MMR) vaccine. Subunit vaccines are composed of subunits of a pathogen that are both nontoxic and immunogenic. Hepatitis B vaccine is an example, as is acellular pertussis vaccine. Hepatitis B vaccine consists of hepatitis B surface antigen (HBsAg) that was originally purified from the plasma of hepatitis B carriers. Because of concerns about using human-derived material, the gene for hepatitis B surface antigen was introduced into yeast that then synthesized pure hepatitis B surface antigen. This is the first human recombinant vaccine. Component vaccines usually consist of the capsular material of common bacterial pathogens. Antibodies to the capsules allow opsonization of the organism. Examples of component vaccines are those to pneumococcus, meningococcus, and Haemophilus influenzae B. These vaccines are often not sufficiently immunogenic in very young infants and have to be specially formulated by conjugation to peptides, which enhance their antigenicity. Toxoid vaccines are bacterial toxins (diphtheria, tetanus) that have been rendered nontoxic, but not nonimmunogenic, by chemical treatment. DNA vaccines are DNA sequences of the gene for an immunogenic antigen and are injected into muscle where they direct the synthesis of the antigenic peptide. This is then presented to the immune system by the “infected” muscle cell, which mimics a natural infection. However, DNA vaccines have proved to be poorly immunogenic in humans and none are available for human use. Vector vaccines consist of a nonpathogenic virus, which has one of its genes replaced by a

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gene for an antigen of interest. Such vaccines are being investigated but are not yet available for human use. COMPLICATIONS OF VACCINATION As mentioned earlier, the benefits of vaccination come with a price. There are several ways that vaccinations can cause adverse effects. Most often, they induce a nonspecific inflammatory reaction with headache, malaise, mild fever, and pain at the injection site. This reaction is self-limited and needs no treatment beyond mild analgesics. More serious adverse effects include contamination of the vaccine with fully virulent virus, reversion of attenuated virus to a fully virulent form, contamination of the vaccine with previously unrecognized agents, the use of inappropriate antigens causing an aberrant immune response with injurious effects, and induction of an immune response with autoimmune character. Some adverse effects are of unknown mechanisms. Some vaccines have inadvertently contained fully virulent virus. In the so-called Cutter incident, inadequate inactivation of the virulent virus during manufacture of the vaccine occurred shortly after the introduction of the Salk inactivated poliovirus vaccine. Procedures for inactivation of the virus by treatment with formalin were not followed precisely. Some of the virus that went into the vaccine was fully virulent, causing cases of paralytic poliomyelitis. Reversion to virulent form occurs rarely with the use of the Sabin vaccine, which is an attenuated poliovirus vaccine. During replication of the virus, mutations that restore pathogenicity can occur rarely and result in vaccine-associated paralytic poliomyelitis. In some cases, the virulent vaccine virus spreads to the vaccinated person's contacts, and small outbreaks of polio can result. Contamination with previously unrecognized agents is an ever-present danger. There are numerous examples. In World War II, U.S. military personnel serving in the tropics contracted hepatitis after being vaccinated for yellow fever. The yellow fever vaccine, an attenuated vaccine, had human serum added to it for stabilization of the attenuated virus. Some of this serum had been obtained from carriers of hepatitis B. Another contaminant of yellow fever vaccine was avian leukosis virus, present silently in chicken eggs, which were used for growing virus for vaccine manufacture. The Salk polio vaccine virus was grown in monkey kidney tissue culture, which contained the SV40 virus in latent form, and the vaccine was thus contaminated with this agent. A more ominous example is that of the contamination of louping-ill vaccine, the virus of which was grown in the brains of sheep and given to animals in Britain. At least one of these sheep had scrapie and the vaccine was contaminated with scrapie prions. This resulted in an outbreak of scrapie in the vaccinated animals. As a consequence, the U.S. Food and Drug Administration (FDA) requires that any animal protein products used in the manufacture of vaccines is from countries certified to be free of bovine spongiform encephalopathy (BSE), which is known to be transmissible to humans. Inactivation of some viruses may render certain important antigens nonantigenic. For example, formalin-inactivated measles vaccine used in the 1960s provided short-term protection but in some cases resulted in “atypical measles,” an unusually severe form of measles often complicated by pneumonia. These patients were found not to have antibodies to the F (fusion) protein of the measles virus, so that the virus was able to spread by cell-to-cell fusion. It is thought that formalin renders the F protein nonimmunogenic, so that the spread of wild virulent virus infection is unchecked. Inappropriate immune responses are well recognized to occur after vaccinations, especially with vaccines made of viruses grown in neural tissue. The classic example is that of the old neurally derived rabies virus, which often resulted in “neuroparalytic accidents.” These were illnesses causing acute demyelination in either the central or peripheral nervous system. Thus, acute disseminated encephalomyelitis (ADEM) and Guillain–Barré syndrome (GBS), involving central and peripheral demyelination, respectively, have both been observed after the use of the older rabies vaccines. Other vaccines have also been thought to have a causal 2 connection to demyelination, but this is rare. Restricted forms of central demyelination, such as optic neuritis and transverse myelitis, have also been described but are rare enough that a causal connection is in doubt. Restricted peripheral forms of demyelination, such as brachial plexopathy, have also been reported. One of the mechanisms of demyelination by vaccines is that of molecular mimicry, in which antigenic epitopes in the vaccine resemble those in myelin. Although this mechanism of mimicry has not clearly been shown to act in central demyelination (except possibly for measles, as discussed later), neurally derived vaccines contain myelin antigens (rather than mimics) and can trigger such disease. It should be noted that peripheral demyelination is known to occur by this mechanism.

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An instructive example of demyelination triggered by a neurally based vaccine is that of rabies vaccine. The idea of using modified infectious material to protect from viral disease was adopted by Pasteur, who used attenuated rabies virus from infected rabbit spinal cord to protect dogs from rabies. His strategy was to take infected rabbit spinal cord and allow it to dry, which attenuated the virus present in the cord. The longer the desiccation, the more attenuated the virus became. Eventually, the virus was sufficiently attenuated that it was innocuous but sufficiently immunogenic that it could prevent infection by fully virulent virus. The vaccine was originally administered as a series of injections of ever less attenuated virus, the idea being to stimulate the immune system with more virulent and therefore antigenic virus. The original Pasteur vaccine was thus rather cumbersome to administer, with multiple painful injections, and frequently gave rise to “neuroparalytic accidents.” This phenomenon inspired experiments by Thomas Rivers, who showed that a similar central demyelination could be induced in monkeys by serial injections of sterile white matter; this was the origin of experimental allergic encephalomyelitis, a model now used to study multiple sclerosis. In order to minimize this complication of neurally based vaccines, vaccines were made from virus that was grown in myelin-free environments. Fuenzalida first produced a myelin-free vaccine in 1956 by propagating virus in neonatal mouse brains, which still contained neural antigens. The first non-neural tissue-based vaccine was the duck embryo vaccine (DEV), in which vaccine virus was propagated in duck eggs. Human cells were used to develop rabies vaccines free of animal proteins, and the human diploid cell vaccine (HDVC), the contemporary standard, was first developed in the early 1960s. Very few “neuroparalytic accidents” have occurred with the current neural antigen-free vaccines. Thus, the more free the vaccines were of neural tissue, the lower was the risk of a “neuroparalytic accident.” In some parts of the world, however, the cheaper neural-based vaccines are still used. Some adverse events are of unknown mechanism. For example, rare episodes of intussusception were reported several years ago after administration of rotavirus vaccine, with 15 cases occurring with administration of 1.5 million doses, leading to that vaccine's 3 withdrawal. DETECTION OF VACCINE ADVERSE EVENTS Detection of vaccine adverse events can be difficult as they are uncommon and often manifest as illnesses that are known to occur in the unvaccinated. Many of these illnesses are not reportable to health departments. However, health officials will take note of an unusually high incidence of disease and launch an investigation. Surveillance for any unusual disease activity can be active or passive. Active surveillance is when cases are actively sought by sending questionnaires to physicians' offices and hospitals or systematically examining records at hospital records rooms. Passive surveillance occurs when physicians or the public send unsolicited information about cases to health department officials. Passive surveillance provides very limited epidemiological information, as it does not indicate the proportion of those with the complication who were actually reported (no numerator information) and how many were actually exposed to the vaccine (no denominator information); furthermore, the clinical details are often insufficient to make a secure diagnosis. Case reports and case series of illnesses following a vaccination may be published, but it is difficult to establish causality on this basis and, in fact, such reports may be misleading. The older literature is replete with case reports of some illness following a vaccination, but a causal connection is never made, and these cases remain curiosities. Certain reports have generated considerable controversies that have led to a decrease in vaccine coverage and to outbreaks of disease. This points to the necessity of performing controlled studies that can address the issue of causality. Analytical population-based studies, comparing vaccinated and nonvaccinated subjects, can, with proper statistical analysis, be quite conclusive about etiological links between a vaccination and an illness. An example would be the analysis of data from patients with Guillain–Barré syndrome that was linked to the influenza vaccine used in 1976. This is discussed later. Randomized, double-blind, placebo-controlled trials of vaccines are required as part of the U.S. Food and Drug Administration approval process and are very reliable, but only common adverse events can be found by this method. The Vaccine Adverse Event Reporting System (VAERS) is a passive surveillance system in which a complication is reported to the U.S. Food and Drug Administration by sending in a completed hard copy form or submitting the information on a Web site form. Another passive surveillance system consists of the National Vaccine Injury Compensation Program (NVICP), which compensates individuals who have

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had a serious and permanent adverse effect from a vaccine and who meet other criteria. The establishment of extensive databases provides a new resource for vaccine safety studies. The U.S. Centers for Disease Control and Prevention is operating a Vaccine Safety Datalink (VSD) project, which links to the databases of eight health maintenance organizations that together have 6 million individuals as members. This database4 has been used for a number of population-based studies, including vaccine safety studies. General information on vaccinations is available from various Web sites (Table 50-2). Click here to view this table....

Smallpox Smallpox (or variola) is a highly contagious disease caused by a double-stranded DNA virus 5 that is airborne. Smallpox is mostly of historical significance at this time, but its potential as a weapon of biowarfare has drawn public health interest in smallpox vaccination issues. The illness begins abruptly with headache, fever, and back pain followed by a characteristic rash. The rash begins on the face, followed by the arms and legs, and finally spreads to the torso. The rash begins with scattered macules and evolves into papules, vesicles, and finally pustules that then dry and crust over. The patient ceases to be contagious after the crusts fall off. There are two broad forms of the disease: the severe form, variola major, which had a mortality rate of about 30 percent, and a milder form, variola minor (alastrim), with a mortality rate of approximately 1 to 5 percent. There are several types of variola major, with the hemorrhagic smallpox form of the disease having a mortality of nearly 100 percent. The original smallpox vaccination (variolation) involved the transfer of material from smallpox pustules or crusts into a scratch in the skin of the subject to be vaccinated. This often resulted in a milder form of the disease, presumably because the preparation of the material from the smallpox lesions attenuated the smallpox virus contained therein. Variolation thus is the first example of an attenuated vaccine. However, the attenuation was often inadequate and some recipients developed full-blown smallpox. Jennerian vaccination uses an animal poxvirus to induce cross-protective immunity against smallpox. However, the actual modern vaccine virus is not cowpox but vaccinia, a related virus. At what point cowpox was replaced by vaccinia or whether the original “cowpox” was some mixture of cowpox and vaccinia viruses is unknown. 6

Vaccinia is quite reactogenic and has a spectrum of systemic complications. These include nonspecific malaise and fever, as well as a number of skin reactions including urticaria, erythema multiforme, bacterial infection of the injection site, and progressive vaccinia infection, which occurs in the immunosuppressed and can be fatal. A few cases of mild myopericarditis have been reported in civilian and military vaccinees, with resolution and return to active duty in 7 to 10 days. Neurological complications are uncommon, but well reported. An idea of the neurological complications of smallpox vaccination with vaccinia can be gained by a report from South Wales in which a large population was vaccinated against smallpox as a result of an epidemic in 1962. More than 800,000 individuals were vaccinated with 7 1,300,000 vials of vaccine, and 39 cases of neurological illness ensued. There were 30 cases of central nervous system (CNS) disease: postvaccinal encephalomyelitis (11 cases), postvaccinal encephalopathy (3 cases), meningism/aseptic meningitis (7 cases), epilepsy (3 cases), and focal lesions of the brain and spinal cord (6 cases). There were 9 cases involving the peripheral nervous system: polyneuritis (5 cases), brachial neuritis (2 cases), and myasthenia gravis (consisting of a relapse in preexisting illness (2 cases). The incidence of neurological complications was thus on the order of 5 per 100,000 subjects vaccinated, and the risk of encephalitis-encephalopathy roughly 2 per 100,000 vaccinations. More recent series suggest that postvaccinal encephalitis is less common. In a literature review of the complications of smallpox vaccination, Fulginiti and associates found postvaccinial encephalomyelitis occurring in 2 to 6 per million primary vaccinees, depending 6 on age. They noted that the risk in Europe was much higher, as high as 1 in 4,000, presumably because a different strain of vaccinia virus was used there. There have been rare reports of isolation of vaccinia virus in the cerebrospinal fluid (CSF) in cases of encephalitis following vaccination. The overall death rate from all causes following smallpox vaccination was 0.5 to 5 per million vaccinees.

Measles, Mumps, and Rubella Measles, mumps, and rubella were once common childhood illnesses in the developed world,

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but they became rare after the introduction of vaccines that prevent them. These vaccines are commonly given together in combination as MMR vaccine. This minimizes the number of injections to which small children are subjected. Formulations containing only some of these have been used in the past: measles (M) vaccine and measles plus rubella (MR) vaccine. Measles Measles is a viral exanthem caused by an enveloped single-stranded RNA virus that is transmitted through the air and initially infects the respiratory epithelium, where it replicates. This gives rise to a primary viremia that implants virus in lymphoid tissues. A secondary viremia follows, and the virus is disseminated throughout the body. During measles, a significant distortion of the immune system occurs, with paradoxical features. There is a nonspecific systemic immune activation, along with immunosuppression, causing susceptibility to bacterial and viral superinfections. The latter are the main causes of morbidity and mortality and are enhanced by malnutrition, making measles a major cause of death in developing countries. The main complication of measles is pneumonia, which is usually due to bacterial superinfection in children and to direct measles virus infection of the lungs in adults. Pneumonia occurs in roughly 10 percent of patients and causes more than 60 percent of the mortality resulting from the disease. Other complications include otitis media and laryngotracheobronchitis. The main neurological complication of measles is ADEM, in which there is acute multifocal inflammatory demyelination, occurring in roughly 1 per 1,000 cases. This may actually be due to molecular mimicry, since T cells from measles-associated ADEM patients proliferate on exposure to myelin basic protein, whereas cells from patients with uncomplicated measles do not. The mortality rate of ADEM is between 10 and 30 percent, and sequelae are common 2 and severe. Measles virus was first isolated and propagated in tissue culture by Enders and Peebles in 1954, and efforts at making measles vaccine followed shortly thereafter. The first vaccines were made from the Edmonston B strain. It is instructive to review the process by which the virulent virus is attenuated. The Edmonston B strain, the actual strain used in the vaccine, was obtained from the original Edmonston isolate (named after the individual from whom it was first obtained) by serial passage in primary kidney cells (24 passages), primary human amnion cells (28 passages), chicken embryos (6 passages), and then in chicken embryo cells. This vaccine was first introduced in 1963, but the high rate of fever and rash prompted its discontinuation. Other vaccine strains were available and less reactogenic. One of these, the Moraten strain, introduced in 1968, was derived from the Edmonston B strain by a further 40 passages in chicken embryo cells. Another strain, the Schwarz strain, was obtained from the Edmonston B strain by a further 85 passages in chicken embryo cells and was used from 1965 to 1976. The Moraten vaccine is the only one used in the United States today. Other vaccine strains are used elsewhere in the world. The effectiveness of vaccination may be gauged from the fact that before vaccination, 4 million cases of measles occurred annually in the United States, whereas there were only 309 cases in 1995. Neurological complications of measles vaccination have been reported but are uncommon. Case reports of encephalopathies are not uncommon, but do not, by themselves, provide evidence of causation. In order to better understand the risk of adverse events to measles vaccine, Weibel and co-workers analyzed data from claims of measles vaccine-induced 8 encephalopathy submitted to the National Vaccine Injury Compensation Program. In the years 1970 to 1993, 403 claims of postvaccination encephalopathy were made and reviewed in their study. The inclusion criteria included an acute encephalopathy 2 to 15 days after vaccination (M, MR, MMR) leading to permanent brain damage or death, with no other known cause that would explain the illness. Of these cases, 48 met the criteria. The mean age of the cases was 17.5 months (range, 10 to 49 months). There were three main groups of complications, with ataxia in 6, behavioral changes in 8, and seizures in 34. Fever preceded the encephalopathy in most, and one quarter of the cases had a measles-like rash that occurred 1 or 2 weeks after vaccination. Cerebrospinal fluid was analyzed in most children and was abnormal in 40 percent: pleocytosis was present in 70 percent (range, 7 to 246 cells/ml), and protein was elevated protein in more than one third (range, 117 to 172 mg/dl). No other viruses were present. When the number of patients with encephalopathy was plotted against the day of onset, a typical epidemic curve was obtained, with a peak at 8 to 9 days, suggesting a causal (rather than merely temporal) connection between the vaccination and the neurological illness. A mere temporal, noncausal relationship would show no such peak since cases would occur at random after the vaccination.

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The final outcomes in these groups were as follows. In the group with acute ataxia, mental retardation occurred in three, a seizure disorder in one, chronic ataxia in four, and sensorineural hearing loss in one. In the patients with initial behavioral change, the outlook was rather more negative, and all rapidly progressed to coma, with two deaths. In the seizure group, there were two immediate deaths, and all survivors had chronic encephalopathy; there were three delayed deaths occurring 3 months to 4 years later. In one case, the autopsy showed cerebral edema with uncal herniation, and in the other, a “viral encephalitis” with hemorrhagic infarctions of the thalamus and pons. The risk of neurological illness can be estimated from the fact that from 1970 to 1993, approximately 75 million children had measles vaccine by age 4 years, based on a 90 percent immunization rate and 83 million births. The limits of risk are, based on 48 claimants meeting criteria and on all 403 claimants, 0.64 to 5.37 cases per million vaccinees. In a study of 1.8 million Finnish MMR vaccinees, actively surveyed from 1982 to 1996, adverse events were tabulated and analyzed. Of 173 potentially serious reactions reported, 77 were neurological and consisted mostly of febrile seizures, with good recovery. One patient later developed Lennox–Gastaut syndrome. Four cases of encephalitis were reported, one of which was due to herpes simplex. The others were uncharacterized. Various other neurological complications were due to other known causes (such as bacterial meningitis). Miscellaneous other cases of Guillain–Barré syndrome (two patients with eventual recovery), transient confusion, and transient ataxia were noted. Interestingly, no cases of autism were 9 found. Recently, measles vaccine has been proposed as a cause of autism, a complex (and probably heterogeneous) neurobehavioral syndrome. Much discussion has been stimulated by a report of 12 children who developed cognitive problems as well as inflammatory bowel 10 disease a few days to a few months after receiving MMR vaccine. However, the ages at which MMR vaccine is given are also the ages when autism manifests clinically, although 11 there is evidence that the beginnings of the disease occur well before birth. Furthermore, there was no population-based study with controls to estimate the relative risk of autism 12 following vaccination. A report from the Institute of Medicine reviewed published and unpublished reports concerning the issue of MMR vaccine13and concluded that there is no clear causal connection between the vaccine and autism. Certainly, autism and inflammatory bowel disease existed well before MMR vaccine was developed, so the vaccine cannot be the sole cause of these disorders. Another hypothesis is that autism was caused in especially susceptible subjects by thimerosal, a mercury-containing preservative that was used in vaccines. The review of the literature cited previously also showed no clear causal connection between thimerosal and autism, and, in any case, thimerosal is no longer used in childhood vaccines. Mumps Mumps is an acute febrile illness caused by rubulavirus, in the paramyxovirus group. The clinical illness in children usually is self-limited, with fever, malaise, headache, and often an acute painful parotitis. The disease can occasionally be complicated by meningitis and rarely by meningoencephalitis, with residual deficits. Sensorineural deafness is an uncommon sequela but can be a major cause of deafness in children during epidemics. In adults, mumps has a higher rate of systemic complications such as orchitis in men and oophoritis and mastitis in women as well as pancreatitis and myocarditis. The main original vaccine virus strains were named the Jeryl Lynn and Urabe strains, after the hosts from which the original unattenuated viruses were isolated. The Jeryl Lynn strain vaccine was tested in two clinical trials, one in Philadelphia nursery school and kindergarten children in 1965 to 1967 and one in schoolchildren from Forsyth County, North Carolina, in 1966 to 1967. Mumps vaccine was first licensed for use in 1967. The number of cases of mumps in the United States was 152,209 in 1968 and decreased to 2,982 in 1985. The number of cases increased briefly after vaccination rates declined but decreased again after mumps vaccination was required for school entry to 751 cases in 1996. Aseptic viral meningitis is the main neurological complication of mumps vaccination and is probably because natural mumps is frequently accompanied by meningitis. The Urabe strain vaccine was discontinued in the United States after it was linked to aseptic meningitis occurring in141 case in 900 vaccinees in one Japanese series to 1 case in 200,000 vaccinees. For the Jeryl Lynn vaccine, the incidence is 1 case in 1.8 million vaccinees. By 14 comparison, aseptic meningitis occurs in approximately 1 in 400 cases of natural mumps. The aseptic meningitis is self-limited.

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Rubella Rubella is a self-limited viral infection in children, with a fever and rash, caused by a single-stranded RNA virus. The virus causes most of its damage by prenatal infection. The congenital rubella syndrome is well described, and the triad of neurological, eye, and cardiac defects is characteristic. The disease also includes a spectrum of disease, including thrombocytopenic purpura, hepatitis, bone lesions, interstitial pneumonitis, diabetes mellitus, 15 and thyroid problems. The vaccine has very few complications in children, with rare mild rash and fever. In adults, the most common side effect is polyarthralgias. A few scattered reports of peripheral mononeuropathies and radiculopathy following rubella vaccination have 16 been published, but a review of these could not establish a causal relationship.

Diphtheria, Pertussis, and Tetanus Diphtheria Diphtheria is a disease caused by strains of Corynebacterium diphtheriae, which make diphtheria toxin, a binary toxin consisting of two molecular components: fragments A and B. Fragment B binds to the target cell and allows access of fragment A to the cytoplasm. Fragment A inactivates elongation factor-2 (EF-2), inhibiting protein synthesis in the cell, causing necrosis. Usually diphtheria infects pharyngeal epithelium, where the superficial layers of the mucosa become necrotic and provide an excellent culture medium for the bacteria. These areas of tissue necrosis with exudation form the so-called diphtheritic “membranes.” Systemic absorption of diphtheria toxin from the pharynx causes cardiac and neurological effects. Patients with diphtheritic myocarditis may develop congestive heart failure, with abnormal electrocardiograms showing heart block. Pathological examination shows interstitial inflammation and hyaline degeneration of fibers. Diphtheritic “neuritis” includes several entities, including an isolated paralysis of soft palate, ocular motor palsies, paralysis of the diaphragm, and a disorder resembling the Guillain–Barré syndrome. The pathogenesis of these various disorders is not understood. In the 1920s, before diphtheria toxoid was introduced, there were approximately 100,000 cases in the United States annually. In the past few decades, no more than a handful of cases has occurred each year. The importance of vaccination is illustrated by the fact that when vaccine coverage decreases, large epidemics of the disease follow, as happened in Russia in the 1990s, when the public health infrastructure could no longer cover the population adequately. The mortality rate of the untreated disease is very high: 30 to 50 percent of cases. After the introduction of antitoxin therapy, the mortality rate declined to 10 to 20 percent of cases; modern intensive care has reduced this to 5 to 10 percent. Originally, vaccination against diphtheria was undertaken by injecting mixtures of toxin and antitoxin. In the early 1920s, it was found that treatment of diphtheria toxin with formalin resulted in a nontoxic immunogenic toxoid. This was incorporated with tetanus toxoid and inactivated whole-pertussis cells, and diphtheria-pertussis-tetanus (DPT) vaccine was marketed to the public in the mid-1940s. There have been remarkably few neurological complications from diphtheria toxoid, although they may be difficult to discern, as the toxoid is usually given in combination with pertussis and tetanus vaccines. Local injection-site reactions can be painful as they are intramuscular; infants may react with prolonged crying, irritability, drowsiness, loss of appetite, and vomiting, and limitation of abduction of the injected arm may occur regardless of age. Pertussis Pertussis, or whooping cough, is caused by Bordetella pertussis, a commonly circulating bacterium that has multiple antigenic components. The disease begins with a seemingly minor upper respiratory infection, with minimal fever and an intermittent cough that becomes severe and progresses to paroxysms in which coughing becomes very vigorous, interfering with breathing and increasing intracranial pressure by a continual Valsalva maneuver. The paroxysmal stage lasts between 2 and 6 weeks before resolving. The disease was commonly lethal in the past. At the beginning of the 1900s, approximately 5 of every 1,000 liveborn infants died of pertussis before 5 years of age. Today, there are fewer than 10 deaths per year in the United States. When vaccine coverage declines, the disease reemerges because pertussis vaccine protects against bacterial toxins but does not necessarily eliminate the pathogen from the population (unlike smallpox, for example). Indeed, decreases in vaccine coverage of a population are commonly followed by outbreaks

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of the disease. The pathogenesis of the disease is not completely known, but is likely due to a toxic effect on respiratory epithelium with denudation of respiratory passages. An important complication of pertussis is pertussis encephalopathy. This is a vaguely described syndrome of encephalopathy and seizures occurring in 0.08 to 0.8 per 1,000 cases, with the youngest infants at highest risk. In the years 1997 to 2000, pertussis 17,18 encephalopathy and seizures occurred in 0.1 and 0.8 percent of cases, respectively. There appear to be two clinical forms, one with an abrupt onset of seizures and coma and the other with the gradual onset of somnolence progressing to coma. The prognosis appears to be rather poor,19with death, permanent cognitive deficits, and recovery each occurring in one third of cases. The pathological changes are characterized by congestion and brain petechiae, but the pathogenesis is unclear and may involve the effects of anoxia and increased venous pressure in the brain from the Valsalva maneuver caused by the severe cough. A toxic element may relate to bacterial toxins or cytokines, although intravenous injection of toxin does not appear to cause neurological complications. Pertussis vaccine has dramatically decreased the burden of disease in vaccinated populations; it declined from about 200,000 cases in the United States in the mid-1930s to a nadir of 1,010 cases in 1976, with a subsequent increase to about 8,000 cases occurring in 2000 for unclear reasons. The original vaccine consisted of inactivated whole bacterial cells. Whole-cell vaccine is reactogenic, causing painful local injection-site reactions and fever. The latter can lead to febrile seizures in children, who are an especially susceptible population. This triggered reports of severe neurological illnesses following pertussis vaccination. To ascertain the risk of neurological illness attributable to pertussis vaccine, an active survey of encephalopathic illnesses was performed in all British children from July 1976 to June 20 1979 in the National Childhood Encephalopathy Study (NCES). A comparison was made of rates of vaccination in those who had or did not have an encephalopathy. The first 1,000 cases of encephalopathy were tabulated and were compared with two matched controls per case. Of the 1,000 cases, 35 had pertussis vaccine, whereas of the 2,000 controls, 34 had pertussis vaccine within 7 days. Thus, within 7 days, encephalopathy occurred in 3.5 percent (35 of 1,000) of cases, whereas the background rate of having been vaccinated in the previous 7 days was 1.7 percent (34 of 2,000) of controls, giving a risk ratio (RR) of 2.4 (P < 0.001). Within 72 hours of vaccination, encephalopathy occurred in 2 percent (20 of 1,000) of cases, with a background vaccination rate of 0.9 percent (18 controls) (RR = 2.6; P < 0.01). All vaccines with a pertussis component, for example, pure pertussis vaccination, DPT vaccination, and diphtheria-pertussis (DT) vaccination, were counted as pertussis vaccination. The 35 cases of encephalopathy following pertussis vaccination were divided into three groups: group A consisted of those who were normal before and at 15 days after vaccination, group B consisted of those normal before but abnormal 15 days after vaccination, and group C were those abnormal before and after vaccination. There were 20 cases in group A, with convulsions in 12, encephalopathy in 4, infantile spasms in 3, and acute infantile hemiplegia in 1. In group B, there were 12 cases, with prolonged convulsions in 2, encephalopathy in 6, infantile spasms in 3, and Reye's syndrome in 1. In group C, there were three cases, all with prolonged convulsions. The ultimate outcomes at 1 year of these cases differed in the three groups. In group A, 18 cases were normal, and one each had a minor or major delay. In group B, four had minor delay, five had major delay, and two died. Thus, the risk of neurological adverse events after pertussis vaccination was small, and the prognosis was dictated by the patient's condition at 15 days. Patients who were normal at 15 days would likely be normal at 1 year, whereas an abnormality at 15 days implied a negative outcome at 1 year. The estimated attributable risk of a serious neurological disorder at 7 days after DPT vaccination is 1:110,000 injections, with a 95 percent confidence interval (CI) of 1:360,000 to 1:44,000. A new acellular vaccine consisting only of a subset of antigenic components of the bacterial 21 cell was introduced in 1996 and appears to be much less reactogenic. Tetanus Tetanus is a neurological disease caused by Clostridium tetani, which is present ubiquitously in soil. The organism has two toxins carried on a plasmid, namely, tetanospasmin, the neurotoxic component, and tetanolysin, which is a hemolysin. Tetanospasmin is elaborated locally and transported to the CNS by both blood and local axonal transport. It interferes with release of the presynaptic inhibitory neurotransmitters glycine and γ-aminobutyric acid (GABA), causing inappropriate disinhibition of spinal cord reflex arcs, with greatly increased tone in the muscles and intermittent painful spasms. Respiratory compromise may lead to a

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fatal outcome. The toxin is very potent: the lethal dose is 2.5 ng/kg. The case fatality ratio of the untreated disease is 25 to 70 percent overall and 100 percent at the extremes of age. With intensive care, the mortality rate decreases to 10 to 20 percent. Tetanus toxoid consists of formalin-treated tetanospasmin, which induces an immune response that provides good protection lasting 10 years. Adverse events are rare and are 22 mostly anecdotal. Brachial plexopathy occurs in 1:100,000 vaccinees within 1 month of vaccination, and there may be a slightly increased risk of Guillain–Barré syndrome (0.4 per million doses). One person had an illness resembling Guillain–Barré syndrome on each of three vaccinations with tetanus toxoid. There is some tantalizing evidence that tetanus toxoid 23 decreases the risk of multiple sclerosis.

Influenza Influenza is an acute, febrile, debilitating viral infection of the upper respiratory tract that causes significant work and school absences each year. It can be complicated by pneumonia and, rarely, by ADEM. In children, the complications of influenza or its treatment include encephalopathies such as Reye's syndrome as well as a toxic encephalopathy of unclear nature, possibly related to cytokine production in the course of disease. The virus was first isolated in 1933 by Smith, Andrewes, and Laidlaw. In 1935, neutralizing antibodies were detected in subjects given subcutaneous injections of influenza virus. The first trial of an influenza vaccine demonstrated some degree of protection in 1936. The virus was grown in a suspension of mouse lung and injected into children. Further studies of influenza vaccination using inactivated influenza virus were carried out by the military in the early 1940s and the benefit of the vaccine was clear-cut. This led to the licensing of influenza vaccines in the United States in 1945. In 1947, a dramatic failure of the vaccine during an influenza epidemic led to the discovery that the vaccine produced immunity to the vaccine virus but not to the epidemic strain. This was the result of antigenic change in influenza virus. Such change can be of two types: (1) antigenic drift, in which the accumulation of mutations in the genes coding for the surface antigens of the virus renders it sufficiently different from the previous strains so that it can cause disease despite exposure to the previous virus and (2) antigenic shift, in which there is reassortment of genes coding for the surface proteins from viruses circulating between birds and pigs. This experience led to the establishment of worldwide sentinel centers by the World Health Organization, which monitor for new strains of influenza virus every year, so that the new strains can be incorporated into the updated vaccine. This is an important activity because new pandemics are expected to occur in the future. The recent circulation of the H5N1 strain in Southeast Asia is of great concern because of the highly lethal nature of the disease and its potential for human-to-human transmission. Current vaccines use two strains of influenza A and one influenza B virus, all grown in embryonated chicken eggs and inactivated with betapropiolactone. In 1975, a fatal case of swine flu in a military recruit prompted the institution of a national swine flu vaccination program in 1976 to 1977 because of the fear that this would resemble the 1918 influenza epidemic that caused such widespread mortality. The vaccine was produced and 45 million doses were administered by mid-December 1976. In late November and early December 1976, cases of Guillain–Barré syndrome were reported to local health departments and prompted an investigation of the relationship to the flu vaccine. Langmuir and co-workers investigated the results of an active surveillance of all such cases reported during the period of vaccination, prompted by reports of a possible causal connection and requested by a court in which a lawsuit had been filed. The study uncovered 1,300 possible 24 cases, of which 944 could be evaluated. There were 504 cases in vaccinees and 440 cases in nonvaccinees. Although the data were insufficient to diagnose Guillain–Barré syndrome definitively, the cases could be classified as to the extent of involvement into “extensive” and “limited” paresis. When the distribution of cases was plotted as a function of time since vaccination, the “extensive” cases followed a typical log-normal epidemic curve, whereas cases of limited paresis showed no such curve. This implies a causal relationship between vaccination and Guillain–Barré syndrome in a small number of cases. The effect of the vaccine lasted 6 to 8 weeks. The actual risk of Guillain–Barré syndrome attributable to vaccine was 4.8 to 5.9 per million vaccinees. Interestingly, no such increased risk was found in England and25,26 the Netherlands, as well as in 1.7 million U.S. military personnel who received Furthermore, there was no increased risk27of Guillain–Barré syndrome a double dose. to 1980 and 1980 to following influenza vaccination in the 1978 to 1979 seasons, the 1979 28 29 1981 seasons, and the 1992 to 1993 and 1993 to 1994 seasons. Despite a theoretical concern for the safety of influenza vaccines in patients with multiple sclerosis and central demyelination, it appears to be quite safe. There was no increase in the onset or relapses of multiple sclerosis in a retrospective study after swine flu vaccine, which

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is known to be associated with peripheral demyelination (albeit weakly). There were no 31 increases in relapse rate in a double-blind trial involving 66 patients with multiple sclerosis. Non–swine influenza vaccines are safe to use in multiple sclerosis. A case-control study of influenza vaccine done by the Vaccine Safety Datalink study group showed that influenza 32 vaccination was not associated with either multiple sclerosis or optic neuritis. In fact, the study showed no association between vaccination against hepatitis B, tetanus, measles, or rubella and either multiple sclerosis or optic neuritis. After a review of controlled studies looking at the risk of relapse of multiple sclerosis after influenza vaccination, the Immunization Safety Review Committee of the Institute of Medicine concluded that there was sufficient evidence to reject any causal relationship between such relapses and influenza 26 vaccination.

Hepatitis B Hepatitis B is caused by a hepadnavirus, a partially double-stranded DNA virus, which is endemic worldwide, especially in sub-Saharan Africa and Southeast Asia. The virus is present in blood and semen and can thus be transmitted sexually and through inadequately processed blood products. The disease is usually self-limited in adults, with a clinical spectrum of asymptomatic infection to severe disease, followed by resolution and clearance of virus. However, in infants and children (80% to 90% of those infected before 1 year) as well as in some adults (approximately 5% of those infected), the acute infection is often asymptomatic but evolves into a chronic active hepatitis, with progression to cirrhosis and hepatic carcinoma. In highly endemic areas such as sub-Saharan Africa and Southeast Asia, this is one of the most common cancers, leading to significant mortality. In 1991, two cases 33 of central demyelination were reported after receipt of recombinant hepatitis B vaccine, one being in a patient with preexisting multiple sclerosis. A report of eight patients with disseminated central demyelination with persisting activity on imaging 34 studies was published in 1999. This report occasioned much controversy in France, and other cases were subsequently reported, but calculations of the expected number of new cases of multiple sclerosis (1 to 3 per 100,000 annually) showed that the disease incidence in the vaccinees (0.65 per 100,000 annually) was actually less than would have been expected, 35 so that the risk of multiple sclerosis following vaccination is unlikely to be increased. More detailed comparisons were done in several studies. A population-based retrospective cohort study of 134,698 members of several health maintenance organizations compared the rate of CNS demyelination in hepatitis B vaccinees with that in nonvaccinees and found no 36 difference between them. In a case-control study from British Columbia, the rates of development of multiple sclerosis in adolescents vaccinated against hepatitis B in the years 1992 to 1998, after universal hepatitis B vaccination became available, were compared with those not vaccinated (in the years 1986 to 1992, before the vaccine was available). There 37 was no statistically significant difference between the two groups. A multicenter hospital-based study in France enrolled 402 cases of central demyelination and 722 controls. The odds ratio of a first CNS demyelinating event within 2 months of vaccination was 1.8 (95% CI: 0.7 to 4.6). For confirmed multiple sclerosis, the odds ratio was 2.0 (95% CI: 0.8 to 5.4). It was concluded that there was no evidence of a strong association between central 38 demyelination and receipt of hepatitis B vaccine. There is thus little evidence of causality between hepatitis B vaccination and multiple sclerosis. Other studies showed no evidence 39 that hepatitis B vaccine triggered relapses in patients with established multiple sclerosis.

Poliomyelitis Poliomyelitis caused by poliovirus type 1, 2, or 3 usually is asymptomatic or consists of a mild febrile illness in early childhood. In older children, adolescents, or adults, the febrile illness may be accompanied by damage to the anterior horn cells in the spinal cord. The disease is spread by fecal-oral contact and caused considerable morbidity before the Salk vaccine. Early attempts at vaccination in the 1930s were disastrous: inadequate attenuation of the virulent virus led to polio in recipients (there was no test for attenuation of viruses), different serotypes were unknown and therefore not protected against, and there were no safety precautions against injecting neurally derived material. In the Cutter incident that was associated with Salk inactivated vaccine, 260 vaccinees and contacts contracted polio. These cases were thought to be related to the vaccine because they occurred in just a few Western states, all were injected by vaccine supplied by a single manufacturer (Cutter Laboratories), the injected extremities were disproportionately affected, and the cases were traced to lots that were found to be inadequately attenuated.

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The Sabin oral vaccine consists of attenuated virus that replicates in the gut and induces immunity in both the vaccinee and contacts (because the vaccinee sheds vaccine virus). Rarely, however, the virus reverts to a virulent form and may cause vaccine-associated paralytic poliomyelitis (VAPP) in 1 per 1 million doses in vaccinees or their contacts. Because the only polio seen in North America was vaccine associated, the Sabin vaccine was withdrawn from use in 1994. It is still in use in other parts of the world and has occasionally caused small epidemics of paralytic disease, with a recently reported outbreak occurring in 40 China in 2004. Previous

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Aminoff: Neurology and General Medicine: Sarcoidosis of the Nervou...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 51 Sarcoidosis of the Nervous System ALLAN KRUMHOLZ • BARNEY J. STERN •

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SARCOIDOSIS PATHOPHYSIOLOGY EPIDEMIOLOGY NEUROLOGICAL MANIFESTATIONS Cranial Neuropathy Meningeal Disease Hydrocephalus Parenchymal Disease Endocrine Disorders Mass Lesions Encephalopathy-Vasculopathy Seizures Myelopathy Peripheral Neuropathy Myopathy NEUROPATHOLOGY DIFFERENTIAL DIAGNOSIS Presence of Systemic Sarcoidosis Diagnosis of Neurosarcoidosis TREATMENT Cranial Neuropathy Peripheral Facial Palsy Other Cranial Nerve Palsies Aseptic Meningitis Hydrocephalus Parenchymal Disease Peripheral Neuropathy and Myopathy GENERAL SUPPORTIVE CARE ALTERNATIVE TREATMENTS PROGNOSIS

Sarcoidosis was first described in 1877 by Sir Jonathan Hutchinson as a disease of the 1,2 skin. At the turn of the century, Caesar Boeck termed the disease multiple benign sarkoid, because of its histological similarity to sarcoma, and from this is derived the modern term

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3

sarcoidosis. Boeck also demonstrated the unifying feature of sarcoidosis as epithelioid cell granulomas that could involve different organs, a view that remains the basis of current thinking. Sarcoidosis is today recognized as a multisystem granulomatous disorder of unknown etiology. Typical presentations include bilateral hilar adenopathy, pulmonary 4 infiltration, and skin and eye lesions. Neurological involvement in sarcoidosis was first reported in the early 1900s by Heerfordt, 5 who described patients with cranial nerve palsies. Neurological manifestations—or neurosarcoidosis—are now recognized to occur in about 5 percent of patients with sarcoidosis and are varied. In addition, neurological manifestations are the presenting feature 6,7 of sarcoidosis for approximately 50 percent of these patients. Neurosarcoidosis manifests in diverse ways, including with cranial neuropathies, aseptic meningitis, mass lesions, encephalopathy-vasculopathy, seizures, hypothalamic-pituitary disorders, hydrocephalus, 8–11 Because its neurological myelopathy, peripheral neuropathy, and myopathy. manifestations are so diverse, its etiology is unknown, and confirmative laboratory tests are lacking, neurosarcoidosis poses major clinical challenges. The diagnosis of neurosarcoidosis is usually based on the identification of a characteristic neurological presentation in an individual with systemic sarcoidosis, as suggested by clinical and imaging findings and confirmed by examination of appropriate pathological specimens. Treatment of neurosarcoidosis is frequently a challenge. Although corticosteroids are regarded as the keystone of treatment, they are not always successful and have serious side effects. Moreover, some patients with neurosarcoidosis are refractory to conventional 6,7,12,13 Optimal management of patients with therapy, and approximately 5 to 10 percent die. neurosarcoidosis requires an understanding of the broad clinical spectrum of systemic sarcoidosis and neurosarcoidosis, appreciation of the best ways of confirming the diagnosis, and awareness of the full range of treatment options. SARCOIDOSIS The first internationally accepted definition of sarcoidosis was proposed in 1975 and remains of value today. It states: “Sarcoidosis is a multisystem granulomatous disorder of unknown etiology, most commonly affecting young adults and presenting most frequently with bilateral hilar adenopathy, pulmonary infiltration, skin or eye lesions. The diagnosis is established most securely when clinical and radiographic findings are supported by histologic14evidence of widespread noncaseating epithelioid-cell granulomas in more than one organ.…” Sarcoidosis usually presents between the ages of 20 to 40 years. However, it also occurs in 15 children and older populations. It appears to have similar clinical manifestations in all age groups. Intrathoracic structures are most commonly affected (87% of patients), followed by lymph node, skin, and ocular disease in 15 to 28 percent of patients (Table 51-1). Although it is generally understood that a diagnosis of sarcoidosis is most secure when it is based on histological confirmation, on average 30 percent of the patients described lack histological 16 confirmation, and the diagnosis is often based solely on clinical and radiological findings. Click here to view this table.... Involvement of any organ by sarcoidosis is possible and may occur with or without major symptoms. Sarcoidosis may be asymptomatic, or it can present with constitutional symptoms and pulmonary or extrapulmonary manifestations. Anatomical presence of the disease in an organ often occurs without overt clinical evidence of dysfunction. It is estimated that 20 to 40percent of patients are asymptomatic at presentation, their disease being discovered by 16 routine chest radiography. In fewer than 10 percent 17,18 of patients with sarcoidosis, the onset of symptoms is neither Neurological manifestations of sarcoidosis are in this category. systemic nor pulmonary. Other forms of extrapulmonary sarcoidosis include skin lesions, lymphadenopathy, parotid gland masses, liver or spleen enlargement, and ocular and cardiac involvement. Many laboratory abnormalities have been described in sarcoidosis, but no specific or highly sensitive diagnostic test is yet available. For example, patients may demonstrate anemia, leukopenia, thrombocytopenia, hypergammaglobulinemia, hypercalcemia, and hepatic or renal dysfunction. Active sarcoidosis may cause an elevation in serum angiotensin-converting 3 enzyme (ACE), which can then serve as a marker of the disease. Serum ACE is thought to be produced by alveolar macrophages and epithelioid giant cells and, in effect, reflects the “granulomatous load” of a patient. Serum ACE, however, is neither highly sensitive, with just 50 to 60 percent of patients with active sarcoidosis showing abnormalities, nor very specific because it is also often elevated in patients with other conditions, such as liver disease, diabetes mellitus, hyperthyroidism, systemic infection, malignancy, and Gaucher's disease (Table 51-2). Nevertheless, although much controversy exists as to the proper place of the

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serum ACE assay in the diagnosis of sarcoidosis, most investigators accept that it is a useful 3 marker of systemic disease activity. Click here to view this table.... Most patients with systemic sarcoidosis have a good prognosis. For approximately two thirds, the disease resolves spontaneously without major difficulties. This benign course is most common in asymptomatic patients with only hilar adenopathy on chest radiographs; they have 19 a 70 to 80 percent likelihood of spontaneous remission. However, for one third of patients, symptoms persist or the disease progressively worsens. Pulmonary dysfunction is the major issue for most patients with a persistent or progressive clinical course; 15 to 20 percent of 3,19,20 such patients have some permanent loss of lung function. Mortality in systemic sarcoidosis is reported as below 5 percent. Deaths are most often due to respiratory failure and sometimes are associated with cardiac problems, such as cor pulmonale and heart failure. However, death due to extrathoracic sarcoidosis17–21 affecting organ systems such as the kidneys and the nervous system is also well described. 4

The basis of therapy for all forms of sarcoidosis is corticosteroids. However, debate as to the precise indications for treatment persists. Indications for treatment are controversial because many patients with sarcoidosis are asymptomatic at the time of presentation and the rate of spontaneous resolution of sarcoidosis is high. In addition, the clinical presentations and course are so varied that treatment studies, particularly large, well-controlled studies, are not available. However, based on experience, there is little disagreement that corticosteroids have proved effective in rapidly suppressing some of the acute manifestations of sarcoidosis. Moreover, chronic therapy is widely considered to be necessary to limit recurrence or progression of disease. However, the value of corticosteroids in the long-term treatment of sarcoidosis remains scientifically unsubstantiated, and corticosteroids are recognized not to be curative treatment for all patients with sarcoidosis. Corticosteroid treatment seems most clearly indicated for patients with significant functional impairment in any organ system, particularly with major pulmonary, cardiac, ocular, or central nervous system (CNS) 19,20–23 Alternative immunosuppressive therapies for refractory sarcoidosis have also damage. 4,7,22 been studied and proposed. PATHOPHYSIOLOGY Although the precise etiology of sarcoidosis remains unknown, major strides have been made in understanding its pathogenesis. For example, there is strong evidence that23–27 This sarcoidosis is caused by heightened immune processes at sites of disease activity. contrasts sharply with 3,28 earlier concepts that had related sarcoidosis to impaired immunity and to generalized anergy. Current understanding of the immunopathology of sarcoidosis derives largely from studies of pulmonary sarcoidosis. The initial lesion in pulmonary sarcoidosis is an alveolitis, an inflammation of the alveolar structures of the lung (Fig. 51-1 and Fig. 51-2). This inflammation provides the appropriate environment for granuloma formation. Evidence indicates that these granulomas contain activated mononuclear cells thatprimarily have a secretory, rather than phagocytic, role. There is activation of T lymphocytes that congregate at sites of disease activity and secrete various cytokines,24,25,27 including interleukin-2, interleukin-1, These immunopathological interferon-gamma, and tumor necrosis factor (Fig. 51-2). mechanisms are certainly not limited to pulmonary sarcoidosis. Undoubtedly, processes similar to those in the lung underlie the pathogenesis of other forms of sarcoidosis, including neurosarcoidosis (Fig. 51-3).

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FIGURE 51-1 Postulated mechanisms of pulmonary damage in sarcoidosis.

FIGURE 51-2 Immunological mechanisms active in the pathogenesis of

pulmonary sarcoidosis.

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FIGURE 51-3 Immunopathogenic mechanisms postulated as responsible for

development of the granulomatous inflammation of neurosarcoidosis. Sarcoidosis can be28–30 thought of as an inflammatory response to an as yet unidentified foreign There has long been a suspicion that sarcoidosis is an inflammatory antigen (Fig. 51-1). disorder; fever, malaise, weight loss, cutaneous anergy, and polyclonal hyperglobulinemia all are consistent with this hypothesis. The central pathological hallmark of sarcoidosis, the granuloma, consists of macrophages, macrophage-derived epithelioid cells, and 31 central multinucleated giant cells that secrete cytokines (Fig. 51-2 and Fig. 51-3). About this 29,32 The core exist CD4 and CD8 lymphocytes, B lymphocytes, plasma cells, and fibroblasts. lymphocytes are thought27to be stimulated by antigen presentation by activated macrophages at sites of inflammation. Unfortunately, the inciting antigen or antigens remain unknown. Among the suspected causes have been infectious agents, organic agents such as pine pollen, and inorganic 18,33,34 Of the various possible infectious causes, mycobacterial infections have substances. 35–38 More recently, Propionibacterium species have also been received the most attention. 39 implicated. In reaction to an antigen, monocytes and macrophages form granulomas, and ultimately irreversible obliterative fibrosis can develop (Fig. 51-1). Furthermore, small foci of ischemic necrosis can be found, probably as a consequence of in situ thrombosis owing to perivascular inflammation. Importantly, granulomas are not specific for sarcoidosis, and indistinguishable or nearly identical lesions occur in a variety of other conditions that must be 32 excluded before a diagnosis of sarcoidosis can be made with certainty. EPIDEMIOLOGY The prevalence of sarcoidosis is estimated to be on the order of 60 per 100,000 population, while the annual incidence is approximately 11 per 100,000 population. However, the exact prevalence and incidence of sarcoidosis are difficult to validate because there is no single diagnostic test for sarcoidosis. Differences in case-finding methods also undoubtedly account for some discrepancies in reported frequencies for sarcoidosis and make difficult any comparisons of its rate of occurrence in different populations. For instance, studies that include only symptomatic patients actually underestimate the true prevalence of sarcoidosis because 20 to 40 percent of persons shown to have sarcoidosis are completely symptom-free at the time of initial diagnosis and are discovered by routine or screening chest 16 radiographs. Reports of disease frequency that rely on the findings of chest radiographic surveys probably give the best indication of the frequency of sarcoidosis because pulmonary inflammation and intrathoracic lymphadenopathy are by far the most common manifestation of sarcoidosis. However, some autopsy series suggest that the true prevalence of sarcoidosis

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may be even higher.


16

Population differences for sarcoidosis have been described. For instance, in the United States there is a reported increased incidence of sarcoidosis in blacks compared with whites; 14,16 Certain areas of the world, such as the disease also seems to be more severe in blacks. Sweden, also seem to have a higher incidence of sarcoidosis, whereas it appears to be quite 18 rare in other areas, such as China or Southeast Asia. These studies also raise the possibility of a genetic predisposition to the development of sarcoidosis. Indeed, sarcoidosis 40 does seem to occur with greater likelihood in some families, but as yet no well-defined genetic pattern has been recognized and no consistent mode of inheritance has been 14,16 discovered. Sarcoidosis can occur at any age. Although the likelihood of sarcoidosis is greatest in the 15,16 The exact third and fourth decades, the youngest reported patient is a 28-month-old child. frequency in children is difficult to assess because most countries understandably limit the use of routine screening chest radiography in children. Clinically, when sarcoidosis affects children, the distribution of organ involvement appears similar 15 to that reported for adult cases, and the patterns of neurosarcoidosis seem analogous as well. An increasing number of studies address candidate genes that may predispose to the development of sarcoidosis. To date, there is no consensus as to a robust genotype that 40 predisposes to sarcoidosis. There is a familial clustering of sarcoidosis. In a multivariate model, the familial adjusted relative risk was 4.7 (95% CI = 2.3–9.7). White patients demonstrated a higher familial relative risk compared with African American patients (18.0 vs. 2.8; P = 0.098). NEUROLOGICAL MANIFESTATIONS Neurological symptoms6,7are the presenting feature of sarcoidosis in one half of individuals with neurosarcoidosis. Some three quarters of patients destined to develop neurological disease do so within 2 years of becoming afflicted with sarcoidosis. The approximate frequency of the various neurological complications is presented in Table 51-3. Only rarely do patients with neurosarcoidosis have no evidence of disease in other organ systems, such as 6,8–10,12,41–43 However, systemic disease may not always be evident early in the lungs. apatient's clinical course and, in some instances, is difficult to find. One third to one half of patients with neurosarcoidosis develop more than one neurological manifestation of their disease. Click here to view this table.... Involvement of the CNS in sarcoidosis is best conceptualized as an inflammatory process affecting primarily the leptomeninges (Fig. 51-4), with sarcoidosis spreading along the Virchow–Robin perivascular spaces to invade the brain, spinal cord, or localized cranial nerves.

FIGURE 51-4 Central nervous system (CNS) sarcoidosis: clinicopathological

relationships.

Cranial Neuropathy 6

The most frequent neurological complication of sarcoidosis is cranial neuropathy. This occurs in approximately three quarters of patients with neurosarcoidosis. Any cranial nerve 6 can be affected, and more than one half of patients have multiple cranial nerve lesions. By far the most commonly affected cranial nerve is the facial, or seventh, nerve.

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Olfactory nerve dysfunction can occur secondary to meningeal sarcoidosis involving the subfrontal region. However, anosmia or hyposmia may also result from local nasal granulomatous invasion by sarcoidosis. Accordingly, in a patient with olfactory complaints, an otolaryngological evaluation is necessary before impaired olfaction can be attributed to CNS disease. Optic nerve involvement is much less frequent than other ocular manifestations of sarcoidosis, such as uveitis. Optic neuropathy can present with visual loss that is acute, 44 subacute, or chronic and can be painful or painless. The visual loss may be due to bulbar or retrobulbar invasion of the optic nerve by granulomas, compression of the optic nerve by a granulomatous mass, or optic atrophy. Optic disc edema may be secondary to papilledema due to sarcoidosis-induced increased intracranial pressure 45 or a direct local invasive effect of sarcoidosis. A chiasmal syndrome also has been reported. Disorders of ocular motility may follow involvement of cranial nerves III, IV, or VI in the 6 granulomatous process. Typically, these nerves are damaged in their extra-axial course in the subarachnoid space as they traverse the meninges. However, they may also be involved in local orbital disease, and rarely brainstem intra-axial pathways can be affected by 45 disordered ocular motility is due to sarcoidosis involving the sarcoidosis. Uncommonly, 46 Occasionally, pupillary dysfunction is caused by extraocular muscles. 45,47–49 For instance, Horner's syndrome due to disruption of the cervical neurosarcoidosis. 48 sympathetic nerves has been reported. 6

Trigeminal nerve disease may present as facial numbness or, rarely, trigeminal neuralgia. Headache may also represent trigeminal nerve dysfunction intracranially. Involvement of the muscles of mastication is unusual. Of the cranial nerve syndromes, peripheral facial nerve palsy is the most common, and it is also the single most frequent neurological manifestation of sarcoidosis. It develops in 25 to 50 percent of all patients with neurosarcoidosis. Although the condition is usually unilateral, bilateral facial palsy can occur, presenting with either simultaneous or sequential paralysis. More than half of all patients with facial palsy also have other forms of nervous system involvement. In patients with an isolated facial palsy, spinal fluid examination typically is normal, but when other manifestations of neurosarcoidosis are present, the spinal fluid examination is abnormal in 80 percent of patients. The specific cause of facial nerve palsy in sarcoidosis is variable. Rarely, the facial palsy is caused by parotid inflammation. More likely, the nerve is compromised as it traverses the meninges and subarachnoid space, or, as 42 suggested by Oksanen, facial paresis is due to intra-axial inflammation involving the facial nerve. In general, the prognosis for the facial palsy is good, with 6,12 more than 80 percent of patients having a good outcome in terms of recovery of function. Eighth cranial nerve involvement is the second most common cranial neuropathy occurring in 50 sarcoidosis. Inflammation may involve the auditory or vestibular portions of the nerve. When either loss of hearing or 51,52 vestibular dysfunction occurs, it may be sudden or insidious If hearing loss occurs, it is typically of the sensorineural and often fluctuates over time. type. As with facial nerve palsy, bilateral eighth nerve disease may occur. In fact, either 6,8 bilateral seventh or eighth nerve dysfunction is suggestive of neurosarcoidosis. Glossopharyngeal and vagus nerve involvement by sarcoidosis causes dysphagia and dysphonia. Hoarseness is more commonly due to laryngeal nerve dysfunction from 53 intrathoracic disease than CNS inflammation involving the vagus nerve. Eleventh and twelfth cranial nerve disease can occur but seems to be rare.

Meningeal Disease Meningeal disease occurs in approximately 10 to 20 percent of patients with neurosarcoidosis and can present as aseptic meningitis or, less commonly, as a meningeal or dural mass lesion. Aseptic meningitis is characterized by headache, meningismus, and a sterile cerebrospinal fluid (CSF) with a predominantly mononuclear pleocytosis, and it may be 54 a recurrent problem in some patients with neurosarcoidosis. Hypoglycorrhachia, or low CSF glucose concentration, is occasionally found, and there is often an elevation of the CSF protein concentration. Since meningeal involvement in sarcoidosis is a common pathological finding, it is surprising that aseptic meningitis is not more common. However, it is not at all uncommon for there to be asymptomatic chronic meningitis within the context of other CNS manifestations of sarcoidosis. When meningeal sarcoid mass lesions occur, they may mimic 55,56 intracranial tumors, such as meningiomas (Fig. 51-5).

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FIGURE 51-5 Cranial magnetic resonance imaging (MRI), coronal section,

T1-weighted image with gadolinium enhancement, demonstrating a convexity sarcoid mass lesion that was initially mistaken for a meningioma.

Hydrocephalus Hydrocephalus is noted in about 10 percent of neurosarcoidosis patients and may have fatal consequences. Patients with acute hydrocephalus may die suddenly of increased intracranial pressure, and even patients with chronic hydrocephalus have the potential to decompensate acutely. Patients with acute hydrocephalus characteristically present with headache, altered mentation or consciousness, and impaired gait. On examination, papilledema or other signs of raised intracranial pressure may be found. Acute decompensating hydrocephalus is a medical emergency that necessitates prompt diagnosis and treatment. Once clinically suspected, the diagnosis of hydrocephalus is best substantiated with imaging studies, such as cranial computed tomography (CT) or magnetic resonance imaging (MRI). A diagnostic lumbar puncture57has been associated with sudden neurological deterioration in patients with hydrocephalus. The hydrocephalus may be of either the communicating or noncommunicating type. Chronic basilar meningitis with obliteration of subarachnoid CSF flow is a major cause of communicating hydrocephalus. In addition, infiltration of the ventricular system by granulomas, granulomatous compression of the aqueduct, or outlet obstruction of the fourth 58 ventricle by granulomas may cause noncommunicating hydrocephalus.

Parenchymal Disease Parenchymal brain disease is reported in about 50 percent of patients with neurosarcoidosis and can present in several forms. Hypothalamic dysfunction is the most common manifestation of CNS parenchymatous disease. When hypothalamic dysfunction occurs, it usually involves the neuroendocrine system or “vegetative functions,” such as thirst, temperature regulation, appetite, sleep, and libido. However, neuroendocrinological disease may also occur secondary 6to pituitary disease. Any of the neuroendocrinological systems can be affected by sarcoidosis.

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Endocrine Disorders Endocrinological dysfunction in sarcoidosis is due to either a hypothalamic59–63 or a pituitary Given the granulomatous mass (Fig. 51-6) or a more diffuse “local” encephalopathy. the relative frequency of such predilection of sarcoidosis for the basal meninges (Fig. 51-4), 63 endocrinological disturbances is not surprising. Potential endocrinological manifestations include thyroid disorders, disorders of cortisol metabolism, and sexual dysfunction. An elevated serum prolactin level, found in 3 to 32 percent of patients with sarcoidosis, may be an indication of hypothalamic dysfunction. In fact, because neuroendocrinological involvement is relatively common in individuals with CNS neurosarcoidosis, patients with more than just an isolated facial palsy probably merit a thorough evaluation with specific attention to hypothalamic hypothyroidism, hypocortisolism, and hypogonadism.

FIGURE 51-6 Cranial MRI, sagittal section, T1-weighted image with gadolinium

enhancement, showing hypothalamic and pituitary involvement by sarcoidosis. Hypothalamic disorders vary in their effect on vegetative functions. A disorder of thirst is the most common hypothalamic disorder related to neurosarcoidosis and is attributed to a 59 of inappropriate change in the hypothalamic “osmostat.” More rarely, the syndrome 7,59 Neurosarcoidosis-induced secretion of antidiuretic hormone or diabetes insipidus occurs. disruptions of hypothalamic function have also been described as59,64,65 causing disorders of appetite, libido, temperature control, weight regulation, and sleep. Mass Lesions An intraparenchymal lesion due to sarcoidosis may present as an isolated mass (Fig. 51-7) or masses in any cerebral area or as multiple cerebral nodules. Such nodules may actually represent an inflammatory reaction in the Virchow–Robin spaces. Subdural plaque-like masses may also occur and are discussed in a later section. Calcifications may be seen. Although intraparenchymal mass lesions were historically considered rare, CT and MRI have shown parenchymatous disease to be more frequent than was previously thought. The symptoms and signs in individual cases depend on the location of the lesion.

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FIGURE 51-7 Cranial MRI, axial section, T1-weighted image with gadolinium

enhancement, demonstrating a frontal intracerebral mass that was proved by biopsy to be neurosarcoidosis. Encephalopathy-Vasculopathy The diffuse encephalopathy and vasculopathy associated with neurosarcoidosis are not well understood. Moreover, it is often difficult, both clinically and pathologically, to differentiate clearly between these entities. In fact, these two manifestations of neurosarcoidosis frequently coexist. For these reasons, we find it best to consider them as a single overlapping 5 entity, while recognizing that in individual patients one form or the other may predominate. The diffuse encephalopathy-vasculopathy found in neurosarcoidosis can involve the cerebral hemispheres or basilar regions. Patients may have a delirium, personality change, or isolated 66–68 memory disturbance as a result of focal or diffuse parenchymal inflammation (Fig. 51-8). Clinical findings correlate with the extent of enhancement on imaging studies and increased signal intensity on T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI.

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FIGURE 51-8 Cranial MRI, axial section, T2-weighted image, showing a large

area of abnormality in the temporal lobe that was proved by biopsy to be sarcoidosis manifesting with a focal encephalopathy-vasculopathy. Encephalopathic patients may have perivascular inflammation or granulomas infiltrating both arteries and veins and extending into brain parenchyma. Several investigators have observed 69,70 Large arteries granulomatous small-vessel arteritis in patients with neurosarcoidosis. have also been involved in the granulomatous process (Fig. 51-9). Microscopic pathology demonstrates arteritis with perivascular inflammation. Typically, the vascular adventitia shows infiltration with granulomas and inflammatory changes, but the media, elastica, and intima of 70–73 Veins can also be involved in sarcoidosis, producing arteries can70,71,73 also be affected. Although disease is rarely evident on angiography, angiographic changes infarctions. suggestive of71,72 vasculitis as well as an ill-defined occlusive process have been documented.

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FIGURE 51-9 Cranial MRI, coronal view, T1-weighted image with gadolinium

enhancement, showing gyral enhancement in the distribution of a posterior cerebral artery branch stroke. Transient56,71–73 ischemic attacks and ischemic stroke due to neurosarcoidosis have been Ischemic stroke usually is the consequence of inflammation and thrombosis reported. involving large or small arteries, but other causes include compressive perivascular mass lesions and emboli from sarcoidosis-associated cardiomyopathy or cardiac arrhythmias. Caplan and co-workers emphasized the arterial and venous involvement of the meninges and parenchyma in the angiitic 73 form of sarcoidosis and related this to observable perivascular causing intracranial hypertension lesions in the optic fundus. Also, dural sinus obstruction 64,74 has been related to inflammation from sarcoidosis. Seizures Seizures are another important manifestation of CNS parenchymal disease due to neurosarcoidosis. They may be75focal or generalized and have been correlated with a poor prognosis in neurosarcoidosis. This is because they reflect the presence of severe CNS parenchymal disease or hydrocephalus, and these manifestations have a higher risk of 13,75 Importantly, seizures in patients with progressive or recurrent disease or death. neurosarcoidosis are relatively easy to control if the underlying CNS inflammatory process is 13 effectively treated. Myelopathy Spinal cord involvement is another form of CNS parenchymal sarcoidosis. Spinal cord sarcoidosis may manifest as intramedullary, intradural but extramedullary, or extradural 76,77 Intramedullary spinal cord disease can also present with a granulomatous masses. myelitis that is analogous to the cerebral encephalopathy-vasculopathy of sarcoidosis. Intraspinal mass lesions due to sarcoidosis present with a nonspecific imaging appearance (Fig. 51-10). Also, spinal arachnoiditis may occur. In addition, sarcoidosis may present as a radiculopathy, polyradiculopathy, or cauda equina syndrome. Finally, spinal cord sarcoidosis may appear, typically in the late stages of spinal cord disease, as focal spinal cord 76,77 atrophy.

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FIGURE 51-10 Spinal MRI. A, Axial view. B, Sagittal view, with gadolinium

enhancement, demonstrating an intraspinal mass due to sarcoidosis.

Peripheral Neuropathy Although sarcoidosis commonly affects cranial nerves, peripheral neuropathy is less frequently described. Still, a variety of peripheral neuropathies are reported in sarcoidosis, including chronic sensorimotor, pure motor, or pure sensory polyneuropathies, mononeuritis 78 The most common form is a chronic multiplex, and an acute demyelinating polyneuropathy. 78 sensorimotor polyneuropathy of the axonal type. Sarcoid neuropathy typically begins months to years following an initial diagnosis of sarcoidosis, but in some instances, symptoms of neuropathy precede the discovery of systemic disease. The neuropathy is usually mild and classically manifests with distal paresthesias, decreased vibration and 78 proprioception sensation, and reduced ankle reflexes. Neuropathy has been attributed to epineurial and perineurial granulomas and an associated granulomatous vasculitis, producing axonal degeneration with associated demyelination. Endoneurial granulomas may also occur and are associated with primary segmental demyelination in patients with sensorimotor 79 neuropathy. Nerve damage may be due to granulomatous vasculitis, the compressive effects of granulomas, or local effects of inflammation. Over the past several years, a80sarcoidosis-associated small-fiber sensory neuropathy has increasingly been recognized. Patients have uncomfortable paresthesias distally in their extremities, with impaired pain and temperature appreciation. Initially patients can experience 81 multiple painful sensory mononeuropathies. These patients typically have normal nerve conduction velocities but have a decreased number of small fibers in cutaneous nerves documented on skin biopsy of the extremities. The pathophysiology of this process is poorly understood. Granulomas are not found on skin biopsy. It is possible that the neuropathy is a response to inflammatory mediators.

Myopathy Sarcoidosis may directly involve muscles and present with myopathy of various types. Manifestations of sarcoid myopathy include acute, subacute, or chronic weakness; fatigue; muscle pain; and palpable muscle nodules. Severe muscle disease can result in fibrosis and contractures. Sarcoidosis may also manifest with myositis, muscle atrophy, or occasional pseudohypertrophy. Muscle involvement by noncaseating granulomas can be demonstrated with muscle biopsy. However, incidental non-caseating granulomas have been found in muscle biopsy specimens in as many as 50 percent of patients with sarcoidosis but no clinical evidence of muscle disease. Differentiating between sarcoid myopathy, polymyositis or dermatomyositis, and granulomatous myopathy may be difficult, 82–84 and it is important to evaluate other organ systems carefully for evidence of sarcoidosis. NEUROPATHOLOGY Noncaseating granulomas and the accompanying diffuse mononuclear cell infiltrates that are characteristic of sarcoidosis can be found in any part of the neuraxis, including peripheral

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nerve or muscle (Fig. 51-11). The most common site of inflammation is the meninges, 9,85 Sarcoid granulomas especially in the basal region of the brain (Fig. 51-4 and Fig. 51-12). may be widely distributed or concentrated in one or more areas43to form a mass. Although sarcoidosis is not usually considered to be a primary vasculitis, arteriolar and venous 9,73,86–88 The granulomatous inflammation infiltration does occur and may lead to infarction. found pathologically may correlate directly with clinical deficits or may be subclinical and 85,89 unexpressed.

FIGURE 51-11 A, Photomicrograph of an intraparenchymal noncaseating

sarcoid granuloma of the brain (200×). B, Photomicrograph of a sarcoid granuloma in the brain, demonstrating a multinucleated giant cell (400×).

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FIGURE 51-12 Coronal midfrontal section of the brain of a patient with

neurosarcoidosis, showing thickening and inflammatory changes of the basal meninges and optic chiasmal region. As previously mentioned, CNS involvement can be conceptualized as an inflammatory process affecting primarily the leptomeninges (Fig. 51-4). Inflammation may spread along the Virchow–Robin perivascular spaces to invade the brain or spinal cord, or it may remain more 85,88,90 Presumably, much of the active inflammation localized and involve the cranial nerves. is reversible at an early stage. Ultimately, as the disease progresses, irreversible fibrosis or ischemic necrosis develops, leading to permanent neurological damage and persisting deficits. Inflammation can also extend to the CSF pathways, leading to hydrocephalus. Brain or spinal cord disease can take the appearance of discrete granulomatous mass lesions or a diffuse encephalopathy-vasculopathy. The hypothalamic region is the most common site of parenchymal disease. Granulomas are apparent in the epineurium and perineurium of peripheral nerve in symptomatic patients. The endoneurium may contain a mononuclear cell infiltrate. Perivascular and vascular inflammation may be seen in the epineurial and perineurial vessels. All nerve fiber sizes can be affected. There seems to be a predominantly axonal neuropathy with only minor segmental demyelination. The exact mechanism of peripheral nerve damage varies, but it includes injury resulting from vascular compromise, direct compression from granulomas, and immunological factors that may affect the peripheral 91 axons or Schwann cells. Muscle pathology is common in sarcoidosis. Muscle biopsy of symptomatic patients reveals typical noncaseating granulomas, and more diffuse inflammation also occurs, with muscle 83,92 Moreover, asymptomatic noncaseating fiber degeneration and regeneration and fibrosis. granulomas have been found in as many as one half of all patients with sarcoidosis having a 83 muscle biopsy. DIFFERENTIAL DIAGNOSIS Diagnostically, two common clinical situations occur in which patients with neurosarcoidosis are encountered: (1) A patient without established sarcoidosis has a clinical picture suggestive of neurosarcoidosis. In this situation, the major goal is to establish the presence of systemic sarcoidosis. (2) A patient with already established systemic sarcoidosis develops neurological symptoms. The focus is then on confirming that the neurological problem is due to neurosarcoidosis rather than to another cause.

Presence of Systemic Sarcoidosis When a patient without documented systemic sarcoidosis develops a clinical syndrome

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suggestive of neurosarcoidosis, evidence of sarcoidosis should be sought in other organ systems. Such systemic disease can best be documented when a thorough, systematic evaluation based on the known natural history of sarcoidosis is undertaken (Table 51-1). In particular, sarcoidosis most frequently affects intrathoracic structures (87% of patients), followed by lymph node, skin, and ocular involvement (15% to 28% of patients). Histological support for a diagnosis of sarcoidosis should be pursued, based on the clinical evaluation and these statistics. Since corticosteroid therapy may mask signs of systemic disease, treatment should be postponed, if possible, while a search for systemic disease is initiated. Pulmonary involvement is so common in sarcoidosis that this possibility should be considered first when one attempts to establish the presence of systemic sarcoidosis. Indeed, nearly 90 percent of patients with sarcoidosis are reported to show radiographic evidence of pulmonary 93 involvement. Still, although an abnormal chest radiograph is often seen in sarcoidosis and can be supportive evidence of that diagnosis, such findings are not necessarily specific or pathognomonic for sarcoidosis. Additional evidence to support pulmonary involvement can be obtained from chest CT and pulmonary function testing, including diffusion capacity. Moreover, when chest imaging or pulmonary function studies suggest pulmonary or intrathoracic lymph node involvement, a diagnosis of sarcoidosis is confirmed by obtaining histological evidence by transbronchial or mediastinal biopsy. Apart from the lungs, other organ systems merit consideration. Because of ease of access, early consideration should be given to a skin or lymph node biopsy of suspicious sites. Clinical information should also guide the evaluation of other organ systems for evidence of systemic sarcoidosis. For instance, nasal mucosal, conjunctival, lacrimal gland, liver, and muscle biopsies can be considered on the basis of individual clinical assessments. A thorough ocular examination is indicated to search for uveitis, retinal periphlebitis, or superficial lesions for conjunctival biopsy. Ocular findings in sarcoidosis include lacrimal gland inflammation, conjunctival nodules, iritis, uveitis, retinal lesions (vascular sheathing, granulomas, vascular occlusions, and 1,94 chorioretinitis), and optic disc pathology (edema, granulomatous nodules, and atrophy). The Kveim–Siltzbach test is not widely available and is no longer much used. However, historically it was yet another means for diagnosing systemic sarcoidosis. Kveim–Siltzbach reagent is a suspension derived from the spleen of a patient with sarcoidosis. This suspension is injected intracutaneously and, when positive, produces a cutaneous nodule that, on biopsy, reveals noncaseating granulomas. Although this represents a specific and sensitive test, it requires a period of 4 to 6 weeks before biopsy can be performed, making this unsatisfactory for patients with acute severe neurosarcoidosis who may require prompt 95 test, a role has corticosteroid treatment. Recently, as an alternative to the Kveim–Siltzbach 41 been proposed for diagnostic biopsy of Mantoux skin test sites. Gallium-67 scanning has been promoted as a valuable imaging method for initial detection of 63 systemic sarcoidosis, but it has limited utility95for longitudinal clinical follow-up because of its expense and the potential radiation exposure. Detection of inflammation in the lacrimal, 96 minor salivary, and parotid glands on a gallium scan is especially suggestive of sarcoidosis. More recently, fluorodeoxyglucose positron emission tomography (PET) scanning has been97 recognized as a sensitive technique for highlighting regions of increased metabolic activity. Although increased activity on PET scans can represent neoplasia or infection as well as granulomatous inflammation, when used in the proper context PET scans can be a valuable tool for documenting systemic disease and targeting a biopsy. Various laboratory measures have been described as abnormal in sarcoidosis. Although none is highly specific for sarcoidosis, they can be of some value. These abnormalities include increased serum ACE; increased serum gamma globulins; hematological disorders, such as anemia, leukopenia, and thrombocytopenia; and metabolic derangements, such as hypercalcemia, hypercalciuria, and hepatic and renal dysfunction. The most specific laboratory test associated with sarcoidosis is determination of the serum ACE level. However, its sensitivity is not high, with just 50 to 60 percent of patients with active sarcoidosis showing abnormalities. In addition, serum ACE is not very specific because it is abnormal in other 98 conditions, as discussed earlier (Table 51-2).

Diagnosis of Neurosarcoidosis Patients with well-documented systemic sarcoidosis who develop neurological disease suspected to be due to neurosarcoidosis merit careful appraisal to exclude causes other than sarcoidosis for their neurological problems. Neurosarcoidosis can be confused with many other neurological diseases, and because it is often not possible or judicious to biopsy

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affected tissue from the nervous system, good clinical judgment becomes critical. Consideration must be given to disease entities that may mimic neurosarcoidosis, particularly infection and neoplasia. Once such disorders have been excluded, treatment for neurosarcoidosis can be instituted. When the response to treatment is disappointing, the diagnosis of neurosarcoidosis should be reconsidered and a more extensive evaluation, including a biopsy, considered to exclude other causes of symptoms. Although not specifically diagnostic, certain tests can support a presumptive diagnosis of neurosarcoidosis. Brain imaging studies can be particularly helpful in confirming the presence, classifying the nature, and monitoring the treatment of neurosarcoidosis. The 99 preferred imaging technique is now MRI with contrast enhancement. T1-weighted images provide less useful information than T2-weighted and FLAIR inversion recovery studies. With T2-weighted and FLAIR imaging, areas of increased signal intensity can be better appreciated, especially in a periventricular distribution. Administration of contrast medium helps by demonstrating leptomeningeal enhancement (Fig. 51-13) as well as parenchymal abnormalities (Fig. 51-5 and Fig. 51-6). Enhancement presumably reflects a breakdown of the blood–brain barrier and implies active inflammation. Spinal MRI may reveal intramedullary disease, which appears as an enhancing fusiform enlargement, focal or diffuse 76,77 Enhancing nodules or thickened or matted nerve enhancement, or atrophy (Fig. 51-10). roots may also be appreciated in MR images of the cauda equina.

FIGURE 51-13 Cranial MRI, axial view, T1-weighted image, with gadolinium

enhancement, demonstrating marked dural enhancement due to sarcoidosis. CSF analysis may be helpful. More than 50 percent of patients with CNS sarcoidosis have 6,49 Reported abnormalities include an elevated CSF pressure, a high some CSF abnormality. protein level, hypoglycorrhachia, and a predominantly mononuclear pleocytosis, with up to 3 several hundred cells per mm . In addition, some patients have oligoclonal bands in the CSF or an elevated immunoglobulin100 G (IgG) index. However, none of these abnormalities is specific for neurosar-coidosis. Newer CSF assays may prove more specific for CNS sarcoidosis. The CSF level of ACE activity tends101–103 to be raised in some 50 percent of untreated patients with CNS although abnormalities are also seen in the presence of infection and sarcoidosis,

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malignancy. The CSF ACE level may be abnormal even with corticosteroid therapy, but less consistently than in untreated patients. The degree of elevation of CSF ACE level may 101–103 CSF ACE is thought to be produced by CNS granulomas, parallel the clinical course. especially those near the meninges. A normal CSF ACE assay, however, does not exclude the diagnosis of neurosarcoidosis, and assay methodology and normative values have not been well standardized; a recent study suggests a cut point of 8 nmol/ml/min (sensitivity 55%, 104 105 specificity 94%), although the overall utility of the assay has been questioned. Evoked potentials are useful in evaluating some patients with neurosarcoidosis. Visual evoked potentials (VEPs) can reveal abnormalities of the anterior visual pathways. They are often abnormal in patients with symptomatic optic nerve disease and may be abnormal in some patients with CNS sarcoidosis but no clinical evidence of optic nerve 6,106,107 Streletz and colleagues reported VEP abnormalities in a high proportion dysfunction. of patients with neurosarcoidosis. Even some patients with sarcoidosis, but without ocular or 106 neurological disease, were found to have abnormal responses. Their study suggests that subclinical neurosar-coidosis may be more common than previously realized, but not all 6 investigators confirm a high incidence of VEP abnormalities in asymptomatic patients. Some investigators suggest, instead, that VEP abnormalities in particular, and evoked potential disturbances in general, are useful in symptomatic neurosarcoidosis, as they demonstrate 6 relevant abnormalities that may be used to monitor the clinical course of the disease. Similarly, brainstem auditory evoked potentials (BAEPs) are often abnormal in neurosarcoidosis in patients with brainstem or eighth nerve symptoms and may be abnormal 107 in neurologically ill patients without overt disease in these areas. However, they are rarely, if ever, abnormal in patients without clinically evident CNS sarcoidosis. Somatosensory evoked potentials have not been comprehensively studied in the assessment of patients with sarcoidosis. Preliminary evidence suggests that their clinical utility is similar to that of VEPs and brainstem auditory evoked potentials in confirming the involvement of a specific sensory 108 system that may be clinically affected. Nerve conduction studies in patients with sarcoidosis-associated neuropathy usually reveal changes compatible with an axonal neuropathy, although slowing is sometimes more 91,109 Electromyography may be pronounced and suggestive of demyelinating disease. indicative of denervation in patients with a neuropathy or radiculopathy and reveal myopathic 84 MRI may reveal a characteristic changes in patients with a symptomatic myopathy. 110 “star-shaped” pattern for muscle nodules. Muscle or nerve biopsy is informative if the diagnosis of neuromuscular disease is in doubt. Muscle biopsy can be targeted to areas of MRI enhancement. Neurosarcoidosis, because of its varied manifestations, is in the differential diagnosis of many unexplained neurological syndromes. Recent data on the clinical presentation of neuromyelitis optica suggest that this disorder may emerge as an important differential 111 diagnostic consideration in patients with optic neuropathies and spinal cord syndromes. The diagnosis of sarcoidosis is most secure when it is based on pathology and when more than one organ system is involved. However, since tissue from the nervous system is difficult to secure for pathological analysis and other tests are not diagnostic of neurosarcoidosis, the diagnosis of neurosarcoidosis, despite all efforts, must sometimes remain tentative. It is 43 We have useful when one considers a diagnosis of neurosarcoidosis to grade its likelihood. 43 found the following categories useful, as adapted from Zajicek and co-workers : Possible neurosarcoidosis: The clinical syndrome and diagnostic evaluation suggest neurosarcoidosis. Infection and malignancy are not excluded or there is no pathological confirmation of systemic sarcoidosis. Probable neurosarcoidosis: The clinical syndrome and diagnostic evaluation suggest neurosarcoidosis. Alternative diagnoses are excluded. There is pathological confirmation of systemic sarcoidosis. Definite neurosarcoidosis: The clinical presentation is suggestive of neurosarcoidosis, other diagnoses are excluded, and there is supportive nervous system pathology or the criteria for “probable” neurosarcoidosis are met and the patient has had a beneficial response to immunotherapy over a 1-year observation period. TREATMENT No rigorous studies compare various treatments for neurosarcoidosis. Corticosteroid therapy is the mainstay of treatment and is indicated for any patient without a specific contraindication to it. Decisions about issues such as the optimal therapeutic dose and duration of therapy are

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made on an individual basis. A treatment paradigm is given in Figure 51-14.

FIGURE 51-14 Treatment paradigm for patients with neurosarcoidosis.

Treatment with corticosteroids is widely accepted and recommended for all forms of neurosarcoidosis. In support of this, many individual case reports and series provide evidence that on a short-term basis it can produce impressive responses and alleviate symptoms. Still, it is not fully established that treatment changes the natural history and long-term course of neurosarcoidosis. A major theoretical goal for long-term treatment with corticosteroids is to diminish the irreversible fibrosis that can develop and to minimize the tissue ischemia that might result from perivascular inflammation. Once treatment with corticosteroids or other immunomodulating or immunosuppressive agents is begun, it need not continue indefinitely, particularly at extremely high doses. The inflammatory process can recede, allowing therapy to be withdrawn gradually. Recommended treatment regimens for the various manifestations of neurosarcoidosis are detailed.

Cranial Neuropathy Peripheral Facial Palsy Facial weakness may improve without any specific treatment. A controlled trial of treatment has not been done, and the long-term prognosis for patients seems favorable. Nevertheless, it seems reasonable to give a short course (2 weeks) of prednisone. For the first week, the recommended prednisone dose is in the range of 0.5 to 1.0 mg/kg daily, or 40 to 60 mg daily. This is followed by a gradual reduction leading to discontinuation of prednisone over the second week, although tapering is probably unnecessary. General supportive care, as for any patient with a peripheral facial palsy, should be provided. Other Cranial Nerve Palsies Patients with other cranial neuropathies may be managed with a corticosteroid protocol similar to that described for peripheral facial palsy. However, often more than 2 weeks of therapy is needed. In particular, patients with optic neuropathy or dysfunction of the eighth cranial nerve may need more prolonged, aggressive therapy, which may not prevent irreversible optic and eighth nerve damage.

Aseptic Meningitis Acute aseptic meningitis may respond to a short (2-week) course of prednisone, 0.5 to 1.0 mg/kg per day. The goal of therapy for chronic aseptic meningitis should not be complete clearing of an asymptomatic CSF pleocytosis. Attempts to completely normalize the spinal fluid may needlessly expose patients to the adverse side effects of corticosteroids or other

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therapeutic agents. There is no evidence that clearing the CSF of an abnormal cellular response necessarily corresponds to clinical well-being in patients with chronic aseptic meningitis who are otherwise asymptomatic.

Hydrocephalus Asymptomatic ventricular enlargement usually does not require therapy. Mild, symptomatic hydrocephalus may respond to corticosteroid treatment, and prolonged therapy is often appropriate. Life-threatening or corticosteroid-resistant hydrocephalus requires ventricular shunting or a ventricular drain. Unfortunately, mild hydrocephalus may evolve to severe, life-threatening disease quite rapidly. Therefore, patients and care-providers should be well educated as to the symptoms of acute progressive hydrocephalus and know how to obtain prompt emergency care. At times, high-dose intravenous corticosteroid therapy (methylprednisolone 20 mg/kg per day for 3 days) can stabilize a patient with life-threatening hydrocephalus, although usually prompt surgical intervention with a ventricular drain or ventriculoperitoneal shunt is necessary. Shunt placement is not without risk in this patient population, which is why “prophylactic” shunting in asymptomatic patients with hydrocephalus is not readily advocated. Shunt obstruction is common, and placement of a foreign object in the CNS of an immunosuppressed host predisposes to infection. To further complicate management, there are case reports of patients with relatively modest hydrocephalus who, following a diagnostic lumbar puncture, develop marked neurological deterioration, 59 sometimes with a fatal outcome.

Parenchymal Disease Corticosteroid therapy may improve the status of patients with a diffuse encephalopathy-vasculopathy or CNS mass lesion. Only rarely, however, does immunosuppressive treatment improve neuroendocrine dysfunction or vegetative symptoms. Corticosteroid treatment of CNS parenchymal disease and other severe neurological manifestations of sarcoidosis usually starts with prednisone, 1.0 to 1.5 mg/kg daily. Critically 112 ill patients may require high-dose intravenous corticosteroid therapy. A short course of methylprednisolone, 20 mg/kg daily intravenously for 3 days, followed by prednisone, 1.0 to 1.5 mg/kg per day for 2 to 4 weeks, is occasionally warranted. The higher doses are used in patients with particularly severe disease. Such patients often require more prolonged therapy, and prednisone should thus be tapered very slowly. The prednisone dose can be tapered by 5-mg decrements every 2 weeks as the clinical course is monitored. Neurosarcoidosis may worsen at a low prednisone dose (approximately 0.1 mg/kg or 10 mg or less daily). Some patients exhibit an individual therapeutic lower limit, or dosage below which worsening can almost be predicted. Once a daily prednisone dose of approximately 10 mg is achieved, the patient should be evaluated for evidence of worsening disease. Clinical disease can be monitored by symptoms, but subclinical disease can also be monitored. For patients with CNS disease, enhanced MRI is useful. Intense enhancement, in the meninges, for example, suggests that neurosarcoidosis is active, and further decreases in the corticosteroid dose may lead to a clinical exacerbation. Other manifestations of neurosarcoidosis can be evaluated for subclinical deterioration on an individualized basis (e.g., by evaluating nerve conduction studies or serum creatine kinase level), but persistent mild CSF abnormalities are usually not an indication for continuing or escalating high-dose corticosteroid therapy. Efforts to “normalize” the CSF often require powerful immunosuppression, with its attendant adverse effects. If the sarcoidosis appears quiescent, a low daily prednisone dose of about 10 mg can be tapered further by 1 mg every 2 to 4 weeks. If a patient has a clinical relapse, the dose of prednisone should be doubled (unless the dose is very modest, in which case a prednisone dose of 10 to 20 mg daily can be prescribed). The patient should then be observed for approximately 4 weeks before another taper is contemplated. Patients may require multiple cycles of higher and lower corticosteroid dosing during attempts to taper medications. Nevertheless, the disease may become quiescent and, without attempts at withdrawing medication, patients may be needlessly exposed to the harmful side effects of long-term, high-dose corticosteroids. Seizures, when they occur, are generally not a major limiting problem and can usually be well controlled with antiepileptic medication if the underlying CNS inflammatory reaction is effectively treated. However, seizures are an indication of or marker for the presence of parenchymatous involvement of the brain, which, in itself, is a serious manifestation of

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neurosarcoidosis.


12,13

In patients with a CNS mass lesion that is unresponsive to high-dose corticosteroids, surgical resection may be considered, especially in life-threatening situations.

Peripheral Neuropathy and Myopathy Patients with a peripheral neuropathy or myopathy may respond to a several-week course of corticosteroids, usually beginning with prednisone, 1 mg/kg per day (or approximately 60 mg/day). Here, too, prolonged treatment may be indicated. Corticosteroids should be tapered slowly, as discussed earlier. GENERAL SUPPORTIVE CARE Patients with neurosarcoidosis, and particularly those receiving treatment with immunosuppressive agents, require close attention to their general medical well-being. Potential adverse effects of treatment should be carefully sought. For example, formal, prescribed exercise and dietary programs are often beneficial in helping the patient avoid the weight gain associated with high-dose and long-term corticosteroid treatment. Rehabilitation services should be utilized as appropriate. Depression is not uncommon, and treatment is often helpful. Sleep disorders, especially sleep apnea syndrome, should be considered as a cause of fatigue or cognitive decline. Therapy for endocrinological disturbances is important. In particular, hypothyroidism, especially hypothalamic hypothyroidism, and hypogonadism are major problems in neurosarcoidosis and should be treated. Patients receiving protracted, low-dose corticosteroid regimens require supplemental doses of corticosteroids during periods of intercurrent illness or stress. Hyperglycemia is a potential side effect of long-term, high-dose corticosteroid treatment but usually is not associated with ketoacidosis. Exercise and dietary programs are useful in managing hyperglycemia, but oral hypoglycemic agents or insulin 113 therapy may occasionally be needed. Patients with sarcoidosis are at risk for osteoporosis, especially from corticosteroid therapy. The treatment of osteoporosis in this context is a challenge because sarcoidosis may cause hypercalcemia and hypercalciuria. Management requires reduction of corticosteroid dosage when possible, cautious use of supplements of calcium and vitamin D, hormonal treatment, 114 and use of other bone-building agents. Screening and serial measurements of bone density may be particularly useful in judging an individual patient's progress. Patients with refractory neurosarcoidosis are at risk from both the sarcoidosis-associated inflammatory process and the complications of treatment. If a patient is not doing well, not only should the original diagnosis of sarcoidosis be questioned but the patient should also be evaluated for intercurrent complications such as infection, malignancy, and epidural lipomatosis. Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin's lymphoma, although a recent survey in Scandinavia failed to 115 find such an association for sarcoidosis. ALTERNATIVE TREATMENTS Treatment alternatives to corticosteroids must sometimes be considered for patients with neurosarcoidosis. Experience in this area is limited, and no alternative treatment to corticosteroids has been studied rigorously. Indications for the use of such treatments include contraindications to corticosteroids as initial therapy, serious adverse chronic corticosteroid effects, and progressive disease activity despite aggressive corticosteroid therapy. Medication alternatives to corticosteroids that have been used to treat sarcoidosis include mycophenolate mesylate, azathioprine, methotrexate, cyclophosphamide, cyclosporine, chlorambucil, hydroxychloroquine, pentoxifylline, thalidomide, and infliximab (and related 7,22,116–119 Radiation tumor necrosis factor alpha antagonists etanercept and adalimumab). therapy has also been reported to have limited success. These various approaches have not been studied in a scientifically controlled manner against placebos or comparable treatments. Such trials are difficult because neurosarcoidosis is a rare disorder with varied clinical presentations. Practically, consideration should be given to introducing alternative therapy whenever a patient shows signs of serious corticosteroid side effects or requires frequent large increases in corticosteroid dosage to control symptoms. Alternative treatment with an immunosuppressive agent or irradiation is a logical adjunctive therapy for refractory neurosarcoidosis based on current concepts of the immunopathogenic mechanisms of the disease. Alternative therapy may allow a gradual decrease in corticosteroid dosage to prevent

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or minimize corticosteroid complications, often without deterioration in the patient's clinical status. Rarely, however, can corticosteroids be eliminated completely. Some patients may continue to deteriorate despite combination therapy, and6,7,12,13 the reported mortality in neurosarcoidosis remains a substantial 5 to 10 percent. The potential adverse effects of the therapy and extent of systemic disease should determine the choice of alternative treatment. It is wise to choose an agent whose adverse effects spare an organ or organ system that may already be compromised. For example, cyclosporine usually should be avoided in patients with significant hypertension or renal disease, and azathioprine may not be the best choice for patients with 120,121 liver or hematological problems or Methotrexate, with its who have a deficiency of thiopurine S-methyltransferase. associated liver and pulmonary toxicity, poses problems for patients with impaired liver or lung function. However, in general, the side effects of these alternative medications are limited and predictable and respond to withdrawal of the offending agent. It is even possible to restart the medication in some cases, without recurrent side effects. Recent series describe promising results with methotrexate for patients with122,123 refractory Good 124 sarcoidosis or who are unable to tolerate the side effects of corticosteroids. results in treating neurosarcoidosis patients with methotrexate have also been reported. Patients in whom methotrexate treatment failed were then treated with intravenous 109 cyclophosphamide. Although these findings are promising and deserve consideration, they are based on nonrandomized and uncontrolled trials. 108

Cyclosporine has had demonstrated efficacy in some patients with neurosarcoidosis. The blood level for cyclosporine should be measured and maintained at a level similar to that used for renal transplantation patients. For some of the other alternative therapies, including azathioprine, chlorambucil, and cyclophosphamide, dosing should be targeted to achieve hematological endpoints, such as lowering the total white blood cell count to approximately 3 3 3,500/mm or the lymphocyte count to 1,000/mm . A major advantage of alternative immunosuppressant medications is that they may enable a gradual reduction of corticosteroids to108 about 15 to 30 percent of the stabilizing dose and thus offer a “corticosteroid-sparing” effect. Even with the use of alternative medication, symptoms may recur when corticosteroids are decreased below 10 mg/day. Attempts to withdraw corticosteroid therapy totally may result in worsening symptoms, suggesting that alternative immunosuppressant medication is best used as an adjunct to corticosteroids. Some patients do quite well on corticosteroid therapy alone after alternative medication has been withdrawn, and others can be maintained on the alternative agent alone. Another viable option for some patients with refractory CNS sarcoidosis is radiation therapy. The small number of reported patients treated in this way precludes definitive conclusions about efficacy. Some case reports suggest a beneficial response, especially if total nodal and craniospinal irradiation is done. A total dose of 19.5 Gy with daily fractionation of 1.5 Gy has 125 been suggested. Total nodal irradiation has also been administered in refractory patients. It appears that although radiation therapy can sometimes be of benefit, continued immunosuppressive therapy is usually necessary. Although it is not possible to predict with absolute certainty which patients with neurosarcoidosis will have disease refractory to conventional corticosteroid treatment, certain patients may have a particularly high-risk clinical profile. For instance, patients with an optic neuropathy or CNS parenchymatous disease (e.g., mass lesions or extensive encephalopathy-vasculopathy) are at especially high risk. Such patients might benefit from the prompt use of adjunctive alternative treatment should they become refractory to corticosteroids or develop intolerable side effects. Patient response to a particular alternative therapy can be determined only by trial: a good clinical response cannot be predicted and patients may show a good response to one agent after an initial failure to respond to another. If a patient is stable for several months on low-dose prednisone and an alternative treatment, slow tapering of the alternative treatment can be pursued while the clinical course is monitored. PROGNOSIS The clinical course and prognosis for neurosarcoidosis varies but is somewhat predictable. For example, some two thirds of patients have a monophasic neurological illness; the remainder have a chronically progressive or remitting-relapsing course. Those with a monophasic illness typically have an isolated cranial neuropathy, most often involving the facial nerve, or an episode of aseptic meningitis. Those with a chronic course usually have CNS parenchymal disease, hydrocephalus, multiple cranial neuropathies (especially involving 12 cranial nerves II and VIII), peripheral neuropathy, or myopathy. Patients with CNS

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parenchymal disease or hydrocephalus are at highest risk for death, from either the inflammatory process itself or complications of therapy. Mortality with neurosarcoidosis is 6,7,12,13 approximately 5 to 10 percent. Because most patients with neurosarcoidosis are treated with immunosuppressive agents, it 6,7 is impossible to determine the natural history of the untreated disorder. Although therapy can certainly improve patients in126 the short term, it is not clear that the ultimate outcome of the disease is necessarily changed. Even in severely ill or impaired patients, the inflammatory process may spontaneously subside over time. Other patients with remitting-relapsing or progressive disease can become severely incapacitated even with aggressive treatment. In monitoring the response to treatment, a target measure, such as a specific clinical sign, symptom, functional assessment, or neurodiagnostic test, should be sought. For instance, a timed walk can be used for clinical assessment in some patients; in patients with an intracranial mass, MRI is a helpful neurodiagnostic measure. This type of approach can be used to judge a response over a relatively short period of time. Despite limitations in our understanding of the natural history of sarcoidosis, treatment with corticosteroids seems to benefit many patients with neurosarcoidosis. Even more importantly, patients benefit most from a comprehensive approach to care based on an understanding of the full clinical spectrum of neurosarcoidosis, an appreciation of the whole range of treatment options, and the anticipation of complications, such as those relating to corticosteroid treatment.

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Aminoff: Neurology and General Medicine: Neurological Complication...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 52 Neurological Complications in Critically Ill Patients CHARLES F. BOLTON • G. BRYAN YOUNG •

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SEPTIC (SEPSIS-ASSOCIATED) ENCEPHALOPATHY Clinical Features Laboratory Features Autopsy Findings Pathogenesis NEUROMUSCULAR PROBLEMS IN THE CRITICAL CARE UNIT Critical Illness Polyneuropathy Motor Neuropathy and Neuromuscular Blocking Agents Chronic Polyneuropathies Neuromuscular Transmission Disorders and Myopathies Transient Neuromuscular Blockade Critical Illness Myopathy Critical Illness Polyneuropathy and Myopathy ELECTROPHYSIOLOGICAL STUDIES OF THE RESPIRATORY SYSTEM MONONEUROPATHIES

The term critical illness has been widely used for many years to describe the condition of any patient with illness severe enough to be considered at risk for death. In modern general medical and surgical intensive care units (ICUs), where at least 25 percent of patients may 1 have this condition, it has become synonymous with the syndrome of sepsis and multiple organ failure. This syndrome has probably always been a component of preterminal illness, but before the advent of modern methods of treatment, the syndrome evolved so quickly that the nature of the preterminal events was not considered. However, with the use of intravenous transfusions, antibiotics, activated protein C, and improvements in assisted ventilation, patients are now kept alive for days, weeks,1,2and even months in intensive or critical care units, and as many as 40 percent recover. Thus, it is now possible to study the syndrome in detail, and its effects on the various major organ systems, including the central and peripheral nervous systems. In the past, sepsis was defined as the systemic response to dividing and invading microorganisms of all types. However, in many instances the offending organism cannot be cultured. For example, blood cultures are negative in half of the patients suspected of being septic. Moreover, the criteria for diagnosing sepsis based on systemic responses are still unsettled. The term systemic inflammatory response syndrome (SIRS) should now be applied

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to a severe clinical insult that arises not only as the result of infection but also as the result of 3 noninfectious processes such as trauma, burns, and pancreatitis. The chief clinical features of this syndrome are two or more of the following: (1) temperature exceeding 38°C or less than 36°C, (2) heart rate greater than 90 beats/min, (3) respiratory rate greater than 20 breaths/min or arterial partial pressure of carbon dioxide (Paco2) less than 32 torr (4.3 kPa), 3 and (4) white blood cell count (WBC) more than 12,000 cells/mm or with more than 10 3 percent immature (band) forms. SIRS may be accompanied by hypotension (blood pressure less than 90 mmHg or a reduction of more than 40 mmHg from baseline in the absence of 4 other causes of hypotension). 2,5

In SIRS, cellular and humoral responses are activated to produce changes in the microcirculation throughout the body (Fig. 52-1). The cellular response involves epithelial and endothelial cells, macrophages, and neutrophils. These induce the humoral response; proinflammatory mediators are activated locally and include interleukins-1, -2, and -6, tumor necrosis factor (TNF)–α, arachidonic acid, coagulation factors, free oxygen radicals, and proteases. These cellular and humoral factors interact with themselves and with adhesion 6 molecules, which are increased in the blood of septic patients. Adhesion molecules adhere to leukocytes, platelets, and endothelial cells; they also induce “rolling neutrophils” and fibrin platelet aggregates that obstruct capillary flow. Endothelial damage increases capillary 2 permeability, which induces local tissue edema. Levels of protein C are reduced in sepsis. Endothelial damage impairs the endothelium-dependent activation of protein C, thus shifting 7,8 the balance to thrombosis. Activation of nitric oxide, now known to be the endovascular relaxing factor, causes arteriolar dilation, which may further slow capillary flow. Thus, essential nutrients fail to reach the organ parenchyma. For example, despite adequate oxygenation via mechanical ventilation, there is5a severe oxygen debt at the parenchymal level contributing to multiple organ dysfunction. Considering the profound disturbances of the microcirculation and the impaired delivery of substrates, especially oxygen and glucose, upon which the nervous system depends, it is not surprising that the nervous system is affected. There is no known specific treatment, but it is known that if the underlying sepsis can be brought under control by either medical or surgical means, the various manifestations of the syndrome disappear and full recovery is possible.

FIGURE 52-1 Schematic, theoretical presentation of disturbances in the

microcirculation to various organs, including brain, peripheral nerve, and muscle, in systemic inflammatory response syndrome (SIRS). The result is impaired perfusion due to excessive vasodilatation through overproduction of nitric oxide, and aggregation of cellular elements through activation of adhesion molecules and deactivation of protein C. Increased capillary permeability causes edema and the potential for entry of toxic substances. (Adapted with permission from Bolton CF: Neuromuscular manifestations of critical illness. Muscle Nerve 32:140, 2005.) The patients who are most susceptible are those suffering from multiple injuries or severe medical illness or who have just had major surgery, particularly if they are elderly or have serious underlying disease that may affect their resistance to infection. Early intubation and transfer to the critical care unit is usually necessary. In the course of time, various intravascular lines are inserted, either for treatment or to monitor vital function. There is little

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doubt that these invasive procedures induce the state of sepsis if it was not already present. Thus, it is generally recognized that patients who have been in the unit for more than 5 days almost invariably become septic and, if that is not controlled, soon develop the syndrome of multiple organ failure. Either the central or peripheral nervous systems may be affected in 70 percent of patients 9 with sepsis and multiple organ failure. Within hours of the onset of sepsis, a mild 9 encephalopathy develops, termed septic or sepsis-associated encephalopathy. When deterioration to a state of multiple organ failure occurs, this encephalopathy becomes severe, but it soon subsides if the sepsis is successfully treated. However, the clinician may then note that it is difficult to wean the patient from the mechanical ventilator. If lung and heart disease are excluded, critical illness polyneuropathy, critical illness myopathy, or a combination of 10 both (critical illness neuromyopathy) is almost always the cause of this circumstance. However, as with encephalopathy, the polyneuropathy or myopathy eventually disappears if the sepsis does not recur and the patient survives. SEPTIC (SEPSIS-ASSOCIATED) ENCEPHALOPATHY The term septic encephalopathy refers to altered brain function related to the presence of microorganisms or their toxins in the blood. This condition has been recognized by surgeons and internists as a component of multiple organ failure, but it has received little systematic study.

Clinical Features The clinical diagnosis of septic encephalopathy is one of exclusion. Altered brain function in the febrile patient can be due to a number of conditions other than the sepsis itself (Table 52-1). Space does not allow a complete discussion of the differential diagnosis, butother entities can usually be ruled out by the history, physical examination, and laboratory tests. It is often necessary to perform a lumbar puncture to exclude bacterial meningitis. Click here to view this table.... 11

We carried out a retrospective study on 12 autopsied patients and a separate clinical, prospective study involving 69 patients, each with fever and12either a positive blood culture or a localized bacterial or fungal infection as inclusion criteria. Patients with a fever and either a positive blood culture or a localized bacterial or fungal infection were included for both studies. We excluded patients younger than 16 years and those with central nervous system (CNS) disorders unrelated to the febrile illness, preexisting metabolic disorders, and conditions that affect the brain other than by a septic mechanism. In the prospective study, we also excluded patients receiving heavy sedation or analgesics and those receiving skeletal muscle relaxants. For this study, using an arbitrary set of bedside criteria, we classified patients as nonencephalopathic, mildly encephalopathic, and severely encephalopathic. In our classification, nonencephalopathic patients cooperated with testing and passed a series of tests of attention, concentration, orientation, and short-term memory. The mildly encephalopathic patients completed testing but failed to “pass,” and the severely encephalopathic patients were too obtunded to test. The clinical picture is similar to that of diffuse or multifocal encephalopathy in general. The level of consciousness varies from clouding of consciousness to coma. Delirium occurs infrequently, preceding stupor or coma. Mildly encephalopathic patients often show considerable fluctuation in their clinical state, and older individuals become especially confused at night. Attention, concentration, and memory are impaired. Writing disturbances occur, as in other acute confusional states. Paratonic rigidity, or gegenhalten (a rate-dependent resistance to passive movement), is almost universal in encephalopathic patients. Tremor, asterixis, and multifocal myoclonus occur in 10 to 25 percent of noncomatose encephalopathic patients. Alterations of pupillary size or reaction, abnormalities of individual cranial nerves, focal neurological signs, or convulsive seizures typically do not occur. Hemiparesis or gaze palsy was found in 6 and focal or generalized convulsive seizures occurred in 5 of the 12 patients in our retrospective (autopsy) series, but were rare in our prospective study. The difference may be accounted for, in part, by the duration of sepsis in the autopsy group and the pathological findings (discussed later). As expected, the mortality rate in our prospective study was12significantly greater among the severely encephalopathic patients than in the other groups. Nearly half of the severely encephalopathic patients but none of the nonencephalopathic patients died. About 25 percent of the nonencephalopathic patients had clinical and electrophysiological evidence of mild peripheral neuropathy. Among the moderately and severely encephalopathic patients, 50

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percent and 75 percent, respectively, had critical illness polyneuropathy; among the patients 12 in the latter group, the polyneuropathy was usually severe. The time courses of the encephalopathy and the polyneuropathy often differed. The encephalopathy peaked earlier and cleared long before the polyneuropathy in the course of the septic illness. Some severely encephalopathic patients were obtunded for a month or more, but CNS function improved soon after the infection and systemic metabolic problems were controlled or resolved. There was a strong association of adult respiratory distress syndrome with severe encephalopathy. Transient hypotension was more common at the onset of sepsis in the severely encephalopathic patients, although there was no difference in blood pressure among the three groups at their initial neurological assessment. The degree of prior hypotension was not sufficient to account for the neurological findings. Interestingly, none of the following correlated with the severity of encephalopathy: age (a trend for correlation of age and degree of encephalopathy did not achieve statistical significance), gender, temperature, or type of organism (no difference between gram-positive and gram-negative organisms, but patients with Candida, although few in number, were more severely affected).

Laboratory Features The electroencephalogram (EEG) is a sensitive monitor of septic encephalopathy. We found it to be more sensitive than our arbitrary clinical assessment of mental status, in that some nonencephalopathic patients had mild EEG abnormalities that resolved on subsequent recordings. The mildest EEG change consisted of mild, generalized slowing (theta activity). More severe EEG abnormalities, which correlated with more profound depression of consciousness, consisted of greater slowing (delta activity), triphasic waves, or a 13 burst-suppression pattern (Fig. 52-2). Using computational nonlinear analysis techniques, Straver and colleagues showed that EEG features correlated with the severity of illness and that the EEG became disorganized with greater severity of illness, suggesting a shift in the 14 processing ability of the brain. Although there is a direct relationship between the degree of EEG abnormality and mortality, some patients with even the most severe categories of abnormality recover. Thus, the EEG cannot be used to predict a hopeless prognosis in septic 13,14 encephalopathy.

FIGURE 52-2 Electroencephalograms (EEGs) from patients with septic encephalopathy.

A, Patient with mild encephalopathy. The EEG shows a mild excess of low-voltage 6to 7-Hz theta rhythms in both left (odd-numbered electrode placements) and right (even-numbered placements) hemispheres. B to D, Severely encephalopathic patients.

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B, Bilateral intermittent rhythmic delta (14 days).

FIGURE 54-1 Anatomical disposition of cubital tunnel and its content (right

elbow flexed): 1, ulnar nerve; 2, ulnar collateral artery; 3, triangular arcuate ligament; 4, medial epicondylar groove; 5, medial lip of trochlea; 6, medial ligament of elbow. (From Perreault L, Drolet P, Farny J: Ulnar nerve palsy at the elbow after general anaesthesia. Can J Anaesth 39:499, 1992, with permission.)

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FIGURE 54-2 Cubital tunnel in extension (A) and 90-degree flexion (B): 1, slack arcuate ligament; 2, flexor carpi ulnaris; 3, taut arcuate ligament. (From Perreault L, Drolet P, Farny J: Ulnar nerve palsy at the elbow after general anaesthesia. Can J Anaesth 39:499, 1992, with permission.)

When patients undergoing coronary artery bypass graft (CABG) procedures are monitored with somatosensory evoked potentials perioperatively,almost 70 percent of patients may show evoked-potential changes during the procedure when surgical retractors are in 56 use and up to 6 percent of patients have evidence of nerve deficits at 1 week postoperatively. There is evidence that group A nerve fibers rely on aerobic metabolism to a greater extent than do C fibers, consistent with the clinical observation that motor function and tactile sensations are lost long before pain sensation is lost in perioperative neuropathies related to nerve ischemia 57 from stretch or positioning. When a tourniquet is used during surgical procedures, arbitrary decisions are often made about the length of time it can be in place as well as the level of pressure chosen to occlude blood flow to the limb. Many suggest that after 2 hours of tourniquet inflation the blood flow be reestablished for 10 to 15 minutes to minimize perioperative neuropathy, although there is little evidence that the 2-hour limit has any physiological basis. Data 58 suggest that 3 hours is a “reasonable” upper limit for safe application of automatic tourniquet. In any event, tourniquet time should be individualized, and decisions should be based on patient as well as surgical factors. When peripheral nerve blocks are utilized during surgical procedures and a neural deficit develops, the regional anesthetic is often suspected to be the cause. In a prospective survey involving more than 100,000 regional anesthetics, the frequency of neurological complications after peripheral blockade was found to be less that that associated with 59 neuraxial anesthesia. Of 34 neurological complications, 21 were associated with paresthesias during needle placement or pain during injection of local anesthetic, suggesting 59 nerve trauma or intraneural injection. It is important to realize that many factors distinct from the regional anesthetic may contribute to postoperative neurological injury. These include pressure injury from improper patient positioning, tightly applied surgical casts or dressings, and trauma from surgery itself. Patient factors such as body habitus or a preexisting 60 neurological deficit may also play a role.

Cardiovascular Monitoring Anesthesiologists are often involved in insertion of central venous catheters for cardiovascular monitoring perioperatively. There are numerous reports of neural injury related

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61–64

to central venous cannulation. As shown in Figure 54-3, numerous neural structures can be injured during cardiovascular cannulation. It may be that significant injury is more likely with cannulation in patients who are already anesthetized because they are unable to describe pain or paresthesias during the insertion.

FIGURE 54-3 Left oblique view of nerves in the neck and supraclavicular fossa

that may be injected during both internal jugular and subclavian central venous techniques. (With permission of the Mayo Foundation.) PERIOPERATIVE SEIZURES There are numerous reasons for patients to exhibit changes in mental status as well as abnormal motor activity in the perioperative period. These include simple “faints” during intravenous cannulation and seizures induced by inhalational agents or related to systemic toxicity of local anesthetics. Simple faints or symptoms compatible with vagal reactions during intravenous cannulation may occur in up to 17 percent of ambulatory patients younger than 65 40 years. It can sometimes be difficult to determine whether an idiopathic seizure has occurred preoperatively or whether the patient has experienced a simple faint. It does seem clear that younger patients are more likely to experience these perioperative events and that the greater the 65 number of attempts to place the intravenous cannula, the higher the incidence 66 of such events. Perioperative seizures may also be psychogenic in origin. Although psychogenic seizures are exceedingly rare in this setting, there are patients for whom this diagnosis needs to be considered.

General Anesthetics As shown in Table 54-9, a number of anesthetic drugs are proconvulsants, with a significant number of these also identified as anticonvulsants, depending on the dose and rate and route 67 of administration. In considering inhalational anesthetic agents, the drug that has been linked to seizure activity most often is enflurane. In the clinical setting, enflurane is known to be potentially epileptogenic. During enflurane anesthesia with hyperventilation, the resultant hypocapnia potentiates seizure-type discharges. This electroencephalographic-activating

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property of enflurane has been used intraoperatively to activate and identify seizure foci in need of surgical resection. In this situation, spike activity not present preoperatively has been 68 observed to persist following surgery. Click here to view this table.... Intravenous anesthetic agents have also been implicated in perioperative seizures. Meperidine neurotoxicity, manifesting clinically as shakiness, tremors, 69 myoclonus, and seizures, is the most frequent cause of opioid-induced seizure activity. The accentuation of abnormal motor movements is attributed to its N-demethylated metabolite normeperidine. Previously identified risk factors for the development of meperidine-related seizures include renal failure, 70 high meperidine dosages, and co-administration of hepatic enzyme-inducing in this setting, and both resolve with medications. Myoclonus generally precedes seizures 71,72 the discontinuation of meperidine administration. An anesthetic drug, ketamine, which frequently is used in trauma patients undergoing surgery, has been linked to the activation of epileptogenic foci in patients with known seizure 73 disorders. It appears that doses larger than 2 mg/kg of intravenous ketamine are needed to influence the incidence of seizures in these patients. In addition to frank seizure activity, some general anesthetics may produce abnormal neurological findings persisting for up to 60 minutes after cessation of the anesthetic. In a prospective study, it was found that neurological abnormalities such as quadriceps hyperreflexia, extensor plantar responses (Babinski's sign), and intense muscle spasticity can be found for up to nearly 1 hour in patients receiving enflurane–nitrous74oxide anesthesia, as well as at a lesser frequency with isoflurane–nitrous oxide anesthesia. The incidence of these neurological findings declined as patients became more alert. In one healthy 38-year-old woman undergoing arthroscopy of the knee, myoclonic jerks involving multiple muscle groups (except those innervated by cranial nerves) occurred75over the first 48 hours postoperatively; neurological findings after this period were normal.

Regional Anesthetics A variety of CNS effects may occur when local anesthetics are used for regional block. The initial symptoms of local anesthetic-induced CNS toxicity include lightheadedness, dizziness, 76 and visual and auditory disturbances such as difficulty in focusing and tinnitus. Objective signs of CNS toxicity are excitatory in nature and include muscular twitching, shivering, and tremors of facial muscles and distal extremities. Ultimately, generalized tonic-clonic seizures occur. Other signs that may precede the occurrence of such seizures include euphoria, dysarthria,77sweating, vomiting, pugnaciousness, loquaciousness, and an inability to respond to reason. Stimulation of the CNS with local anesthetics may occur from unintended intravascular injection or rapid systemic uptake from the regional block site. The initial phase of CNS excitation may be due to a selective inhibition of inhibitory pathways in the cerebral cortex, thus allowing facilitatory neurons to discharge in an unopposed fashion. The net stimulation of glutamate release, an excitatory amino acid neurotransmitter, may also play a role. With an increase in the dose of local anesthetic, activity of both inhibitory and excitatory 78 pathways is inhibited, leading to a generalized state of CNS depression. A number of investigators have published on the incidence of seizures secondary to the clinical use of local anesthetics, and the centers most experienced in the use of regional block report a 77 figure of approximately 0.1 to 0.33 percent. There is a predictable pattern of peak serum levels, depending on the site of regional block, but most systemic toxic reactions result from direct intravascular injection of local anesthetic rather than from rapid systemic uptake. If signs of CNS toxicity or frank convulsions occur, a number of steps must be followed to minimize adverse outcomes. With seizures induced by local anesthetics, hypoxemia, hypercapnia, and acidosis rapidly develop, and symptomatic treatment of the toxicity must involve treatment of these factors. Oxygen should be given via a bag and mask; tracheal intubation is indicated only in cases of ineffective ventilation. The next step in therapy remains controversial, involving administration of either succinylcholine or anticonvulsant drugs. Succinylcholine is often recommended because seizures are usually short-lived, and pharmacologically induced muscle relaxation facilitates ventilation and decreases the magnitude of metabolic acidosis. Nevertheless, it does not prevent seizures or decrease cerebral metabolism. In addition to the toxic CNS effects, cardiovascular collapse and arrhythmias may also result from a systemic reaction to local anesthetics. It was originally postulated that toxicity (both CNS and cardiovascular) of local anesthetics parallels anesthetic potency; current information suggests that the long-acting agents bupivacaine and 79–81 etidocaine are proportionately more cardiotoxic than their anesthetic potency predicts. This relative increase in cardiotoxicity appears to result from more potent effects on sodium

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channels by long-acting drugs. Thus, if a seizure and cardiovascular collapse occur owing to a local anesthetic, resuscitation may require 1 to 2 hours because it may take an extended period of time to “wash out” the long-acting local anesthetic from the myocardium during the low-flow states that are produced with cardiopulmonary resuscitation. PERIOPERATIVE HEADACHE Chronic headaches occur in 10 percent of the general population. Since approximately 25 million people undergo surgery in the United States each year, a considerable number of these patients will have chronic headaches. When headaches occur perioperatively, it is important to determine whether they correspond to prior headache patterns or represent an entirely new symptom complex. Table 54-10 lists some causes of perioperative headache. The perioperative period is stressful, and tension and stress-related headaches may be exacerbated during this time. A significant percentage of the population consumes caffeine-containing drinks on a regular basis, and the perioperative period often limits caffeine intake. One review of 287 patients undergoing minor elective procedures with general anesthesia suggests that headaches related to caffeine withdrawal may begin 24 hours after cessation of caffeine intake and may 82,83 The use of nitrous oxide in patients with inflamed sinuses or last for up to 5 or 6 days. air-containing middle-ear spaces may result in sinus or ear block and thus headache. The etiology is related to increases in pressure from nitrous oxide equilibrating with the air contained in these structures; the diagnosis is often made by exclusion. General anesthesia may be accomplished by the use of face masks that produce pressure on terminal trigeminal nerve branches, such as the supraorbital or infraorbital nerve; long-standing headaches may 84 then result from compression neuropathy. Other causes of headache are intracranial mass lesions that may occur in patients at any time; these need to be distinguished from benign causes of new-onset headache in the perioperative period. The complicating feature is that spinal anesthesia (with dural puncture) may be associated with headaches in from 1 to 5 percent of patients, depending on gender, age, and type of needle utilized for the anesthetic. The headache related to spinal puncture (decreased intracranial pressure) is possibly related to traction on trigeminal, glossopha-ryngeal, or vagal fibers, though85,86 there is increasing evidence that cerebrovascular vasodilatation may also be involved Click here to view this table.... Post–spinal puncture headaches are more common in women than in men and in the young than in the elderly; they are also more common when a large needle is used for dural puncture, especially when the bevel of the needle results in dural fibers being cut 87,88 It should be emphasized that an arbitrary period of recumbency after spinal transversely. 89 anesthesia has not been found to decrease the incidence of such headache, and some data indicate that early ambulation may actually decrease the incidence of post–spinal 90,91 Approximately 50 percent of these headaches do not interfere with puncture headache. daily activities, whereas 35 percent92are severe enough that daily activities are affected and the patient must rest intermittently. It is important that patients with post–spinal puncture headaches be referred for definitive treatment with an epidural blood patch when appropriate. The safety and efficacy of this approach (>90% efficacy in relieving headache per epidural 93–95 If an epidural blood patch is unsuccessful in relieving patch) have been well documented. headaches ascribed to dural puncture, further questioning should ascertain whether the headaches have the “postural hallmark” of being dramatically relieved in the supine position. In selected patients, it may be clinically appropriate to administer a second epidural blood patch without further diagnostic evaluation, but if a headache does not respond to this second patch, further consultation should be undertaken to exclude underlying structural lesions. PERIOPERATIVE VISUAL CHANGES Visual changes can occur after both general and regional anesthesia. While the patient is anesthetized, pressure transmitted to the globe of the eye can occlude retinal artery flow, resulting in postoperative blindness. A specific subgroup of patients who are at increased risk for visual loss following surgery are patients undergoing complex spine surgery during which general anesthesia is administered. Visual loss following spine surgery is an uncommon occurrence, with ophthalmic complications reported to occur in less than 0.2 percent of spine 96–98 Investigations suggest that the visual 99 loss is due to ischemic optic neuropathy, surgeries. central retinal artery occlusion, or cerebral ischemia. The American Society of Anesthesiologists Task Force on Perioperative Blindness identified high-risk patients as those who undergo spine procedures while positioned prone, those who have prolonged 100 procedures, and those experiencing substantial blood loss. The practice advisory suggested measures to be taken when providing anesthesia care to patients at risk for

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postoperative visual loss. Intraoperatively, high-risk patients should be positioned with the head maintained in a neutral position, level with or higher than the heart. Avoidance of direct pressure on the eyes is imperative. Colloids in addition to crystalloids should be used to maintain intravascular volume. Finally, consideration should be given to the staging of 101 procedures that are anticipated to be lengthy and associated with substantial blood loss. Spinal puncture may be followed by cranial nerve palsies, the most frequent involving the 102,103 The most commonly proposed abducens nerve (bilaterally on rare occasion). explanation for the predominance of sixth cranial nerve changes following development of low cerebrospinal fluid pressure is that the nerve's relatively long intracranial course renders it susceptible to both pressure and stretch. Others promote the concept that the abducens palsy is due to increased venous pressure in the cavernous sinus, since the nerve courses through this site. Venous dilatation occurs in the cranium in compensation for a decrease in cerebrospinal fluid pressure, which may occur following spinal anesthesia. It is clear that the needle size is crucial for both post–spinal puncture headache and abducens nerve palsy. At one neurology clinic in a large university in Germany, 800 patients underwent diagnostic lumbar puncture yearly with 22-gauge needles and in less than 5 percent of cases, with 20-gauge needles. Over a 14½ -year period, 2 patients experienced abducens palsy, 104 translating to a risk of less than 1 in 5,800 spinal punctures. Pupillary changes may follow epidural and spinal anesthesia. There are numerous case reports of the development of 105–107 These are related to local anesthetic effects Horner's syndrome after epidural block. upon sympathetic nerves, but the level of the central block surprisingly does not correlate with 108 the development of Horner's syndrome, at least in the parturient. Among 150 parturient patients undergoing epidural anesthesia for cesarean section or labor, the frequency of Horner's syndrome was 1.3 percent for labor analgesia and 4 percent when the epidural 108 block was used for cesarean section. Horner's syndrome occurs only for the duration of local anesthetic block and, accordingly, should not confound postoperative pupillary assessment except in rare circumstances. Horner's syndrome has also been noted with other regional techniques, and continuous brachial catheter local anesthetic infusions have also 109 been associated with its development. Thus, if postoperative pupillary changes complicate neurological diagnosis, attempts should be made to determine whether a regional block technique might have produced Horner's syndrome. Trigeminal nerve changes have also 109 been found following epidural anesthesia and analgesia. Once again, this is an unpredictable accompaniment of the epidural local anesthetic, and time will clarify its relationship to the regional block. One final ocular alteration that may confuse neurological diagnosis in the immediate perioperative period is the pupillary dilatation that follows “total” spinal anesthesia. This occurs most frequently when an intended epidural anesthetic injection is unintentionally administered into the subarachnoid space. This produces unconsciousness as well as markedly dilated pupils. Symptomatic support of the circulation and ventilation is necessary, and time (1½ to 4 hours) will help clarify the patient's clinical course. It is important to understand that these pupillary changes are a predictable accompaniment of unintentional “total spinal” anesthesia, and diagnosticians should not be misled by the unusual appearance of the widely dilated pupils. PERIOPERATIVE AUDITORY CHANGES Similar to visual changes following anesthesia, auditory changes can accompany either general or regional anesthetic techniques. Auditory changes following general anesthesia are most commonly related to “ear block” that develops110 following the use of nitrous oxide in patients susceptible to eustachian tube obstruction. The ear block is similar to that found after ear blocks associated with air travel. Symptoms resolve with time, although nasopharyngeal decongestants may also help reduce mucosal edema to the point that the ear block can be cleared. Patients who have undergone spinal anesthesia and who are not experiencing headaches from spinal puncture may show a decrease in the ability to hear if sensitive testing is used. Wang and colleagues studied 28 patients receiving spinal anesthesia for transurethral resection of the prostate and found that as larger needles were111utilized, more marked (perhaps subclinical) changes in auditory function were found. None of their patients had headaches; thus, decreased hearing may occur in isolation. The decrease in hearing may relate to a decrease in cerebrospinal fluid volume that reduces the perilymphatic pressure; as the endolymphatic pressure equilibrates slowly compared with the perilymphatic pressure, endolymphatic hydrops results. Thus, a decrease in intralabyrinthine pressure probably causes the transient hearing loss. Hyperacusis may also develop following spinal 112 anesthesia.

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EVALUATION OF PERIOPERATIVE NEUROLOGICAL COMPLICATIONS When neurological changes occur postoperatively, many physicians and nurses assume that “something” must have gone wrong intraoperatively. As the American Society of Anesthesiologists closed-claims analysis of perioperative injury indicates, many perioperative neuropathies have no ready explanation, and our inability to define the etiology of such nerve injuries probably reflects an incomplete understanding of perioperative nerve function. The first step in managing a perioperative neurological change is to obtain a comprehensive evaluation by a skilled neurologist. It is also important to minimize speculation in the medical record and simply document facts. Time is often helpful in identifying the etiology of neurological changes, and early electrodiagnostic studies should also be considered, when appropriate, since preexisting nerve damage may evidence itself in the perioperative 113,114 This is important because abnormal spontaneous activity is unlikely to appear in period. affected muscles until 2½ to 3 weeks following nerve injury; the presence of such activity in the immediate postoperative period suggests that the nerve lesion existed before operation. Time is of the essence if a major injury of the neuraxis is being evaluated. If concern is present about an epidural hematoma following either epidural or spinal anesthesia, imaging studies should be obtained immediately, since recovery of neural function is related to the duration of neural compression by the hematoma. Finally, if perioperative neural changes are present, both the surgeons and the anesthesiologists involved in the patient's care should be included in consultation. Contemporary surgical and anesthetic care has become complex, and these individuals may offer unique insights into predictable perioperative changes that other physicians would find difficult to uncover.

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Keyword Index

Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 55 Neurological Complications of Thermal and Electrical Burns MARC D. WINKELMAN •

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THERMAL BURNS Central Nervous System Complications Metabolic Encephalopathies Central Nervous System Infections Cerebrovascular Disease Blindness Peripheral Nervous System Complications Mononeuropathies Polyneuropathy ELECTRICITY AND LIGHTNING Effect on the Nervous System Clinical Syndromes Transient Loss of Consciousness Transient Paralysis Injury of Peripheral and Cranial Nerves Spinal Cord Injury Brain Injury

Fires and burns are the fifth leading cause of accidental death in the United States. Each year, 1.2 million people seek medical attention for a burn; 50,000 are hospitalized, and 3,900 1 complications can follow a burn has been known since the die. That serious neurological 2 nineteenth century. The complications of thermal burns differ considerably from those of electrical burns and therefore are considered separately. Electricity is encountered in two forms: lightning and man-made current. The neurological effects of these two forms are much the same, and they are considered together. THERMAL BURNS The term thermal burn refers to a burn caused by contact with flames, hot metal, or hot water, or by the flash of radiant heat from an explosion. The extent of a burn is expressed as the percentage of the total body surface area involved. The depth is gauged as full thickness when the dermal appendages are destroyed and partial thickness when they are spared. Patients with extensive, full-thickness burns are more likely to die or to sustain neurological complications than those with less severe burns. They are the ones who require the intensive

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care of a burn unit and with whom this chapter is concerned. Neurological diagnosis is difficult because extensively burned patients are difficult to examine. Their burned eyelids are swollen shut; their faces are swollen and move poorly. It is hard for the patient to move swollen and bandaged limbs and for the doctor to assess their tone and reflexes. Under these circumstances, a full neurological examination cannot be performed; hence, focal signs may escape detection. Peripheral neuropathies may go unnoticed, and symptoms of focal, structural cerebral lesions may be attributed to metabolic or toxic encephalopathies. The limitations of the neurological examination must be appreciated, and cerebral imaging, examination of the cerebrospinal fluid (CSF), and nerve conduction studies may be required more often than for other types of patient.

Central Nervous System Complications Because the brain and spinal cord lie deep in the body, they are not injured by the heat of flash or flame. Most victims are neurologically normal immediately after their burn. Those who are not have usually sustained head trauma or anoxic encephalopathy caused by carbon 3,4 monoxide poisoning or cardiopulmonary arrest due to smoke inhalation. Most disorders of the central nervous system (CNS) arise later, during hospitalization, not as a direct consequence of the burn but as a result of some other complication: a systemic infection, 4 disseminated intravascular coagulation (DIC), hypotension, or metabolic abnormalities. Most of them bear a characteristic temporal relationship to the burn, which may provide a valuable clue to diagnosis. The overall frequency of CNS complications was 5, 6.6, and 14 percent in reports of three 2,5,6 Metabolic encephalopathies, cerebrovascular large clinical series of patients with burns. lesions, and CNS infections are the major types of complications and occur in that order of 2,4,6 4 Adults and children are equally affected. Many patients have more than one frequency. 4 CNS complication, for several reasons. First, a systemic infection can affect the brain by direct invasion, by an intermediary mechanism of disease (e.g., DIC or septic shock), and by leading to systemic metabolic abnormalities. A patient may thus be affected in more than one way. Second, patients may have several independent CNS complications: infectious and noninfectious, metabolic and structural. Third, elderly patients may have coexisting cerebral diseases in addition to complications of their burn. Often a single diagnosis is an adequate but incomplete explanation for a cerebral symptom. For example, a patient with an atherosclerotic cerebral infarct or a metabolic encephalopathy may also have a CNS infection. Therefore, diagnostic evaluations must be extensive, and the response to treatment may be difficult to interpret. Metabolic Encephalopathies Burned patients are liable to a variety of metabolic derangements, many of which cause encephalopathy. Anoxemia, hyponatremia, serum hyperosmolality, and uremia, treated in 2,7 detail in the following sections, are the major ones, but there are others. Hypernatremia, due to insensible water loss through the burn wound, is the most common electrolyte abnormality. A burn causes a marked increase in metabolic rate. There is increased production of glucose, and this may lead to hyperglycemia. Insulin resistance and intravenous hyperalimentation are other causes of hyperglycemia in this setting. Hypoglycemia is usually associated with overwhelming systemic infection. Sequestration of calcium in burned skin may cause hypocalcemia, which in turn can lead to seizures and confusion. Hypomagnesemia, with muscle cramps or hallucinations, occurs occasionally. Anoxic Encephalopathy

A severe burn is attended by the rapid and massive accumulation of edema in the burned 7 and unburned skin (“burn edema”). Intravascular volume depletion and hypotension follow, leading to ischemic tissue damage. This state is called burn shock. Anoxic encephalopathy is the most common neurological complication of a burn, and burn shock is its most common 4,6 After the first week, septic shock becomes the cause in the first few days after a burn. 4 major cause. Hyponatremic Encephalopathy

Fluid resuscitation for burn shock can result in dilutional hyponatremia, the most common 5,6,8 cause of early confusion and seizures in burned patients, especially children. 7 Later in the hospital course, hyponatremia is most often associated with systemic infection.

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Uremic and Hepatic Encephalopathy

Uremic encephalopathy is most often due to acute renal failure, which in turn is caused by 4 acute tubular necrosis or DIC. The causes of acute tubular necrosis are much the same as those of anoxic encephalopathy. In patients with chronic liver disease, hepatic 4 encephalopathy can develop during convalescence from a burn. Precipitating causes include a systemic infection, narcotic analgesics, hypovolemia, and bleeding from a Curling ulcer of 7 the stomach. Central Pontine Myelinolysis

Burned patients, like people with alcoholism, are especially susceptible to central pontine myelinolysis (p. 350). In a retrospective autopsy study, 9this disorder was found 25 times more often in burned patients than in the general population. It was associated with a prolonged period (≥3 days) of extreme serum hyperosmolality (≥360 mOsm/kg) but not with hyponatremia or the correction of hyponatremia. Infection was a major factor in the genesis of the hypernatremia, azotemia, and hyperglycemia that contributed to hyperosmolality. Central pontine myelinolysis was a late complication; it began after the second hospital week in most cases and never in the first week. The lesions were often small and asymptomatic. Even when the lesion is large, diagnosis is difficult. Metabolic coma may hide the motor signs of central pontine myelinolysis, or they may be missed as a result of the difficulties of neurological examination described earlier. Late development of quadriplegia, pseudobulbar palsy, the locked-in syndrome, or coma unresponsive to correction of serum hyperosmolality suggests the diagnosis. Magnetic resonance imaging (MRI) can confirm it. Central Nervous System Infections Infection is the most common cause of morbidity and mortality in burned patients, because they are immunocompromised in several ways. The burn destroys the skin barrier to microorganisms, and the devitalized eschar of the burn wound makes an ideal culture medium. Inhalation of smoke injures the local defense mechanisms of the tracheobronchial tree. Intravenous and urethral catheters and endotracheal tubes promote intraluminal ingress of organisms.10In addition, both the cellular and the humoral immune systems sustain complex impairments. CNS infection is the 4result of hematogenous spread of microorganisms from a source outside the nervous system. Burn wound infection, pneumonia, suppurative thrombophlebitis, and infective endocarditis are the most common sources. Candida species, Pseudomonas 4 aeruginosa, and Staphylococcus aureus are the most common pathogens. Most CNS infections arise in the second and third weeks after the burn; they occur only rarely in the first 4,6 week and never in the first few days. This delay occurs because the CNS is a secondary rather than a primary target of invading microorganisms. Serious infections, including those of the CNS, do not follow minor burns but extensive, deep7 burns, that is, full-thickness burns that involve at least 30 percent of total body surface area. The foregoing facts may help in neurological diagnosis. A week or more after receiving extensive burns, a patient with a systemic infection is at high risk for development of a CNS infection. In contrast, patients without a known site of infection, positive blood cultures, or systemic signs of infection and those in the first week after their burn are unlikely to have an 4 infection of the CNS. Similarly, a patient with a burn involving less than 30 percent 4of total body surface is unlikely to have a CNS infection, even if there is a systemic source. Such patients have less suppression of systemic immune function than those with a major burn 10 and are better able to contain a local infection. Pseudomonas aeruginosa 4,6

Bacterial meningitis develops in 1 to 4 percent of extensively burned patients. P. 4,6 aeruginosa infection is the most common etiology. Moreover, in one autopsy series, meningitis developed in 15 percent of burned patients who had a systemic Pseudomonas 4 infection. A burn wound infection was the most common source. Blood cultures were positive. This is the only CNS infection that has been reported to begin in the first week after 4,6 a burn. Other gram-negative enteric organisms, such as Escherichia coli, but no 4 gram-positive bacteria or fungi have been reported to cause meningitis in burned patients. Gram-negative rods have not caused other types of intracranial infection, such as brain 4,6 abscess. The diagnosis of meningitis may be difficult because the burn surgeon will probably have

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initiated treatment of the primary (source) infection by the time of neurological consultation. This may eliminate the headache and stiff neck of meningitis without eradicating the infection. In some patients, only confusion, stupor, or coma is found. Hence, a metabolic or septic encephalopathy may be diagnosed. However, a gram-negative infection outside the CNS, especially one due to P. aeruginosa, occurring in the setting of an extensive burn that is more than 1 week old, should prompt lumbar puncture. Evidence of meningitis, perhaps partially treated, may be found. If cultures and smears of CSF are negative, antibiotics effective against P. aeruginosa meningitis should be prescribed because that is the likeliest pathogen. 4 Many burned patients have more than one systemic infection. Adequate coverage should also be provided for meningitis due to all other microorganisms grown in systemic culture. If the skin of the back is burned, it may be impossible to do a lumbar or cervical puncture. This is the case in the most extensively burned patients; unfortunately, they are the ones most likely to develop meningitis. If such a patient has a systemic infection due to a gram-negative rod, particularly P. aeruginosa, an antibiotic with good CSF penetration should be prescribed so that meningitis, although impossible to document, should not go untreated. Candida Species

The frequency of Candida infections is increasing among burned patients—a result of the use of broad-spectrum antibiotics for bacterial infections, longer survival of older and more extensively burned4,10 patients, and the use of central intravenous catheters and intravenous Half the patients with invasive candidiasis have cerebral involvement at hyperalimentation. 4,11 This most often takes the form of disseminated microabscesses; large autopsy. 4,11–13 Patients abscesses, meningitis, and mycotic aneurysms are much less common. Candida have almost always had at least one previous, treated bacterial infected with 4 infection. This is reflected in the relatively late onset of cerebral candidiasis—usually late in 4 the second hospital week, and never in the first week. 14

The antemortem diagnosis of disseminated cerebral microabscesses is difficult. They typically produce drowsiness, confusion, stupor, or coma. Fixed, focal cerebral signs and focal seizures are unusual. The CSF remains normal. Often less than 3 mm in diameter, the abscesses are too small to be detected by computed tomography (CT) scanning, but they do appear as small, bright foci on T2-weighted and fluid-attenuated inversion recovery (FLAIR)–sequence MRI, and they probably enhance with contrast. Thus, it may require MRI to distinguish multiple cerebral microabscesses from a metabolic or septic encephalopathy. The diagnosis of cerebral candidiasis may be difficult because the CSF is usually normal, and the diagnosis therefore requires the demonstration of infection outside the CNS. The primary site of infection may not be apparent, and metastatic foci of infection may be hidden as 11 microabscesses in the myocardium or kidney. Pneumonia, evidence of which can be seen on a chest radiograph, is not common. Positive urine, sputum, fecal, and wound cultures can mean colonization rather than infection. Blood cultures are often negative. Without 4 candidemia, the diagnosis is usually made only after death. There is currently no single test that identifies every case of invasive candidiasis. The diagnosis begins with a high index of suspicion in patients with unexplained systemic signs of infection; deep, extensive burns; and a prior bacterial infection. Blood cultures, biopsy of the burn wound (the most frequent site of infection), serological tests, and repeated clinical evaluation for involvement of the skin and eye may help with diagnosis. In an autopsy study, almost half the burned patients with 4 candidemia had cerebral involvement. Therefore, a positive blood culture should prompt systemic antifungal therapy. Staphylococcus aureus 4

S. aureus spreads to the brain by way of endocarditis in burned patients. Intracranial spread 15 from other sites has been reported only once in this group of patients. The sequence of events is burn wound infection, bacteremia, infection of a heart valve, and embolism of infected material to the brain, with infarction or microabscess formation. Other cerebral complications of endocarditis, such as meningitis and mycotic aneurysm, presumably occur in burned patients but have not been reported. Intracranial staphylococcal infections begin relatively late—in most cases more than 10 days after the burn—presumably because the brain is infected after the burn wound and endocardium. The frequency of CNS infection with this organism has declined since the mid-1970s because better antibiotic treatment of burn wound infections prevents the development of endocarditis. The diagnosis of staphylococcal cerebral microabscesses is as hard as that of microabscesses due to Candida, but the identification of S. aureus as the cause is easier because blood cultures are positive. The diagnosis of a staphylococcal CNS infection should prompt a search for endocarditis.

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Cerebral infarction and S. aureus infections are discussed later. Cerebrovascular Disease Cerebrovascular lesions typically present as a stroke (i.e., the sudden onset of a focal neurological deficit), but in burned patients this often is not the case, for three reasons. First, there is the difficulty of neurological examination, described earlier. Second, multiple cerebral complications, the general debility of patients, and the use of narcotic analgesics may obscure the acute onset of cerebrovascular accidents. And third, cerebral infarcts and 4 hemorrhages are often multiple and bilateral in patients with burns, turning an asymmetric neurological picture into one of relative symmetry. Thus, an infarct or hemorrhage may present not as a stroke but in the guise of a metabolic encephalopathy; therefore, any unexplained cerebral symptom or sign should lead to brain imaging. Septic Infarction

Cerebral infarction is due more often to complications of the burn than4 to atherosclerosis, atrial fibrillation, and other premorbid conditions unrelated to the burn. Each major infection discussed earlier can cause septic occlusion of cerebral blood vessels, with infarction of brain. Meningeal infection can extend into the walls of arteries and veins that run through the subarachnoid space, leading to inflammation and occlusion of affected vessels. This is a common4 complication of P. aeruginosa meningitis and can occur in the first week of disease. Embolism of infected material with occlusion of cerebral arteries is a classic complication of infective endocarditis. Only one burned patient with cerebral aspergillosis has been reported, but Aspergillus is a common cause of systemic infection in patients with 4,10 burns.11,12 Aspergillus and Candida species invade and occlude blood vessels at their portal of entry. The fungi then spread through the blood stream, causing inflammation and 12 In the brain, infarction is the major thrombosis of blood vessels in distant organs. 16 Aspergillus. Candida causes mainly microabscesses; infarcts are pathological effect of 4,13 fewer. Radiological features do not distinguish septic infarcts from those caused by premorbid 4 vascular disease, but certain clinical points are helpful. Septic infarction may affect patients of any age and does not occur during the first week after a burn. Patients have extensive burns and systemic signs of sepsis. Focal neurological deficits do not improve. In contrast, infarction caused by premorbid conditions may occur at any time during the hospital course and regardless of the severity of the burn or the presence of systemic infection. Patients are usually elderly, have conventional risk factors for cerebral infarction, and may have had previous cerebral infarcts or coronary or peripheral vascular disease. When a burned patient has a cerebral infarct and a septic cause seems likely, it is important to determine the mechanism involved—meningitis, endocarditis, or fungal invasion of a vessel—and the responsible micro-organism. If the patient was neurologically normal before cerebral infarction, meningitis is unlikely. Physical signs of meningitis, infective endocarditis, or disseminated candidiasis may be found. The mechanism and etiology of septic infarcts correlate with one another. Cerebral infarction in a patient with S. aureus bacteremia suggests the presence of endocarditis. A systemic P. aeruginosa infection suggests that meningitis due to that organism underlies the infarct. If meningitis is found, it is the likely mechanism of infarction, and P. aeruginosa is the probable cause. Thus, examination of the CSF should always be considered. If evidence for neither meningitis nor endocarditis is found, fungal invasion of cerebral blood vessels should be suspected. Cerebral infarction in a patient with invasive candidiasis or aspergillosis suggests that the infection has spread to the brain. A cerebral infarct in a patient with systemic signs of sepsis but negative cultures suggests the possibility of infection with Candida or Aspergillus. Disseminated Intravascular Coagulation 17

DIC is a well-known complication of burns. Bacteremia or fungemia with or without 4,17 Fibrin thrombi occlude capillaries and small arteries and veins hypotension is the cause. throughout4,18 the body. In the brain, disseminated hemorrhagic infarcts and microinfarcts are 18,19 They may or may not produce focal cerebral signs. DIC, like disseminated the result. microabscesses, may simulate a metabolic or toxic encephalopathy. CT scanning detects the larger infarcts. Microin-farcts may appear as small, bright foci on T2-weighted and FLAIR-sequence MRI. DIC is unlikely to be the cause of early neurological symptoms; it 4,17 usually begins later than the first week after a burn, and never before the fourth day. The diagnosis of DIC can be difficult in a patient with burns. A bleeding diathesis may be

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4

absent. None of the elements of the typical coagulation profile is specific for DIC. Consumption of platelets and clotting factors in 17 the burn wound itself may result in thrombocytopenia and prolonged clotting times. Bacteremia itself and certain drugs may cause thrombocytopenia. Nutritional deficiency and antibiotic-induced alteration of the flora of the gut may deplete the body of vitamin K and consequently of vitamin K–dependent clotting factors. Moreover, titers of fibrin degradation products are elevated early in all patients with 17 burns. Helpful findings in the diagnosis of DIC are a sudden decline in the platelet count or the plasma concentration of fibrinogen (sometimes from an elevated level into the normal 17,18 Heparin has not been proved helpful in range) and a positive biopsy of unburned skin. treating DIC in patients with burns. Treatment of the infection and hypotension underlying DIC and replacement of depleted platelets and clotting factors are the recommended 20 approaches. Border Zone Infarction

Cerebral infarction in the arterial border zone may occur4early in the hospital course as a complication of burn shock and, later, with septic shock. The location of the infarct on brain imaging and the clinical setting point to the diagnosis. Venous Infarction

Cerebral infarction caused by occlusion of dural sinuses and large and small cerebral veins 21 has been reported in burned patients. Meningitis was not associated. DIC or intravascular volume depletion may have been responsible. Magnetic resonance venography or simple MRI can detect occlusion of large venous channels. Nonbacterial thrombotic endocarditis and deep venous thrombosis with paradoxical embolism are possible but unreported causes of cerebral infarction in burned patients. Intracranial Hemorrhage 4

Intracranial hemorrhage occurs much less often than cerebral infarction. Lobar hemorrhage, subarachnoid hemorrhage, and widespread parenchymal petechiae (“brain purpura”) have 4,22 A bleeding diathesis related to DIC or thrombocytopenia, resulting, in turn, been reported. 4 from bacteremia, 4is the cause. Cerebral hematomas and infarcts may both be present in patients with DIC. Blindness 23–30

Several patients with binocular blindness after a thermal burn have been reported. The cases are heterogeneous, and no syndrome of blindness emerges that is specifically related to burn injury. Cortical blindness appeared suddenly and resolved substantially in three 24,26,27 Bilateral occipital lobe infarction was patients during their convalescence from a burn. the likely cause. Various optic neuropathies caused blindness in the other patients. The 25 24 bacterial meningitis, dural sinus underlying causes included nutritional deficiency, 24 23,29,30 24 and neuromyelitis optica. In some patients, blindness and thrombosis, hypotension, signs of optic neuropathy were part of an acute, widespread cerebral disease that probably 23,24 Recently, Unsold and caused increased intracranial pressure but went undiagnosed. colleagues, reporting two cases of burn-associated optic neuropathy and reviewing the literature, speculated that28demyelination caused by a circulating toxin released from burned skin could be the cause.

Peripheral Nervous System Complications Mononeuropathies In a prospective study, 26 percent of patients hospitalized with burns developed a 31 mononeuropathy. The figure would be more meaningful and useful if electrical burns had been distinguished from thermal burns. Heat may cause coagulation necrosis of nerve trunks 32 involved in a thermal burn. Superficial nerves, such as the ulnar nerve at the elbow and the sensory branch of the radial nerve in the hand, are more liable than deep nerves to thermal damage. Such injuries cannot be treated surgically. Many limbs burned deeply enough to involve nerves require amputation. Blunt trauma from a fall is another cause of nerve injury in burned patients and may affect nerves in unburned or burned limbs. Reference was made earlier to burn edema, the massive swelling that follows a serious burn.

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When the indistensible eschar of a burn surrounds a limb, the hydrostatic pressure within may be sufficient to shut off the flow of blood. Thus, in a circumferential burn, a tourniquet 32 effect may lead to ischemic necrosis of distal muscle and nerve. This is the major nerve injury that presents in the first day or so after a burn. Loss of peripheral pulses or Doppler-audible flow in the distal vascular arches and digital arteries of a limb is an indication 32 for immediate escharotomy. In very deep burns, edema develops below the skin and 33 subcutaneous fat, inside the osteofascial compartments that envelop muscle and nerve. Blood flow may be obstructed to such an extent that ischemic necrosis of tissue results, but the deep fascia, not the burn eschar, is responsible, and fasciotomy, not escharotomy, is the appropriate treatment. These compartment syndromes are rare in thermal burns but common in electrical burns. 32,34

Nerves can be lacerated during Most nerve injuries occur as complications of treatment. escharotomy. The ulnar nerve at the elbow, the peroneal nerve as it winds around the head of the fibula, and the sensory branch of the radial nerve are especially vulnerable because they are superficial. The same nerves are liable to compression by tight dressings or malpositioning. 32

Heterotopic bone formation can cause a mononeuropathy late in the hospital course. The ossification is usually periarticular. The elbow is the joint affected most often, and the ulnar nerve may be compressed. Treatment consists of decompression and transposition of the nerve. The cause of heterotopic bone formation is unknown, and recurrence is common. Marquez and associates described several patients with multiple mononeuropathies in burned and unburned35limbs that could not be attributed to the mechanisms of injury discussed previously. They speculated that thrombosis of the vasa nervorum or a circulating neurotoxin derived from burned tissue was responsible but had no supportive evidence. Polyneuropathy Helm and co-workers studied 57 patients with thermal burns in whom neuromuscular 34 symptoms developed during hospitalization. Thirty-one of them (54%) were found to have a polyneuropathy. Weakness in the distal muscles of the extremities was the major neurological sign; sensation was normal in most patients. Most patients recovered after their burns had healed. Three prospective studies have addressed the frequency of 31,36,37 Polyneuropathy was reported to develop in polyneuropathy in severely burned patients. 15, 29, and 41 percent of patients treated in a burns intensive care unit. There are several possible reasons for the discrepancy among these figures: inclusion of patients with electrical burns, lack of distinction between the syndromes of polyneuropathy and multiple 31,36 different levels of burn severity among the study populations, and small mononeuropathy, 31,37 numbers of patients. The cause of burn-associated polyneuropathy has not been determined. Critical illness 35,38,39 A polyneuropathy (discussed in Chapter 52) has been reported in four burned patients. fifth patient, with pneumonia, gram-negative bacteremia, adult respiratory distress syndrome, 40 and acute renal failure, is probably another example. Perhaps burn-associated polyneuropathy is critical illness polyneuropathy that develops in the burn unit. That the occurrence of polyneuropathy correlates with measures of severe illness, such as the depth and extent of the burn and the length of stay in the intensive-care unit, is in keeping with that 31,34,36,41 Margherita and associates suggest, in contrast, that burn-associated idea. polyneuropathy is37a direct specific result of thermal injury, but they do not offer a precise idea of pathogenesis. ELECTRICITY AND LIGHTNING Serious electrical injuries are much less common than serious thermal burns. They account 1,42–44 Electricity causes three types of for only 3 to 7 percent of admissions to burn units. burn. High-voltage current often jumps a gap between its source and a victim. This “arc” can attain a temperature of 4,000°C and cause a severe burn, identical to a flash burn. Ignition of a victim's clothing may cause a flame burn. These thermal burns make the victim of electrical trauma liable to the neurological complications discussed earlier. The third type of burn is produced only when the victim becomes part of an electrical circuit, and current flows through the body on its way to ground. Burns mark the points of entry and exit. These “contact burns” are much deeper than flash and flame burns and often involve nerves. Structures between the entry and the exit wounds, including nerves, spinal cord, and brain, conduct the current and sustain its direct effects. Also of importance are two indirect mechanisms of neurological damage: cardiac arrest and trauma. Passage of an electrical current through the heart

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causes asystole or ventricular fibrillation, with syncope or anoxic encephalopathy occurring as a result. An electrical shock often causes the victim to fall, and this may result in head injury. Moreover, emanating from the axis of a45,46 lightning channel is a cylindrical shock wave of Like the force of an explosion, it may cause expanded, displaced, and returning air. trauma directly or by throwing the victim to the ground.

Effect on the Nervous System Man-made electricity or lightning can injure any structure in the peripheral or CNS through 43,47,48 A which it passes. The degree of damage is directly related to the amount of current. small current produces only a derangement of function, and clinical manifestations are transient. Larger currents cause structural damage that may be reversible or irreversible; neurological deficits may be permanent or may resolve with time. The quantity of current varies directly with its voltage and the duration of its passage and inversely with the resistance of the skin, which it must breach before it reaches neural 49 structures. An arbitrary division is made at 1,000 V between high-tension and low-tension electrical current. Household current is 110 or 220 V; high-tension wires carry current of several thousand volts. Alternating current causes muscle tetany, which may prolong an electrical shock by causing the victim's hand to grip the contact. Thus, alternating current is more dangerous than direct current. A high-tension circuit is often completed by arcing before contact is made. A massive contraction of axial and limb musculature ensues, and this can throw the victim to safety. Thus, low-tension alternating current may cause more damage to the nervous system than high-tension current. 50

Electricity takes the shortest pathway through the body to ground. Identifying the entry and exit wounds is important, because the current injures only structures between them. When current travels from hand to hand, the nerves and muscles in the arms, the brachial plexus, and the cervical spinal cord lie in its pathway, but the brain does not. A current pathway from head50to feet includes the brain, the entire spinal cord, and the nerves and muscles in the legs. A bolt of lightning can exceed 200 million V, which is far larger than the voltage of the highest-tension electrical wire. A direct strike need not, however, be fatal, for two reasons. 51 First, the duration of the electrical discharge is short, approximately 149millisecond. Second, most of the current flows over the surface of the body, not through it. Lightning, considerably attenuated after striking a tree, can “splash” or “spray” onto a nearby person. Moreover, once lightning has struck the ground, the weakened current can run up one leg and down the other leg of a bystander (stride potential). Such phenomena probably explain 52 how one bolt of lightning can injure many people gathered together. In addition to entrance and exit burns, lightning figures may be present on the skin. They are arborescent red lines 53,54 As they fade, they may that indicate the path of lightning over the surface of the body. leave pigmentary changes in their place. Their presence on a victim's back may help account for myelopathy after a stroke of lightning. As current flows through the resistance of tissue, electrical energy is turned into heat (Joule effect). This is the cause of many electrical lesions of the nervous system, but some may be due to nonthermal effects. Three arguments support this idea. First, the peripheral nerve and brain of animals can43,48,55 be damaged experimentally by electrical current without an appreciable Second, some victims43,53 of electrical trauma are left with a rise in temperature. Third, neurological symptoms may begin neuropathy or myelopathy but no electrical burn. a considerable time after an electrical shock. Lee has suggested electrical breakdown of cell 56 membranes—electroporation—as a nonthermal mechanism of tissue injury. Perforations in the plasma membrane large enough to alter the electrochemical balance between the intracellular and extracellular compartments would result in a cellular metabolic disorder that might cause the eventual death rather than the immediate death of a cell.

Clinical Syndromes Transient Loss of Consciousness Lightning or man-made electrical current passing through the head causes immediate loss of consciousness. Patients awaken in minutes to hours. Agitation, confusion, retrograde amnesia, headache, and even a convulsive seizure often follow, but complete recovery is to 43,52,53,57 Some patients may have sustained cerebral concussion caused by a be expected. fall or the cylindrical pressure wave of the lightning bolt, but electrically induced seizure activity or inhibition of cerebral function is the likely pathophysiological mechanism in most

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cases. Brief loss of consciousness often follows passage of lightning or high-tension current outside the head. Transient cardiac asystole, ventilatory failure caused by tetanic contraction or paralysis of the thoracic musculature, acute intracranial 43,53,55,58 hypertension, and loops of current Loss of consciousness is that find their way into the head are possible mechanisms. sometimes delayed rather than immediate, or it may occur immediately and then again 53,58,59 A similar phenomenon can follow mild head trauma and probably somewhat later. represents vasodepressor syncope. Pa tients who lose consciousness for more than a few hours or have focal cerebral signs do not fall into this category; anoxic encephalopathy or a serious head injury should be suspected. Transient Paralysis Immediate and transitory sensorimotor paralysis is the neurological syndrome that typically results from lightning stroke. Charcot coined the term keraunoparalysis (“lightning paralysis”). Symptoms and signs correspond to the sites in the peripheral nervous system, spinal cord, and occasionally the brain through which lightning has passed. Paraplegia is most common, but quadriplegia, monoplegia, bibrachial paralysis, hemiplegia, ventilatory paralysis, cranial 53,60 Signs of involvement of the autonomic neuropathies, and aphasia have been reported. nervous system are common and include pupillary abnormalities and61,62 loss of peripheral Prolonged pulses, as well as coldness and pallor or cyanosis of the weak limbs. ventilatory paralysis and binocular mydriasis can simulate death. This accounts for the clinical dictum that some patients who “die” after lightning stroke can “live again” if given 63 to hours and cardiopulmonary resuscitation long enough. Lightning paralysis lasts minutes 52,59,64 seldom more than a day, although minor paresthesias may linger for weeks. High-tension electrical current can occasionally produce the same syndrome, and one case 43,44,58,65,66 The pathophysiological basis of following a low-voltage shock has been reported. the syndrome is unknown. Injury of Peripheral and Cranial Nerves High-Tension Current

A focal peripheral or cranial neuropathy is the44most common serious neurological complication of a high-tension electrical burn. In three large series of patients, the frequency 42,44,67 The lesion is usually located in the midst of a contact burn was 13, 22, and 34 percent. 43,68 It consists of coagulation necrosis but may be elsewhere 69 in the pathway of the current. parallels that of thermal damage to surrounding muscle, and is caused by heat. Its severity 43 If the nerve sheath and blood vessels, and tendons. Symptoms begin immediately. 44 damage to peripheral nerves vasculature are intact, some function may return. Permanent 43 does not extend beyond the area of local tissue damage. 70

High-tension electrical current, including lightning, causes coagulation necrosis of muscle in its path-way. Swelling begins within hours. Massively swollen muscles, encased in compartments of fascia and bone, may compress adjacent blood vessels. The result is ischemic necrosis of tissue, including muscle and nerve. The diagnosis of this compartment syndrome can be difficult. Unburned skin may cover a vast extent of burned muscle (“hidden muscle damage”). The swollen muscle is confined by fascia, over which the skin may be loose, not taut. Distal pulses may be present. Myoglobinuria and acute renal failure are clues to the diagnosis. More than one peripheral nerve may be affected: the median, musculocutaneous, and radial nerves in the anterior arm and the median and ulnar nerves in the anterior forearm. Wick catheters (to measure the pressure inside a muscle compartment) and nerve conduction studies may help in diagnosis, but most surgeons perform emergency fasciotomy on clinical indication. Swelling of burned tissue can cause acute entrapment of nerves that pass through tight anatomical canals. The median nerve may be affected in the carpal tunnel or between the heads of the pronator teres muscle (pronator syndrome), the ulnar nerve in Guyon's canal or the cubital tunnel, and the posterior interosseous nerve in the arcade of Frohse. The most common clinical problem is a deep burn of the anterior wrist associated with a median or ulnar neuropathy. Many surgeons routinely open the carpal tunnel and Guyon's canal in such 32,71 Patients who respond presumably have a compressive neuropathy; those circumstances. who do not may have a primary electrical neuropathy. Scar tissue in healing electrical burns may grow around or within a peripheral nerve, thereby impeding regeneration or causing a new mononeuropathy late in the hospital course. This 43 happens most often with deep burns of the wrist. The responsible scar is usually apparent on the surface of the body.

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Low-Tension Current

Peripheral nerve injury by low-tension current is uncommon but can occur when the 63,72,73 Electrical resistance of the skin is lowered by water or when contact is prolonged. burns, if present, are minor, and the neural lesion lies far from where current entered the body. For example, current flow from hand to hand may cause a brachial plexopathy or an axillary or radial neuropathy, and from hand to foot, an ipsilateral long thoracic 72–74 Usually only one nerve is involved. Pain in the limb begins with the shock, neuropathy. and muscle weakness appears instantly or after a delay of hours to days; in one case, there 65 was a delay of 2 weeks. Symptoms may worsen over several hours. Full or almost full spontaneous 61,75,76 recovery is the rule, although reflex sympathetic dystrophy may ensue as a complication. A nonthermal mechanism of injury is probably responsible. Experimental studies illustrate the probable physiological and anatomical changes that occur. When low-tension electrical current was applied to the sciatic nerve of the cat, limb paralysis and nerve conduction abnormalities increased in duration from minutes to weeks and then became permanent, as 43,48 No morphological change was found after very brief the quantity of current increased. periods of paralysis. Demyelination of axons was associated with paralysis that lasted for 2 to 3 weeks; recovery of strength was probably due to remyelination. In animals with permanent paralysis, there was destruction of axons as well as myelin. Heavily myelinated fibers were 77 more vulnerable than lightly myelinated and unmyelinated ones. Other authors hold that focal neuropathies long delayed in onset or progressive in course are due to heat-induced 78,79 perineural fibrosis or damage to vasa nervorum. Lightning

Limb neuropathies have been reported more often than cranial neuropathies with man-made electricity, but with lightning the reverse is true. This is probably because lightning often involves the head. These cranial neuropathies resemble low-tension rather than high-tension electrical neuropathies in two important respects. First, they are usually reversible, 49 probably because most of the current flows over the80victim, and burns tend to be superficial. Second, their onset may be delayed for a few days. Optic neuropathy, ocular palsies, Horner's syndrome, internal ophthalmoplegia, and lesions of the facial, vagus, and glossopharyngeal 51,62,80–83 45 Deafness is83especially common. In one case, autopsy nerves have been recorded. showed loss of hair cells from the organ of Corti, but most victims have conductive 45,48,84 deafness caused by thermal injury or rupture of the tympanic membrane or middle ear. Three cases of acute paraplegia or tetraplegia after a lightning strike or electrical shock were 85–88 attributed to polyneuropathy, but the evidence was unconvincing. Spinal Cord Injury Delayed Electrical Myelopathy

This is the most characteristic neurological effect of electricity. Estimates of its frequency 44,89–92 The following analysis is based range from less than 1 percent to 9 percent of victims. 83,89–96 High-tension current (usually >5,000 V) or lightning, a on a review of 25 patients. current pathway crossing or running the length of the spinal cord, and at least some deep electrical burns are typical. If the victim's skin is wet, enough household current can flow to 96 damage the spinal cord. Neurological symptoms may appear immediately, but a delay of 1 day to 6 weeks—1 week on the average—is typical. Neurological signs worsen for 2 to 14 days, usually for approximately 5 days. One third of patients recover fully, one third make a partial recovery, and one third do not recover at all. Those with signs of a complete spinal cord lesion or with prolonged progression of signs do not recover completely. Almost all patients have pyramidal signs (paraparesis or quadriparesis with spasticity, hyperreflexia, and Babinski signs). A few show atrophy of muscle innervated by segments of the spinal cord through which the current flowed. Sensory signs are less prominent than motor and may be transitory. Joint position sense and vibratory sense are affected more than pain and temperature. Sphincter paralysis is uncommon. In one patient, only Lhermitte's sign 65 MRI showed hyperintense signal within a developed. In another patient, T2-weighted 97 three-segment span of the spinal cord. 83,91,94,95,98

Five patients have had postmortem examinations. The abnormal portion of the spinal cord corresponded to the pathway of the current. The white matter was more affected than the gray matter, and the lateral and posterior columns were affected most. They showed demyelination with relative preservation of axons. Central chromatolysis, necrosis, and mild loss of anterior horn cells were also found. In three patients, some segments of the cord were

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necrotic. There were no vascular changes. The preponderance of long-tract signs over muscle atrophy correlates with that of damage to white matter over gray matter. Spinal cord compression due to intervertebral disc herniation or fracture of99the spine—usually the thoracic spine—is the major consideration in the differential diagnosis. It can result from a fall or from tetanic contraction of the paraspinal muscles during electrical shock. The absence of pain in electrical myelopathy is a useful diagnostic point. Spinal Atrophic Paralysis

Panse coined the term spinal atrophic paralysis for a syndrome of focal muscular atrophy 53 occurring after a shock from man-made electricity. No figure of its frequency is available, but it must be quite rare, since no new case has been published since Panse's original review 53 in 1955. Low-tension current, a pathway from hand to hand (across the cervical spinal cord), and either minor or no burns typify the context in which the syndrome occurs, but it may also follow lightning stroke. Pain or paresthesia in the arm through which current entered begins at once but disappears within days or weeks. Weakness begins immediately or after a few days' or weeks' delay. Muscle wasting becomes evident weeks to months later. The muscles of the shoulder girdle or the hand are affected (those supplied by the middle or lower cervical segments). Involvement is usually unilateral. Some but not all patients have weakness and spasticity in the legs. Sensory signs may be present in the arms or legs. Horner's syndrome, cyanosis and coolness in the hand, and trophic changes in the fingernails are occasionally present, as is sphincter incontinence. The weakness and muscle atrophy worsen for a few months but then stabilize or improve. If the current flows from hand to foot or from foot to foot, the muscles of the leg may atrophy. 53

Panse contrasted the syndrome to that of delayed electrical myelopathy. In the latter disorder, high-tension current injures mainly the white matter of the spinal cord by means of heat; the gray matter is relatively spared. In spinal atrophic paralysis, low-tension current injures mainly the gray matter of the cord—specifically, the anterior horn cells—by a nonthermal mechanism, and the white matter is relatively spared. There are no postmortem studies of the disorder, but Langworthy found experimentally that the anterior horn cells of the 47 spinal cord are especially vulnerable to electrical current. Amyotrophic Lateral Sclerosis

Delayed electrical myelopathy and spinal atrophic paralysis resemble amyotrophic lateral sclerosis (ALS) in some respects: there are upper and lower motor neuron signs, whereas sensory and sphincter functions are often spared. Reports of patients with progressive rather than self-limited disease have advanced the idea of an association between electrical shock 53,100,101 In these patients, signs developed pointing to parts of the brain and spinal and ALS. cord outside the pathway of electrical current. Hence, a direct effect of current could not have 100 caused them. Patten speculated that an autoimmune mechanism might be the cause. Epidemiological studies have found electrical shock and lightning stroke, like other types of 102 trauma, to be more frequent in ALS than in control patients. The meaning of this finding is unclear because all these retrospective analyses depend on adequate memory of events by subjects and on valid selection of the control population. Brain Injury Electrical Burns of the Skull

The skull's resistance to electrical current protects the brain from electrical injury. Only high-voltage current passes through the skull. The heat generated by this passage causes coagulation of the blood in the underlying dural sinuses and coagulation necrosis of the 43,53,103 Distant cerebral structures in the pathway of the current may also be underlying brain. affected. For example, a man with an electrical burn of the occipital bone is reported to have had thrombosis of the torcular herophili and necrosis of the cerebellum as well as necrosis of 104 Skull burns with open dura are conducive to the development of the optic nerves. 42,67 meningitis,43,53 and necrotic skull bones (not yet sequestered) to epidural abscess formation. Lightning Strike to the Head 53

This is fatal in most victims. Most survivors sustain no cerebral damage, but several cases 53,105,106 In animals, cerebellar Purkinje cells seem to of cerebellar ataxia have been reported.

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47,55

be particularly vulnerable to electrical current. That may be the pathological basis of the clinical syndrome in humans. Parkinsonian signs and hemiplegia have also been reported, 53,57,60 Some of these patients may but no pathological or neuroimaging data are available. have had the syndrome of delayed parkinsonism after cardiac arrest. Cerebrovascular Complications

A small number of reported patients have had cerebral infarction, subarachnoid hemorrhage, 53,65,107–115 The precise or intracerebral hemorrhage after electrical shock or lightning stroke. cause of these complications is unclear; however, intense constriction of the lumen for 1 to 55,116 Structural 10 minutes follows the experimental passage of current through an artery. changes also occur. Heat causes coagulation necrosis of the endothelium and muscular 116,117 Deprived of the support of the intima and coat, but the adventitia is little changed. media, the artery becomes dilated, and a fusiform aneurysm may develop. Complications include thrombosis, the formation and embolism of mural thrombi, and rupture with 118 or cerebral infarction soon or long hemorrhage. These may lead to intracranial hemorrhage 53,65 Dural sinus thrombosis may also after an electrical current has passed119 through the head. cause venous infarction of the brain. Other mechanisms may also lead to cerebrovascular complications. For example, an electrical shock can induce acute hypertension (with blood 53,120 and such effects on the blood pressure may pressures up to 400 mmHg) in animals, 107 lead to cerebral hemorrhage. Trauma caused by a fall or the cylindrical shock wave of a lightning bolt may also lead to intracerebral or subarachnoid bleeding or to arterial dissection 46,108–111 Cardiac arrest may cause cerebral infarction in the arterial with cerebral111 infarction. a patient may have a stroke soon after—but unrelated to—an border zone. Finally, 112 electrical shock. Dystonia 121–126

Nine patients with dystonia after electrical shock have been reported since 2002. Low-tension current (eight patients) and lightning (one patient) were involved and caused minor burns, if any. In five patients, a fixed dystonic posture developed in the upper limb through which current had entered; two patients had cervical dystonia, and two had dystonia of the tongue. The onset of dystonia was delayed by a few days to weeks in all but122 two patients. Reflex sympathetic dystrophy developed in the same limb in one patient. No other neurological signs, electrophysiological evidence of peripheral nerve injury, or brain imaging abnormality was present in any of the patients. Seven patients were treated with botulinum toxin and three responded; one patient improved spontaneously. Dystonia has been reported 127 123 after other types of limb trauma. It is psychogenic in some patients but not in others. Why it might occur is unknown, but speculation centers on a “central resetting” of basal 123 ganglia outflow after disruption of sensory input. Previous

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Aminoff: Neurology and General Medicine: Abnormalities of Thermal...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 56 Abnormalities of Thermal Regulation and the Nervous System DOUGLAS J. GELB •

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THERMOREGULATORY SYSTEM NEUROLOGICAL CAUSES OF ABNORMAL THERMOREGULATION Hypothalamic Lesions Lesions of Effector Pathways Miscellaneous Lesions Thermoregulatory System Overload Malignant Hyperthermia Neuroleptic Malignant Syndrome NEUROLOGICAL CONSEQUENCES OF ABNORMAL THERMOREGULATION HYPERTHERMIA Non-neurological Causes Neurological Manifestations Systemic Manifestations Patient Management HYPOTHERMIA Non-neurological Causes Neurological Manifestations Systemic Manifestations Patient Management Therapeutic Hypothermia

The human thermoregulatory system serves to maintain the body temperature near 37°C (98.6°F). Both the central nervous system (CNS) and the peripheral nervous system are important for thermoregulation, so a variety of neurological disorders may produce thermoregulatory abnormalities. At the same time, the nervous system is highly sensitive to the effects of body temperature, so thermoregulatory disorders may produce a variety of neurological problems. This chapter covers both the neurological conditions that produce thermoregulatory disorders and the neurological conditions that may result from abnormal temperature regulation. THERMOREGULATORY SYSTEM A thermoregulatory “center” in the preoptic and anterior hypothalamus is believed to integrate thermal inputs and to produce an output that adjusts body temperature to match a

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1–7

set-point. Thermoregulatory disorders may be produced either by malfunction of this thermoregulatory system or by conditions that overwhelm the capacity of the system. Thermoregulatory disorders should be distinguished from other causes of abnormal body temperature, in which the thermoregulatory system functions properly but the set-point is shifted. The most common condition of this type is fever, which is thought to be produced by 8–12 Shifts in the set-point may also be responsible an abnormal upward shift of the set-point. for variations1,13 of body temperature with the menstrual cycle and for diurnal temperature fluctuations. The afferent limb of the thermoregulatory system is concerned primarily with the core body temperature. In particular, neurons in the preoptic and anterior hypothalamic areas are sensitive to the temperature conditions existing in the thermoregulatory center itself. There are also thermosensitive neurons in the brainstem and spinal cord and, possibly, in the 6,14,15 The specific cold and warm thermoreceptors in the skin contribute abdominal viscera. relatively little to thermal equilibrium (although rapid, transient thermoregulatory responses may follow rapid changes in skin temperature before any significant change in brain 1 temperature occurs). The efferent limb of the system serves to generate or dissipate heat, as necessary. Basal metabolic activity produces heat, and within a narrow range of ambient temperatures called the thermoneutral zone, the core temperature can be maintained primarily by adjusting 16,17 Outside this range, heat generation is achieved primarily by metabolic1,18,19 rate. Brown adipose tissue contributes to heat production in neonates exposed to shivering. 16,17,20 Heat dissipation is achieved by evaporation (sweating) cold, but not in older individuals. 19,21 Evaporative and by nonevaporative heat loss (conduction, convection, and radiation). 1,19 heat loss is the most important of these mechanisms in most clinical situations. Nonevaporative heat loss can occur only when the ambient temperature is lower than the skin temperature. When that is the case, the amount of heat dissipated is a function of vasomotor activity: increased skin blood-flow promotes heat dissipation, whereas reduced skin blood-flow minimizes heat dissipation. These thermoregulatory vasomotor effects are controlled by both the hypothalamus and local reflexes. The local vasomotor reflexes can override the hypothalamic regulation when there are sufficiently extreme local temperature 14,21,22 conditions. NEUROLOGICAL CAUSES OF ABNORMAL THERMOREGULATION In principle, thermoregulatory disorders could be produced by abnormal function of the thermoregulatory center or by interruption of its afferent or efferent connections. Because the major afferent input comes from neurons that are themselves located in the hypothalamus, afferent disruption is not a significant concern. Consequently, the main neurological causes of abnormal thermoregulation are diseases of the hypothalamus and its autonomic outflow. In addition, a few neurological disorders result in excessive heat production that overwhelms the thermoregulatory system. Table 56-1 and Table 56-2 summarize the main causes of hyperthermia and hypothermia, respectively. Click here to view this table.... Click here to view this table....

Hypothalamic Lesions Hypothalamic lesions may produce either hyperthermia or hypothermia, although 23–25 Hyperthermia has been described with hypothalamic hypothermia is more common. 26–28 29 27,29,30 stroke, and encephalitis. Head trauma and brain surgery involving the tumors, 26,31 Hypothermia has been reported with hypothalamus may also produce hyperthermia. 27,29,32 33 34,35 33,36 strokes, subarachnoid hemorrhage, sarcoidosis, and hypothalamic tumors, 37 It is common in Wernicke's encephalopathy and may be the presenting idiopathic gliosis. 38–40 Its occurrence in Wernicke's encephalopathy has been attributed to lesions in feature. 39 the posterolateral hypothalamus and in the floor of the fourth ventricle. In contrast, although fever is also common in Wernicke's encephalopathy (occurring in about 12% of patients), an 39 Accidental hypothermia has been seen in infection is almost always found to account for it. 41 ; again, thishas been attributed to hypothalamic two patients with Parkinson's disease 41,42 Prominent abnormalities of sweating (anhidrosis or hypohidrosis) have abnormalities. 43–45 and been described both in primary autonomic failure and in multisystem atrophy, hyperthermia may be of major concern when patients with these disorders live in hot climates without air conditioning.

Lesions of Effector Pathways

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Interruption of the autonomic outflow from the hypothalamus may produce either hyperthermia or hypothermia by impairing the effector mechanisms necessary for heat 23,46,47 Lesions of the spinal cord above the high dissipation or production, respectively. thoracic level may interrupt descending pathways that influence the intermediolateral cell 48,49 Spinal cord column, producing both vasomotor abnormalities and disorders of sweating. lesions also interrupt descending input48,50 to anterior horn cells, impairing or eliminating Any neuromuscular disease that is severe enough shivering below the level of the lesion. to cause profound weakness may produce the same result. Finally, both acquired and hereditary polyneuropathies may51–53 involve autonomic fibers and produce abnormalities of Either hypothermia or hyperthermia may result. vasomotor activity and sweating. 54 Hypothermia is more common in diabetic patients 52,55 than in normal subjects, for example, In contrast, some diabetics manifest a probably because of impaired vasomotor reflexes. syndrome of heat intolerance that is attributed to anhidrosis. Because the autonomic nerve involvement in diabetes is usually predominantly distal, these patients sometimes51,56 exhibit profuse sweating over the head and upper trunk (“compensatory hyperhidrosis”).

Miscellaneous Lesions Disorders that produce widespread damage to the CNS can impair thermoregulation, but the 57 causes precise mechanism is often difficult to establish. Intracranial hemorrhage often 25,57–59 elevation of body temperature that is not explained by hypothalamic damage. 60–62 Degenerative diseases can be associated with hypothermia. Hypothermia has been seen 40,63–65 ; postmortem examination of the hypothalamus in patients with multiple sclerosis 65 64 revealed plaques of demyelination in one patient but not in another. One patient has been reported in whom a syndrome like Wernicke's encephalopathy (with hypothermia and eye movement abnormalities) was attributed to a hematoma at the mesencephalic-diencephalic 66 junction. Agenesis or dysplasia of the corpus callosum may be associated with episodic hyperhidrosis 67–69 There may also be associated abnormalities in and hypothermia (Shapiro's syndrome). the septal region, cingulate gyrus, and posterior hypothalamus. A similar syndrome 68,70–75 has occasionally been seen without any associated abnormality of the corpus callosum. The periods of sweating may last from minutes to hours, and the hypothermia may last from 30 minutes up to several weeks. Episodes may be separated by intervals of months to years. There is often ataxia and impaired cognition during the hypothermic episodes. Some of these patients have been found to have abnormalities in the anterior hypothalamus or infundibular nuclei. Recurrent hypothermia has also been attributed to “diencephalic epilepsy,” but 68 Episodic hypothermia without electrographic seizures have not been demonstrated. 76 hyperhidrosis has also been described. Cases of periodic hyperthermia associated77,78 with agenesis of the corpus callosum (“reverse Episodic hyperthermia or hypothermia Shapiro's syndrome”) have been reported. associated with other manifestations of autonomic dysfunction have also been described 79,80 81 and in a patient with aneurysmal subarachnoid hemorrhage. after head trauma 26

Hyperthermia has been reported after operations in the posterior fossa and in patients with 82 acute hydrocephalus. It is difficult to make inferences about localization from such patients, however, because of the presence of mass effect. Hyperthermia associated with ischemic lesions in the posterior fossa has also been reported, but the details provided were 83 insufficient to judge the extent of pathological involvement. As a general rule, even when a patient has CNS disease, hyperthermia should not be attributed to “neurogenic factors” unless there is clear involvement of the hypothalamus or effector pathways.

Thermoregulatory System Overload Several neurological diseases produce thermoregulatory disorders by creating conditions that overwhelm the capacity of the thermoregulatory system. Just as paralysis may eliminate effective shivering and result in hypothermia, muscle hyperactivity may result in hyperthermia. 84 Elevated body temperatures are common after generalized seizures,85 for example, and are tetanus, of prognostic relevance in patients in generalized status epilepticus. Generalized 9 delirium tremens, and catatonia are also associated with hyperthermia. Two noteworthy examples of hyperthermia associated with increased muscle activity are malignant hyperthermia and neuroleptic malignant syndrome. Malignant Hyperthermia Malignant hyperthermia is characterized by vigorous muscle contractions and an abrupt

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increase in temperature on exposure to certain drugs, notably inhalational anesthetics and 86–92 The hyperthermia is probably a direct result of the heat produced by succinylcholine. sustained muscle activity, which, in turn, is likely to be due to defective regulation of intracellular free calcium. Malignant hyperthermia is inherited as an autosomal-dominant trait with variable penetrance, and about 50 percent of cases are linked to mutations in the gene for the ryanodine receptor, a protein that provides the primary channel for release of calcium 93–97 Patients with primary muscle disorders, notably stored in the sarcoplasmic reticulum. central core disease and Duchenne muscular dystrophy, have an increased incidence of malignant hyperthermia. In fact, central core disease also results from mutation in the gene for the ryanodine receptor, although the specific mutations and the clinical manifestations are 93–96,98 Although patients with different in central core disease and malignant hyperthermia. myotonic dystrophy may also have adverse effects from anesthesia (contractures after administration of succinylcholine, and increased susceptibility to respiratory depression after receiving barbiturates or opiates), they do not appear to have an increased risk of malignant 88 hyperthermia. Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome is also characterized by hyperthermia and muscle rigidity, 99–102 although altered consciousness and cardiovascular lability are cardinal features as well, 99,100,102,103 and the hyperthermia may be mild or delayed. Although the elevated body temperatures are at least partly due to the muscle activity, there may also be an elevation of the hypothalamic temperature set-point. This condition is typically triggered by exposure to neuroleptic agents, but it has also been described in patients being treated for presumed Parkinson's disease after sudden withdrawal of dopaminergic agents or changes in their medication regimen. When associated with neuroleptics, the condition typically arises within 2 weeks of starting therapy or increasing the dose, but at times it may begin within hours or after a delay of months. The pathophysiology of neuroleptic malignant syndrome is not fully understood. A sudden and profound reduction in dopaminergic activity is considered the principal abnormality, 104 although dysregulated sympathoadrenal hyperactivity has also been proposed. NEUROLOGICAL CONSEQUENCES OF ABNORMAL THERMOREGULATION Most cases of abnormal thermoregulation occur in individuals without a primary neurological disease. These individuals are exposed to external temperature conditions (or, less commonly, to internal metabolic derangements) that overwhelm the thermoregulatory system. Regardless of the underlying cause of the hyperthermia or hypothermia, neurological manifestations are prominent. Neuronal function is significantly affected by even moderate changes in temperature. Basic electrical parameters, such as membrane capacitance, axoplasmic resistance, maximal sodium and potassium conductances, and ion channel rate constants, vary systematically with temperature. Consequently, the amplitude, duration, maximal rate of rise, net ionic 105 movements, and conduction velocity of the action potential all are affected by temperature. 106 These parameters, in turn, determine the likelihood of propagation107,108 or conduction block. Such considerations apply to both central and peripheral neurons. With respect to the peripheral nervous system, these effects have long been recognized because of their impact 109–112 For example, the maximal motor conduction on clinical electrophysiological tests. 110 velocity of human ulnar nerve falls by 2.4 m/sec for every 1°C decline in temperature. 109,111,112 Compound action potential amplitudes increase with falling temperatures. The duration of motor unit action potentials increases and mean amplitude112 declines as temperature drops, and polyphasic potentials become more frequent. Short-term and sustained hypothermia also113 prolong the latencies of visual, somatosensory, and brainstem auditory evoked potentials. Although these alterations in function can have significant clinical consequences, they do not represent actual injury to the nervous system. At extreme temperatures, however, such injury does occur. Direct thermal injury to the brain and spinal cord results in the production of a variety of cytokines and altered expression of heat-shock proteins, leading to endo thelial cell injury and diffuse microvascular thrombosis, and ultimately to cell death, edema, and 114,115 Cerebellar Purkinje cells are particularly vulnerable. There is an increase hemorrhage. in the cerebral metabolic rate116at temperatures between 38°C and 42°C, but at 43°C cerebral with rising metabolic rate is decreased. Cerebral oxygen metabolism also increases 116,117 temperatures up to 42°C, but it declines as temperatures rise further. With extreme reductions in temperature, there is a roughly exponential decline in metabolic

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rate, with a reduction of approximately 50 percent in the rate of chemical reactions for every 118 cerebral oxygen consumption by about 50 10°C. There is a corresponding reduction in119–121 This reduction in metabolic rate is percent for119–127 every 10°C decline in temperature. but neural damage still occurs. In experimental studies using hippocampal protective, slices, the critical survival time for complete recovery of neural activity after oxygen and 118 glucose deprivation was 10 minutes at 37°C, 15 minutes at 28°C, and 45 minutes at 21°C. In patients who died of hypothermia, autopsy has revealed perivascular hemorrhages in the 128 region of the third ventricle, with chromatolysis of ganglion cells. It is difficult to know to what extent these metabolic and pathological abnormalities result from direct damage to neural elements and to what extent they reflect systemic effects (including cardiovascular collapse) that secondarily injure the nervous system. It is clear, however, that they are associated with symptomatic manifestations that often dominate the clinical course of both hyperthermia and hypothermia. HYPERTHERMIA The neurological causes of hyperthermia were considered earlier.

Non-neurological Causes Conditions in which the thermoregulatory system is overwhelmed by extremely high external 9,23,129–132 The most severe form of heat stress temperatures are called heat stress disorders. disorder is heat stroke, which is defined as a core body temperature above 41°C associated with CNS dysfunction such as delirium, seizures, or 114,130–134 coma. Heat stroke is also characterized Heat exhaustion is a milder by hot, dry skin, but this is not a diagnostic criterion. form of heat stress disorder, characterized by progressive lethargy, headache, vomiting, tachycardia, and hypotension; the main distinguishing feature is that the level of 23 consciousness is depressed in heat stroke but not in heat exhaustion. These two conditions form a continuum: if untreated, heat exhaustion may progress to heat stroke. The term classic heat stroke refers to the disorder that results from prolonged exposure to high environmental temperatures while the individual undertakes normal activities; the term 9,19,23,114,130–132,135–138 exertional heat stroke applies in situations of physical exertion. Exertional heat stroke typically occurs in healthy young individuals, often athletes and military personnel. Inadequate cardiovascular conditioning, poor acclimatization, dehydration, heavy clothing, low work efficiency, and reduced ratio of skin area to body mass all 139,140 are risk factors. Classic Congenital or acquired abnormalities of sweat gland function may contribute. heat stroke, in contrast, is typically seen in the elderly, especially those with chronic diseases (e.g., alcoholism, malnutrition, diabetes, cardiovascular dysfunction, obesity). Anticholinergic and diuretic medications are predisposing factors. People in lower socioeconomic groups are at particular risk, especially those living in urban areas, because they are exposed to a 9,19,23,141 greater thermal load and often live in apartments with inadequate ventilation. The most common cause of hyperthermia is simple dehydration because it results 9,131,134 in vasoconstriction and decreased sweating, thereby interfering with heat dissipation. 142 143 Heat dissipation may also be impaired9 in advanced scleroderma or in miliaria, or by 144 extensive use of occlusive dressings. Both thyrotoxicosis (mainly during thyroid storm) 145 and pheochromocytoma can cause hyperthermia on the basis of hypermetabolism. Drug exposure can produce hyperthermia in several ways, including increased metabolic rate, 9,23,133,135,146–153 hyperactivity, and impaired heat dissipation (Table 56-3). Click here to view this table....

Neurological Manifestations The earliest neurological manifestations of hyperthermia include thirst, weakness, and 23 fatigue. Skeletal muscle cramps may occur in the exertional heat stress disorders and are probably due to hyponatremia. Patients with heat exhaustion are frequently agitated and may develop delirium and incoordination. Tetany or paresthesias sometimes occur from hyperventilation. In general, hyperthermia that is severe enough to cause stupor or coma occurs only with heat 154 stroke. Heat stroke may present with the sudden onset of stupor or coma, or patients may pass through a prodromal period that can include headache, drowsiness,156confusion, 155 of patients. Examination agitation, and delirium. Seizures occur in 60 to 70 percent 155,156 Caloric responses are intact 155 reveals pupils that154 are usually small and often pinpoint. except terminally. Diffuse hypertonia is common, but flaccidity has also been described.

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Hemiplegia, cerebellar deficits, and papil-ledema may also occur. Cerebrospinal fluid (CSF) from patients with heat stroke is usually normal but may show an135,155 increased protein Slowing of the concentration, xanthochromia, and mild lymphocytic pleocytosis. electroencephalogram (EEG) occurs at temperatures above 42°C. Most patients who recover from heat stroke have no157–159 permanent neurological sequelae, but and a157 few cases of persistent some develop a syndrome of ataxia and dysarthria, hemiparesis, myelopathy, or quadriparesis have been reported. There are reports of persistent polyneuropathy after whole-body hyperthermia160for cancer, and localized of severe heat stroke neuropathies after hyperthermic isolated limb perfusion. Survivors 161 may also develop premature cataracts, attributed to dehydration.

Systemic Manifestations The mildest manifestations of heat stress disorders are mild dependent edema and syncope. Possible explanations for the edema include salt supplementation, heat-induced vasodilatation with consequent oliguria, and increased aldosterone production. Syncope has been attributed to vasodilatation, postural pooling of blood, diminished venous return to the heart, reduced cardiac output, and a global reduction in cerebral perfusion. Skeletal muscle cramps also occur in mild heat stress disorder, as noted earlier. 19,130,135,137,156,162,163

Heat stroke is associated with diffuse systemic derangements. Respiratory alkalosis is almost always present, and tetany may occur. Hypoxia, metabolic acidosis, hypokalemia, hyperkalemia, hypernatremia, hypophosphatemia, hypomagnesemia, and hypoglycemia may each be seen. Peripheral leukocytosis in the range of 20,000 to 3 30,000 cells/mm is common. Cardiovascular manifestations include low cardiac output and low diastolic pressure. Subendocardial hemorrhages may occur. Minor electrocardiographic changes (transient 164 conduction abnormalities and inverted or flattened T waves) are sometimes found. Apart from the respiratory alkalosis, pulmonary manifestations may include pulmonary edema and adult respiratory distress syndrome in the presence of disseminated intravascular coagulation (DIC). Rhabdomyolysis is almost universal in exertional heat stroke but is uncommon in classic heat stroke. Elevated serum creatine kinase levels occur in both conditions. Elevated serum levels 162 of lactate dehydrogenase correlate with a poor prognosis. Acute renal failure occurs in about 25 percent of patients with exertional heat stroke but is uncommon in classic heat stroke. Elevated serum amylase levels are common. Serum concentrations of liver enzymes are often elevated also, and cholestasis and patchy hepatic necrosis have been described. Diarrhea and vomiting are common; hematemesis and melena may occur in severe cases. Clinically significant coagulopathies are common. Contributing factors include abnormal hepatic function with resultant impairment in clotting factor synthesis, thermal activation of either clotting factors or platelets, thrombocytopenia, and fibrinolysis. In severe heat shock, disseminated intravascular coagulation is almost always present.

Patient Management There are three components to the management of the hyperthermic patient: treatment of the underlying cause (when possible), cooling, and treatment or prevention of common 19,114,130–133,135,137,156,163 complications. Most of the hypothalamic causes of hyperthermia are not amenable to acute treatment, although dexamethasone administration is appropriate when there is vasogenic edema. Certain spinal cord lesions associated with hyperthermia (e.g., epidural hematoma or abscess) may require immediate treatment, but no acute treatment is possible for other lesions. Hyperthermia caused by excessive muscle activity is treated by reducing or eliminating the muscle activity. Patients in status epilepticus may require neuromuscular blockade (in addition to continuing measures for controlling their seizures) if temperatures 165 exceed 40°C for a prolonged period. Patients with malignant hyperthermia are treated by stopping the responsible anesthesia, instituting hyperoxygenation, and intravenously 86–90,92,135,166 Dantrolene is a skeletal muscle relaxant that administering dantrolene. uncouples excitation and contraction by preventing the release of calcium from the 87,89,91,166 It has also been used successfully to treat neuroleptic sarcoplasmic reticulum. 90,92,99–101,166 Because of the apparent role of dopaminergic systems in malignant syndrome. neuroleptic malignant syndrome, bromocriptine and amantadine have also been tried 92,99–102 Electroconvulsive therapy therapeutically, and favorable results have been reported.

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99–102

may be useful in severe, refractory cases.

Non-neurological causes of hyperthermia may also be amenable to specific treatment. Thyrotoxic crisis is treated with β-adrenergic antagonists, glucocorticoids (because of increased requirement and reduced adrenal reserve), and large doses of an antithyroid agent such as propylthiouracil. Patients with pheochromocytoma are treated with α-adrenergic antagonists. Dehydrated patients are rehydrated as necessary. For hyperthermic patients in whom a precipitating drug can be identified, treatment is directed at minimizing the drug's toxicity. Patients in delirium tremens require large doses of benzodiazepines. For the hyperthermia of heat stress disorders, treatment of the underlying cause simply consists of removing the patient from the hot environment. Cooling may be achieved by either evaporative or direct external 23,114,130–133,135,146,156,167–169 Evaporative methods involve wetting the skin with tepid methods. water and directing bedside fans at the patient. Direct external cooling involves immersion of the patient in ice water, use of a hypothermic mattress, or packing the patient in ice. These direct external cooling techniques produce vasoconstriction, which impedes removal of heat from the core. To counteract this response, these cooling methods are applied (either simultaneously or in alternation) with vigorous skin massage, tepid (40°C) water spray, or exposure to hot moving air (45°C). Cooling is more rapid and more effective with direct external methods than with evaporative methods, but evaporative techniques are often adequate and permit more convenient patient management and monitoring. In rare instances, neither method is sufficient; more aggressive options include peritoneal lavage with iced saline, gastric lavage or enemas with ice water, and hemodialysis or 9,132,135,168–169 cardiopulmonary bypass with external cooling of blood. Regardless of the cooling method used, shivering often occurs as the body temperature falls. It can be treated with phenothiazines, benzodiazepines, or nondepolarizing muscle relaxants. As the patient's core temperature reaches 38°C or 39°C, cooling is stopped to avoid overshoot hypothermia. Centrally acting antipyretic medications exert their effect by lowering the temperature set-point. They are therefore appropriate for use in fever, where the set-point is abnormally high. In thermoregulatory disorders, however, the problem lies not in the set-point itself but in the system's inability to attain it. It follows that manipulation of the set-point has no effect on body temperature, so central antipyretic medications are of no help in this situation. The most important complication of hyperthermia is hypotension, which should be treated 131,135,167 131 Vasopressors may be used if necessary. Dopaminergic with fluid administration. and α-adrenergic agonists should be avoided because of their tendency to produce vasoconstriction. Patients should receive 100 percent oxygen until adequate oxygenation is documented. Serum electrolyte and glucose concentrations should be assessed frequently, and abnormalities treated as necessary. To promote urine output, patients are given an initial 132,135,156 If disseminated dose of mannitol and subsequent doses of diuretics as necessary. intravascular coagulation occurs, it should be treated in the same way as in any other setting. 156 When seizures occur, they are usually treated with benzodiazepines. The prognosis for patients with hyperthermia depends on the peak temperature reached and the duration of 156 Mortality rates as high as 70 percent have been symptoms before initiation of treatment. 146 most recent series suggest a mortality rate of 5 to 10 percent with reported in the past, but9,155,156 appropriate management. HYPOTHERMIA Neurological causes of hypothermia were discussed earlier.

Non-neurological Causes As with hyperthermia, hypothermia is usually due to conditions that overwhelm the thermoregulatory system, rather than to a primary malfunction in the system. Accidental hypothermia is defined as an unintentional decline in the core temperature below 35°. It is most commonly seen in neonates, the19,170–174 elderly, and those who are unconscious or immobile, In the United States, hypothermia is seen most especially because of drug exposure. 171,175–177 Alcohol is a vasodilator, a CNS depressant, an anesthetic, frequently in alcoholics. and a risk factor for trauma and environmental exposure, all of which increase the risk of hypothermia. Other drugs predispose to hypothermia in various ways, including depression of the hypothalamic center, inhibition of shivering by neuromuscular blockade, and 23,171–173,175–180 vasodilatation (Table 56-4).

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Click here to view this table.... Patients with severe burns, exfoliative dermatitis, or other dermatological conditions may develop hypothermia because of increases in both evaporative and nonevaporative heat loss 181,182 Hypothermia and the inability to regulate these processes through vasoconstriction. may also occur 128,144,175,177,183 in the setting of several endocrine disorders that impair178 metabolism, including 178 hypoadrenalism, and hypopituitarism. Hypoglycemia, hypothyroidism, 175,177 diabetic ketoacidosis, and hyperosmolar coma are also associated with hypothermia, but it is not clear whether this is because of a hypometabolic state or a direct effect on the hypothalamic thermoregulatory center. Malnutrition may be complicated by fatal hypothermia, presumably on the basis of hypometabolism, hypoglycemia, and loss of subcutaneous 178 and hypothermia that tissue. One reported patient with thymoma had hyperhidrosis 184 resolved after treatment with intravenous gamma globulin.

Neurological Manifestations The neurological manifestations of hypothermia progress in a relatively predictable 171,174,176,177,185 Thought processes may be normal with rectal temperatures as low as manner. 34°C, but below this temperature most patients exhibit psychomotor retardation, speech perseveration, lethargy, or confusion. A few patients have been described as alert with rectal temperatures as low as 31°C, but this is uncommon. Dysarthria develops at temperatures below 33.5°C, and below 28°C most patients only grunt in response to questions, although some patients remain verbally responsive at temperatures as low as 23.5°C. Most patients still make purposeful responses to noxious stimuli even with temperatures approaching 20°C. Pupillary size is not affected by hypothermia in a consistent way, but pupillary reaction to light becomes progressively more sluggish as temperatures decline below about 32°C. Eye 177 movement abnormalities were frequent in one series but did not correlate with temperature; they may have reflected the presence of Wernicke's encephalopathy, since they occurred mainly in alcoholic patients. Deep tendon reflexes are typically normal or even increased at temperatures as low as 29.5°C, but they become progressively diminished at lower temperatures. Extensor plantar responses are rare at any temperature. Increased muscle tone is frequent even in mild hypothermia, and it is universal at temperatures below 29.5°C. Myotonia is common. Focal dystonias and dyskinesias are rare, but patients may exhibit a characteristic posture consisting of flexion in all four limbs, with the limbs held close to the torso. Even in hypothermic patients who have a stiff neck, examination of the cerebrospinal fluid 177 produces a fall in cerebrospinal fluid pressure fails to reveal pleocytosis. Hypothermia 186 has also been shown experimentally because of reduced cerebral blood-flow ; hypothermia 187 changes to reduce cerebrospinal fluid secretion in animals. The EEG frequency spectrum188,189 with hypothermia, with increased beta and theta activity and reduced alpha activity. 190 Triphasic waves have been reported in a patient whose rectal temperature was 34°C. At temperatures below 28°C, there is progressive slowing in the recording. As the temperature falls further, a burst-suppression pattern appears, and the EEG becomes isoelectric below 10°C to 20°C. Brainstem auditory evoked potentials (BAEPs) show increasing latencies of 113,191 Visual evoked potential (VEP) latencies waves I, III, and V as temperature decreases. 113,188 The changes that occur in also increase progressively as temperature declines. electromyographic (EMG) and nerve conduction studies were discussed earlier. Patients who recover from hypothermia usually have no long-term neurological problems.

Systemic Manifestations During the shivering phase (typically between 35°C and 30°C), there is an initial rise in metabolic rate and oxygen consumption, but at temperatures below about 30°C19,172–174,176,178 shivering ceases and there is a rapid decline in metabolic rate and oxygen consumption. As shivering abates, respiration slows and becomes shallow. This is primarily a reflection of 176 reduced respiratory requirements rather than pathologically depressed respiratory drive. Similarly, the heart rate slows and cardiac output declines with decreasing temperatures, but it is sufficient to meet systemic metabolic requirements. Clinically significant hypotension 19,176 The principal cardiac does not occur until temperatures of 25°C and below are reached. concern is the risk of arrhythmia. Arrhythmia is preceded by characteristic J-point elevation 171–173,176,178,192 The J wave (or “Osborn wave”) becomes that appears at about 33°C. increasingly prominent as the temperature falls and is consistently present below 25°C. Atrial 176,192 Prolongation of PR and QT intervals occurs, with fibrillation is common below 33°C. progressively more advanced degrees of heart block or bradycardia as the temperature

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continues to fall. Below 28°C the 171–173,176,178,192 myocardium becomes extremely irritable, and ventricular fibrillation or asystole may occur. Mild hypothermia induces diuresis because peripheral vasoconstriction redistributes blood to internal organs, including the kidneys, and also because of a blunted response to antidiuretic 171–173,176 As hypothermia progresses and cardiac output falls, renal blood-flow and hormone. 172,173 Because glomerular filtration rate decline also, ultimately resulting in acute renal failure. of hemoconcentration, the hematocrit rises by about 2 percent for every 1°C drop in core 176,178 Platelet count is reduced and function is impaired, producing temperature. 172,173,176,193 The intrinsic and extrinsic clotting pathways are both affected coagulopathy. 172 176,193 also. Granulocytopenia may occur with temperatures below 28°C. 172,173,176

Moderate elevations in serum glucose concentration are sometimes seen.172,176 Endocrine and functions generally remain normal. Ileus frequently occurs in hypothermia, asymptomatic pancreatitis is common (diagnosed on the basis of elevated serum amylase 128,172,194 Hepatic detoxification and conjugation functions are levels and on autopsy findings). 172 impaired, resulting in prolonged drug half-lives. Because the depressed level of consciousness blunts protective airway reflexes, there is a high incidence of pneumonia.

Patient Management The management of hypothermia is analogous to the management of hyperthermia. The three principal components are treatment of the underlying cause (when possible), rewarming, and treatment or prevention of common complications. The comments made previously regarding treatment of hypothalamic and spinal cord pathology causing hyperthermia also apply to hypothermia from these causes. In addition, thiamine should be given routinely to hypothermic patients unless Wernicke's encephalopathy can be excluded with confidence. The spells of some patients with episodic hyperhidrosis and hypothermia have reportedly responded to cyproheptadine, clonidine, anticonvulsants, dopamine agonists, or peripheral muscarinic blockade with oxybutynin or 68,69,71,73,78,195,196 glyco-pyrrolate. With regard to non-neurological causes of hypothermia, naloxone should be routinely administered to hypothermic patients in coma because of the high incidence of drug exposure in this setting and the lack of evidence for any harmful effect of naloxone in hypothermia. Any metabolic derangement predisposing to hypothermia should be144,171,176,183 corrected. ; In particular, exogenous thyroxine is usually required in treating myxedema coma when it is not given, the mortality rate is high. For patients with dermatological conditions and those without any predisposition to hypothermia other than environmental exposure, treatment of the underlying cause consists of simply drying them and removing them from the cold environment. There are three rewarming methods: passive external rewarming, active external rewarming, 128,163,170,171,173–176,178,197–199 Passive external rewarming is the and active central rewarming. slowest and least invasive of these techniques. Patients are placed in a warm environment and covered with blankets or aluminized body covers, and intravenous fluids are warmed to a temperature of 36°C to 39°C. This technique is usually adequate for patients with a core temperature of 32°C or above as long as the external hypothermic stresses are removed. Caution is necessary in patients who must avoid the cardiovascular stress of shivering, however. Active rewarming may be indicated in such patients; alternatively, shivering can be suppressed by giving meperidine, or it can be eliminated by inducing neuromuscular blockade (in patients who are already sedated and receiving mechanical ventilation). Active external rewarming consists of heating the skin with heating pads, heated blankets, hot water bottles, a forced air heating system, or radiant heat from a light source, or by immersion in warm water. Concern has been raised about these methods, however, because warming the skin before the core may result in peripheral vasodilatation and consequent hypotension. It may also cause an abrupt return of blood to the core from relatively hypoperfused regions, resulting in acidosis. Active central rewarming techniques include the administration of heated oxygen by face mask or endotracheal tube, warm gastric or bladder irrigation, peritoneal lavage, pleural lavage, and hemodialysis or cardiopulmonary bypass with extracorporeal blood rewarming. The most effective of these methods are peritoneal lavage, pleural lavage, and extracorporeal blood rewarming, but these are also the most invasive procedures. In general, they should be reserved for patients with temperatures below 30°C, although decisions in individual cases will be influenced by cardiopulmonary status and underlying disease.

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Because aspiration and pneumonia are common complications of hypothermia, all patients with a depressed level of consciousness should be intubated. Patients should receive 100 percent oxygen until adequate oxygenation has been documented. Blood gas interpretation is complicated in these patients, because blood pH increases by 0.015 for each 1°C decline in temperature, and the partial pressure of carbon dioxide (Pco2) declines by 4.4 percent and Po2 by 7.2 percent. Thus, if blood is warmed to 37°C before analysis, the measured Pco2 and Po2 values will be higher than those that actually exist in the patient. Even so, the pH and 172–174,176 Pco2 do not need to be corrected for the patient's body temperature. Human acid-base regulation changes with falling body temperature to produce an alkaline shift by relative hyperventilation. This adaptation helps preserve protein and enzyme function as temperatures drop. In effect, the “normal” values of pH and Pco2 change with falling body temperature in such a way as to cancel the changes that occur in anaerobically warmed blood. However, Po2 must be corrected for body temperature, or the value will be overestimated. Hypotension in hypothermic patients is generally due to dehydration, which, in turn, results from increased urine output. Fluid resuscitation is usually adequate. When it is not, more aggressive rewarming may be necessary, since dobutamine and dopamine have reduced efficacy in this situation and they are arrhythmogenic. Similarly, cardiac arrhythmias in hypothermic patients are resistant to many pharmacological agents, pacing efforts, and defibrillation. Aggressive rewarming techniques may provide the only hope for effective treatment. In particular, electrical defibrillation is usually ineffective at temperatures below 30°C. Lidocaine and procainamide have been of little benefit in this situation, although 171,176 bretylium may be effective. Electrolyte concentrations in the blood must be monitored closely, and abnormalities managed as necessary. Potassium levels vary greatly during treatment. Treatment may also produce hypophosphatemia. Patients should be assessed for coagulopathy, including disseminated intravascular coagulation, and treated as necessary. A nasogastric tube should be inserted and serum amylase level checked because of the risk of pancreatitis and ileus. The prognosis in hypothermia is influenced more by the patient's age and underlying disease 172,175,176,178 Some patients have been than by the magnitude of the temperature drop. successfully resuscitated after 2 hours of apparent arrest, and others have survived temperatures below 20°C. This has prompted some to advocate warming all patients to normal temperatures before concluding that resuscitation is futile (“nobody is dead unless they are warm and dead”). Although this recommendation puts appropriate emphasis on the marked protective effects of hypothermia, it is probably best to judge each case based on the specific clinical situation.

Therapeutic Hypothermia Efforts to exploit the protective effects of hypothermia date back at least to the 1940s, but serious complications prevented the widespread adoption of therapeutic hypothermia. Interest has recently been revived, and both internal and external cooling techniques have been studied in a variety of acute neurological contexts, including head trauma, spinal cord trauma, cardiopulmonary arrest, ischemic stroke, subarachnoid hemorrhage, hepatic 123–127 The results encephalopathy, infantile viral encephalopathy, and perinatal asphyxia. have been mixed, with the most convincing evidence of benefit in patients resuscitated after cardiac arrest. Previous

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Aminoff: Neurology and General Medicine: The Neurology of Aging: ...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 57 The Neurology of Aging RICHARD K. OLNEY • MICHAEL J. AMINOFF •

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AGE-RELATED CHANGES IN THE NERVOUS SYSTEM Decline in Cognitive Function Changes in Cranial Nerve Function Changes in the Motor System Alterations in Station and Gait Changes in Tendon Reflexes and the Sensory System Reappearance of Release Signs Pathological Reflexes Postural Tremor NEUROLOGICAL DISEASES THAT ARE COMMON WITH AGING Alzheimer's Disease, Frontotemporal Dementia, and Vascular Dementia Metabolic Encephalopathy Parkinsonism Nonparkinsonian Gait Disorders Peripheral Neuropathy Orthostatic Hypotension Falls Hypothermia and Hyperthermia Sleep Disorders OTHER NEUROLOGICAL DISEASES

The diagnosis of neurological disease requires the recognition of symptoms and signs that are not present in normal individuals of comparable age. The clinician's diagnostic acumen is especially challenged when he or she is confronted with a patient older than 75 years because the clinical manifestations of normal age-related changes that occur in the nervous system differ more quantitatively than qualitatively from the early signs of common neurodegenerative diseases of older individuals. The normal age-related changes that occur in the findings on neurological examination are reviewed in this chapter, as are certain common neurological diseases that are associated with aging, with emphasis on their distinguishing features. AGE-RELATED CHANGES IN THE NERVOUS SYSTEM Normal age-related changes are defined as progressive and irreversible changes in the

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findings on neurological examination that develop with advancing age in most individuals without overt disease. These changes are observed with variable frequency and severity depending on the study design and the rigor with which associated diseases are excluded. With regard to study design, cross-sectional studies tend to magnify the frequency and severity of age-related changes, in part because it is difficult to exclude the increasingly common effects of associated diseases and differences in social, educational, and environmental factors. Longitudinal studies minimize age-related effects, partly because long-term follow-up is more readily attained in those individuals who maintain normal function and because subjects who develop overt disease are later excluded. Thus, although they are described with variable magnitude and frequency, there are1,2 a number of important changes in the normal neurological examination with advancing age.

Decline in Cognitive Function The normal age-related decline in cognitive function has been characterized with increasing accuracy and precision over the past four decades. Since the late nineteenth century, measures of intelligence have been identified that reach a peak in young adulthood and then 3 decline throughout the remainder of life. In the 1950s, intelligence quotients (IQs) derived from the Wechsler Adult Intelligence Scale (WAIS) were interpreted to support this belief because performance IQs declined more than 40 percent and verbal IQs decreased half as much with increasing age from the late twenties to the early seventies. Subsequently, the effect of slower motor responses on timed performance tasks and the confounding influence of cohort differences were recognized as factors that cause an overestimation of the 3 measured age-related decline in intelligence in cross-sectional studies. Longitudinal studies have generally demonstrated stability rather than decline in verbal intelligence before the age 4 of 60 years. Verbal intelligence often declines thereafter by an average of less than 5 4 percent through the seventh decade and by less than 10 percent through the eighth decade. 5 Cognitive function is even relatively stable in most individuals during the ninth decade. With regard to specific aspects of cognitive function that decline with aging, the influence of 1 speed on successful completion of the task is an important consideration. Apart from slowness of movements (discussed later), the speed of central processing is reduced with advancing age. This can be demonstrated neuropsychologically as slowness of perceptual processing and neurophysiologically as a delay in event-related evoked potentials. Experiments with visual word identification have shown that slowness of processing does not develop abruptly in old6 age but occurs continuously with aging from the third through the eighth decades of life. Other experimental studies demonstrate similar degrees of slowing for processing of language and information and longer retrieval time for information from 7–9 short- and long-term memory. Reduction in the speed of central processing with advancing age can also be demonstrated neurophysiologically. An event-related evoked potential is the electrocerebral activity that occurs in response to the information content of a specified signal or event. These potentials are often recorded as the response evoked by an infrequent auditory signal that is inserted at random into a sequence of more frequent auditory signals of a different pitch. The event-related evoked response occurs between 200 and 500 msec after the infrequent auditory signal, and attention is usually directed at the peak of the positive waveform at approximately 300 msec (the P300). The mean latency for this component is approximately 300 msec in the third decade of life. Thereafter, as reflected in several studies, the latency increases by 9 to 17 msec per decade with aging, so that the mean latency is 350 to 380 10 msec by the age of 70 years. Thus, both neurophysiological and neuropsychological investigations support the general concept that the speed of central processing is reduced with advancing age. Mild memory impairment is another specific aspect of cognitive function that declines with advancing age. Although slowness of central processing underlies many aspects of the measured age-related decline in cognitive function, the deficit in recent memory and learning can be demonstrated apart from processing speed with untimed supraspan learning tasks. A supraspan is an amount of information just beyond that which can be recalled immediately from the working memory. An example of a supraspan memory test is serial digit learning, in which a subject is given 12 trials to learn and recall eight or nine digits in a standardized but untimed protocol. Published normative data for this test reflect mild impairment in recent memory and learning in older individuals, with subjects aged 65 to 74 years generally scoring 11 10 percent lower than younger subjects with similar educational backgrounds. In a longitudinal study of 212 community-based healthy persons, the acquisition and early retrieval of new information declined over the 3-year study, but not memory retention, language, 12 visuospatial ability, or abstract reasoning.

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The terms benign senescent forgetfulness and age-associated memory impairment were coined in recognition that the mild impairment in memory with normal aging is distinct from early dementia. This is manifested clinically as difficulty in retrieving the name of a vague acquaintance, remembering to buy every needed item at the grocery store without a list, or recalling where an object was placed, rather than as difficulty in remembering significant personal events. Such common complaints of the elderly are due more to decreased learning than to increased forgetfulness. In evaluating the memory function of 161 community-dwelling, cognitively normal individuals ranging in age from 62 to 100 years, learning or acquisition of memory for pictures and words declined uniformly with advancing age; however, delayed recall or forgetfulness was similar at all ages if adjusted for number of 13 initially learned objects. This reinforces the observation that preservation of delayed recall discriminates normal older individuals from those with mild dementia better than other 14,15 cognitive attributes among a large battery of neuropsychological tests. Thus, it is generally agreed that there is an age-related decline in the speed of central processing, performance on timed tasks, and recent memory and learning, whereas verbal 1 intelligence is well preserved at least through the seventies. Several short, standardized tests are available that are clinically useful for distinguishing these normal age-related changes in cognitive function from mild dementia. Two of the more commonly used tests are the Mini-Mental State and the six-item Orientation-Memory-Concentration Test; their utility 16–18 and limitations are discussed else-where.

Changes in Cranial Nerve Function Changes in the cranial nerve examination relate primarily to an age-related decline in sensory 19–23 With regard to vision, contrast sensitivity and functions, especially for vision and hearing. 20 visual acuity decline with advancing age. The pupils become progressively smaller with age and are less reactive to light and accommodation, reducing the amount of light that reaches 19,20 Increasing opacity of the lens and vitreous further decreases the visual input, the retina. 20 and increasing rigidity of the lens reduces its accommodative ability. These preretinal and retinal factors are the major causes of presbyopia. A restriction in the range of eye movements, especially vertically, develops with advancing 19–21 Whereas young adults normally have 35 to 45 degrees of upgaze, 15 to 20 degrees age. of upgaze is normal in those in their eighth decade. When limited upgaze and diminished visual acuity are combined with decreased mobility of the neck, vision above the horizontal may be functionally impaired (e.g., with loss of ability to read signs mounted high on the walls or hung from the ceiling). Approximately 10 percent of the population has a hearing loss sufficient to impair 22 communication; among those older than 65 years, 40 percent are so affected. Hearing worsens with age, but the severity of auditory impairment at any given age is quite variable. Presbycusis, usually described as a progressive elevation of the auditory threshold (especially for higher frequencies), has distinct peripheral and central components. The peripheral component relates to loss of hair cells in the cochlea, degeneration of cells in the spiral ganglion, atrophy of the stria vascularis, and thickening of the basement 22,23 The central component22,23 relates to changes in the auditory pathways and membrane. structures in the brainstem and cortex.23 The peripheral component primarily accounts for the elevation of the auditory threshold, whereas the central component affects speech perception (“age-related auditory processing disorder”), leading to poorer comprehension of 22,23 speech in noise or with rapid or indistinct speech. 24

Risk factors for presbycusis include noise exposure; cigarette smoking ; medication use; 23 hypertension; and family history. The use of aminoglycoside antibiotics, cisplatin, loop diuretics, or anti-inflammatory agents may contribute to hearing loss.

Changes in the Motor System A progressive decline in muscle mass (“sarcopenia”) and strength and in the speed and coordination of movement has long been recognized as an accompaniment of aging. The muscle wasting occurs diffusely but is most notable in intrinsic hand and foot muscles. In cross-sectional studies, strength consistently and progressively declines with increasing 25–27 In one comprehensive cross-sectional study of 61 normal men ranging in age from age. 20 to 80 years, the maximal force that could be exerted by various arm and leg muscles decreased across the age range by 21 to 45 percent, with hip extension28,29 showing the greatest 25 Diminished decline. The decline in strength is more marked in the legs than arms. 26 strength with advancing age is less prominent in longitudinal studies but still quite apparent.

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Grip strength did not decline in only 15 percent of subjects over the age of 60 years during a 26 9-year longitudinal study. Declining strength and progressive loss of muscle mass accompany each other with advancing age, but the loss of muscle bulk is insufficient to 26,27 explain the degree of decreased strength. The pathophysiology of this mild generalized weakness is multifactorial, and the sedentary life-style and decreased caloric and protein intake of many elderly30,31 subjects may be Electromyographic contributory; however, a neurogenic basis is of prime importance. studies have consistently shown features of chronic partial denervation with reinnervation as the usual accompaniment of advancing age. The results of neuropathological studies on muscle biopsies of normal elderly subjects are consistently but mildly abnormal. Features of neurogenic change (fiber type grouping and grouped atrophy) are far more prominent in most studies than other features, such as those of disuse, fibrosis, and myopathic change (type II atrophy, increased numbers of central nuclei, and other nonspecific features of myopathy). The mild but widespread neurogenic component of these generalized changes in muscle is 32 largely due to a mild amount of anterior horn cell degeneration. Motor unit number estimates for the tibialis anterior muscle are less in old (61 to 69 years) than in young men (23 to 32 years) and even less in very old men (80 years or older), but strength is not reduced until beyond 80 years, suggesting that age-related motor unit loss, at least in this muscle, 33 does not limit function until a critical threshold is reached. Furthermore, the stiffer muscle34 structure and prolonged myosin cross-bridge cycles of aged muscles may be contributory. In addition to strength, the speed and coordination of movements decline with advancing 31 age. Thus, the speed of simple tasks (e.g., hand and foot tapping) slows by 20 to 24 percent from ages 20 to 80 years, and coordination for the manipulation of small objects and 25 for tracking decreases by 14 to 27 percent. Activities of daily living (e.g., putting on a shirt, zipping a garment, and rising from a chair) required 31 to 40 percent more time in older 25 individuals. On the routine neurological examination, these changes are manifested as mild bradykinesia with all motor tasks and as mild incoordination without dysmetria on the finger-to-nose and heel-to-shin tests.

Alterations in Station and Gait 25,35

The station and gait show conspicuous changes with advancing age. Both depend on adequate sensory input, efficient integration of this input with motor control programming, and an adequate motor response. In two comprehensive cross-sectional studies of the normal changes that occur in neurological function with aging, the single 25,36 greatest change among Whereas most young many tests occurred in the ability to maintain balance on one leg. adults could maintain station on one leg with the eyes closed for the full test time 25 of 30 seconds, few older subjects could perform the task for more than a few seconds. In a study that compared optimally healthy elderly subjects, the 17 young old, aged 65 to 74 years, could stand on one leg with eyes closed for 3 to 4 seconds on average, whereas the 34 36 oldest old, aged 84 to 100 years, were unable to do so usually for even 1 second. In this study, the age-related change in balance was more obvious for one-leg standing time with the eyes open, with the younger group having a mean of 20 seconds and the older group a mean of 3 25,37,38 seconds. Although increased postural sway is virtually universal with advanced postural righting reflexes are preserved in most people during the seventh and age, 36 eighth decades. Increased postural sway relates more consistently to diminished sensation for vibration and joint position in the lower limbs than to visual or vestibular changes with 37,38 In addition to increased postural sway, dynamic posturography demonstrates a age. 39 the elderly diminished capacity to process conflicting sensory input with aging. Furthermore, 40 have a reduced ability to use visual information to improve control of balance. 35

Changes in gait among the elderly are well recognized. Qualitatively, the normal gait of an octogenarian is usually described with the same adjectives as are used to describe a parkinsonian gait. Thus, the gait is slightly broadened and the steps mildly shortened, with a modest diminution in the arm swing and a slightly stooped posture. In one study of optimally healthy elderly subjects, the group of oldest old took more steps and more time36to walk 30 feet than the group of young old, but both groups had a similar step cycle rate.

Changes in Tendon Reflexes and the Sensory System The most prominent age-related change in the findings on sensory examination is a decrease 25,36,41,42 Although in the sensitivity of vibratory perception, especially distally in the legs. vibratory threshold is elevated by 52 to 58 percent at 80 years compared with 20 years at the clavicle, shoulder, and elbow, the change is 64 to 67 percent at the tibia and wrist, 86 percent 25 at the ankle, and 97 percent at the toe. A less prominent distal diminution in the perception

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of painful and tactile stimuli is described in some but not other cross-sectional studies. Quantitative sensory testing has demonstrated an obvious effect of age on vibratory and cooling detection thresholds in a population-based sample of control subjects of normal 43 health ranging in age from 20 to 74 years. Changes in the deep tendon reflexes are similar to those described for vibration, with a mild generalized reflex depression and a more marked depression or absence of the Achilles 42 tendon reflex. During the seventh decade, the Achilles tendon reflex was absent in only 3 percent of healthy control subjects in a randomly selected, population-based study, although 43 at least 7 percent had a depressed or absent Achilles tendon reflex. The frequency of absent ankle 36,43 reflexes is 8 to 29 percent in the eighth decade and over 50 percent after 85 The knee and upper-limb reflexes are absent in 0 to 6 percent of subjects in years of age. 36,43 the seventh and eighth decades. This distal depression of deep tendon reflexes and sensory function is primarily due to distal degeneration of sensory axons. Age is inversely correlated with the amplitudes of both 44 sensory and motor responses on nerve conduction studies, but especially with the amplitude of sensory nerve action potentials, which correlates with 44 a loss of sensory axons. Conduction velocity also declines in both motor and sensory fibers, although the correlation between conduction velocity and age has varied widely in different studies and is not always evident. Neuropathologically, degeneration of both myelinated and, to a lesser extent, 45 unmyelinated peripheral sensory fibers has been identified with advancing age (Fig. 57-1). Similar axonal degeneration has been described in mixed sensorimotor nerves. Studies of 46 intra-epidermal nerve fibers has shown a length-dependent loss of fibers with aging, and45 selective loss of sensory receptors has also been documented, as is reviewed elsewhere.

FIGURE 57-1 Fiber density of large and small myelinated axons in human sural

nerve at different ages. (Data derived from Tohgi H, Tsukagoshi H, Toyokura Y: Quantitative changes with age in normal sural nerves. Acta Neuropathol [Berl] 38:213, 1977.)

Reappearance of Release Signs Although the reappearance of release signs may support the concept that a loss of cortical suppression has occurred, the prevalence of these signs in normal individuals is important36,47 to recognize. The palmomental reflex is present in 0 to 947,48 percent of normal elderly subjects. The suck reflex has been observed in 1 to 8 percent. The glabellar reflex is present in 0 to 6 percent of young old (aged 65 to 74 years) and old old (aged 75 to 84 years) but has a 36,47,48 The snout reflex is more frequency of 21 percent in the oldest old (over 84 years). common, being present in 7 to 29 percent of the young old and old old and 44 percent of the 36,47,48 However, the grasp reflex is rare in normal healthy elderly subjects up to 100 oldest old. 36,47,48 Bilateral grasp reflexes may occur with degenerative or diffuse vascular years of age.

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disease involving the frontal lobes, but more precise localization of responsible lesions may not be possible; lesions in the49–51 supplementary motor cortex or cingulate gyrus have been Thus, a positive palmomental, glabellar, snout, or suck implicated in some instances. reflex should be interpreted with caution, because these reflexes may be observed in normal elderly individuals. Only the reappearance of the grasp reflex is a reliable sign that more cortical suppression has been lost than is normal for age. Although a bilateral palmomental response may be regarded as physiological, a unilateral response is sometimes taken to suggest a localized contralateral lesion. However, no significant association between the side of the reflex and that of a hemispheric lesion was found by Gotkine and associates, indicating that a unilateral response should not be 52 accorded localizing value.

Pathological Reflexes An extensor plantar response is not usually accepted as a normal age-related change in the neurological examination but is assumed to reflect some underlying pathological process. However, an extensor plantar response was observed in 6 percent of the young old (aged 65 to 74 years) and in 12 percent of the36oldest old (over 84 years) in a study of optimally healthy, functionally independent individuals.

Postural Tremor A patient with essential tremor typically comes to medical attention during middle age. A similar postural tremor that develops with advanced age is frequently labeled a senile 53 tremor. In addition to a postural upper-limb tremor, the head, voice, or lower limbs may be affected. The prevalence of postural tremor increases with advancing age. In a population-based study of community-living people 65 years or older, postural tremor was identified on examination in 16.5 percent of those aged 65 to 74 years, in 20.7 percent of 54 those aged 75 to 84 years, and in 25.6 percent of those 85 years or older. Furthermore, a parkinsonian rest tremor was observed in 5 to 6 percent in each age group, with only half having the diagnosis of Parkinson's disease. In that study, the overall prevalence of parkinsonism (defined by a combination of bradykinesia, gait disturbance, rigidity, and tremor, with two or more being required for diagnostic purposes) was 14.9 percent for people aged 65 to 54 74 years, 29.5 percent for those aged 75 to 84, and 52.4 percent for those aged 85 and older. The prevalence of tremor was approximately 15 percent in another study of men and women aged between 50 and 89 years, with the tremor being due to parkinsonism in 2.75 percent and reflecting an exaggerated physiological or essential tremor in 12.5 percent; In subjects aged between 80 and 55 89 years, the prevalence of parkinsonism was 33 percent in men and 22 percent in women. NEUROLOGICAL DISEASES THAT ARE COMMON WITH AGING

Alzheimer's Disease, Frontotemporal Dementia, and Vascular Dementia Alzheimer's disease is a dementia with insidious onset and progression that usually occurs in middle or late life. The diagnosis can be definitively confirmed only by histopathological examination of the brain. The disease was initially described in a 51-year-old woman by Alzheimer in 1907 and was considered a presenile dementia for the first half of the twentieth 56 century. However, a broader definition that is independent of age has become accepted. Based on clinical or pathological criteria, or both, the incidence of Alzheimer's disease is 123 per 100,000 per year in adults over the57age of 29 years, with the incidence of dementia of all types being 187 per 100,000 per year. However, the incidence of Alzheimer's disease increases exponentially with advancing age, at least through the ninth decade, so that the 57 incidence at 80 years of age is 100 times greater than at 50 years. The prevalence of Alzheimer's disease increases from 1 to 15 percent from 65 to5885 years of age, and more than half of the residents of nursing homes have this disease. Clinical criteria for the diagnosis of probable Alzheimer's disease were proposed by the Work Group on the Diagnosis of Alzheimer's Disease, established by the National Institute of Neurological and Communicative Disorders and Stroke59(NINCDS) and the Alzheimer's Disease and Related Disorders Association (ADRDA). Dementia of any type is diagnosed clinically by behavioral changes that include a decline in memory and other cognitive functions. The clinical diagnosis of dementia cannot be made while an alteration in the level of consciousness is present because drowsiness and agitation interfere with the assessment of cognitive function. If the patient is alert, possible decline in cognitive function is determined by comparing the present and previous levels of performance as well as by neurological and

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neuropsychological examinations. Specifically, deficits in two or more areas of cognition must be established, and progressive worsening of memory and other cognitive functions must be documented. Impaired recall of recently learned material is usually the first sign of an early 13–15 Neuropsychological examinations are important to document objectively that dementia. two or more areas of function are impaired quantitatively to a greater extent than normal for age and that these cognitive deficits are progressive over time. The Mini-Mental State and the Blessed Dementia Scale are two16–18 specifically recommended tests that may be used The Blessed Dementia Scale or a shorter derived clinically to aid in this determination. form of it, the six-item Orientation-Memory-Concentration Test, are particularly useful in 16 identifying a mildly demented patient. The estimate of severity of dementia based on either of the Blessed tests also correlates with the number of neuritic plaques documented 16 neuropathologically, so either of these tests has utility in staging the severity of dementia. The Mini-Mental State examination is particularly useful in staging the severity of dementia because it assesses language and praxis in addition to memory, and its scores correlate well 60–62 with the neuropathological estimates of synaptic density in the frontal lobes. More extensive neuropsychological testing is important for documentation of the range and severity of cognitive impairment in the clinical setting of an early or uncertain diagnosis and in research studies. Impairment of delayed recall is the most sensitive measure to distinguish early dementia from normal aging, but measures of learning and memory are not useful in 63 staging the severity of dementia. Combined measurements of fluency, praxis,63and recognition memory best differentiate mild from moderate or severe dementia. Once the presence of dementia is documented, other criteria for the clinical diagnosis of probable Alzheimer's disease include an insidious onset between the ages of 40 and 90 years and the absence of systemic disorders or other brain diseases that by themselves 56,59 The diagnosis is could account for the progressive deficits in memory and cognition. further supported by documentation of impairment in activities of daily living and alteration in behavioral patterns. A positive family history is obtained in approximately 5 percent of cases. Laboratory tests are important to confirm other specific causes for dementia. Normal cerebrospinal fluid, an electroencephalogram that is either normal or shows nonspecific abnormalities, and evidence for cerebral atrophy with computed tomographic scanning or magnetic resonance imaging are supportive of probable Alzheimer's disease. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are likely to become increasingly important with the development of radioligands for the detection of 64–66 Various biomarkers in the the pathology of Alzheimer's disease or the brain amyloid load. cerebrospinal fluid (such as concentrations of total tau, phosphorylated forms of tau, and beta amyloid) may be important in suggesting the likely development of Alzheimer's disease in patients with mild cognitive impairment or in helping support a clinical diagnosis of 67,68 Alzheimer's disease, but they are not routinely determined. Neuropathologically, neuronal cell loss is present 69 in the brains of patients with Alzheimer's is primarily seen in the large disease relative to age-matched control subjects, and this loss 2 62 neurons that have cross-sectional areas of more than 90 μm . Furthermore, this neuronal cell loss is particularly seen in the cholinergic cells of the nucleus basalis and the 62 serotonergic cells of the raphe. Synaptic loss has also been described and correlates well 70 with cognitive decline; synaptic dysfunction undoubtedly precedes synaptic or neuronal loss. Nevertheless, measurement of neuritic plaques and neurofibrillary tangles of phosphorylated tau protein remains the routine basis for pathological confirmation of Alzheimer's disease. The diagnosis of definite Alzheimer's disease requires confirmation of the characteristic neuropathological features, which primarily consist of an abnormal number of neuritic plaques (Fig. 57-2) and neurofibrillary tangles (Fig. 57-3). Although often present in small numbers in normal elderly subjects, numerous neuritic plaques and neurofibrillary tangles are present in 71,72 (Fig. 57-4). The necessary brain sites in which the pathognomonic Alzheimer's disease neuritic plaques and71,72 neurofibrillary tangles must exist to confirm the diagnosis are less Whereas some neuropathologists require only lesions in the uniformly accepted. hippocampus, others demand involvement of the neocortex with or without hippocampal lesions. The frequency of pathological confirmation of the clinical diagnosis of probable Alzheimer's disease, based on the NINCDS-ADRDA criteria, has been studied. In 57 cases, an increased concentration of plaques and tangles was found more often in the hippocampus than in the neocortex of patients with probable Alzheimer's disease; an increased number of lesions was never found in the neocortex without a concomitant increase in the 72 hippocampus. The clinical diagnostic criteria proposed by the NINCDS-ADRDA Work Group resulted in 71,72 pathological confirmation in 84 to 100 percent of cases with examination of the hippocampus.

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FIGURE 57-2 Neuritic plaque with central core of amyloid protein (Bielschowsky

silver stain, original 250×).

FIGURE 57-3 Neurofibrillary tangle (Bielschowsky silver stain, original 250×).

FIGURE 57-4 Numerous neuritic plaques and neurofibrillary tangles in

advanced Alzheimer's disease (Bielschowsky silver stain, original 100×). Whereas pure Alzheimer's disease accounts for 50 to 60 percent of cases, frontotemporal dementia is less common and is important to distinguish from Alzheimer's disease. Three major anatomic subtypes are described, in all of which the frontotemporal regions of the brain are selectively affected while more posterior regions are spared. These subtypes consist of frontal variant (behavioral variety), temporal variant (semanticdementia), and a left

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frontal-predominant subtype called progressive nonfluent aphasia. The disorder, which is often familial, is characterized by marked changes in personality and social behavior, typically 73 commencing in middle or later life, with survival for several years. The disorder may masquerade as a major depression. It progresses more rapidly than Alzheimer disease; 74 progression is especially fast in the frontal variant or with coexisting motor neuron disease. Multi-infarct dementia is the second most frequent56cause of dementia and is the primary pathological process in5610 to 20 percent of cases. The two disorders co-exist in another 10 to include to 20 percent of cases. The concept of multi-infarct dementia has been expanded 75,76 a broader array of vascular disease that is capable of producing vascular dementia. Although the cumulative risk is higher for women than men to develop Alzheimer's disease from 65 to 95 years of 77 age, the cumulative risk for development of vascular dementia is similar for both sexes. The criteria for vascular dementia that were proposed at an International Workshop sponsored by the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l'Enseignement en 76 Neurosciences (AIREN) are listed in Table 57-1. Clinical criteria for probable vascular dementia are the presence of dementia, the presence of cerebrovascular disease, and a temporal relationship between the two. Dementia is diagnosed in a manner similar to that for Alzheimer's disease. Diagnosis of cerebrovascular disease requires the presence of focal neurological signs and abnormal brain imaging that supports vascular disease. The findings on brain imaging may consist of multiple large-vessel infarcts, a single strategically placed infarct (e.g., involving the angular gyrus, thalamus, or basal forebrain), multiple lacunae, extensive periventricular white matter lesions, or combinations of these. The temporal relationship may consist of onset of dementia within 3 months after a recognized stroke or of a course that is not insidiously progressive. The criteria for definite vascular dementia include the preceding probable clinical criteria and pathological confirmation of vascular and no other disease. Click here to view this table.... The relationship between dementia and white matter lesions that are seen on computed tomography (CT) scans or magnetic resonance imaging (MRI) has been clarified. Such white matter lesions do correlate with cognitive impairment if they are large or confluent, but are not 76,78–80 Furthermore, the prevalence of small relevant to dementia if they are less extensive. white matter lesions in patients with Alzheimer's disease is not significantly different from that in age-matched healthy control subjects if both groups are screened equally to exclude 81 cerebrovascular disease risk factors. Not surprisingly, then, in a neuropathological study, the exclusion of only those cases with vascular lesions larger than 50 ml from pure Alzheimer's disease produced the highest agreement with the clinical72 diagnosis of probable Alzheimer's disease by the NINCDS-ADRDA criteria (88% accuracy). The pathophysiology of dementia of the Alzheimer's type remains uncertain, but Alzheimer's disease may represent a syndrome in which the cumulative effects of one or more different 62,82 In some pathophysiological processes converge to produce a consistent clinical picture. individuals, the predominant pathophysiological process may involve a molecular genetic abnormality, such as a point mutation in the amyloid precursor protein. In others, abnormalities of tau protein or mitochondrial function may be more relevant to loss of synaptic density on cholinergic cells of the nucleus basalis or serotonergic cells of the raphe. Certain patients may have a genetic risk factor, such as the presence of the apolipoprotein E 82 ε-4 allele, but additional factors must also be present for the disease to develop. Protective factors have been identified also, such as the presence of the apolipoprotein E ε-2 allele. Women have an increased risk for Alzheimer's disease, but the risk of gender may be 77,82 The mechanisms for protection afforded by mitigated by estrogen replacement therapy. higher education and the use of nonsteroidal anti-inflammatory drugs may offer other treatment opportunities. Studies of treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) for hypercholesterolemia have suggested83that the risk of Alzheimer's disease is reduced in patients receiving these agents in midlife. Treatment strategies may have to be multifactorial and individualized for each patient. The beneficial effect of treatment with acetylcholinesterase inhibitors on some patients supports 84,85 although the scientific basis for use of these the cholinergic hypothesis to 86 some extent, agents has been questioned. Memantine is beneficial when assessed by functional and global87measures, but its effect on cognitive scores and behavior and mood outcomes is less effects on cognition but may improve clear. Testosterone replacement therapy has minimal 88 quality of life in patients with Alzheimer's disease. More effective treatments that prevent or alter the course of the disease are being sought. In regard to management, physicians are often asked to provide information about the driving ability of patients with early Alzheimer's disease, and in some states physicians are required to report all patients with cognitive impairment to public health authorities. In one study, an experienced neurologist's

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assessment of driving competence seemed to be a valid predictor of driving performance in patients with early disease, although a professional driving instructor was the most stringent 89 rater of driving performance. In patients with advanced Alzheimer's disease, attention to end-of-life measures is important, as discussed in Chapter 63.

Metabolic Encephalopathy Metabolic encephalopathy is a diffuse but potentially reversible disorder of cerebral function that often impairs the state of arousal and cognitive function and is due to a metabolic or toxic cause. When such a metabolic disturbance develops acutely, an alteration in arousal with either drowsiness or agitation is common. This state alerts the clinician that evaluation of metabolic factors may be etiologically important and at the same time precludes the diagnosis of dementia. However, when the metabolic disturbance develops insidiously over weeks or months, arousal is often not affected. Metabolic encephalopathy may then be difficult to distinguish from dementia. Furthermore, the two disorders commonly coexist in the elderly. When they are coexistent, chronic metabolic encephalopathy is the remediable aspect of cognitive impairment in an insidiously developing dementia. The incidence of metabolic encephalopathy in 200 elderly outpatients with suspected 90 dementia has been studied prospectively with follow-up of outcome. The patients had a mean age of 76 years, with a range from 60 to 94 years; more than 89 percent lived in the community, either alone or with a relative. Whereas Alzheimer's disease was diagnosed clinically in 75 percent, a total of 248 medical diagnoses were made in 124 of the 200 patients, and more than 30 percent had more than one condition contributing to their dementia-like presentation. Metabolic encephalopathy was the primary reason for cognitive impairment in 18 patients. It resulted from adverse drug reactions (10 patients), hypothyroidism (3), hyperparathyroidism (2), hyponatremia (2), and hypoglycemia (1). Even after excluding depression, 45 of the 200 patients experienced cognitive 90 improvement for 1 month or longer because of treatment of the identified medical condition. Adverse drug reactions as91the cause of cognitive impairment were the focus of a subsequent report by the same group. Of 308 elderly patients, 35 were identified who had cognitive impairment for over 3 months without alteration in the level of arousal and who improved with discontinuation of the causal drug. The most common offending drugs were benzodiazepines (13 patients), other sedative or tranquilizing drugs (9), antihypertensives (5), and cimetidine (3). The patients with these adverse drug reactions took an average of twice the number of prescription drugs as the others (an average of four vs. two). However, reductions in the dosage or discontinuation of antihypertensives may be associated with long-term detriment. Untreated high blood pressure is associated with an increased risk of cognitive decline, which 92 is reduced with antihypertensive therapy.

Parkinsonism Certain movement disorders, particularly tremor, restless legs syndrome, and parkinsonism, have a high prevalence with increasing age55in the general community but are underrecognized and treated inadequately. In some instances, movement disorders are iatrogenic. For example, drug-induced parkinsonism occurs in about 1 percent of men and 2 55 to 3 percent of women aged between 50 and 89 years. This section reviews those aspects of Parkinson's disease that deserve special consideration in the elderly; it is not intended to be a comprehensive review. The average annual incidence of Parkinson's disease is93,94 approximately 20 per 100,000, or In contrast to the incidence of approximately one sixth of that for Alzheimer's disease. 57 Alzheimer's disease, which increases throughout life, the incidence of Parkinson's disease 93,94 increases with advancing age until it reaches a peak at approximately 75 years of age. Although93,94 the incidence of Parkinson's disease is lower during the ninth than during the eighth the prevalence continues to increase through the ninth decade because decade, 93,94 The overall prevalence of parkinsonism was reportedly 33 long-term survival is common. 55 or 52 percent for percent in men and 22 percent in women aged between 80 and 89 years 54 many instances the diagnosis was unrecognized or patients the group aged 85 and older. In 55 were not receiving standard care. With current treatment strategies, the life expectancy is normal in Parkinson's disease if the adverse effects of significant coexisting disorders are 95 dementia is a coexisting disorder that becomes increasingly common considered. However, 96 higher in community-dwelling parkinsonian with advancing age. The risk of death is twofold 54 individuals than in those without parkinsonism, probably because of associated dementia and other diseases.

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Although a considerable number of elderly subjects have a slow, shuffling gait with a stooped posture, these parkinsonian features are not considered adequate by many clinicians to 97,98 A rest tremor, rigidity, and an establish the diagnosis of Parkinson's disease in the elderly. exaggerated glabellar reflex or a definite beneficial response97,98 to levodopa, or both, are usually An asymmetrical onset is necessary to diagnose Parkinson's disease with confidence. likely. Older patients with Parkinson's disease more often have difficulty in walking than do 99 impairment may relate to the combined younger patients. The severity of gait and postural 100 effect of the disease and the aging process. Otherwise, the features of Parkinson's disease are similar in the elderly and the middle-aged adult. The treatment of Parkinson's disease requires special consideration in the elderly, primarily 99 because of the greater sensitivity of elderly patients to adverse drug reactions. Confusion is a major side effect of anticholinergic medications, especially in the elderly with preexisting minor cognitive impairment. Constipation in both sexes and urinary retention in men are two other frequent side effects of anticholinergic medications. Hallucinations, delusions, and chorea are often dose-limiting side effects of dopaminergic medications, especially in the elderly, whether levodopa or dopamine agonists are prescribed. In contrast to the anticholinergic medications, the dosage of dopaminergic treatment can usually be adjusted to provide functional improvement with fewer adverse effects. Thus, treatment of Parkinson's disease in the elderly often requires the slow introduction and careful adjustment of levodopa/carbidopa therapy and avoidance of anticholinergic drugs.

Nonparkinsonian Gait Disorders 35,101

Over 20 percent of people use mechanical aids for35,101 walking by the age of 80 years. Various gait disorders are seen in elderly patients. One102general pattern is associated with decreased arm swing and other signs of bradykinesia. Some patients with this general pattern of gait disorder also have the specific, previously discussed, diagnostic features of Parkinson's disease or Alzheimer's disease. However, a large number of elderly patients with this gait disturbance lack these specific diagnostic features, leaving101 a nonspecific bradykinetic senile gait as the presumptive diagnosis by exclusion. The distinction between this nonspecific gait and a mildly parkinsonian-appearing “normal” gait is largely based on clinical experience and judgment. 35

A second type of disorder is the cautious gait. In some series, this is the most common 35 pattern. Patients with a cautious gait do not hesitate to initiate walking, but do so slowly, with a short stride and a normal or slightly broadened base. Although turns are en bloc, the normal cadence and quick initiation of walking distinguish this from the previous pattern. 35,101

A third pattern is a gait with ataxia or dysequilibrium. This gait may be associated with other signs of cerebellar, posterior column, or peripheral nerve disease. However, elderly patients often have falls and an ataxic gait that is associated with decreased proprioception and vibratory perception but not with other signs of a specific neurological disease. Hence, classification of an abnormal senile gait may be difficult even in a patient with frequent falls.

Peripheral Neuropathy The distinction of polyneuropathy, especially distal axonal polyneuropathy, from normal age-related changes that occur in the peripheral nervous system is often a quantitative 103 one. Normal changes with aging do not produce positive symptoms (e.g., paresthesias or dysesthesias) or significant negative symptoms (e.g., weakness that interferes with activities of daily living). Although distal sensory impairment for vibration and depressed or absent Achilles tendon reflexes are often found in normal elderly subjects, the development of a painless pressure sore on a foot or bilateral partial footdrop indicates a severity of distal axonal degeneration that is far greater than normal for age. Diabetes mellitus is the most common cause104 of distal axonal polyneuropathy in the elderly, as it is in middle-aged and and nutritional deficiency polyneuropathies are also common younger adults. Alcoholic 104 causes in the elderly. In this age group, a mild sensory neuropathy may be a more common presentation of cobalamin deficiency than subacute combined degeneration of the 105 spinal cord.

Orthostatic Hypotension Orthostatic hypotension is present in 10 to 30 percent of subjects older than 65 years if defined as a decline of more than 20 mmHg in systolic pressure or of more than 10 mmHg in diastolic pressure for more than 1 minute. The presence of orthostatic hypotension is a risk factor for increased mortality over 4 years that is independent of other associated diseases,

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such as diabetes mellitus, hypertension, cerebrovascular disease, and coronary artery 106 disease. Orthostatic hypotension most commonly has a non-neurogenic cause; medication such as antihypertensives and tricyclic antidepressants are often responsible. A significant factor underlying the increasing frequency of orthostatic hypotension with age may be 107 diminution in baroreceptor sensitivity with advancing107 age. The elderly have not only less reduction in heart rate in response to pressor drugs but also a blunted increase in heart rate with standing even in the absence of hypotension. In addition to blunting of the autonomic response as a predisposing factor to orthostatic hypotension, compensatory mechanisms that restrict volume depletion are also impaired in the elderly. Syncope becomes more common with advancing age, and orthostatic hypotension is a 108 common cause. However, this diagnosis is accepted only when postural changes in blood pressure can be demonstrated by examination. Management of symptomatic orthostatic hypotension is initially with nonpharmacological methods; patients are encouraged to make slow position changes, to increase their fluid and salt intake, to use compression garments, and to elevate the head of the bed. Pharmacological treatment is typically with fludrocortisone or midodrine. Further discussion of autonomic function in the elderly is provided in Chapter 8.

Falls Injuries are a common reason for death in subjects over the age of 75 years, with falls accounting for most of these injuries. When a fall at home causes a hip fracture, placement in a nursing home at discharge from the hospital is commonly a permanent move. People who have had a hip fracture have markedly reduced quadriceps strength and increased body 109 sway compared with age- and sex-matched control subjects. Thus, falls in the elderly have a special significance as a cause of morbidity and mortality and as a sign of impending loss of independence. The potential causes of falls include a large number of differential diagnostic possibilities. Approximately half of falls are related to tripping. Individuals who walk faster and take longer strides have a higher risk of tripping but are more likely to recover their balance after tripping. Because the incidence of falls is determined more by the frequency of tripping than the ability 110 to recover, the likelihood of falling can be reduced by not hurrying while walking. Syncope due to orthostatic hypotension is another identifiable cause for falling. Additional111–113 risk factors for falls include cognitive impairment, loss of vision, and peripheral neuropathy.

Hypothermia and Hyperthermia The ability to maintain thermal homeostasis diminishes as age increases, with hypothermia 108 recognized as a cause of death more commonly than hyperthermia. Hypothermia is defined as a core body temperature below10835°C. The annual mortality rate from hypothermia is 17 per million over the age of 74 years. In the elderly, both heat production and heat 108,114 The basal metabolic rate and the ability to produce heat conservation are impaired. 114 through shivering and other muscular activity become lower with advancing age. Likewise, the ability to 115 conserve heat is diminished through a decreased ability to vasoconstrict peripherally. Hyperthermia is defined as a core temperature above 41.1°C, or above 40.7°C with anhidrosis or altered mental status. Impairment of heat loss in a warm environment is the 116 Reduced peripheral vasodilatation is more important than cause of hyperthermia. 115,116 Further discussion of this topic is provided in Chapter 56. diminished sweating.

Sleep Disorders 108,117

The pattern of daily sleep normally changes with advancing age. Typically, elderly subjects report a shorter nocturnal sleep duration with more frequent arousals during the night and earlier awakening in the morning, but they also nap more frequently in the daytime. Polysomnography indicates that normal elderly subjects have a marked decrease in stage IV sleep time, a moderate reduction in total sleep and rapid eye movement (REM) sleep times, and more frequent nocturnal awakenings. Non-REM and REM sleep cycles are similar to those of young adults except for a shorter first cycle due to the reduction in stage IV sleep. Therefore, normal sleep in the elderly may be described as having a weaker monophasic circadian rhythm. 108,117

Because these disorders do not differ in Disorders of sleep are common in the elderly. elderly and younger subjects, the reader is referred to Chapter 32 for a review of sleep disorders in general. Two aspects, however, warrant particular consideration in the elderly.

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First, the possible effect of an enforced cycle must be considered in evaluating a complaint of insomnia or excessive daytime drowsiness in the institutionalized elderly patient. Nursing home environments typically require all patients to retire and awaken on a predetermined schedule. Although this strong environmental pattern successfully induces synchronized circadian rhythms in most of the population, such synchronization may be difficult for some individuals, resulting in complaints of disordered sleep. Second, although the sleep apnea syndrome is among the most common causes for excessive daytime somnolence, sleep-disordered breathing is common in normal elderly subjects, and different criteria need to be defined for the diagnosis of sleep apnea in older patients. The sleep apnea syndrome may be diagnosed in young adults when five or more apneic or hypopneic episodes occur during one night. However, 27 percent of healthy, asymptomatic subjects118 older than 60 years have five or more such episodes of sleep-disordered breathing per night. Furthermore, elderly subjects with and without118 sleep-disordered breathing are similar in terms of daytime alertness and cognitive function. OTHER NEUROLOGICAL DISEASES The epidemiology of many neurological diseases changes with advancing age. Cerebrovascular disease becomes particularly common with advancing age. New-onset epilepsy is also common; seizures are often symptomatic partial seizures that are readily controlled, and tolerability and safety of medication are important considerations in selecting an antiepileptic agent. Sedating agents such as phenobarbital are best avoided in the elderly, as also are enzyme-inducing agents such as phenytoin and carbamazepine because of their potential for drug interactions. Gabapentin and levetiracetam have good safety and cognitive profiles and do not interact with other drugs; several of the other newer agents are also 119 worthwhile in this regard. Patients older than 63 years have a different pattern of risk patients, suggesting that factors for the development of carpal tunnel syndrome than younger 120 different underlying pathogenetic mechanisms are operative. Because discussion of these disorders is provided in standard neurological textbooks, they are not considered here. Previous

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Aminoff: Neurology and General Medicine: Seizures and General Med...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 58 Seizures and General Medical Disorders JACK M. PARENT • MICHAEL J. AMINOFF •

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RENAL FAILURE HEPATIC DISEASE CARDIAC DISEASE SEIZURES IN CRITICALLY ILL PATIENTS General Considerations Nonconvulsive Status Epilepticus Seizures Caused by Anoxic-Ischemic Encephalopathy CONNECTIVE TISSUE DISEASES HEPATIC PORPHYRIAS SEIZURES IN TRANSPLANT RECIPIENTS HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND SEIZURES SEIZURES ASSOCIATED WITH SYSTEMIC CANCER PULMONARY DISEASE ENDOCRINE OR METABOLIC DISORDERS Disorders of Glucose Metabolism Thyroid Disease Disorders of Sodium Homeostasis Calcium and Magnesium Imbalance SEIZURES RELATED TO ALCOHOL AND DRUGS OF ABUSE POST-TRAUMATIC EPILEPSY

Seizures commonly arise as a symptom of neurological dysfunction in various general medical disorders. The occurrence of epileptic seizures in medically ill patients often carries significant implications regarding the treatment and prognosis of the primary disease. In addition, the treatment of epilepsy due to primary disturbances of central nervous system (CNS) function, or of seizures caused by general medical disorders, may be complicated or influenced by factors associated with systemic disease. The occurrence and management of seizures in common medical conditions that may either produce acute or recurrent seizures, or exacerbate an existing epilepsy syndrome, are discussed in this chapter. Attention is also directed at certain uncommon medical diseases in which seizures are a relatively frequent complication, and at the treatment of preexisting epilepsy in patients with medical conditions that might complicate management. The general topic of drug-induced seizures1,2 arising during the treatment of various medical diseases has been reviewed elsewhere and is not addressed. Specific therapeutic agents that may cause seizures are discussed in the context

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of the relevant disorders. RENAL FAILURE Seizures are a common manifestation of uremic encephalopathy. In acute uremia, generalized tonic-clonic seizures occur and may appear in flurries; they typically develop 3,4 between 7 and 10 days after the onset of renal failure, while the patient is anuric or oliguric. Focal seizures or even epilepsia partialis continua may also occur but should prompt investigations to exclude an underlying structural cerebral lesion. Uremic convulsions usually appear with advanced chronic renal4 failure, especially if a significant encephalopathy is present or at a preterminal stage. Seizures occur in less than 3 10 percent of cases of chronic renal insufficiency. This represents a decline in recent years, perhaps because of more aggressive treatment of renal failure and related seizure risk factors such as hypertensive encephalopathy, metabolic disturbances, and altered renal 3 clearance of proconvulsant medications such as penicillin. Generalized tonic-clonic seizures are the seizure type most frequently encountered in uremic patients, although partial and 4 myoclonic seizures occur as well. Treatment requires the correction of metabolic abnormalities and renal failure, although often no specific cause of the convulsions can be identified and anticonvulsant treatment is necessary. Phenytoin, phenobarbital, and valproic 4,5 acid are effective. Status epilepticus occurs rarely in the context of chronic renal failure and is managed as is status epilepticus due to other causes. The dialysis dysequilibrium syndrome may be accompanied by generalized convulsions, which occur most commonly during the late stages or several hours after a hemodialysis session. Fluid shifts may be responsible, leading to cerebral edema from increased brain 6 osmolality6,7in the uremic state. Improved dialysis techniques have reduced the incidence of seizures. Dialysis encephalopathy is a syndrome associated with chronic hemodialysis. Distinctive speech abnormality, psychiatric disturbances, cognitive changes, asterixis, myoclonus, gait ataxia, and seizures are typical. The electroencephalogram (EEG) is abnormal, with bursts of frontally predominant high-voltage delta or spike-wave activity as 8 discussed in Chapter 18. The syndrome has been attributed to increased aluminum levels in the brain. The aluminum may derive from the water used in the dialysate, and 6–8 the disorder has declined in frequency with treatment of the dialysate to remove aluminum. Seizures occur most commonly during or immediately after dialysis and are usually generalized 4 convulsions, although myoclonic and simple or complex partial seizures are also seen. With 4,8 disease progression, seizures become increasingly resistant to pharmacological therapy. In patients with preexisting renal disease, anticonvulsant use may be complex because of altered protein binding and renal excretion; dialysis may also lead to removal of anticonvulsant agents. Phenytoin, for example, is normally 90 percent bound to plasma proteins, primarily albumin. In severe renal failure, the free (unbound) fraction commonly increases from 10 to 20 percent, which leads to5,9a greater volume of distribution and lower total (bound + unbound) serum concentrations. The concentration of pharmacologically active (unbound) phenytoin is unchanged, however, so that the benefit of a given dose is maintained. The therapeutic range of total phenytoin concentrations decreases from the 9 usual 10 to 20 μg/ml to approximately 5 to 10 μg/ml in severe renal disease. Free phenytoin levels may be used to monitor treatment in uremic patients, with a therapeutic range of 1 to 2 μg/ml in both normal and altered protein-binding states. Phenytoin accumulation is unlikely if hepatic function is preserved, so the total daily dose need not be lowered. However, it is probably best given in divided doses rather6 than as a single daily dose because the half-life may be decreased with renal insufficiency. Supplemental doses are9 not required after dialysis because phenytoin is not removed to any significant extent. Myoclonic and generalized tonic-clonic seizures may respond particularly to valproic acid in 5 uremic patients. Valproate undergoes pharmacokinetic changes similar to phenytoin in renal insufficiency. Plasma protein binding decreases, but the free concentration remains 9 constant. Thus, the therapeutic range of valproic acid may be decreased. Supplemental doses are not required because of dialysis. Plasma levels of phenobarbital are unchanged in uremia, but lower maintenance doses should be used when phenobarbital is given chronically to patients with severe renal 5,9 insufficiency. Phenobarbital, which is 40 to 60 percent protein bound, may be partially 9 removed by hemodialysis; additional doses may be needed in some patients after dialysis. 5 Primidone, like phenobarbital, may accumulate and lead to clinical toxicity in uremic patients, 9 whereas serum levels of carbamazepine are unchanged in uremia. Ethosuximide levels 9 decline with hemodialysis, and supplementation is necessary. Experience is more limited with the newer antiepileptic agents, but many have reduced

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clearance in11the setting of12impaired renal function; included among them are felbamate, 13 14 15 gabapentin, topiramate, levetiracetam, vigabatrin, pregabalin, and oxcarbazepine 16 and its active metabolite monohydroxycarbazepine. Gabapentin and pregabalin should be used cautiously in patients with renal impairment, given their extensive renal 11,15,17–19 Gabapentin dosage should be reduced in proportion to the reduction in clearance. creatinine clearance or, in the setting of hemodialysis, it should be given as a single dose 20 after each session. Hemodialysis19also reduces pregabalin concentrations such that additional doses may be required. Topiramate elimination occurs mainly through urinary excretion, although to a lesser extent when hepatic enzyme-inducing medications are 12,21 Doses of topiramate should be lowered when renal insufficiency is coadministered. 22 and supplemental doses may be present, as is the case with gabapentin and pregabalin, 12 in hemodialysis patients, necessary after hemodialysis. The same is true of levetiracetam 13 with doses of 250 to 500 mg typically given after dialysis sessions. Zonisamide is up21,23 to 50 percent protein bound and undergoes both hepatic metabolism and With moderate or severe renal failure, doses may need to be reduced. renal clearance. Zonisamide protein binding may be decreased in patients with severely impaired renal function undergoing hemodialysis. Because of the low clearance with end-stage renal failure, supplemental zonisamide often is unnecessary if a single daily dose is given after each 24 by moderate or dialysis session. Tiagabine pharmacokinetics apparently are not altered 25 This also appears to be severe renal insufficiency, and dosage adjustment is unnecessary. 26 renal impairment may prolong its half-life and it is the case for lamotrigine, although severe 27 cleared extensively with hemodialysis. HEPATIC DISEASE Despite early reports that convulsions are common in patients with acute hepatic encephalopathy, Plum and Posner28found a relatively low incidence when seizures related to Either focal or generalized seizures may occur, usually in alcohol withdrawal were excluded. 29 stage 3 hepatic encephalopathy. Treatment involves management of the hepatic dysfunction and hepatic encephalopathy. Anticonvulsant therapy often is not required except when an underlying cause of epilepsy (e.g., prior cerebral trauma) is present. 30

Chronic liver disease does not usually cause convulsions. The occurrence of seizures in alcoholics with hepatic cirrhosis is usually related to prior trauma, intracranial hemorrhage, or 31 and rarely in Wilson's alcohol withdrawal. Seizures occur commonly in Reye's syndrome 29 disease. Convulsions in patients with acute hepatic necrosis are frequently associated with severe hypoglycemia. Unless hepatic dysfunction is severe, liver disease usually does not have a major effect on anticonvulsant pharmacokinetics. Decreased protein binding of phenytoin and valproic acid 5,9 correlates well with levels of serum albumin and bilirubin. However, clearance is usually unchanged. Dosages of these medications may need to be decreased if liver disease is severe but usually not otherwise; serum drug concentrations should be determined frequently. Valproic acid is potentially hepatotoxic and thus should be used with care in 5 patients with established liver disease. Barbiturates, benzodiazepines, and other sedatives or CNS depressant drugs can provoke 31 hepatic encephalopathy in patients with preexisting but compensated liver disease. They are therefore best avoided in this context. Carbamazepine exhibits slightly decreased protein binding in patients with hepatic disease, but this does not affect serum carbamazepine 5 concentrations. The clearance of many of the newer antiepileptic agents is altered by hepatic disease. Lamotrigine metabolism is reduced in patients with significant liver disease, necessitating a 32 decrease in dosage. Dosage reduction is required also in patients with unconjugated hyperbilirubinemia (Gilbert's syndrome) because lamotrigine clearance is only about two 33 thirds of normal in this setting. Tiagabine is metabolized extensively by the liver. Reduced elimination with hepatic dysfunction 13 therefore requires12lowering of the dose or an increase in 34 the dosing interval. Levetiracetam and topiramate clearances are reduced only modestly with liver impairment, and no dosage adjustments are necessary unless kidney function also is compromised. Gabapentin and pregabalin are not metabolized to any15,20 significant extent by Felbamate should the liver, and therefore their use is not complicated by hepatic disease. not be used in patients with liver dysfunction because of the probable increased risk of 20 felbamate-induced hepatic failure. CARDIAC DISEASE Cardiac disease may lead to seizures as a result of focal cerebral ischemia from cardiogenic

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embolism or of global cerebral ischemia after cardiac arrest. Convulsive or myoclonic seizures are common after cardiac arrest, and status epilepticus occurs occasionally (see p. 35 1081). Seizures may also infrequently complicate coronary bypass surgery. Heart disease and epilepsy often coexist, especially in the elderly. This may complicate the treatment of acute seizures and status epilepticus because of the increased risk of adverse effects from anticonvulsant drugs. Although intravenous benzodiazepines and phenytoin are important for controlling convulsions and status epilepticus, they may cause hypotension and cardiac arrhythmias, especially in patients of advanced age or with underlying cardiac disease. These adverse effects relate to the rate of drug delivery; the toxicity of the phenytoin diluent, propylene glycol, may be responsible, although direct cardiac effects of phenytoin also contribute. In patients with preexisting cardiac disease, intravenous phenytoin should be administered at 25 rather than 50 mg/min with continuous electrocardiographic monitoring and frequent blood pressure measurements. If hypotension or arrhythmias do occur, they usually respond to temporary cessation of the infusion, but the rate may have to be decreased to 10 mg/min or less when it is restarted. Fosphenytoin, a water-soluble prodrug of phenytoin that does not require propylene glycol as a diluent, may have a lower risk of 36 hypotensive and arrhythmogenic events than parenteral phenytoin. However, the advantages of this more expensive therapy remain to be firmly established. Chronic administration of anticonvulsant drugs has rarely been associated with significant cardiovascular complications. Symptomatic arrhythmias have been reported in patients receiving carbamazepine in therapeutic dosages, but underlying cardiac abnormalities usually 37,38 Routine electrocardiograms should probably be obtained in patients have been present. with preexisting cardiac disease who receive either carbamazepine or phenytoin on a long-term basis. In such circumstances, events associated with loss of consciousness may relate to either arrhythmia or seizures, and thus complicate patient evaluation. Anticonvulsant agents may also interact with certain cardiac medications. The concomitant 39 use of phenytoin and quinidine may increase ectopy in patients with ventricular arrhythmias. The metabolism of quinidine, digoxin, lidocaine, and mexiletine may be increased by 39 phenytoin and phenobarbital because of40induction of hepatic microsomal enzymes. Amiodarone increases phenytoin levels, and calcium-channel blocking agents, such as verapamil, can increase serum carbamazepine concentrations. Thus, in epileptic patients with cardiac dysfunction, serum levels of anticonvulsant drugs may have to be monitored at frequent intervals, and cardiovascular function followed closely when either antiepileptic or cardiac medications are introduced or altered. SEIZURES IN CRITICALLY ILL PATIENTS

General Considerations Seizures are among the most common neurological complications of severe medical 41 illnesses treated in the intensive care setting. In a study by Bleck and colleagues, neurological complications occurred in 217 (12.3%) of a total of 1,758 patients admitted to an intensive care unit with a non-neurological primary diagnosis. Seizures occurred in 61 cases (28.1%) and were the most frequent neurological complication after metabolic encephalopathy. Seizures most commonly resulted from vascular lesions, but infection, metabolic derangement, mass lesion, hypoxia, and a variety of other causes were found. Approximately two thirds of patients experienced focal-onset seizures, and the remainder had seizures of presumed generalized onset. Status epilepticus occurred in six cases, two of which were refractory to standard treatment and required management by pentobarbital-induced coma. Neurological complications in this study were associated with increased mortality rates and longer lengths of stay in the intensive care unit and in the hospital. The evaluation of seizures in patients with severe medical illness involves first distinguishing between a primary neurological disturbance and a systemic etiology. Suspicion of a brain lesion should be particularly high in patients experiencing seizures of focal onset, although it is important to keep in mind that generalized tonic-clonic seizures may be either focal or generalized in onset, and that certain metabolic disturbances may cause focal seizures. A thorough clinical evaluation and metabolic screening is necessary in all cases. Medications should be carefully scrutinized, bearing in mind the possibility of drug-induced seizures. Because the physical examination is often complicated and vascular and infectious causes of 41 seizures are common in the critically ill, neuroimaging and cerebrospinal fluid (CSF) evaluation are often required. The EEG may provide evidence for a focal cerebral disturbance and is the only means for determining the presence of ongoing nonconvulsive seizures.

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Several important considerations arise with regard to the treatment of seizures in the critically ill patient. More aggressive antiepileptic drug therapy of discrete seizures is often warranted given the increased risk of seizure-related complications in patients who are already compromised by severe illness such as multiorgan system failure. However, anticonvulsants are ineffective in controlling seizures caused by various metabolic derangements such as severe hypoglycemia or hyperglycemia, hyponatremia, and hypocalcemia. In these instances, therapy should be directed at correcting the underlying abnormality. When antiepileptic drug treatment is necessary, the increased potential for complex drug interactions in patients receiving numerous other medications, altered pharmacokinetics due to factors such as renal or hepatic impairment, and adverse systemic effects must be considered. For example, in the hypoalbuminemic patient, it may be necessary to monitor free anticonvulsant drug levels when using an antiepileptic drug, such as phenytoin, that exhibits significant serum protein binding. Treatment may also be further complicated by the requirement for parenteral administration in patients with gastrointestinal dysfunction. For discussion regarding specific treatment issues in cases of severe organ system disease, the reader is referred to the individual disease sections in this chapter. Experience is limited in the use of newer anticonvulsant agents in this setting, especially given the lack of parenteral formulations.

Nonconvulsive Status Epilepticus Nonconvulsive seizures and nonconvulsive (absence or complex partial) status epilepticus 42 may occur in critically ill patients. Although its incidence is not known, nonconvulsive status epilepticus is probably under-recognized based on studies of patients in neurological 43,44 This condition should be intensive care units using continuous EEG monitoring. suspected in any critically ill patient with altered mental status of unknown cause. Subtle motor activity, such as rhythmic twitching of fingers or eye movements, should raise suspicion of seizure activity in this setting. Prompt recognition and treatment is essential because delay in44diagnosis and longer duration of seizure activity have been associated with a poor outcome.

Seizures Caused by Anoxic-Ischemic Encephalopathy Seizures resulting from global anoxic-ischemic cerebral damage occur acutely after 45–48 They typically resuscitation from cardiopulmonary arrest in 15 to 44 percent of survivors. commence within 24 hours of cardiopulmonary arrest and may consist of generalized tonic-clonic,46,49 tonic, myoclonic, or partial seizures, as well as tonic-clonic or myoclonus status Electrographic status epilepticus with restricted clinical manifestations epilepticus. (usually limited solely to extraocular or facial muscles) is 50 also well described after cardiopulmonary arrest, but may be difficult to recognize. The occurrence of seizures or even generalized tonic-clonic status epilepticus does not 46,47,49 However, influence the eventual clinical outcome of patients in postanoxic coma. myoclonus status epilepticus, that is, continuous myoclonus for at least 30 minutes with or 46,51,52 does suggest a poor prognosis after global cerebral without other seizure types, 46,48,51,53 It may begin at any49,52,53 time within approximately 5 days after hypoxic-ischemic insult. Generalized myoclonus may be52,53 cardiopulmonary arrest, most often within 24 hours. synchronous or asynchronous, but sometimes involves the facial muscles predominantly. The EEG typically reveals generalized spike-wave or polyspike-wave bursts on an abnormal background or a burst-suppression pattern; a diffuse alpha-frequency pattern is sometimes 48,52,53 Neuropathological examination shows diffuse anoxic-ischemic damage involving found. cerebral cortex, hippocampus, cerebellar Purkinje cells, thalamus, basal ganglia, and to a 48,52,53 lesser extent, the brainstem and spinal cord. 48,52,53

Myoclonus status epilepticus is poorly responsive to anticonvulsant therapy and may48 well represent a marker of severe anoxic-ischemic brain injury that rarely permits survival. Some instances of pure anoxic cerebral injury, such as isolated pulmonary failure, may have a somewhat better prognosis. Treatment decisions in these settings should be individualized using data from the clinical examination and neurophysiological studies. CONNECTIVE TISSUE DISEASES The connective tissue diseases are discussed in detail in Chapter 29. Cerebral vasculitis or vasculopathy may cause seizures in a variety of these diseases. In Sjögren's or Behçet's syndromes, convulsions may be associated with a flare of disease activity. Seizures rarely result from cerebral involvement in rheumatoid arthritis, scleroderma, or mixed connective 54 tissue disease. Systemic or isolated CNS vasculitides may also lead to seizures. Seizures may arise in certain of these disorders as a consequence of the involvement of other organs,

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such as the kidneys, or from complications of treatment, especially with immunosuppressive agents. Systemic lupus erythematosus (SLE) probably has the highest incidence of seizures and other neurological or psychiatric manifestations. The incidence of seizures in SLE ranges 55–58 Generalized convulsions occur most commonly, but simple between 10 and 54 percent. 55 or complex partial, absence, and akinetic seizures also occur; status epilepticus is rare. Occasionally, seizures or other neurological abnormalities59are the initial features of SLE, and systemic manifestations may not develop for many years. In patients with SLE and seizures, cerebral microinfarcts and, less often, subarachnoid and intracerebral hemorrhages are found on 60 pathological examination and may relate to an immunologically mediated vasculopathy. Convulsions may also arise from infections related to immunosuppressive therapy, lupus nephritis with associated uremia, or hypertensive 56,57 Evaluation therefore requires brain imaging, CSF encephalopathy, or as a terminal event. examination, metabolic studies, and assessment of systemic disease activity. The treatment of seizures in SLE depends on their cause. Convulsions resulting from a flare of cerebral lupus may not require anticonvulsant therapy because they are frequently solitary and self-limited. However, if several seizures occur over 24 to 48 hours or more, anticonvulsant medications can be prescribed for a limited time (e.g., 3 months) while the underlying SLE is treated. In severe cerebral lupus associated with recurrent seizures, immunosuppression with corticosteroids or other 55 immunosuppressive agents, such as cyclophosphamide and azathioprine, is indicated. Neuropsychiatric manifestations imply a poorer prognosis for SLE than otherwise, but the presence of seizures or psychosis without 55 other neurological features or significant renal disease does not reduce survival. Anticonvulsant drug therapy in SLE is complicated because many anticonvulsants may cause 61,62 Drug-induced drug-induced lupus (e.g., hydantoins, trimethadione, and ethosuximide). 63,64 65 61 valproic acid, primidone, and lupus also has been reported with carbamazepine, 66 lamotrigine. Drug-induced SLE typically occurs months after anticonvulsant therapy is initiated and usually remits days, weeks, or months after discontinuation of the offending agent. Laboratory findings are unlike those of idiopathic SLE because complement levels are 61 usually normal and antibodies to native DNA are typically not found. 67

There is no evidence that antiepileptic medications exacerbate idiopathic SLE, and anticonvulsant treatment should not be withheld from patients with SLE when it is required for seizure control. HEPATIC PORPHYRIAS Acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria are the three autosomal-dominant forms of hepatic porphyria that produce neurological manifestations. In acute intermittent porphyria, partial deficiency of porphobilinogen deaminase causes accumulation of δ-aminolevulinic acid and porphobilinogen, which are excreted by the kidneys. Partial deficiencies of coproporphyrinogen oxidase and protoporphyrinogen oxidase lead to hereditary coproporphyria and variegate porphyria, respectively. The acute hepatic porphyrias may cause peripheral neuropathy, autonomic dysfunction, and neuropsychiatric disturbances. Between 5 and 20 percent of patients with acute intermittent 68,69 They may be porphyria have seizures, which occasionally are the presenting feature. 70,71 71,72 and sometimes occur in flurries or even as status epilepticus. partial or generalized Their etiology is unknown but may relate to γ-aminobutyric acid (GABA) receptor binding by 73,74 68 which causes seizures when infused directly into rat brain. In δ-aminolevulinic acid, addition, defects in hepatic heme synthesis can alter brain levels of neurotransmitter 68 substrates, such as tryptophan, which may be important. During acute porphyric attacks, seizures may also relate to fluid and electrolyte disturbances, such as from excessive vomiting and inappropriate antidiuretic hormone secretion. 75–78

Thus, Porphyria sometimes coexists with idiopathic or symptomatic epilepsy. anticonvulsant treatment may be needed on both a short-term and a long-term basis in patients with hepatic porphyria. Almost all of the older antiepileptic agents, including phenobarbital, phenytoin and other hydantoins, primidone, carbamazepine, valproic acid, succinimides, oxazolidines, and 70,71,75–81 are held to exacerbate hepatic porphyria by stimulating hepatic benzodiazepines, δ-aminolevulinic acid synthase activity. With regard to the newer antiepileptic agents, experimental studies suggest that lamotrigine, felbamate, topiramate, or tiagabine use will 82,83 These studies are supported clinically in the case of exacerbate hepatic porphyrias.

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lamotrigine, which was suspected to have induced a porphyric attack and resultant 84 have not been incriminated in multiorgan system failure. Bromides and magnesium sulfate70,78,79 Gabapentin, pregabalin this way and have been used safely in patients with porphyria. and levetiracetam do not lead to significant hepatic microsomal enzyme induction and are therefore also probably safe to use, although experience is limited. Treatment of seizures during acute porphyric attacks includes intravenous carbohydrate, usually as a 10 percent dextrose solution, infusions of hematin or heme-arginate, and correction of associated metabolic abnormalities such as hyponatremia. If seizures persist or status epilepticus supervenes, magnesium sulfate may be infused intravenously to keep 71,72 The acute use of serum magnesium concentrations between 2.5 and 7.5 mmol/L. 79 paraldehyde or intravenous benzodiazepines may be safe but remains controversial. Successful treatment of patients with hepatic porphyria and acute seizures or status 85–87 88,89 or levetiracetam. epilepticus has been described with gabapentin Long-term pharmacotherapy of recurrent seizures in patients with hepatic porphyria 70,76,79 is difficult. Bromides are often used despite their toxicity and narrow therapeutic index. Serum bromide concentrations should not exceed 90 mg/dl. In addition, despite evidence that 70,79 low-dose clonazepam may be safe in the chronic clonazepam is porphyrinogenic, 75,76,78 treatment of patients with hepatic porphyria. 85–89 The treatment of choice, however, is Although one report described the probably either gabapentin or levetiracetam. 90 successful use of oxcarbazepine in a case of porphyria cutanea tarda, its use in hepatic porphyrias is questionable given the hepatic enzyme–inducing properties of oxcarbazepine. In all cases, urinary δ-aminolevulinic acid and porphobilinogen levels must be monitored closely during therapy. If seizures continue, empirical therapy with other anticonvulsants may have to be instituted. SEIZURES IN TRANSPLANT RECIPIENTS The neurological complications of organ transplantation are summarized in Chapter 46. Transplant recipients are at risk for seizures that may relate to their underlying illness, prior treatments (e.g., irradiation or chemotherapy), and perioperative metabolic abnormalities or complications such as cerebral ischemia. After surgery, the effects of immunosuppression, therapeutic agents, and rejection are also important causes.91–96 Children in general appear to be at greater risk than adults for post-transplantation seizures. Immunosuppressive agents, especially cyclosporine, have been associated with seizures. Seizures due to cyclosporine have been reported in 1.5 percent of renal transplant recipients 97 but higher incidences have also been noted, and 5.5 percent of bone marrow recipients, 98,99 92,93 and in children. Such seizures may occur with especially after liver transplantation serum levels of cyclosporine within or exceeding the therapeutic range. They may relate to a 100 cyclosporine metabolite, but various metabolic and systemic abnormalities, as well as other therapeutic agents, have been reported to potentiate them. These factors91,99,104 include con 101,102 103 hypertension, hypomagnesemia, comitant methylprednisolone therapy, 98 105,106 hypocholesterolemia, microangiopathic hemolytic anemia, and (after renal 107 transplantation) aluminum overload. Other immunosuppressive agents may also cause post-transplantation seizures. FK506 (tacrolimus) has 108–110 neurological complications similar to cyclosporine, including seizures and and the antirejection agent OKT3 can cause seizures as part of a encephalopathy, 111 cytokine encephalopathy. Sirolimus (rapamycin), one of the newer immunosuppressive agents, did not cause seizures or other neurotoxicity in at least one series consisting of 112 busulfan, either alone or kidney and liver transplant recipients. In bone marrow recipients, 113,114 in combination with cyclophosphamide, may cause seizures. Seizures may also result from CNS infections or relate to noninfectious structural and metabolic abnormalities that require specific treatment. Cerebral ischemia or hemorrhage, hyponatremia with central pontine myelinolysis, hyperosmolar states, hypoglycemia, delayed 93 malignancy related to prior treatment, or multiorgan system failure may be responsible. Finally, transplant rejection may lead to an encephalopathic syndrome that includes 92,115 116 sometimes as the first manifestation of rejection. seizures, 91,99

The approximate percentage incidence of seizures is 17 to 25 for liver transplantation, 3.7 96,117 105,118 3 to 11.5 after marrow replacement, and 1.5 to 5 in to 22 after lung transplantation, 97,107 Seizures occur in approximately 15 percent of heart renal allograft recipients. 119 transplantation cases. In bone marrow recipients, prior irradiation, intrathecal or systemic chemotherapy, systemic complications (e.g., thrombocytopenia), or relapse of disorders such as leukemia may be responsible. Renal transplant recipients may have seizures as a result of

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uremia or other metabolic abnormalities, or from post-transplantation cerebral 93 reticuloendothelial tumors. Heart and liver recipients are likely to have early postoperative seizures from focal or global cerebral ischemia. The occurrence of seizures necessitates a thorough evaluation to determine the specific cause. Biochemical screening tests, determination of blood levels of immunosuppressive agents, CSF examination, and neurophysiological and brain magnetic resonance imaging (MRI) studies may be necessary. The treatment of seizures in transplant recipients may be difficult. When seizures are self-limited and caused by correctable abnormalities that are not recurrent, anticonvulsant therapy is probably not required. Prolonged seizures or those placing the patient at high risk of complications should be controlled with benzodiazepines. Long-term anticonvulsant therapy is required for recurrent seizures. An anticonvulsant agent is selected, bearing in mind the type of transplantation procedure undergone by the patient and the immunosuppressive drugs in use. Valproic acid is best avoided in liver recipients because of its potential hepatotoxicity; low-dose levetiracetam (500 mg twice daily) is a reasonable 120,121 Carbamazepine should not be used in bone alternative, although experience is limited. marrow recipients because it may cause myelosuppression. Bone marrow engraftment occurs 2 to 6 weeks after transplantation, and phenytoin and valproic acid are best avoided 93 over this period in favor of phenobarbital or a newer agent. The enzyme-inducing anticonvulsants may affect immunosuppressive agents metabolized by the liver. Thus, the clearance of cyclosporine and corticosteroids is increased by 93,122–124 necessitating increased dosages of phenobarbital, phenytoin, and carbamazepine, corticosteroids by 25 to 30 percent and of cyclosporine depending on serum 122,125 cyclosporine 104 levels. The use of valproic acid avoids such pharmacokinetic interactions. Oxcarbazepine add-on therapy led to decreased serum cyclosporine and sodium concentrations in a single report involving a renal transplant patient, but the abnormalities 126 reversed with reduction in the dose of oxcarbazepine. Levetiracetam does not appear to influence immunosuppressive drug levels, has been used successfully in liver transplant recipients, and therefore may be a good initial choice for antiepileptic drug therapy in the overall transplant population. The lack of hepatic enzyme–inducing activity of pregabalin and gabapentin suggests that they also may be useful in this context. HUMAN IMMUNODEFICIENCY VIRUS INFECTION AND SEIZURES 127

Seizures are common in adults (but not in children 128) infected with human immunodeficiency virus (HIV), may occur at any stage of HIV disease, and are sometimes the presenting 129 in symptom of HIV infection. Generalized tonic-clonic seizures occur most commonly 128,129 but simple patients with HIV infection or acquired immunodeficiency syndrome (AIDS), and complex partial seizures may also occur. Convulsive status epilepticus is reported 128,129 to have occurred at presentation in 8 to 10 percent of HIV-infected patients with seizures, 128 and nonconvulsive status epilepticus has also been described. Unlike the finding of persistent lateralizing clinical signs, the occurrence of partial seizures does not necessarily relate to an opportunistic CNS infection or intracerebral mass lesion. For almost half of the patients with HIV infection or AIDS evaluated for seizures, no cause other than the HIV infection can be found. Evidence of HIV encephalopathy may be present 128 clinically or at autopsy. Other CNS disorders associated with AIDS also cause seizures, such as cerebral toxoplasmosis, primary CNS lymphoma, cryptococcal meningitis, or cerebrovascular events. A detailed diagnostic evaluation is therefore required when HIV-infected patients experience a new onset of seizures, and may include biochemical screening tests, cerebral MRI, CSF examination (including cytology), and determination of cryptococcal antibody titers in serum and CSF. Further details are provided in Chapter 45. Patients with HIV-infection or AIDS presenting in status epilepticus should be treated urgently with the usual protocols. Because of the relatively high risk of recurrent seizures or status epilepticus in HIV-infected persons, chronic anticonvulsant treatment should be instituted 128,129 Most of the older antiepileptic agents are best avoided in patients after an initial seizure. with HIV infection or AIDS. For example, phenytoin interacts with protease inhibitors, is associated with a high incidence of hypersensitivity and other adverse reactions, and has caused intoxication in patients treated concurrently with fluconazole, an antifungal agent used 130–132 The high incidence of cognitive adverse effects with commonly in AIDS patients. phenobarbital makes its use undesirable in the AIDS population. Carbamazepine should be avoided because of the risk of bone marrow suppression in patients who may be predisposed to this complication because of concurrent medications. Thus, monotherapy with one of the newer antiepileptic agents that do not significantly induce hepatic microsomal enzymes, such

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as levetiracetam, pregabalin or gabapentin, is preferable as first-line therapy. SEIZURES ASSOCIATED WITH SYSTEMIC CANCER Seizures may arise as a complication of systemic cancer or its treatment. In a prospective study of 851 (mainly adult) patients with systemic cancer referred for neurological 133 consultation, seizures prompted the referral in 5.4 percent. Intracranial metastasis was identified in one half, metabolic factors were deemed causative in one third, and the remainder had cerebral hemorrhage, preexisting epilepsy, or an uncertain etiology of their seizures. Seizures are a more common neurological complication of systemic cancer in children. Thus, Antunes and De Angelis reported that seizures were the second most 134 common reason for neurological referral in a series of 157 children with systemic cancer. Of the 29 cases (18% of total referrals), a cerebral structural abnormality was identified in approximately one third. Seizure types are partial with or without generalization, or primarily generalized tonic-clonic, depending on the etiology. In addition, nonconvulsive status 135 epilepticus may lead to an altered mental status in patients with systemic cancer. A number of potential etiologies must be considered when convulsions occur in the patient with cancer (Table 58-1). Direct effects of cancer include parenchymal metastasis, which is particularly common with melanoma, lung, breast, renal cell, gastrointestinal, and germ cell 136 tumors, as well as leptomeningeal and dural metastatic disease. Partial or secondarily generalized tonic-clonic seizures arise in these circumstances. Seizures may also result from cerebrovascular events due to hypercoagulable states or nonbacterial thrombotic endocarditis associated with cancer. CNS infections, including fungal or parasitic abscesses, may result from immunosuppression after chemotherapy and produce seizures. Convulsions are an uncommon complication of chemotherapy, but may be seen with etoposide, l-asparaginase, alkylating agents such as chlorambucil or busulfan, immunotherapies, 136 methotrexate, and cytosine arabinoside. Other causes include cancer-induced metabolic disturbances, paraneoplastic encephalitis, and drugs used to treat cancer complications, such as pain medications or antibiotics. Click here to view this table.... A cerebral structural abnormality must be sought in any patient with systemic cancer presenting with seizures of unknown etiology. Cerebral MRI is the study of choice. In the absence of a brain lesion, CSF evaluation with cytological analysis is necessary to assess for infection or meningeal tumor involvement. Coagulation studies and biochemical screening are also warranted, and imaging studies of the cerebral venous system should be performed if clinical suspicion exists for venous sinus thrombosis. EEG evaluation may be needed if the type of seizure and etiology remain uncer tain. Finally, any medications used that predispose to seizures should be identified. Antiepileptic drug treatment is necessary unless the seizure is symptomatic of a reversible cause. Certain situations may, however, complicate the selection of the appropriate anticonvulsant agent. Phenytoin should not be used in patients receiving137 whole-brain cranial irradiation because of an increased risk of Stevens–Johnson syndrome. Carbamazepine, which often causes a mild leukopenia, is best avoided in those at risk for bone marrow suppression. Another potential complication of anticonvulsant therapy involves interactions with chemotherapeutic agents used to treat cancers. Similarly to most anticonvulsants, many chemotherapeutics undergo hepatic metabolism or influence hepatic microsomal enzymes. Thus, coadministration of drugs in these two classes may lower the effectiveness of cancer 138 chemotherapy, interfere with seizure control, or induce anticonvulsant toxicity. Because of these potential interactions, the use of antiepileptic agents with limited hepatic metabolism and enzyme induction, such as levetiracetam or pregabalin, should be considered in individuals undergoing cancer chemotherapy. PULMONARY DISEASE Asthma and epilepsy are both relatively common, and the two disorders may coexist in the same patient. Epilepsy may rarely result from recurrent severe hypoxic episodes during asthmatic attacks, and hypoxia-induced seizures occur infrequently during acute asthma ex-acerbations. Seizures may result from certain antiasthmatic medications and especially as a complication of theophyl-line use. This complication is most likely due to the inhibition of 1 may phosphodiesterase, which may reduce adenosine-mediated CNS inhibition. Seizures 139 occur with serum levels in the therapeutic range or that are only mildly elevated. Partial or generalized seizures, or status epilepticus, occur with acute overdose; status epilepticus140 may be unresponsive to anticonvulsants and require hemodialysis or hemoperfusion therapy.

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Theophylline is best avoided in epileptics because of the risk of seizure exacerbation and 141,142 potential pharmacokinetic interactions with anticonvulsant drugs. Isoniazid, an antituberculosis agent, 1may also cause seizures in therapeutic doses, but more generalized convulsions and status frequently does so with overdosage. Repeated 143 epilepticus are common after an overdose. Convulsions probably relate to a lowering of brain γ-aminobutyric acid levels through the antagonism of a pyridoxine-dependent cofactor involved in its synthesis. Prolonged seizures may respond to intravenous pyridoxine and 1 benzodiazepines. ENDOCRINE OR METABOLIC DISORDERS

Disorders of Glucose Metabolism In a prospective study of 125 patient visits to an urban emergency department 144 for symptomatic hypoglycemia, documented seizures were observed in 7 percent. Both focal motor and generalized seizures were characteristic; however, seizure flurries or convulsive status epilepticus also occurred. Other neurological abnormalities included depressed level of consciousness, behavioral changes, tremor, and hemiparesis. These deficits correlated poorly with level of hypoglycemia, although in symptomatic patients levels were usually below 54 40 mg/dl. Hypoglycemia must be considered in any patient with seizures; it is treated by intravenous administration of dextrose and correction of any other metabolic abnormalities. Patients usually do well with prompt therapy but are best hospitalized for54observation because hypoglycemia may recur hours after adequate initial treatment. 145

Seizures are relatively common in nonketotic hyperglycemia. Partial motor seizures or 146,147 occurring in 19 percent of epilepsia partialis continua may be the presenting feature, 145 occur in nonketotic hyperglycemia, including cases. Virtually any type of seizure may 146,148,149 Patients are typically middle-aged or older, movement- or posture-induced seizures. may have no history of diabetes, and have recurrent partial motor seizures. A mildly altered level of consciousness and focal neurological deficits may also be present, as discussed in Chapter 21. The range of glucose elevation is broad and may be associated with only mild 146 elevation of serum osmolarity. Seizures are refractory to anticonvulsant medication but respond to correction of hyperglycemia with insulin and intravenous fluid replacement. 146 Associated focal neurological abnormalities are usually transient, and recovery is typically complete if treatment is initiated before coma occurs. Underlying focal cerebral structural abnormalities are uncommon, but it is nevertheless prudent to obtain neuro-imaging studies when seizures first occur in association with nonketotic hyperglycemia and in patients with persistent neurological deficits. Anticonvulsant therapy is not required for seizures related to nonketotic hyperglycemia. Convulsions may recur despite anticonvulsant drugs if control of 147 specifically be avoided because it can blood glucose is not maintained, and phenytoin must150 exacerbate hyperglycemia by inhibiting insulin release. The pathogenesis of seizures in nonketotic hyperglycemia may involve localized cerebral ischemia, cortical deformation from brain dehydration, or54,149 increased γ-aminobutyric acid metabolism through the succinic semialdehyde pathway. Depressed brain γ-aminobutyric acid levels presumably lower the seizure threshold by decreasing cortical inhibition.

Thyroid Disease Seizures are not uncommon in hypothyroidism, and if myxedema coma ensues, the 151 frequency approaches152,153 20 percent. They are usually generalized and remit with treatment Anticonvulsant drugs, such as phenytoin and carbamazepine, of the hypothyroidism. may reduce serum thyroxine and triiodothyronine measurements because of competition for serum binding proteins; however, patients remain clinically euthyroid because free thyroxine 154,155 and triiodothyronine fractions are increased. 152

Seizures are uncommon in thyrotoxicosis, but hyperthyroidism or excess thyroxine may occasionally cause seizures or exacerbate preexisting epilepsy. Thus, thyroxine reduces the seizure threshold in certain animal models of156 epilepsy, whereas thyroidectomy protects Both partial and generalized seizures may against pharmacologically induced seizures. 157,158 157,159 and in those receiving thyroxine for hypothyroidism. occur in hyperthyroid patients In addition, worsening of both partial and generalized epilepsies may occur with increased 160,161 When seizures occur in the setting of thyrotoxicosis, the hyperthyroid thyroxine levels. state should be corrected; anticonvulsants usually are not required except occasionally in the acute setting.

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Disorders of Sodium Homeostasis Hyponatremic encephalopathy relates to an osmotic imbalance between the extracellular fluid 162 and brain cells, and to the effects of a compensatory loss of intracellular cations. Symptoms reflect the rate of development of hyponatremia rather than absolute serum 163 138 sodium levels, and chronic hyponatremia is surprisingly well tolerated. A full account of the neurological manifestations is provided in Chapter 19. Both partial and generalized seizures occur with hyponatremia and may be the first sign of symptomatic water intoxication. Hyponatremic convulsions are especially common in infants 164 and young children. They require aggressive treatment in the form of intravenously administered hypertonic saline. This should be given at a controlled rate so that the serum sodium concentration increases by no more than 1 mmol/L per hour, until the patient is either asymptomatic or the sodium concentration has increased by a maximum of 12 mmol/L over 162,165 More rapid correction of the first 24 hours and 25 mmol/L in the initial 48 hours. 165–167 ; hypertonic162saline is hyponatremia may cause pontine and extrapontine myelinolysis best avoided once the plasma sodium concentration reaches 125 to 135 mEq/L. The causes and features of hypernatremia are discussed54in Chapter 19. Generalized or partial seizures may occur, especially during rehydration. Cautious correction of hypernatremia with half-isotonic saline may lower the risk of convulsions during treatment.

Calcium and Magnesium Imbalance The causes and clinical features of hypocalcemia are discussed in163 Chapter 19. Altered sensorium and seizures are common neurological manifestations. Hypocalcemic seizures are usually generalized, but partial seizures occur in 20 percent of patients and may include motor or sensory phenomenology. Between 30 and 70 percent of patients with hypoparathyroidism experience seizures, often accompanied by an altered sensorium and 54 tetany, although tetany is occasionally absent. Treatment of hypocalcemic seizures involves correction of serum calcium levels and treatment of any underlying cause. 168

especially Multifocal and generalized seizures may also be provoked by hypomagnesemia, 163 Convulsions in when the serum magnesium concentration decreases below 0.8 mEq/L. 163,168 administered such circumstances are treated with parenteral magnesium salt solutions by slow intravenous bolus after the adequacy of renal function has been determined; calcium 163 gluconate should be available to counteract transient hypermagnesemia. SEIZURES RELATED TO ALCOHOL AND DRUGS OF ABUSE Seizures are a common consequence of alcohol (see Chapter 37) and recreational drug abuse (Chapter 38). Alcohol-related seizures are usually self-limited convulsions that occur within 48 hours after cessation of alcohol use, often accompanied by other169signs and symptoms of alcohol withdrawal. They may be isolated or occur in flurries and are usually attributed to brief abstinence or acutely declining ethanol levels in long-standing heavy drinkers. Seizures sometimes have focal features, often because of prior cerebral trauma. However, alcoholics are at high risk for head injury, CNS infection, cerebrovascular disease, and metabolic derangements, and detailed clinical and laboratory evaluation is therefore necessary whenever seizures occur. Hematological, bio chemical, and toxicological testing is indicated, and brain computed tomography (CT) or MRI studies should be obtained when a 169 focal cerebral lesion is suspected or for a first convulsion. CSF examination is necessary when meningitis or encephalitis is a consideration, and the EEG is useful if the seizure type or etiology is uncertain. Because alcohol-related seizures are self-limited and alcoholics are poorly compliant, long-term anticonvulsant therapy is rarely indicated. Phenytoin is of limited utility for treating 170 but benzodiazepines may control seizures in the setting of acute alcohol withdrawal, 171 seizures and other symptoms of ethanol withdrawal. This is supported by a randomized, double-blind trial of lorazepam for the prevention of alcohol-related seizures, which demonstrated that lorazepam decreased the risk of recurrent convulsions over a 6-hour 172 observation period compared with placebo. Furthermore, significantly fewer patients in the treatment group were admitted to the hospital or returned to an emergency department with seizure recurrence after173 the observation period. Convulsive status epilepticus may also result from alcohol withdrawal and should be treated with intravenous benzodiazepines and phenytoin according to standard protocols.

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Patients with seizures solely in the setting of alcohol or drug abuse do not, by definition, have epilepsy. However, approximately 2 to 4 percent of patients with alcohol-related seizures 169 Heavy ethanol intake may exacerbate seizures in epileptic have preexisting epilepsy. 174 patients, and patients should be advised against chronic or heavy alcohol intake and isolated drinking binges that are often associated with lack of sleep. Seizures may be induced by acute intoxication with illicit drugs or, less frequently, may appear as a withdrawal phenomenon. Such seizures are typically isolated convulsions that are self-limited and do not require acute or chronic treatment with antiepileptic medications; therapy should be focused instead on the problem of substance abuse. Prolonged seizures and status epilepticus resulting from illicit drugs do, however, necessitate urgent treatment. 175 The drug of abuse most commonly implicated as a cause of convulsions is cocaine. 169 Seizures resulting from cocaine abuse are increasing in frequency. Cocaine-induced convulsions may result from direct CNS stimulant effects through blockage of neurotransmitter reuptake at dopaminergic and noradrenergic nerve terminals, a possible kindling effect with chronic administration, cerebrovascular or systemic effects, and as a 1,169 Between 2 and 8 percent of patients terminal event in massive cocaine overdose. presenting to the emergency department with cocaine toxicity exhibit seizures, usually single, 176 generalized tonic-clonic convulsions. Anticonvulsant therapy is not warranted except for prolonged seizures or status epilepticus. Focal-onset seizures or those associated with abnormal neurological findings in cocaine users should raise concerns about an acute intracranial process and lead to evaluation by CT and possibly MRI or cerebral 176 Neuroimaging should also be performed in patients with new-onset angiography. 169 seizures. Seizures are infrequent in intoxication with other recreational drugs. Amphetamine is an uncommon cause of generalized convulsions, which occur more commonly after intravenous 175 use and administration of high doses. Focal features or abnormal findings on examination 169 should raise concerns for the presence of an underlying cerebral structural abnormality. Seizures are also uncommon with phencyclidine (PCP). Generalized convulsions occurred in only 3.1 percent of 1,000 patients coming to an emergency department with177phencyclidine intoxication, although 16 percent of seizure patients had status epilepticus. Heroin use has been associated with convulsions, although this may relate to175,178 anoxia and chemical Complications of adulterants rather than to a convulsant effect of heroin itself. intravenous drug abuse that may cause seizures, including infectious endocarditis and HIV infection, should be sought in patients with convulsions associated with the use of heroin or other intravenous drugs. Marijuana is often used concurrently with heroin and 178 other recreational drugs but seems independently to lower the risk of a first seizure. Finally, an abstinence syndrome that includes withdrawal seizures similar to those observed in 1 alcoholics may relate to chronic sedative administration. Seizures caused by barbiturate and benzodiazepine withdrawal have become less common, although they are more likely to 1 occur with short-acting agents and should be treated with parenteral benzodiazepines. POST-TRAUMATIC EPILEPSY Head injuries are a significant cause of recurrent seizures in the general population. Post-traumatic epilepsy occurs most frequently when the dura is breached. Most seizures appear179,180 within the first year after head injury, but an increased risk is present for at least 5 years. Seizures occurring after head injury can be divided into early and late categories. Early seizures occur within 7 days of injury, are more common in young children, have an incidence 179 convulsions or partial seizures without of 2 to 6 percent, and typically consist of generalized 181 generalization; complex partial seizures are rare. The occurrence of early seizures does not necessarily imply that recurrence will occur, but seizures developing more than 1 hour 179,182 Other risk factors for the after injury suggest an increased risk of late seizures. occurrence of late seizures include focal lesions (hematoma, contusion) or neurological 181,183 With penetrating injuries, the signs, dural penetration, and prolonged coma or amnesia. risk of seizures relates to the volume of brain tissue destroyed 180,184 and is increased with lesions Regardless of whether located centroparietally or when metal fragments are retained. early seizures occur, these late seizures consist of either generalized convulsions (sometimes with a focal onset) or, less commonly, partial seizures with either simple or 181 complex symptomatology. The EEG is disappointing as a predictor of the risk for development of post-traumatic epilepsy. In one study, EEGs recorded at 1 month were normal in 8.3 percent of patients with 183 partial seizures and in 27.3 percent of those with generalized seizures after head injury.

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There is controversy about the role of prophylactic anticonvulsant treatment of patients with head trauma. The ideal therapy would block the formation of an epileptogenic focus and thereby prevent the development of epilepsy. Certain early reports suggested a decreased incidence of seizures after head injury in patients treated prophylactically with one or two anticonvulsants (usually phenytoin, sometimes combined with phenobarbital). However, these studies are difficult to interpret on methodological grounds. More recent prospective 185–187 but despite more trials show no effect of such prophylactic antiepileptic medications, 188 rigorous designs, these studies have also been criticized methodologically. A more definitive study by Temkin and colleagues showed that phenytoin prevented seizures for the first week after cerebral injury but was no better than placebo in exerting a protective 189 effect during the remainder of the study period. It was therefore concluded that phenytoin should be given to patients at risk for post-traumatic seizures but discontinued after the first week following injury unless further seizures occurred. Additional randomized or quasi-randomized monotherapy studies have shown no benefit of prophylaxis with other antiepileptic drugs, including phenobarbital, carbamazepine, and valproic acid, on the 190,191 ). Glucocorticoids also development of late post-traumatic seizures (reviewed elsewhere appear192to have no benefit in preventing the development of seizures after traumatic brain injury. Studies using some of the newer anticonvulsant agents are ongoing, but novel antiepileptogenic strategies clearly are needed. Previous

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Aminoff: Neurology and General Medicine: Movement Disorders Asso...



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Michael J. Aminoff

NEUROLOGY and GENERAL MEDICINE 59 Movement Disorders Associated With General Medical Diseases CHADWICK W. CHRISTINE • MICHAEL J. AMINOFF •

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CHOREA AND DYSTONIA Hypoxic-Ischemic Disorders Toxins Drug-Induced Dystonia and Chorea Infectious Disorders Bacterial Infections Viral Infections Fungal and Parasitic Infections Autoimmune, Inflammatory, and Paraneoplastic Disorders Metabolic Disorders Approach to Diagnosis Treatment MYOCLONUS Hypoxia-Ischemia Metabolic Disorders Autoimmune and Inflammatory Disorders Drug- and Toxin-Induced Myoclonus Paraneoplastic Disorders Infections Injury by Physical Agents Approach to Diagnosis Treatment TREMOR Stroke Medications Toxins and Recreational Agents Metabolic Disorders Infections Immune Disorders Other Causes of Tremor Approach to Diagnosis Treatment PARKINSONISM Vascular Causes

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Medications and Bone Marrow Transplantation Toxins Metabolic Disorders Infections Autoimmune and Paraneoplastic Disorders Trauma Other Causes of Parkinsonism Approach to Diagnosis Treatment

CHOREA AND DYSTONIA Dystonia or chorea occurs in a wide variety of medical disorders. Although chorea is typically a more fluid, “dance-like” undulation of a limb, and dystonia is a slower movement or a sustained abnormal posture of a limb or the trunk, it is sometimes difficult to distinguish between them. Approximately 25 percent of dystonias and most choreas are symptomatic or secondary to a neurodegenerative disorder, hereditary metabolic defect, or systemic medical disorder. Responsible neurodegenerative or inherited metabolic disorders are reviewed 1,2 elsewhere. In a series of 51 cases of chorea from Italy, vascular causes were identified in 40 percent, drug-induced causes in 14 percent, acquired immunodeficiency syndrome (AIDS)–related causes in 10 percent, Huntington's disease in 10 percent, hyperglycemia in 4 percent, and hyponatremia in 4 percent; single cases (2 percent each) of borreliosis (Lyme disease), 3 Sydenham's chorea, and acanthocytosis were also identified. The epidemiology will differ in regions where AIDS or other infectious conditions are more prevalent. Chorea is usually associated with dysfunction of the thalamus or basal ganglia. In most cases, the physiological effect of the disorder reduces inhibitory input from the globus pallidus interna to the motor 2 thalamus, resulting in excessive thalamocortical motor facilitation. Dystonia is characterized by impaired inhibition at multiple levels of the central nervous system, and altered levels of several neurotransmitters have been reported in various diencephalic nuclei, as well as the putamen, globus pallidus, red nucleus, and4 subthalamic nucleus. Nonetheless, the generation of dystonia remains poorly understood.

Hypoxic-Ischemic Disorders Chorea and dystonia due to hypoxia-ischemia may result from global or focal cerebral hypoperfusion as well as cellular hypoxia, such as in mitochondrial toxicity. Hypoxia-ischemia 5 induces numerous metabolic changes in striatal function. A decrease in the levels of inhibitory neurotransmitters occurs, with hypoxic-ischemic necrosis of medium-sized γ-aminobutyric acid (GABA)–ergic striatal spiny neurons and enkephalinergic putamenal projections to the external pallidum. In contrast, the striatal cholinergic system becomes upregulated after hypoxia-ischemia, and it is therefore interesting that anticholinergic agents often reduce dystonic movements. Onset of a movement disorder is often delayed after hypoxic injury. This may reflect the time required for remyelination, inflammatory changes, ephaptic transmission, oxidation reactions, maturational or aberrant synaptic reorganization, 6 trans-synaptic neuronal degeneration, or denervation supersensitivity to occur. Stroke may cause a variety of movement disorders depending on the location of the lesion and age of the patient. In a series of 1,500 patients with stroke, Alarcon and colleagues found that movement disorders occurred in about 4 percent of these patients; chorea occurred in 36 percent, whereas dystonia, tremor, and parkinsonism were less common, occurring in 28, 25, 7 and 10 percent, respectively. The average age at onset of chorea was 75 years, whereas that for dystonia was 48. Hemichorea occurred most commonly with contralateral thalamic strokes but also occurred with other lesions of the basal ganglia (putamen and subthalamic nucleus), white matter tracts (corona radiata, internal and external capsule), and pons. Putamenal strokes caused dystonia most frequently, although lesions of the pons or globus pallidus and larger strokes of the frontal lobe were also sometimes responsible. The time to onset of the movement disorder was shorter for chorea—usually within 1 week of the stroke—whereas dystonia and tremor developed 2 to 3 weeks after stroke. Focal ischemia or stroke to the contralateral basal ganglia is the most common cause of acquired 8 Most patients who develop chorea or dystonia after a stroke improve over hemidystonia. 7 time. The prognosis of chorea and9 dystonia resulting from global hypoxic-ischemic injury differs in infants, children, and adults. In infants and children, the interval before the movement 10 disorder develops is longer and abnormal movements are more likely to generalize. In

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adults, chorea or dystonia becomes manifest as any hemiparesis resolves and it usually remains localized. Only in young children with postpump chorea and adults with post-thalamotomy syndrome does the movement disorder commonly begin within a week of injury. Such differences may relate to differences in neuroplasticity or variability in the 9 metabolic response of the brain to injury. What determines whether global cerebral hypoxia-ischemia causes dystonia or parkinsonism? Marsden and colleagues have noted that at the time of anoxia the mean age of patients developing the akinetic-rigid syndrome was 41 years, whereas for those developing pure dystonia it was 13.5 years, suggesting that there is an age-dependent difference in the effect of cerebral hypoxia. Moreover, injury to the putamen is more likely to cause a dystonic picture, whereas lesions of the globus pallidus are usually associated with 10 parkinsonism. Perinatal hypoxic-ischemic injury may lead to any pattern of dystonia, often after a long interval. At onset the dystonia is focal or, rarely, segmental, and commonly spreads over a period of6,86 months to 28 years, resulting in segmental dystonia, hemidystonia, or generalized dystonia. The longer the latency to onset or the period of progression, the less certain it is that hypoxia is responsible. Thus, complete evaluation for other causes is always important. The most frequently observed pathological finding is a marble-like appearance of the striatum due to altered myelination (“status marmoratus”). Postpump chorea consists of chorea or ballismus, episodic eye deviations, and hypotonia. It occurs in infants or children within 12 days of cardiac surgery involving hypothermia, cardiopulmonary bypass, and often complete circulatory arrest, and may be severe. Although this surgical complication was previously common, occurring in up to 20 percent of children, 11 current techniques have drastically reduced its incidence to well under 1 percent. Infants younger than 6 weeks are less susceptible; in older infants, the chorea is often mild and reversible. The pathophysiology is poorly understood, although it seems likely that hypoxic-ischemic mechanisms secondary to surgical technique (including deep hypothermia) 12 play a role. Previously normal children and young adults sustaining acute hypoxic injury usually have focal or unilateral findings clinically and on imaging studies, despite the global insult. Dystonia 10 may develop after 1 week to 3 years and typically generalizes over the following months (up to 5 to 10 years); imaging shows abnormalities especially in the putamen. Polycythemic chorea occurs for uncertain reasons. Polycythemia rubra vera has a male predominance, but polycythemic chorea is more common in women. Neurological manifestations of polycythemia are common, occurring in 50 to 80 percent of patients and include headache, vertigo, stroke, visual symptoms, tinnitus, and paresthesias. Chorea is a 13 rare complication, occurring in 0.5 to 5 percent of patients. Examination may also show a plethoric complexion and splenomegaly. The chorea may begin suddenly or gradually, is sometimes episodic, and typically becomes generalized but affects particularly the facial, lingual, and brachial muscles. The limbs are hypotonic, with pendular patellar tendon reflexes. The chorea may persist for up to several years, with spontaneous remissions and recurrences. Treatment is of the underlying polycythemia, but the relationship between red blood cell counts and chorea is often weak.

Toxins Exposure to certain gases and heavy metals is a rare cause of encephalopathy, parkinsonism, and dystonia, probably as a result of cellular hypoxia from mitochondrial dysfunction or the generation of free radicals. Carbon monoxide toxicity appears to result from a combination of tissue hypoxia and direct cellular toxicity. Carbon monoxide binds to 14 hemoglobin and cytochromes, thereby inhibiting the electron transport chain. After initial recovery, about 10 percent of survivors will develop parkinsonism several weeks to months 15 later; approximately 80 percent recover within 6 months. Imaging often reveals focal injury particularly to the pallidum and diffuse white matter changes, and magnetic resonance 16 Treatment with spectroscopy of white matter lesions are consistent with demyelination. 15 levodopa and anticholinergic agents is not helpful. 17

Cyanide poisoning usually results in death but may cause parkinsonism and dystonia. The movement abnormalities may initially improve, only to worsen days to months later, followed by stabilization and gradual but incomplete recovery. Cyanide reacts with cytochrome c oxidase, causing cellular hypoxia. Imaging studies show lesions in the caudate and lentiform nuclei, precentral cortex, and cerebellum. Functional imaging shows reduced dopamine 18 transporter uptake suggestive of nigral neuronal loss. Ingestion of methanol results in the production of formaldehyde by the liver; the liver and

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erythrocytes synthesize formic acid, which inhibits cytochrome oxidase and, thus, mitochondrial electron transport and tissue adenosine triphosphate production. Metabolic acidosis injures the retina and optic nerves and leads to necrosis of the putamen, subcortical white matter, cerebellum, brainstem, and spinal cord, resulting in parkinsonism, bradykinetic 19,20 Initial treatment relies on correction of the metabolic dystonia, tremor, and blindness. acidosis with ethanol and elimination of methanol with hemodialysis. Gradual improvement may occur with time, and treatment with amantadine and dopaminergic medications 19 sometimes helps. Manganese toxicity may occur as an occupational exposure (e.g., in miners of the ore or with chronic exposure to metal alloys, batteries, paint, varnish, enamel, or colored glass) or as a consequence of liver failure. Manganese increases free radical formation, inhibits antioxidant function, may reduce mitochondrial energy production, and perhaps increases glutamate neurotoxicity. It leads to apathy, restlessness, and bradykinesia, and eventually to rigidity, dystonia, hyperreflexia, Babinski signs, gait instability, and rest or postural tremor. Remission may occur in mild cases if further exposure is prevented, but the course21is otherwise progressive, although there are reports of improvement after chelation. Pathological examination reveals damage to the globus pallidus and substantia nigra pars reticulata (which are downstream from the nigrostriatal dopaminergic pathway), consistent with the 22 failure to respond to levodopa. Magnetic resonance imaging (MRI) may show hyperintensity of the putamen on T1-weighted images. Organic mercury poisoning, as seen formerly with the ingestion of certain fungicides and shellfish (Minamata disease), causes visual loss, ataxia, paresthesias, and cognitive dysfunction. Choreoathetosis, parkinsonism, and tremor also occur, and dystonic posturing is occasionally seen. Inorganic mercury poisoning, seen in glass blowers, hatters, and battery 23 workers, produces a psychotic encephalopathy and tremor. Dystonia secondary to copper accumulation occurs in Wilson's disease. If hepatic damage is mild, significant improvement follows chelation therapy with penicillamine or trientine. Liver transplantation may be required for nonresponders and patients with severe liver 24 dysfunction. This movement disorder may respond to trihexyphenidyl, levodopa, bromocriptine, or amantadine. Cellular and global hypoxia-ischemia have been implicated in disulfiram overdose in adults 25,26 and children. In one such case, psychomotor slowing and parkinsonism were evident several days after awakening from coma, and over 10 years progressed to include dystonia of a lower limb and speech, and blepharospasm. Brain computed tomography (CT) shows hypodense lesions, and MRI shows hyperintense lesions in the pallidum and inferior 25 putamen.

Drug-Induced Dystonia and Chorea Medications may cause dystonia (Chapter 36) and chorea (Table 59-1). Acute iatrogenic dystonic reactions are idiopathic, reversible, and common. They may occur almost immediately (minutes to hours) after the first dose of a medication, or days to weeks later. For dystonia, the most common offenders include antipsychotics (both typical and atypical), benzodiazepines, anticonvulsants, dopamine agonists, and tricyclic antidepressants. Reactions have been encountered less often with calcium-channel blockers, propranolol, 27 histamine blocking drugs (cimetidine, ranitidine, cetirizine), 28 substituted benzamides (metoclopramide, sulpiride, clebopride, and domperidone). Selective serotonin-reuptake inhibitors (including fluoxetine, paroxetine, fluvoxamine, and sertraline) have been associated 29 with dystonia. Patients with AIDS dementia complex are particularly sensitive to neuroleptic-related acute dystonic reactions because of underlying dopaminergic 30 dysfunction. Click here to view this table.... Treatment involves a gradual reduction and discontinuation of the offending medicine and, if necessary, administration of an anticholinergic or a benzodiazepine. Diphenhydramine, benztropine mesylate, chlorpheniramine, diazepam, or lorazepam may be given orally or intravenously; treatment for several days is sometimes necessary, especially if the causal agent was taken regularly or in depot form. Chorea has been reported secondary to a variety of medications including anticonvulsants (phenytoin, carbamazepine, valproate, and gabapentin), stimulants (amphetamine, cocaine, methylphenidate, pemoline), benzodiazepines, estrogens, lithium, levodopa (with or without catechol-O-methyltransferase [COMT] inhibitors), dopamine agonists, tricyclic

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antidepressants, and antihistamines, as well as other agents such as baclofen, cimetidine, 2,31 thyroxine, cyclosporine, and aminophylline. 32Azar and colleagues reported chorea and encephalopathy associated with ciprofloxacin. Disulfiram overdose or poisoning (discussed earlier) may present clinically with encephalopathy, ketotic hyperglycemia, and dystonia. Tardive dyskinesias typically involve repetitive orolingual facial movements or repetitive movements of the head, trunk, and extremities. The dyskinesia may take the form of dystonia, chorea, akathisia, tremor, or myoclonus. It is not clear what determines the type of movement disorder that develops; there is no correlation with type or number of neuroleptic agents taken or duration of their use. Orofacial dyskinesias typically develop after 1 to 2 years of antipsychotic use but may occur after only months. Older patients seem more susceptible than young persons. The antipsychotic should be discontinued if feasible; this may initially exacerbate the dyskinesia, but the movement disorder ultimately decreases or disappears in up to 50 percent of patients, persisting unchanged in the remainder. Other dopamine-blocking drugs, including certain calcium-channel blockers (especially cinnarizine and flunarizine) and rarely serotonin reuptake inhibitors, have been associated with the development of tardive dyskinesias. Dopamine-depleting agents (reserpine, tetrabenazine) are the most useful adjunctive treatments, followed by benzodiazepines and by dopamine and γ-aminobutyric acid agonists; 33 anticholinergic drugs may exacerbate the syndrome. Tardive dystonia may be indistinguishable from idiopathic dystonia and may respond to sensory tricks. It may be focal, segmental, or generalized; however, the head and neck region are most commonly affected, resulting in torticollis, blepharospasm, or oromandibular 33 dystonia. Orobuccal-lingual dyskinesia or other tardive movements may occur in tardive dystonia, unlike in idiopathic dystonia. The onset is insidious, typically after several years of antipsychotic use, but may occur with exposures shorter than 1 year. Tapering the antipsychotic occasionally produces gradual or partial remission of tardive dystonia, often after an initial worsening. An increase in dose of the antipsychotic or its continuation may lead to temporary benefit, but probably worsens the long-term outlook. If treatment with an antipsychotic is necessary, replacement of the original neuroleptic with clozapine or sometimes quetiapine has been helpful. Approximately 50 percent of patients benefit from dopamine-depleting or -blocking agents (e.g., reserpine or tetrabenazine) and anticholinergic 33 treatment. For patients with focal or segmental dystonia, botulinum toxin injections are beneficial. Stereotactic surgery, including pallidotomy and pallidal deep brain stimulation, has 34 been successful for severe tardive dystonia. Among the medications known to cause dyskinesias, antipsychotic agents—especially haloperidol—remain the most common offenders and cause dystonia by blocking dopamine receptors in the basal ganglia. The “atypical” antipsychotic agents appear to be less frequently associated with the development of tardive dyskinesias, although they still occur. A recent study on injectable risperidone found a 1-year rate for developing dyskinesia of 1.2 35 percent. However, aside from the well-recognized antipsychotics, other less well recognized dopamine-blocking agents such as antiemetics and gastrointestinal agents such as prochlorperazine, promethazine, and metoclopramide can cause tardive syndromes. Some medications appear to cause chorea in the setting of preexisting basal ganglia injury. For example, dose-related 36 dyskinesias develop in a large proportion of parkinsonian patients taking carbidopa/levodopa. Similarly, many patients who develop chorea while taking oral contraceptives have had striatal abnormalities on imaging studies or a past history of37 Sydenham's chorea, chorea gravidarum, or chorea with Henoch–Schönlein purpura. Other medications do not require a preexisting basal ganglia abnormality: for example, dopamine agonists and anticonvulsants (particularly when more than one is taken) may cause dyskinesias or frank chorea. Rarely, children treated with theophylline for an asthma attack have developed transient orobuccal-lingual dyskinesias or generalized chorea; hypoxia, other possible metabolic abnormalities, and the concomitant use of other 38,39 medications make the precipitating factor unclear. Among illicit drugs, cocaine and amphetamines (Chapter 38) have been most frequently associated with dyskinesias. Both influence central dopaminergic mechanisms, and cocaine also decreases serotonin turnover and degradation. Both may lead to choreoathetoid movements of the extremities, less often the head or trunk, or buccolingual dyskinesias within 24 hours of use, which typically resolve without treatment in 2 to 6 days. However, in chronic users, chorea persisting for more than 1 year after discontinuation of these stimulants has 40,41 been described.

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Infectious Disorders Infections may cause the full spectrum of movement disorders (Table 59-2). Movement abnormalities usually develop during the acute illness and are transient, but abnormal movements sometimes begin or persist after the infection has cleared. One mechanism is vasculitic ischemia of the basal ganglia, although direct neuronal injury by the organism or a toxin, and autoimmune cross-reactivity with basal ganglia epitopes are also postulated to play a role. Click here to view this table.... Bacterial Infections Sydenham's chorea is a transient chorea associated with rheumatic fever and preceding infection with group A beta-hemolytic streptococci, usually occurring in childhood between 42 ages 7 and 12, with a range of 3 to 17 years. After 10 years of age, it is more common in girls. The chorea42is usually generalized (80% of cases), and may be the presenting feature of and associates found rheumatic fever. An encephalopathy occurs in 10 percent. Cardoso 42 that rheumatic fever presented with chorea in 9 of their 13 patients. Behavioral abnormalities are common; a recent study found obsessive-compulsive disorder and 43 attention deficit and hyperactivity in about 25 percent of patients. The pathogenesis of Sydenham's chorea may be related to the development of anti–basal ganglia antibodies, 44 which have been found in patients with this disorder. Although the condition is usually self-limited over months, symptomatic treatment with valproic acid or carbamazepine can be considered in those with severe chorea. Dopamine-receptor blocking drugs are reserved for 2,31 Recurrences frequently occur, usually those who do not respond to these anticonvulsants. within 2 years of the initial episode. Secondary prophylaxis with penicillin should be considered to avert further rheumatological injury. Neuroimaging studies may be normal or 45 show contralateral or bilateral striatal abnormalities that resolve as the chorea settles. 46 Positron emission tomography (PET) scanning shows reversible striatal hypermetabolism. Tuberculous meningitis may cause dystonia or chorea. Brain imaging may be normal or may show ischemic or hemorrhagic infarcts as well as hydrocephalus. Direct infection or infarction of the basal ganglia may account for the development of the movement disorder. Treatment 47 is with antituberculous therapy. Most patients improve over several weeks. Mycoplasma pneumoniae causes pneumonia but also affects the central nervous system 48 (CNS) in approximately 5 percent of patients requiring hospitalization. Aseptic meningitis, cranial neuritis, transverse myelitis, or encephalitis may occur, and neurological symptoms may precede pulmonary ones. Generalized choreoathetosis and dystonia have been 48,49 Cerebral imaging may be unremarkable or show abnormalities in the caudate, described. putamen, and globus pallidus. The cerebrospinal fluid (CSF) is normal or exhibits a mild lymphocytosis with elevated protein concentration. The diagnosis is made by respiratory cultures and tests for serum and CSF complement-fixing and cold agglutinin antibodies. In legionnaires' disease (Legionella pneumophila), high fevers and pulmonary involvement may be 50 accompanied in approximately 20 percent of cases by headache and, rarely, by chorea. The CSF and head CT scan are normal, and the diagnosis is made by serological studies. The chorea may persist for up to 2 years. 3

51

Chorea has also been reported in rare patients with Lyme encephalitis or neurosyphilis and in one infant each with52Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis infection. Viral Infections Viral encephalitis may be accompanied by movement disorders, particularly in children. Japanese encephalitis, endemic to much of Asia, causes dystonia53or parkinsonism several weeks after infection. Brain MRI typically shows thalamic lesions. Varicella has been associated with transient chorea and dystonia or, less often, with hemichorea or generalized 54 early feature of herpes simplex encephalitis in infants but more chorea. Chorea can be an 55 frequently signals a relapse. In adults, human immunodeficiency virus (HIV) infection may present with hemichorea-hemiballism or with generalized chorea, usually in the presence of 56 to dementia. Most AIDS-related cases are secondary to toxoplasmosis but may also relate 30 HIV encephalitis, cryptococcal infection, or progressive multifocal leukoencephalopathy. Fungal and Parasitic Infections

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In HIV-seropositive patients, cerebral toxoplasmosis is the most common cause of dyskinesia. Toxoplasma abscesses in various diencephalic structures have been associated 57,58 with contralateral limb ballism, choreoathetosis, and dystonia. Treatment of the infection is usually successful, but improvement in the dyskinesia is seen in only57 approximately 25 percent of instances, suggesting irreversible injury to the basal ganglia. Improvement of the dyskinesia may occur with dopamine-blocking agents or dopamine depleters such as 30 only rarely in tetrabenazine. Hemichorea and hemiballismus have been reported 59 cryptococcal meningitis and may respond to antifungal treatment.

Autoimmune, Inflammatory, and Paraneoplastic Disorders Three possible mechanisms may explain the occasional occurrence of dystonia or chorea in autoimmune and connective tissue diseases. An antibody-generated cerebral vasculitis may cause transient or permanent ischemic injury to the basal ganglia. Alternatively, antibodies with stimulatory, inhibitory, or cytotoxic activities60may recognize basal ganglia epitopes, resulting in dysfunction of the neuronal circuitry. Finally, nonimmune systemic metabolic disturbances in these disorders may also play a role. In systemic lupus erythematosus (SLE), choreoathetosis develops in 1 to 2 percent of 61 the chorea occurs before the patients and may be the presenting feature. In most patients, 62 age of 30 years and tends to manifest during a lupus flare. It may be generalized or lateralized and is usually transient, lasting for a few days up to 3 years; recurrence occurs in approximately 25 percent of cases. Rarely, the chorea is permanent. The chorea may be self-limited or respond to steroid or symptomatic treatment. Imaging studies may be 62 abnormal, but the location of any lesions does not always explain the chorea. Patients with SLE and chorea may possess antiphospholipid antibodies (lupus anticoagulant or anticardiolipin antibody) that predispose to endovascular thrombosis and cerebral 62 infarction. Approximately 30 percent of patients with SLE with these antibodies have thrombotic events. Laboratory studies reveal that whole-blood clotting time is prolonged, and the prothrombin time and the Russell's viper venom time may be abnormal. The antibodies inhibit protein C activation and prostacyclin and antithrombin III activity, and may affect platelet membranes. Chorea in several patients with SLE and antiphospholipid antibodies has improved within days on warfarin or aspirin therapy, consistent with a vascular mechanism. Thus, chorea in SLE may result from autoimmune vasculitic62cerebral microthrombosis or direct antibody-mediated basal ganglia dysfunction, or both. In patients without SLE, the primary antiphospholipid syndrome is a hypercoagulable 61 state in which antiphospholipid antibodies are associated with venous or arterial thromboses. The pathology of the disorder remains unknown although most of the manifestations are believed to be thrombotic in origin. In addition to lupus anticoagulant and an immunoglobulin (IgG) anticardiolipin antibody, many patients have a low titer of antinuclear antibody, 30 percent have a false-positive Venereal Disease Research Laboratory (VDRL) test, and some have antithyroid antibodies. Chorea (either lateralized or generalized) has been the most frequently reported movement disorder62in 1 to 4 percent of patients with primary or secondary antiphospholipid syndrome, although tics, dystonia, myoclonus, and corticobasal syndrome 62,63 Brain MRI shows lesions more often than CT does, but the lesions do not may occur. 64 always explain the chorea, and some patients have normal imaging studies. This variability has led to speculation about a direct effect of the antibodies on the basal ganglia. The most effective treatment for symptomatic patients with antiphospholipid antibodies, with or without a diagnosis of SLE, is anticoagulation with warfarin to an international normalized ratio (INR) of 2 to 3, with or without 75 mg of aspirin daily. Anticoagulation reduces the risk of recurrent venous thrombosis by 80 to 90 percent and may prevent recurrent arterial 65 thrombosis. Chorea is a rare complication of polyarteritis nodosa and isolated angiitis of the CNS. 66 Patients with Behçet's67syndrome may present with chorea, jaw-opening dystonia, or paroxysmal dystonia. Typically, these patients have had an increased68CSF protein concentration and lymphocytosis, and respond to pimozide or steroids. Early reports also exist of chorea occurring in Churg–Strauss syndrome. In Hashimoto's thyroiditis, five major thyroid-related autoantibodies can lead to thyroid dysfunction and cause an encephalopathy 69,70 The CSF protein concentration is usually that may be accompanied by choreoathetosis. elevated, and some samples have oligoclonal bands or a mononuclear pleocytosis. Characteristically, the electroencephalogram (EEG) shows epileptiform activity, and transient or permanent areas of increased T2 signal are seen on brain MRI, particularly in the frontal and temporal lobes. Patients respond to prednisone, 40 to 80 mg daily, with a slow taper once improvement is stable. Complete remissions can be anticipated, although relapses

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sometimes occur or a deficit remains. Spontaneous remissions are rare. Dystonia and tremor 71 may be part of a movement disorder associated with celiac disease. Paraneoplastic chorea has been described in a series of 16 patients; most had limited 72 small-cell carcinoma of the lung, 1 had renal cell carcinoma, and 1 had lymphoma. Serological testing revealed that all had collapsing response-mediator protein (CRMP)–5 antibodies; 6 also had ANNA-1 (anti-Hu) antibodies. In most of these patients, chorea was the initial symptom. Brain imaging showed basal ganglia abnormalities, and autopsy showed perivascular inflammation and microglial activation. Four patients improved with 72 chemotherapy, and two improved with intravenous methylprednisolone. Laryngospasm, jaw-opening dystonia, and cervical dystonia have been described in paraneoplastic syndromes 73 associated with antineuronal antibody type 2 (ANNA-2, also known as anti-Ri antibodies).

Metabolic Disorders The association between thyrotoxicosis and choreoathetosis or dystonic posturing was recognized by Gowers in 1893, particularly in young women, but patients of either sex may be 74 affected. The course of the dyskinesia usually parallels that of the hyperthyroidism. Choreoathetoid movements typically involve the limbs, sometimes unilaterally, and are most conspicuous distally; the neck and face may also be affected. Paroxysmal (rather than more continuous) choreoathetosis may occur in rare instances, and paroxysmal74,75 and kinesigenic No cerebral choreoathetosis has also been reported with exogenous hyperthyroidism. lesions have been noted on MRI or at autopsy. The chorea responds to dopamine receptor blockers or propranolol even before hyperthyroidism has resolved. Altered dopamine turnover or increased dopamine receptor sensitivity may be responsible for the dyskinesia. Since chorea may occur in both hyperthyroidism secondary to Graves' disease and iatrogenic thyrotoxicosis, it is hypothesized that the disorder results from a direct effect of thyroxine on 75 the basal ganglia, perhaps by increasing dopamine receptor sensitivity. Hypocalcemia from idiopathic hypoparathyroidism may rarely cause dystonia or 76 choreoathetosis. The abnormal movements may be the presenting complaint, may be asymmetric, are usually paroxysmal, and rarely are kinesigenic. Patients are usually younger than 30 years, with calcium levels of 4 to 6 mg/dl, elevated serum phosphorus levels (5 to 12 mg/dl), and low serum magnesium. Brain imaging sometimes reveals basal ganglia calcification that persists after treatment of hypocalcemia and resolution of chorea or dystonia. Generalized chorea or hemiballism-hemichorea may occur in nonketotic hyperosmolar 77 hyperglycemia. Brain CT may show high-density lesions, and MRI often shows high T1 signal and hypoperfusion in the caudate or putamen contralateral to the side involved clinically. These imaging findings are considered to be a consequence of hyperviscosity and 78 cytotoxic edema, not petechial hemorrhage. The chorea may resolve with correction of hyperglycemia; however, dopamine-depleting agents or dopamine-blocking agents may be useful treatments until the condition resolves. Severe hypoglycemia may be accompanied by 79 either generalized chorea or hemichorea that resolves as euglycemia is reestablished. Dystonia or chorea80has rarely been noted in hypernatremic dehydration, hyponatremia, and 81,82 An encephalopathy hypomagnesemia and also after central pontine myelinolysis. associated with choreoathetosis has been reported in a patient with a splenorenal shunt83 without cirrhosis; improvement followed treatment with a low-protein diet and lactulose.

Approach to Diagnosis The evaluation of patients with involuntary movements or postures requires a detailed history, including an account of perinatal events, ethnicity, parental consanguinity, psychiatric disorders, past medications, exposure to infectious agents, immunological status, substance abuse, and exposures to toxins. The age of onset and pattern of progression further direct the evaluation. The examination of patients with dyskinesias should exclude non-neurological etiologies for the abnormal postures or movements. The disorder may also be more widespread than the location of the chief complaint. Characterization of the movement disorder and its distribution, together with findings such as organomegaly, skin lesions, retinal or optic nerve disease, or neurological deficits narrows the differential diagnosis. The relaxed patient must be observed carefully while lying, sitting, standing, and walking to determine whether any abnormality is exacerbated by movement or rest. The patient should perform tasks that are particularly impaired because certain movement disorders are solely task specific.

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The age of onset and the pattern of involvement and progression vary with the etiology. Focal or task-specific dystonias, often associated with a dystonic or essential-type tremor, onset in adulthood, a benign history, and no other abnormalities on examination, are usually idiopathic. Limb dystonia beginning as action dystonia is usually idiopathic, whereas dystonia beginning at rest is sometimes symptomatic. Dystonia with onset in the legs is usually idiopathic in children but symptomatic in adults. Chorea or dystonia of acute or subacute onset or having a rapidly progressive course is more likely to be symptomatic. Hemidystonia at any age suggests a secondary etiology, and approximately 75 percent of patients have contralateral basal ganglia abnormalities on imaging, a history of hemiparesis, or both. One third of hemidystonic patients have infarction or hemorrhage of the contralateral basal ganglia, especially the putamen. Generalized dystonia beginning at an early age may be idiopathic or symptomatic, but it is more often symptomatic when onset is in adulthood. Childhood-onset dystonias tend to become generalized, whereas those commencing in adulthood often remain focal or segmental. Similarly, tardive dystonia may be generalized in children, but it usually remains focal or multifocal in adults. Thus, dystonia of sudden onset, rapid progression, onset in infancy, cranial onset in children, lower-extremity onset in adults, or hemidystonia at any age is more likely symptomatic and requires full evaluation. A large number of factors contribute to decision making in the evaluation of chorea and dystonia. Brain MRI has a high yield, and basic laboratory studies include a complete blood count and blood electrolytes, calcium, phosphorus, uric acid, and liver and thyroid function tests. Any patient with chorea or dystonia younger than 40 years must be evaluated for Wilson's disease. Evaluation for vascular disease, a hypercoagulable state, connective tissue disorders, and antiphospholipid antibodies may be required. Serum antistreptolysin O or antihyaluronidase titers and an electrocardiogram are useful when Sydenham's chorea is suspected. Neurodegenerative and hereditary metabolic disorders require a separate battery 2,4 of studies, which are described elsewhere.

Treatment The treatment of secondary dystonia or chorea is difficult. In symptomatic cases, the underlying pathological process should be treated first, as discussed earlier. General therapeutic measures may provide symptomatic benefit when specific treatments of the underlying lesion have failed to temper the movement disorder satisfactorily. Anticholinergics, dopaminergics, antidopaminergics, benzodiazepines, anticonvulsants, and certain other medications (discussed later) are used, based on patient age, tolerance, coexisting medical illnesses, and interactions with other medications taken concomitantly. All of these medications are disappointingly variable in their efficacy. Unfortunately, there is a paucity of adequate trials demonstrating therapeutic benefit or comparative efficacy because patient numbers are small, common side effects make double-blinding difficult, and nonspecific effects such as sedation can diminish abnormal movements. Moreover, spontaneous remissions, partial or complete, and transient or permanent, may occur unpredictably. Anticholinergic medication, of which trihexyphenidyl is the best studied, is more effective in mild dystonia and in younger patients. Approximately one third of patients with secondary 84 dystonia benefit, and up to 50 percent of those with perinatal hypoxic injury improve. The selected agent is started at a low dose, which is increased slowly, depending on response and tolerance. (A particular daily dose may take several weeks to produce maximal benefit.) Side effects can be dose-limiting, particularly with advancing age. Tricyclic antidepressants and diphenhydramine are also sometimes used for their anticholinergic effects. The useful antidopaminergic medications include dopamine depleters (reserpine, tetrabenazine) or dopamine receptor antagonists (phenothiazines, haloperidol, pimozide). Tetrabenazine (not yet approved by the U.S. Food and Drug Administration) has been the most useful single agent, particularly in tardive dyskinesia, tardive dystonia, Huntington's chorea, and idiopathic generalized dystonia; patients with focal or hemidystonia or 85,86 The dose-related side effects of antidopaminergics blepharospasm do not respond. include parkinsonism, sedation, depression, and drooling, and sometimes other movement disorders, depending on the agent used; they occasionally necessitate a reduction in dosage. Dopaminergic supplementation using levodopa is singularly effective in patients with dopamine-responsive dystonia, which may be present in 5 to 10 percent of patients with childhood-onset hereditary dystonia beginning in the legs, with or without diurnal fluctuations. It is less useful in treating symptomatic dystonias. Nevertheless, amantadine or dopamine agonists are worthy of a trial in symptomatic dystonia. Anticonvulsants have been tried, usually with disappointing results. Carbamazepine is used most frequently, but in a study of 67 patients with dystonia, only 11 percent obtained

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84

moderate or greater benefit from the drug. Baclofen, a presynaptic γ-aminobutyric acid agonist, is also frequently tried and occasionally is effective. Intrathecal baclofen, delivered by an implanted pump, has been beneficial especially in those with spasticity and painful 87 spasms. Other medications that have been tried alone or in combination, with the same variability in benefit, include benzodiazepines, particularly clonazepam (27% with secondary 84 dystonia may benefit ), muscle relaxants, cyproheptadine, and lithium. Adult-onset cranial dystonias 88 are best treated with intramuscular botulinum toxin, which also benefits focal limb dystonias. Finally, surgical approaches may sometimes be warranted. Deep brain stimulation of the globus pallidus has been introduced for medically refractory dystonia, and a prospective study 89 for has found benefit in primary torsion dystonia. Deep brain stimulation has also been used 34,90 cervical dystonia and tardive dystonia, but experience with these conditions88,91 is limited. Selective peripheral denervation has been successful for cervical dystonia. The use of 92 deep brain stimulation for chorea is being explored. MYOCLONUS Myoclonus is an acute, brief, involuntary jerk caused by a sudden muscle contraction (positive myoclonus) or relaxation (negative myoclonus). It can be classified by distribution, the location of the generator, or the underlying etiology. It may recur in the same muscle groups (focal or segmental myoclonus) or asynchronously and asymmetrically in different muscle groups (multifocal or generalized myoclonus), and it may occur at rest (spontaneous), on movement (action or intentional myoclonus), or in response to specific stimuli (reflex myoclonus). Myoclonus occurs in healthy individuals (hiccups, hypnic jerks) or as a movement disorder with an idiopathic (essential), epileptic, or symptomatic etiology. Symptomatic myoclonus is the most common variety and may be due to primary neurological causes, but93it is more commonly seen in a general medical setting, to which this section is devoted. Myoclonus may be generated from spinal, subcortical, or cortical circuits and involves the somatotopically organized dorsal column/lemniscal and corticospinal systems superimposed 93 on the spinoreticular and reticulospinal circuits.

Hypoxia-Ischemia In 1963, Lance and Adams described posthypoxic action myoclonus in survivors of 94 cardiopulmonary arrest. Two forms of myoclonus are recognized in this context: acute posthypoxic myoclonus, which develops soon after hypoxia and is characterized by generalized myoclonus, and chronic posthypoxic myoclonus, which begins after a delay and 95 is characterized by action myoclonus. Multifocal myoclonus begins as the patient regains consciousness and is aggravated by voluntary motor activity. Cerebellar ataxia and cognitive impairment are often associated. Typically these signs improve with time, although some positive myoclonus and gait difficulty due to negative myoclonus may persist, resulting in falls. Acute posthypoxic myoclonus is characterized by severe, generalized myoclonus in 95 comatose patients. The jerk-like movements develop within the first day after hypoxia and are characterized by violent flexion movements. If myoclonus persists for more than 30 minutes or for most of the resuscitation day, it is often called myoclonus status epilepticus, despite the lack of evidence that the myoclonus is epileptic in nature. Wijdicks and associates found that in over 95 percent of patients with myoclonus, an EEG performed on the first hospital day demonstrated a burst-suppression pattern, alpha-pattern coma, or 96 polyspike-wave activity. Myoclonus status epilepticus occurs in 30 to 40 percent of comatose adult survivors of cardiopulmonary resuscitation, is difficult to control, and has a poor prognosis. A meta-analysis of 134 patients with myoclonus status epilepticus found that 89 percent died, 8 percent remained in persistent vegetative state, and 3 percent survived (2 97 patients are described as having had a good outcome). Chronic posthypoxic myoclonus, also known as the Lance–Adams syndrome, occurs within days to weeks after hypoxic injury, usually while the patient is still in coma. The myoclonus predominantly involves the limbs and is precipitated by active or passive movement; it 9 occasionally spreads to other portions of the body. It may95be stimulus sensitive, and negative myoclonus may also occur, predisposing patients to falls. The physiology of posthypoxic myoclonus is unclear. Analysis of CSF from affected patients has shown low levels of 5-hydroxyindole amino acid, a serotonin metabolite. Animal models also provide support for a role of the serotonergic system, showing reduced striatal serotonin 98 and cortical 5-hydroxyindole amino acid. Treatment with the serotonin precursor

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5-hydroxytryptophan has been effective in some patients and animal models. PET imaging with fluorodeoxyglucose in patients with posthypoxic myoclonus has99shown increased metabolism in several regions, including the ventrolateral thalamus. Treatment of chronic posthypoxic myoclonus is not satisfactory. However, clonazepam, valproate, and piracetam are often helpful. Treatment with 5-hydroxytryptophan (often with 9,100 Other carbidopa to limit nausea), levetiracetam, and sodium oxybate may also be helpful. 95 agents such as baclofen, diazepam, ethanol, and methysergide are sometimes helpful.

Metabolic Disorders Metabolic disorders are commonly associated with mental status changes and negative myoclonus (asterixis), which is usually of brainstem reticular origin. Renal failure and its treatment may both be associated with neurological dysfunction. Generalized and multifocal positive and negative myoclonus occur in uremic encephalopathy (Chapter 18). It may occur at rest, on movement, or in response to a stimulus. Myoclonus also occurs in patients with dialysis dementia (Chapter 18). The myoclonus is exacerbated during and after dialysis and is most prominent in the face and upper limbs. In hepatic insufficiency, asterixis or negative myoclonus is typical, but multifocal positive myoclonus also occurs. Any cause of hepatic insufficiency may result in myoclonus. Treatment requires addressing the underlying disorder. In rare instances, Wilson's disease 24 may present with progressive myoclonus. Hyperglycemia is the most common metabolic disturbance causing focal motor phenomena. In nonketotic hyperglycemia, severe hyperglycemia, hyperosmolality, and dehydration are accompanied by segmental or generalized myoclonic seizures in up to 20 percent of 101 102 patients. Asterixis or negative myoclonus is also seen. The EEG shows diffuse slowing, sometimes with a spike-wave pattern. The glucose level is typically over 600 mg/dl and osmolality above 300 mOsm/kg H2O, with mild or absent ketoacidosis. The myoclonus resolves with treatment of the hyperosmolality, and not with anticonvulsants, but therapy should be gradual, repleting approximately half the fluid deficit in the first 12 hours and the remainder over the next 24 hours because faster rates may precipitate CNS hyperglycemia and cerebral edema. 103

Vitamin B12 deficiency and its replacement may cause myoclonus in children and 104,105 adults. The myoclonus resolves after treatment with vitamin B12. In the infantile presentation, typically, the mother is vegetarian and the infant has received only breast milk. Initially, development is normal but, between 5 and 10 months of age, irritability and apathy are noted, with regression of milestones, followed by pallor, hypotonia, hyperreflexia, and a combination of tremor and myoclonus, which are most pronounced in the tongue and face but also involve the limbs and trunk. The myoclonus described in adult patients is generalized 104 or spinal and responds to vitamin B12 repletion. Alcohol-related pellagra (niacin deficiency) is characterized by the triad of myoclonus, altered 106 mental status, and generalized hypertonicity; a dermatitis is sometimes present. In 107 one case, only myoclonus and ataxia occurred, so a high index of suspicion is necessary. Typically, the myoclonus involves predominantly the face and limbs and is aggravated by startle, but not by movement or posture. Early replacement of niacin is required. Hypernatremic dehydration has also been associated with transient myoclonus and chorea in 80 chronic alcoholism.

Autoimmune and Inflammatory Disorders 108

Myoclonus occurs in autoimmune thyroiditis causing Hashimoto's encephalopathy. Any combination of cognitive impairment, encephalopathy, psychosis, transient neurological deficits, myoclonus or tremor, seizures, somnolence, or coma develops and fluctuates over weeks to months. The myoclonus may be generalized or multifocal and spontaneous or 109 reflex-evoked, and is without EEG correlates. Patients are clinically euthyroid, with elevated antithyroid antibodies, the levels of which correlate poorly with the clinical state. Further clinical and laboratory details are provided in Chapter 20. 63

Myoclonus has been described in the antiphospholipid syndrome.

Nonvasculitic autoimmune inflammatory meningoencephalitis may present with the rapid onset of dementia, parkinsonism, and myoclonus. In a single case, the EEG pattern consisted of persistent periodic sharp waves suggestive of Creutzfeldt–Jakob disease; 110 dramatic clinical improvement occurred with corticosteroids.

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A myoclonic syndrome often accompanied by ataxia may occur in celiac disease, despite 111 normal vitamin B12 and E levels. Typically, patients have a gastrointestinal syndrome that may include chronic diarrhea and abdominal pain, although gastrointestinal complaints may 112 be subtle (only nausea and vomiting episodes during infection in one report). Action or reflex myoclonus may occur in patients with established celiac disease, but whether this relates to inadequate dietary restriction or poor compliance is uncertain. The myoclonus may initially be focal but usually becomes multifocal; generalized convulsions may develop. The jerks are usually preceded by a time-locked polyspike EEG discharge, supporting a cortical origin. In some cases improvement occurs after a gluten-free diet is instituted. Anticonvulsant or benzodiazepine therapy is commonly required but is incompletely effective. Opsoclonus-myoclonus has also been described in a child with celiac disease and responded 113 to a gluten-free diet. Multifocal myoclonus has been reported in patients approximately 50 days after bone marrow 114 transplantation. The myoclonus may be spontaneous or triggered and is associated with parkinsonism and encephalopathy. Corticosteroid therapy is usually curative.

Drug- and Toxin-Induced Myoclonus Neuroleptic malignant syndrome may complicate neuroleptic treatment but also occurs with dopamine-depleting agents and on withdrawal of dopaminergic treatments. It is primarily due to functional dopamine deficiency, which leads to disinhibition of cortical and subcortical 115 excitatory pathways; norepinephrine and serotonin may also be involved. Its incidence is between 0.2 and 1.4 percent of patients exposed to neuroleptic agents. Most cases occur within a month of starting the neuroleptic agent. Fever, rigidity, and serum creatine kinase (CK) elevation (the major criteria) and tachycardia, labile blood pressure, tachypnea, diaphoresis (autonomic instability), altered mental status, and leukocytosis (the minor criteria) develop over 24 to 72 hours. Altered mental status and rigidity are often the first signs and are each present in over 95 percent of instances. The presence of all three major or two major and four minor criteria is highly predictive of the syndrome. The movement disorder is primarily an axial rigidity with tremor, choreoathetosis, dystonia, or myoclonus in the limbs. Rhabdomyolysis, renal insufficiency, respiratory failure, adult respiratory distress syndrome, disseminated intravascular coagulation, myocardial infarction, pulmonary embolism, and coma may complicate the picture. Treatment involves discontinuing the offending drug (or reinstituting dopaminergic medication) and supportive therapy; it may require administering the muscular excitation–contraction uncoupler dantrolene sodium at 2 to 8 mg/kg four times daily (maximum 10 mg/kg per dose) and the dopamine agonist bromocriptine at 5 mg four times daily (up to 50 mg/day) or subcutaneous apomorphine. Levodopa/carbidopa and amantadine 115 may also be used. With earlier recognition, the mortality rate had decreased from 75 to 11 percent by the late 1980s; rhabdomyolysis and renal failure continue to be the greatest predictors of poor outcome. Survivors almost always achieve complete recovery. The serotonin syndrome is a potential complication of treatment with antidepressants and related medications that increase cerebral serotonin neurotransmission. It is characterized by 116 mental status changes, autonomic hyperactivity and neuromuscular abnormalities. The prerequisite is a recent increase in the dosage of a serotonergic agent or the addition of a new one. Cognitive and behavioral changes include confusion, hypomania, and agitation, and myoclonus, ataxia, hyperreflexia, or tremor may also be present. Autonomic disturbances include nausea, vomiting, diarrhea, labile blood pressure, fever, shivering, and diaphoresis. The symptoms may begin as early as 2 hours after the medication is taken and usually resolve within 24 hours on discontinuation of the offending agent. When severe, serotonin syndrome may be indistinguishable from neuroleptic malignant syndrome and has a similar risk of multiple organ failure and death. Treatment requires discontinuation of precipitating drugs, supportive care, treatment for hyperthermia using benzodiazepines or neuromuscular paralysis, and administration of a 5-HT2A antagonist such as cyproheptadine (4 to 8 mg, followed by 4 mg116 six times daily to a total of 0.5 mg/kg daily) or chlorpromazine (50 to 100 mg intramuscularly). Of the non-neuroleptic psychiatric medications capable of causing myoclonus, lithium toxicity is well described. A variety of presentations occur including action, spontaneous, or stimulus-sensitive myoclonus, sometimes with opsoclonus.117 The myoclonus is of cortical origin but is not associated with epileptiform abnormalities. Vomiting and a decreased level of consciousness may also be present; in rare instances the presence of cognitive changes and characteristic EEG findings suggests the erroneous diagnosis of Creutzfeldt–Jakob disease. Full recovery is usual. Overdose with tricyclic antidepressants may result in

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myoclonus because of their ability to inhibit reuptake of serotonin and norepinephrine. 119 Myoclonus may occur with levodopa treatment. Patients usually also have dyskinesias, and the myoclonus occurs in the “on” phase, at rest, during drowsiness, and commonly during sleep. Usually there is a single, bilateral jerk of the legs or arms, although unilateral myoclonus, short repetitive jerks, and multifocal myoclonus have also been reported. Reducing the levodopa dosage may diminish the myoclonus. Tardive myoclonus due to neuroleptic medications is the least common of the tardive syndromes. It usually affects the face, neck, or upper limbs and responds to withdrawal of the neuroleptic treatment, but the movements may take several months to resolve. 33 Benzodiazepines are sometimes useful. A number of other medications and120 toxins have occasionally been associated with myoclonus and are summarized in Table 59-3. Click here to view this table.... In the eosinophilia-myalgia syndrome (a condition that was associated to contaminated l-tryptophan supplement), in addition to myoclonus, characteristic findings include a low-grade fever, myalgia, arthralgia, pulmonary symptoms,121 stiffness, skin rash, edema and induration of the limbs, peripheral neuropathy, and tremor. The eosinophil count is prominently elevated, the serum CK remains normal, and rarely there is a mild elevation in the CSF protein concentration. The myoclonus is multifocal and spontaneous or action induced, without EEG accompaniments. Unfortunately, symptoms and signs may not resolve with discontinuation of the supplement. Among illicit drugs, cocaine most commonly causes movement disorders. Myoclonus can be seen in the122setting of a cocaine-induced disorder resembling neuroleptic malignant or as multifocal rest and action myoclonus together with opsoclonus and syndrome 123 ataxia. Lead intoxication occasionally develops in one-time or chronic gasoline-sniffers, with encephalopathic symptoms developing at a serum lead level of 80 μg/dl and including myoclonus, which may be segmental or generalized and occurs spontaneously, with 124 movement, or in response to an external stimulus. The condition may respond to chelation treatment with dimercaprol and calcium disodium edetate, although repeated exposures may result in a permanent encephalopathy. Bismuth encephalopathy was initially recognized in the 1970s with the use of bismuth salts for treatment of a variety of gastrointestinal symptoms including gastric ulcers. High serum levels of bismuth result in confusion followed by severe myoclonus, truncal ataxia, dysarthria, tremor, and sometimes generalized convulsions and 125,126 The syndrome can evolve slowly over months or acutely over days and has coma. sometimes been confused with Creutzfeldt–Jakob disease or rapid-onset Alzheimer's disease. The myoclonus may be multifocal or a massive generalized movement, and may occur spontaneously, on action, and in response to stimuli. Recovery over 3 to 12 weeks is the rule when the bismuth intake is discontinued early; chelation with dimercaprol may 125 enhance renal clearance but has been associated with clinical deterioration in one patient. Diazepam, clonazepam, or valproic acid may reduce myoclonus.

Paraneoplastic Disorders Multifocal myoclonus with opsoclonus is most commonly seen as a paraneoplastic syndrome in approximately 2 to 3 percent of children with neuroblastoma. It may respond to corticosteroids, adrenocorticotropic hormone, or corticosteroids together with intravenous immunoglobulin (IVIg). In adults, it is usually associated with small-cell lung cancer or breast cancer and rarely with other tumors. The CSF protein may be mildly elevated, with a lymphocytic pleocytosis, oligoclonal bands, and elevated immunoglobulin index. Specific antibodies associated with paraneoplastic myoclonus include the anti-Hu (also called antineuronal nuclear autoantibodies or ANNA-1) and anti-Ri (ANNA-2) antibodies. PET with CT may be useful if initial radiological screening is negative and early detection and treatment 127 of the tumor appears to be useful. Occasionally the myoclonus improves with treatment of the underlying malignancy or prednisone, rarely with plasmapheresis, intravenous immunoglobulin, cyclophosphamide, or immunoadsorption therapy with a protein A column. 127 Myoclonus may respond to antiepileptic drugs. Action and 128 postural myoclonus has also been reported 129 in the setting of carcinomatous meningitis, in a child with a cerebellar ganglioglioma, and with other rare tumors. Axial myoclonus, fasciculations, and dementia have occurred with angiotropic lymphoma 130 (malignant angioendotheliomatosis).

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Infections Viral encephalopathies are the most common infectious cause of myoclonus (Table 59-2). In subacute sclerosing panencephalitis, myoclonus is time-locked to generalized bursts of high-voltage sharp waves (periodic complexes) occurring approximately every 5 to 15 seconds on EEG. The movements may be sufficiently severe to precipitate drop attacks and may persist during sleep. The myoclonus is relatively resistant to treatment, but sodium valproate, phenobarbital, carbamazepine, and clonazepam may be tried. Herpes simplex virus encephalitis and postviral acute demyelinating encephalomyelopathy may also cause myoclonus. Segmental spinal myoclonus has occurred as a late complication of herpes 131 myelitis. Progressive rubella panencephalitis may present with dementia, spasticity, and visual and cerebellar pathway involvement, together with asymmetric myoclonus; the course 132 usually is progressive. Myoclonus occurs rarely with HIV infection. In a study of 2,460 inpatients with HIV infection, 133 only 4 had myoclonus (2 with spinal myoclonus and 2 with generalized myoclonus. The myoclonus tends to be most prominent in the face, trunk, and proximal limbs and may be spontaneous or stimulated. Rarely, the myoclonus occurs with seroconversion, but usually the affected patients are significantly ill, often taking multiple medications and contending with and being susceptible to other medical problems, which must be evaluated as potential causes of the movement disorder before it can be attributed solely to HIV encephalopathy. Treatment depends on the underlying cause; in some cases, myoclonus has134,135 resolved with antimicrobial treatment for opportunistic infections or with retroviral therapy. Benign myoclonus occurs rarely with mumps. Multifocal myoclonus of the face, neck, and trunk develops within days of the infection and is associated with opsoclonus, tremor, and 136 cerebellar ataxia. The CSF may show a pleocytosis, the EEG may reflect only opsoclonus-related eye movements, and the syndrome is self-limiting in approximately 2 weeks. Viral infections associated with spinal myoclonus include human T-lymphotropic virus III 137 and myelopathy causing self-limited abdominal myoclonus and transient segmental 134 brachial myoclonus preceding or occurring during a herpes zoster outbreak. Multifocal myoclonus has been reported after an uncomplicated episode of chickenpox and 138 influenza-like illness, with spontaneous resolution over several months. Other viruses and viral infections causing encephalitis and myoclonus, sometimes with opsoclonus, include parainfluenza virus type 3, coxsackievirus B3, poliovirus, St. Louis encephalitis, JC virus causing progressive multifocal leukoencephalitis, and encephalitis lethargica. 139 Opsoclonus-myoclonus may also be the presenting symptom of West Nile virus infection. Bacterial infections associated with myoclonus are less common than viral infections.140,141 Spinal myoclonus and opsoclonus-myoclonus have been reported in Lyme neuroborreliosis 142 and in typhoid (enteric fever) due to Salmonella typhi. Opsoclonus-myoclonus has also been described as a sequela of group A β-hemolytic streptococcal infection. Initially, there is a febrile illness with pharyngitis, which is followed by the development of opsoclonus, myoclonus, and ataxia as well as behavioral changes. Laboratory investigation shows an elevated antistreptolysin titer (as well126 as antineuroleukin antibodies). The clinical syndrome responds to corticosteroid treatment. Myoclonus is seen in approximately 20 to 25 percent of patients with Whipple's disease due to the gram-positive bacillus Tropheryma whippelii, 143 although oculofacial myorrhythmia is the most characteristic movement disorder described. Further discussion of this disease is provided in Chapter 15. Multifocal myoclonus has been described as part of the postmalaria neurological syndrome, which also includes encephalopathy, tremor, and ataxia, beginning days to weeks after 144 and oculopalatal treatment of malaria, and responds rapidly to steroids. Multifocal 145 146 tuberculosis meningitis. myoclonus have also been reported in neurocysticercosis and 147 Cryptococcal encephalitis has caused generalized myoclonus.

Injury by Physical Agents 148

Spinal myoclonus may develop as a late complication of spine irradiation for cancer. The high-pressure neurological syndrome, which occurs on diving beyond a depth of 100 meters, 149 consists of cognitive impairment and hyperkinesis. Myoclonus is seen at a depth of 300 to 500 meters or 50 to 60 atmospheres. Segmental myoclonus has been reported in the setting 131 of electrical injury.

Approach to Diagnosis

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The clinical approach to evaluation of myoclonus requires a detailed history including the mode of onset, history of drug or toxin exposure, and full neurological and general medical examination. If the myoclonus is considered pathological and no offending drug or toxin is appreciated, screening blood studies may include a complete blood count and erythrocyte sedimentation rate; determination of electrolyte and glucose levels; thyroid, renal and hepatic function tests; and drug and toxin testing. An EEG to exclude an epileptic basis, and brain and spine MRI to exclude structural causes, are important. Paraneoplastic antibody testing may also be helpful.

Treatment When possible, myoclonus should be treated by addressing the underlying medical disorder. Thereafter, the location of the generator of the myoclonus can guide treatment. Cortical myoclonus responds best to anticonvulsants, particularly sodium valproate (0.6 to 3 g daily), primidone (50 to 1,000 mg daily), clonazepam (0.5 to 12 mg daily), levetiracetam (1,000 to 150 3,000 mg daily), and piracetam (2 to 20 g daily). Reticular reflex myoclonus and spinal myoclonus may respond to clonazepam, but there is no specific treatment for negative myoclonus. Other medications that have been anecdotally useful include anticholinergic agents, baclofen, tetrabenazine, acetazolamide, and opiates; γ-aminobutyric acid receptor agonists may also be effective. Combinations of two or three medications may be more 150 effective than monotherapy. TREMOR Tremor is the most common of all involuntary movements and is defined as an involuntary, rhythmic oscillation of a body part. It can be physiological (normal) or pathological, and is characterized by its frequency, amplitude, and distribution, and the position in which it occurs. Tremor is most easily classified as rest or action tremor. Some forms of tremor are generated primarily by a central oscillator, as in151 essential tremor, and others, such as physiological tremor, are mainly mechanical in origin. Central tremor is generated in the cerebellothalamocortical and dentatorubro-olivary pathways, with a poorly understood contribution from basal ganglia circuits. Rest tremor is characteristic of parkinsonism, which itself may occur secondary to a variety of causes. Such rest tremor is often accompanied by rigidity, bradykinesia, or postural instability, but may occur in isolation. Mechanical tremors decrease in amplitude and151 frequency with a load, whereas centrally generated tremors decrease only in amplitude.

Stroke Tremor may occur as a consequence of stroke. The most common lesions involve the thalamus, mesencephalon, rubro-olivary tract, and cerebellar tracts. Limb tremor may occur 47 with lesions of the cerebral cortex.

Medications Medications can cause the full spectrum of tremor subtypes (rest, postural, or kinetic), 152 although postural tremor is most common (Table 59-4). Intention tremor refers to the subtype of kinetic tremor that becomes more prominent as the limb approaches the target. Commonly used medications such as adrenergic agonists, including all β-agonists, lithium, caffeine, corticosteroids, tricyclic antidepressants, cyclosporine, and thyroid excess, usually cause postural tremor. Dopaminergic and anticonvulsant medications also cause an enhanced physiological tremor. Lithium- or valproic acid–induced tremor is present at rest and enhanced with posture or action. The antiarrhythmic amiodarone may cause a postural and terminal movement tremor in 20 to 30 percent of patients. Central cholinergic agonists such as nicotine, anticholinesterases, and aminopropanols are also tremorgenic. Click here to view this table.... Central monoaminergic stimulation by neuroleptics, phenylethylamines, and indoles may result in a parkinsonian rest tremor and a postural tremor. Specifically, tremor is seen in neuroleptic malignant syndrome and serotonin syndrome (see pp. 1105–1106). Dopamine receptor–blocking drugs and dopamine-depleting agents such as tetrabenazine and reserpine may also trigger a rest tremor.

Toxins and Recreational Agents

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A variety of toxins cause tremor directly or as part of a withdrawal syndrome (Table 59-4). Tremor may occur with acute cocaine intoxication, and persists in abstinent cocaine-, alcohol-, and opiate-dependent subjects for months after 153 the last use; rest tremor is reportedly more common in those with prior cocaine use. Alcohol and other drug withdrawal states enhance, sometimes asymmetrically, postural physiological tremor, which decreases with time but can be treated with propranolol or benzodiazepines. The intention tremor of chronic alcohol abuse, however, is the result of cerebellar injury by alcohol. With cannabis use, withdrawal symptoms may occur after as little as 7 days of use and include 154 tremor, irritability, restlessness, anorexia, fever, and other sympathetic effects. Intoxication with heavy metals and organic compounds may produce a rest or action tremor, and improvement after withdrawal of the toxin depends on the severity and duration of exposure.

Metabolic Disorders Almost any metabolic derangement may be associated with tremor. Thyrotoxicosis is the most common, producing an enhanced physiological tremor. It affects any age group and responds to treatment of the underlying disorder, but it can also be ameliorated by propranolol. Tremor is one of the first and most prevalent signs of hypoglycemia and may be seen in nonketotic hyperglycemia along with myoclonus, chorea, and dystonia. In renal insufficiency, a postural and action tremor is often evident before asterixis develops, and may foreshadow encephalopathy. The tremor in Wilson's disease may be postural, kinetic, or at 24 rest. A coarser movement of the upper limb (“wing beating” tremor) also occurs. It is present in the proximal arms and occasionally the head in the flexion-extension plane, and is due to thalamocapsular and cerebellar system pathological processes. Chelation therapy and liver transplantation can reverse the neuropathological process, but there is no effective symptomatic treatment. Hemochromatosis is associated with tremor, parkinsonism, and dementia due to iron deposits in the155 basal ganglia; progression may be forestalled by phlebotomy or liver transplantation. Variegate porphyria and the hyperadrenergic state associated with pheochromocytoma may also cause tremor, as can striatal injury in the 156 setting of hypoxic-ischemic encephalopathy. Hypomagnesemia and hypocalcemia may lead to tremor, muscle twitching, and irritability, and a severe, movement-associated, distal157 flapping tremor has been reported in hypercalcemia due158to hyperparathyroidism. Tremor has been reported with hyponatremia and its correction. Severe vitamin E deficiency (levels 200 mmol/L) establishes the diagnosis. Phytanic acid deposition in Schwann cells and the endoneurial space leads to a distal, symmetric sensorimotor neuropathy. Reduction of phytanic acid concentrations by dietary restriction, plasmapheresis, or lipid apheresis improves ichthyosis, sensory170neuropathy, and ataxia but may not affect the retinitis pigmentosa, anosmia, and deafness. Tangier Disease

Tangier disease is a rare autosomal-recessive disorder caused by mutations in both alleles of the adenosine triphosphate–binding cassette A1 gene (ABCA1). The protein deficiency causes decreased lipid removal from cells, widespread tissue accumulation of cholesteryl 171 esters, and the absence of plasma high-density lipoproteins (HDLs). Absent high-density lipoproteins with normal triglyceride level and the presence of enlarged orange tonsils differentiates Tangier disease from other lipoprotein disorders. Patients may develop corneal opacities or hypersplenism. Despite the high-density lipoprotein deficiency, atherosclerosis does not develop earlier than normal. Polyneuropathy may take one of three forms: asymmetric, relapsing-remitting sensorimotor mononeuropathies, usually associated with normal conduction velocities; symmetric, slowly progressive distal polyneuropathy; and a slowly progressive neuropathy affecting the face and upper limbs with distal hand weakness and facial diplegia and accompanied by dissociative sensory loss that may mimic the presentation of a syrinx. There is currently no specific treatment for Tangier disease. NEUROMUSCULAR JUNCTION DISORDERS In disorders of the neuromuscular junction (Table 60-10), patients present with weakness but not numbness. The congenital myasthenic syndromes are discussed elsewhere. Click here to view this table....

Botulism Botulism is an acute paralytic illness caused by a toxin produced by Clostridium bacteria. Botulism results from (1) ingestion of the preformed toxin with absorption through the intestines, accounting for the vast majority of cases of adult food-borne botulism; (2)

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Aminoff: Neurology and General Medicine: Neuromuscular Complicat...


ingestion of clostridial spores that colonize the intestines and produce the toxin, accounting for virtually all forms of infant botulism and occurring rarely in adults with altered intestinal flora; or (3)172–176 infection of a wound with local production and absorption of the toxin (“wound Improperly preserved food is the most common cause of food-borne botulism”). botulism. In California,wound botulism has become a recognized complication of intravenous 177 among patients treated with “black tar” heroin use. Botulism may occur in rare instances 178 botulinum toxin for dystonia or other movement disorders. Adult food-borne botulism is characterized by rapidly progressive cranial nerve palsies, 173,176 The most common symptoms and descending weakness, and autonomic dysfunction. signs include dysphagia, hypoactive gag reflex, dry mouth, diplopia, ptosis, extraocular movement abnormalities, fixed or dilated pupils, bulbar or limb weakness (especially proximally), constipation, nausea, and vomiting. Stretch reflexes are usually hypoactive or absent but may be normal. Mental status, sensation, and CSF are usually normal. There is usually no response to edrophonium chloride (Tensilon). Atypical symptoms, signs, and 173 ancillary test results are not uncommon and do not exclude the diagnosis. The symptoms and signs in infant botulism are similar to those in adults, with the additional features of 174 hypotonia, poor suck, and failure to thrive. Symptoms usually begin 18 to 36 hours after ingestion of the spores and progress rapidly over 2 to 4 days; recovery begins within a few 172 weeks. Eight toxin types have been described (A, B, C1, C2, D, E, F, and G), but human botulism is associated only with types A, B, and E and, rarely, with F and G. Clostridium botulinum produces the type A, B, and E toxins. Clostridium butyricum can also produce the type E toxin, and Clostridium barati produces the type F toxin. In all forms of botulism, the toxin initially becomes disseminated via the systemic circulation before uptake by the terminals of peripheral cholinergic axons. Once the toxin is inside the nerve terminals, essential proteins for acetylcholine release are cleaved. Subsequently, both muscarinic and nicotinic nerve terminals degenerate. Recovery from botulism, therefore, requires regrowth of axon terminals and restoration of the neuromuscular junction. The diagnosis of botulism is usually confirmed by the detection of the toxin in the serum, stool, or wound. In addition, the wound and stool specimens are cultured to identify the offending organism. Electrodiagnostic studies are also helpful. The presence of post-tetanic facilitation of the compound muscle action potential amplitude and increasing amplitude with 20- to 50-Hz repetitive nerve stimulation is often seen, although the increase is less dramatic than in Lambert–Eaton myasthenic syndrome (LEMS). Needle EMG reveals small, short-duration, polyphasic motor unit potentials in weak muscles and may show fibrillation potentials if the test is performed several days after symptom onset. Treatment of botulism consists of early antitoxin administration and supportive care. For adults, an equine trivalent antitoxin is effective against the type A, B, and E toxins. Recently, an effective human antitoxin (BabyBIG) has become available specifically for infants that has 179 a much lower risk of anaphylaxis than the equine product. In the United States, state health departments release the equine antitoxin to providers. In order to obtain BabyBIG, the physician must contact the Infant Botulism Treatment and Prevention Program by telephone or electronically. Wound débridement and antibiotics are indicated for wound botulism but should probably be delayed until the antitoxin is given. Prognosis is usually excellent with proper supportive and respiratory care. Recovery may take several weeks to months, depending on the degree of nerve end-terminal destruction.

Lambert–Eaton Myasthenic Syndrome LEMS is an autoimmune disorder in which antibodies directed against presynaptic voltage-gated calcium channels cause proximal limb and trunk weakness. Significant ptosis and bulbar weakness are uncommon. A striking clinical feature of LEMS is that strength often improves following brief exertion. Autonomic symptoms such as a dry mouth, constipation, and urinary retention are frequent. Tendon reflexes are usually hypoactive or absent but may improve after brief exercise. Approximately 50 to 60 percent of patients with LEMS have an associated small-cell lung 180 carcinoma. Approximately 3 percent of patients with small-cell lung cancer develop LEMS. Nonparaneoplastic LEMS also occurs, particularly in younger individuals. Marked post-tetanic facilitation of the compound muscle action potential establishes the diagnosis. Detecting the presence of calcium-channel antibodies also confirms the diagnosis. Survival in paraneoplastic LEMS depends on the treatment of the underlying neoplasm.

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Anticholinesterase drugs alone may modestly benefit strength. More effective is the orphan drug 3,4-diaminopyridine, which blocks potassium channels and thereby prolongs the activation of voltage-gated calcium channels. The increased concentrations of calcium in the axon terminals facilitate acetylcholine release presynaptically. The benefit of this drug was 181 demonstrated in a double-blind, placebo-controlled, crossover study. Because it is not an FDA-approved medication, it is available only at select centers in the United States. Other treatments that may be effective include plasmapheresis, IVIg, prednisone, and azathioprine.

Myasthenia Gravis Myasthenia gravis is an autoimmune disorder in which antibodies directed against nicotinic acetylcholine receptors cause fluctuating muscle weakness due to defective neuromuscular transmission. There are two clinical forms of myasthenia gravis: ocular and generalized. In the ocular form, weakness is restricted to the eyelids and extraocular muscles. Individuals with generalized myasthenia frequently also have weakness of those muscles plus variable weakness of bulbar, respiratory, or limb muscles. About 50 percent of patients present with ptosis or diplopia. Of these, about half will progress to generalized myasthenia gravis. A number of autoimmune diseases may be associated, including autoimmune thyroid disease and, more rarely, rheumatoid arthritis and systemic lupus erythematosus (SLE). Approximately 75 percent of myasthenics have thymic abnormalities. Thymic hyperplasia is the most common abnormality; about 15 percent of patients have a thymoma, usually a noninvasive cortical182thymoma. Approximately one third of patients with a thymoma develop myasthenia gravis. Because of the risks of thymoma, MRI or CT of the mediastinum is necessary for all newly diagnosed myasthenic patients. Thymectomy is generally recommended for all patients with thymomatous myasthenia gravis. In rare instances, myasthenia gravis has been associated with small-cell lung cancer and Hodgkin's disease. Rarely, a medication such as d-penicillamine can induce the onset of autoimmune myasthenia gravis, possibly through antigenic mimicry. The diagnosis is made by the history, examination, presence of acetylcholine receptor antibodies (present in up to 90% of cases of generalized disease), edrophonium chloride test, and electrophysiological studies. Approximately 35 to 50 percent of patients testing negative for acetylcholine183receptor antibodies have antibodies to the muscle-specific receptor tyrosine kinase (MuSK). It is rare for patients to have antibodies both to the acetylcholine receptor and to MuSK. Most patients with MuSK antibodies are women, and many have prominent 184,185 Standard electrodiagnostic tests for bulbar, neck, and respiratory weakness. myasthenia gravis may be normal or only mildly abnormal in patients with MuSK-seropositive myasthenia. Recently, however, Oh and colleagues have shown 186 that repetitive stimulation of the facial nerve may be a useful diagnostic test in these patients. Treatment of myasthenia gravis consists of anticholinesterases, immunomodulation, thymectomy, or some combination of these approaches. The first major prospective, multicenter trial on the benefit of thymectomy for seropositive, nonthymomatous generalized myasthenia gravis is planned 187 to enroll subjects in the near future.

Medications Causing Abnormalities of Neuromuscular Transmission A number of medications impair neuromuscular transmission. Corticosteroids, adrenocorticotropic hormone (ACTH), calcium-channel blockers, citrate, intravenous radiographic contrast medium, and intravenous gadolinium impair acetylcholine 188–192 Anticholinesterase drugs may cause depolarizing blockade. The tetracyclines, release. polymyxins, phenothiazines, fluoroquinolones, and trimethaphan cause weakness by blocking acetylcholine receptors. Aminoglycosides, lincosa-mides, procainamide, quinidine, lidocaine, β-adrenergic blockers, chloroquine, phenytoin, trimethadione, lithium, thyroid hormone, and 193,194 quinine have both pre- and postsynaptic effects.

Toxins A number of industrial and animal toxins affect neuromuscular transmission. Organophosphate and carbamate insecticides inactivate acetylcholinesterase at neuromuscular, autonomic, and central cholinergic synapses, leading to depolarizing 195 blockade. Symptoms include diarrhea, increased salivation, miosis, bradycardia, hypotension, and confusion.

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Venom from snakes may either block196 acetylcho-line receptors or decrease the release of acetylcho-line from the end-terminal. Venom from the black widow spider and scorpion 197,198 venom deplete acetylcholine stores through increased release of the neurotransmitter. Tick paralysis occurs 199 through a neurotoxin that appears to cause weakness by impairing acetylcholine release. MYOPATHY Myopathies usually present with symmetric, proximal weakness. Involvement of the neck flexors and extensors and the facial muscles is not uncommon, but weakness of the extraocular muscles is rare. Muscle atrophy and depressed reflexes occur in advanced cases. The common causes of myopathy are listed in Table 60-11. The congenital and genetic myopathies are beyond the scope of this discussion and are covered in general neurology textbooks. Although myalgia may occur with certain myopathies, most myopathies (including the inflammatory myopathies) are painless. Exercise intolerance and exercise-induced muscle cramps are clues to one of the metabolic myopathies. Click here to view this table.... The evaluation for a suspected myopathy begins with measurement of serum creatine kinase (CK) activity. Increased serum CK levels usually imply sarcolemmal injury. Normal serum CK levels may occur with disuseatrophy, corticosteroid myopathy, mitochondrial myopathies, and critical illness myopathy associated with thick-filament loss. Many of the metabolic myopathies are associated with normal serum CK levels between attacks. Mild to moderate serum elevations of CK are generally seen with the inflammatory myopathies, toxic myopathies, and adult-onset muscular dystrophies. High serum CK levels are associated with severe toxic/necrotizing myopathies (related to medications or severe electrolyte disturbances) and muscular dystrophy presenting in childhood. Needle EMG supports the clinical diagnosis and excludes the possibility of a neuropathy. The electromyographer may also advise the best target for a muscle biopsy, which is often required for a definitive diagnosis.

Endocrine-Related Myopathy Acromegaly Slowly progressive proximal weakness not associated with muscle atrophy occurs in about half of acromegalic patients. Many patients have decreased exercise tolerance. Serum CK levels may be mildly elevated. When growth hormone levels normalize, the myopathy usually resolves. Corticosteroid Myopathy Corticosteroid myopathy may occur with either excessive exogenous or endogenous corticosteroids and is characterized by the insidious onset of proximal limb weakness. Patients who develop weakness usually have other stigmata of long-term corticosteroid use, including a moon facies, suprascapular fat pad, and fragile skin. Old age and cancer are risk 200 factors for corticosteroid myopathy. Myalgias may occur. Serum CK levels are typically normal. The dose and duration of corticosteroid treatment associated with the development of a myopathy vary widely, but most patients have received therapy for at least 4 weeks. With high-dose corticosteroids, however, the weakness may occur within 2 weeks of starting therapy. The fluorinated corticosteroids, including triamcinolone, betamethasone, and dexamethasone, are particularly likely to cause myopathy. Pathologically, there is selective atrophy of the type 2, glycolytic muscle fibers without muscle degeneration or inflammation. The pathogenesis probably relates to impairment of muscle protein and carbohydrate metabolism. The goal of treatment is to lower the corticosteroid dose to as low a level as possible. Recovery may take weeks to months but is usually excellent. A severe, acute necrotizing myopathy can result from large doses of intravenous corticosteroids combined with a neuromuscular blocking agent, usually in the setting of 201–203 There is probably overlap between this condition and treatment for status asthmaticus. critical illness myopathy, as discussed in Chapter 52. Hyperparathyroidism and Osteomalacia

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Proximal muscle weakness may be associated with primary and secondary hyperparathyroidism, vitamin D deficiency, and other disorders of vitamin D metabolism. Patients with primary hyperparathyroidism often complain of weakness and fatigue, but objective loss of muscle power is uncommon. Proximal weakness may be associated with discomfort on movement. Muscle stretch reflexes tend to be brisk. Serum CK levels are normal. Pathologically, atrophy of type II muscle fibers is a consistent feature. Secondary parathyroidism usually occurs in the setting of renal failure. The myopathy associated with uremia is discussed later. Osteomalacia presents with proximal weakness and bone pain. Nutritional deficiency of vitamin D is the leading cause of osteomalacia worldwide, but gastrectomy and celiac sprue are responsible for most of the cases in the United States. Renal tubular acidosis and anticonvulsant therapy may also cause osteomalacia by interfering with vitamin D metabolic pathways. Vitamin D deficiency may lead to secondary hyperparathyroidism; it may then be difficult to determine which factor is more important in the pathogenesis of the weakness. When vitamin D–deficient patients are supplemented with vitamin D, the response is variable and any improvement occurs over many weeks. Hyperthyroidism or Hypothyroidism Approximately 50 percent of thyrotoxic patients develop weakness. The pattern of weakness is typically proximal; patients frequently complain of fatigue and breathlessness. Myalgia is common. Usually the onset is insidious, although the onset may be more rapid in severe hyperthyroidism. In fact, rhabdomyolysis with myoglobinuric renal failure may occur in the setting of a thyroid storm. In general, however, severe generalized weakness in thyrotoxic patients should raise the suspicion of concomitant myasthenia gravis. Serum CK levels are usually normal. The EMG reveals small, short, polyphasic motor units without abnormal spontaneous activity. In addition to nonspecific myopathic findings, muscle biopsies may reveal a lower proportion of type I fibers. Following treatment, the proportion of type I fibers increases. Prognosis for recovery is excellent once a euthyroid state is achieved. Thyrotoxic periodic paralysis is characterized by recurrent attacks of generalized weakness lasting for minutes to days. The weakness may be provoked by a carbohydrate meal, cold, or rest after exercise. It is usually seen in young Asian or Native American adults. The paralytic attacks are not related to the duration or severity of the thyrotoxicosis. Treatment of acute paralytic attacks includes potassium supplements. The paralytic attacks disappear once the patient is maintained in a euthyroid state. Hypothyroidism causes a myopathy characterized by proximal weakness, fatigue, slowed 204 movements and reflexes, cramps, stiffness, myoedema, and muscle enlargement. The serum CK level is elevated even in asymptomatic hypothyroid patients and is frequently elevated more than 10 times the upper limit of normal in symptomatic patients. The EMG findings may be normal. Nonspecific myopathic findings are seen on muscle biopsy. After thyroid supplementation, recovery is excellent.

Infectious Myopathies Human Immunodeficiency Virus Infection As discussed in Chapter 45, several different types of myopathy have been associated with HIV infection. First, an inflammatory myopathy resembling polymyositis (PM) both clinically 205 and pathologically may occur. Although it may present at any stage of HIV infection, it is usually a complication of AIDS. Patients present with slowly progressive proximal arm and leg weakness. Serum CK levels are elevated, often more than 10 times the upper limit of normal. Pathologically, the findings are similar to idiopathic PM. Viral particles have not been identified in muscle cells. Most cases respond to corticosteroid therapy. Second, 206,207 a nemaline Third, rod myopathy may occur with or without associated inflammation in HIV patients. inclusion-body myositis (IBM) has been described in HIV patients. It is clinically and pathologically indistinguishable from sporadic IBM, except that the age at onset is earlier. Fourth, muscle atrophy and weakness occur in the HIV wasting syndrome. Pathologically, there is atrophy of the type II muscle fibers. Tumor necrosis factor α (TNF-α) is implicated in the pathogenesis of this syndrome. Fifth, myoglobinuria (sometimes recurrent) may occur at 208 any stage of HIV infection. Multiple factors, including concomitant medication use, probably contribute to its pathogenesis. Sixth, a pyomyositis manifesting as localized pain and swelling 209 in a limb may occur. It is usually associated with Staphylococcus aureus infection. Seventh, a proximal myopathy associated with myalgias in the thighs and calves may occur

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210

with high-dose zidovudine (AZT) treatment. Serum CK levels may be normal or mildly elevated. Pathologically, many fibers reveal “ragged red” features consistent with mitochondrial toxicity. Discontinuation of the medication usually results in improvement but sometimes not full recovery. Viral Myositis Viruses implicated with causing a myopathy include adenovirus, coxsackievirus A and B, echovirus, influenza A and B, Epstein–Barr virus, adenovirus, echovirus, parvovirus, parainfluenza virus, paramyxovirus, CMV, hepatitis211,212 B, herpes simplex virus, herpes zoster, Myalgia is the most common human T-lymphotropic virus 1 (HTLV-1), and HIV. neuromuscular symptom associated with viral illness. After the viral illness, swollen muscles and sometimes rhabdomyolysis with myoglobinuria occur. For many of the virus strains mentioned here, there is no clear evidence that the virus actually infects or replicates within human muscle tissue. In such cases, the pathogenesis of the muscle injury is uncertain. Other Infections The three most common parasitic infections of muscle are toxoplasmosis, cysticercosis, and trichinosis. Toxoplasmosis is the most common protozoan infection to cause a myositis, the others being sarcocystis, trypanosomiasis, microsporidiosis, and malaria. Toxoplasma gondii is transmitted to humans by ingestion of undercooked meats and by contact with cat feces. Patients present with a fever accompanied by any one of multiple possible systemic features, including lymphadenopathy, pericarditis, hepatosplenomegaly, meningoencephalitis, and myositis. The myositis associated with toxoplasmosis resembles idiopathic PM and dermatomyositis (DM). Pathologically, cysts containing bradyzoites may be seen in muscle fibers or near inflammatory infiltrates. Prognosis for a full recovery is excellent following treatment. Cestode (tapeworm) infections resulting in myopathy include cysticercosis, echinococcosis, coenurosis, and sparganosis. Cysticercosis caused by Taenia solium infection may result from eating uncooked infected meat (particularly pork) and by the fecal-oral route. Patients may present with enlarged yet weak muscles (pseudohypertrophy). Myalgia and muscle 176 tenderness are common. Nematode (roundworm) infections associated with a myopathy include trichinosis, toxocariasis, cutaneous larva migrans, and dracontiasis. Trichinosis occurs after ingestion of inadequately cooked meat. Following a prodrome of abdominal cramps and diarrhea, patients develop generalized weakness that may be accompanied by the classic cutaneous stigmata 213 of DM. Serum CK levels are elevated and eosinophilia is present.

Idiopathic Inflammatory Myopathies DM, PM, and IBM present with subacute to chronic, symmetric proximal limb weakness with sparing of the ocular muscles. All share evidence of lymphocytic infiltration of the muscle, but important differences exist among these diseases, particularly in mechanisms of pathogenesis and response to214 treatment. Many cases previously labeled as PM may have had IBM or another myopathy. Dermatomyositis and Polymyositis The annual incidence of DM and PM in the general population is 0.1 to 1 per 100,000. Women are affected more often than men. Most patients present with a several month history of subacute proximal weakness, usually without significant muscle atrophy. Typically, the onset of the weakness cannot be precisely recalled. Other symptoms may include dysphagia, nasal regurgitation, or aspiration from weakness of oropharyngeal muscles or the 215 upper esophagus. Myalgias and muscle tenderness occur in 25 to 50 percent of cases but tend to be mild. Muscle pain is more prominent in viral or bacterial myositis, the inherited metabolic myopathies, polymyalgia rheumatica, and fibromyalgia. In DM, various cutaneous manifestations may precede or accompany the onset of weakness. These include Gottron's sign (scaly, erythematous rash over the extensor surfaces of the metacarpophalangeal and interphalangeal joints; a similar rash may occur over the extensor surfaces of the elbows and knees), diffuse flat erythema in the anterior neck and chest and other sun-exposed areas, swelling and reddish violaceous discoloration of the upper eyelids

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(heliotrope rash), periungual erythema, dilated nail-bed capillary loops, and rough, cracked skin at the fingertips (so-called mechanic's hands). Of note, patients with DM and SLE often share the same 308A polymorphism of the tumor necrosis factor-α promoter region, which suggests that ultraviolet light–induced production of tumor necrosis factor-α may contribute to 216 light sensitivity in both diseases. Interstitial lung disease is an important complication of PM and DM. Particularly for PM, the presence of interstitial lung disease is 217 associated with antibodies to the histidyl-transfer RNA precede the myopathy or (histidyl-tRNA) synthetase (anti–Jo-1). The lung disease may 218 accompany it in 5 to 40 percent of patients with DM and PM and may present acutely with a nonproductive cough, dyspnea, hypoxemia, and lung infiltrates or chronically with dyspnea. 219 Sometimes it is discovered in asymptomatic patients on screening chest radiographs.220 The presence of interstitial lung disease is a poor prognostic factor for long-term survival. Patients with DM and PM may have cardiac involvement, which may manifest as 217 supraventricular arrhythmias, atrioventricular conduction blocks, and bundle branch block. Congestive heart failure has also been described. An associated malignancy, in particular ovarian, pancreatic, stomach, and colorectal cancers and non-Hodgkin's lymphoma, is seen 221,222 in 6 to 45 percent of DM patients and in 0 to 28 percent of PM patients. PM and DM may overlap with a number of connective tissue diseases, including scleroderma, SLE, and, rarely, rheumatoid arthritis and Sjögren's syndrome. In scleroderma, a bland myopathy with mild to absent elevations of serum CK levels is common. In a small percentage of patients, severe proximal muscle weakness occurs with significant serum CK 223 elevations. Overall, the incidence of myositis in scleroderma ranges from 5 to 17 percent. In North American patients, the anti–PM-Scl antibody is a marker for scleroderma-myositis. PM and DM also occur in association with SLE. The presence of autoantibodies against nuclear components helps distinguish a PM-SLE overlap syndrome from idiopathic PM. In a 224 cohort of 330 patients with SLE, 10 had a myositis. Serum CK levels are usually elevated in PM and DM and generally reflect the disease activity; levels are generally higher in PM than DM and may even be normal in active DM. Serum antibody tests to nuclear and cytoplasmic components help support the clinical diagnosis of PM or DM, assist the diagnosis of overlap syndromes, and categorize subgroups of inflammatory myopathies. Muscle-specific antibodies have specific associations with HLA haplotypes and certain disease manifestations. These include antibodies to aminoacyl transfer RNA synthetases, components of the signal recognition particle (SRP), and nuclear helicase/adenosine triphosphatase Mi-2. About 50 to 75 percent of those with antibodies to 225 cytoplasmic transfer RNA synthetases (including anti–Jo-1) have interstitial lung disease. Patients with anti-SRP antibodies often have acute-onset severe myositis without an associated rash or lung disease. Patients with anti–Mi-2 antibodies usually have a florid rash 226 and an abrupt onset of weakness. MRI shows evidence of inflammation in muscles and subcutaneous fat, fibrosis, and 227 calcification. Because MRI is noninvasive, it can be performed serially to assess disease progression and monitor response to treatment; it may also be used to identify a site for biopsy. EMG typically reveals increased insertional activity and fibrillation potentials with myopathic (low-amplitude, short-duration, polyphasic) motor unit potentials. Ideally, a muscle biopsy should be performed on a superficial muscle with abnormal findings on EMG of the homologous contralateral muscle. Pathologically, the inflammation in PM is perivascular, perimysial, and endomysial. There is no evidence of damage to the capillaries. There is invasion of non-necrotic muscle fibers + ubiquitously expressing major histocompatibility complex (MHC)-1 by cytotoxic CD8 T 228 cells. These findings support the hypothesis that the cytotoxic T cells recognize an antigen bound to major histocompatibility complex-1. The identity and origin of this putative antigen are not known. Major histocompatibility complex-1 is normally not expressed on the surface of muscle fibers. In PM, the inflammation is predominantly in the perivascular or interfascicular space and less + so in the endomysium. The inflammatory infiltrate is primarily composed of B cells and CD4 T cells. Unlike PM, the immune attack appears to be primarily directed against the vascular endothelium. The sequence of events is thought to include antibody deposition on the endothelial cells, followed by complement activation, and, finally, membrane attack complex 229 (MAC)–mediated microvascular injury. Chronic ischemia is thought to produce perifascicular atrophy, a hallmark pathological feature of DM. Corticosteroids are widely recognized as first-line treatment for PM. The typical daily dose is 1

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to 1.5 mg/kg. This dose is continued until strength improves and then a careful, slow taper is started. A number of agents, including azathioprine, methotrexate, or mycophenolate mofetil, may be used concurrently or subsequently for a corticosteroid-sparing effect. In a study comparing the treatment of prednisone to prednisone plus azathioprine, those taking230 both For had a better functional outcome and needed a lower prednisone maintenance dose. 231,232 Plasmapheresis did not refractory cases of DM and PM, IVIg appears to be effective. 233 show a benefit in a double-blind, placebo-controlled trial. Inclusion-Body Myositis IBM is a slowly progressive, debilitating myopathy of unknown cause. It is the most common 234,235 Early involvement of the finger flexors, wrist myopathy in patients older than 50 years. flexors, knee extensors, and ankle dorsiflexors is common. Dysphagia may occur, which may be treated with a cricopharyngeal myotomy. A wide variety of autoimmune diseases have been described in association with IBM. Hyporeflexia is common; some patients have clinical 236 and electrodiagnostic evidence of a peripheral neuropathy. The serum CK level can be normal or up to 10-fold above the upper limit of normal. The EMG findings are similar to those of DM and PM, except that long-duration motor unit potentials are commonly observed and do not exclude the diagnosis of IBM. +

Pathologically, there is endomysial inflammation with a CD8 T-lymphocyte predominance, 237 basophil-rimmed vacuoles with eosinophilic inclusions, and intracellular amyloid deposits detected by fluorescence microscopy of Congo red–stained sections or electron microscopy demonstrating 15- to 18-nm tubulofilaments. The vacuoles contain various products of muscle degradation including myeloid bodies, membrane fragments, and debris. In addition, numerous proteins also expressed in Alzheimer's disease are found in muscle fibers. This has led to the notion that IBM is a degenerative disease associated with aging. It is important to note that vacuolated fibers occur in certain hereditary myopathies and in toxic myopathies caused by colchicine and chloroquine. There is generally no effective immunomodulating treatment, although240individual patients 238,239 mycophenolate mofetil, and high-dose have responded to corticosteroids, IVIg, 241 vitamin C. Sarcoidosis Granulomatous inflammation of muscle is usually associated with sarcoidosis but can244 also be 242,243 inflammatory bowel disease, foreign body reactions, seen in infectious disease, 245 246 thymoma, lymphoma, and myasthenia gravis. It may also occur without any evidence of systemic disease. Asymptomatic involvement of the muscle occurs in 50 to 80 percent of cases of sarcoidosis. Symptomatic involvement occurs in less than 3 percent of cases. Most patients with sarcoid 247 Rarely, patients present myopathy present with slowly progressive, proximal weakness. 248 with acute myositis or a palpable nodular type of myopathy. The response to corticosteroid therapy is unpredictable. Compared with sarcoid myopathy, patients with isolated granulomatous myopathy have milder, predominantly distal weakness, and the response to 249,250 corticosteroids tends to be better. Polymyalgia Rheumatica Polymyalgia rheumatica presents with 251 achiness and morning stiffness in the shoulder and hip girdles in patients older than 50 years. Malaise, fever, and anorexia with weight loss are common. There is an association with temporal arteritis and rheumatoid arthritis. The erythrocyte sedimentation rate is almost always increased. There is no weakness. Although muscle biopsy specimens are generally normal, MRI or ultrasonography of the shoulders 252,253 The symptoms usually respond to low-dose consistently reveals evidence of bursitis. corticosteroids.

Critical Illness Myopathy Patients with critical illness may develop an acute, acquired myopathy associated with 254 exposure to high-dose corticosteroids and neuromuscular blocking agents (Chapter 52). Critical illness myopathy may be suspected first when patients fail to wean from mechanical ventilation. Patients have flaccid, diffuse weakness that affects the limbs, neck flexors, and diaphragm. Tendon reflexes are usually depressed. Approximately one third of ICU patients

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treated for status asthmaticus develop critical illness myopathy. Other risk factors include 256 severe medical illness, renal failure, and hyperglycemia. Patients with critical illness myopathy may also have clinical and electrodiagnostic features of critical illness polyneuropathy. Critical illness myopathy should be distinguished from rhabdomyolysis with myoglobinuria, which can also occur in the ICU setting. Electrodiagnostic testing helps to clarify the diagnosis. Needle EMG reveals fibrillation potentials in limb muscles of some but not all patients. Short, small, poly phasic motor unit potentials are seen. Electrical inexcitability of the muscle to direct needle stimulation occurs in this entity but not in 257 polyneuropathy. Most patients have elevations of serum CK levels, but a normal level does not exclude the diagnosis. Pathologically, there is muscle-fiber atrophy with evidence of a disrupted intramyofibrillar network. Loss of thick filaments (myosin) is a characteristic feature. The pathogenesis is uncertain but may involve glucocorticoid-induced proteolysis of contractile proteins in the setting of muscle-fiber denervation. There is no specific treatment for critical illness myopathy, but corticosteroids and neuromuscular blocking agents should be limited, if possible. Neurological recovery is usually excellent, assuming that the patient 258 recovers from the underlying medical illness.

Metabolic and Toxic Myopathies Alcohol Alcoholics may develop an acute necrotizing or chronic myopathy. The acute form presents as an attack of pain and swelling in a limb, usually the calf or thigh. In severe cases, myoglobinuria occurs. The attack usually occurs in the course of a heavy drinking binge. If probed, patients may recall prior bouts of pain and swelling in the limbs associated with earlier drinking binges. Serum CK levels are often markedly elevated. Recovery usually occurs over 1 to 2 weeks, but patients are prone to have subsequent episodes of acute myopathy if drinking is resumed. The chronic form presents as chronic limb-girdle weakness with preserved reflexes. Serum CK levels are usually normal but may be elevated. Muscle biopsy specimen abnormalities are usually mild and include type II fiber atrophy. Hyperkalemia or Hypokalemia Hyperkalemia causes acute generalized weakness and cardiac arrhythmias. The weakness typically begins in the legs and then generalizes over hours to days. Respiratory failure occurs in about 50 percent of cases. Painful dysesthesias may precede the onset of weakness. Reflexes are usually absent. In most cases, the serum potassium level exceeds 7.5 mEq/L. Paralysis only occurs in patients with some degree of chronic hyperkalemia. Electrodiagnostic testing has shown slowing of259 nerve conduction velocities and low compound muscle action potential amplitudes. The immediate treatment goal is to prevent a cardiac arrhythmia, which can be achieved with an infusion of calcium gluconate. Hypokalemia may be associated with acute paralysis or subacute myopathy. Acute hypokalemic paralysis occurs in patients with chronic potassium depletion. The onset of weakness occurs over hours to days. Once it starts, the weakness tends to accelerate. In mild cases, weakness may be limited to the legs, but in severe cases, tetraplegia with neuromuscular respiratory failure may occur. Extraocular muscles are spared. The potassium level is always below 3.0 mEq/L. The subacute myopathy associated with hypokalemia is characterized by the onset of proximal limb weakness over weeks to months. Serum CK levels are elevated, sometimes markedly. Pathologically, there is muscle-fiber necrosis with multiple vacuoles in some muscle fibers. Occasionally, the course may be more rapid, associated with myalgia, tenderness, and myoglobinuria. Once the hypokalemia is corrected, recovery is rapid and complete. Uremia Uremic myopathy refers to the clinical syndrome characterized by proximal weakness, limited endurance, and rapid fatigability seen in patients with end-stage renal disease. It usually only 260 occurs with glomerular filtration rates below 25 ml/min. It has been estimated that approximately 50 percent of dialysis patients have this condition. Often, the weakness is mild, and EMG and serum CK levels are normal. Pathologically, there is atrophy of type II muscle fibers. A number of metabolic derangements are thought to contribute to this condition, including secondary hyperparathyroidism, impaired vitamin D metabolism, carnitine 261 deficiency, and reduced clearance of toxic “middle molecules.” Insulin resistance,

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alterations of mitochondrial metabolism, and anemia may also have roles in pathogenesis. Although there is currently no specific treatment for uremic myopathy, an emphasis should be placed on preventing secondary hyperparathyroidism and improving the patient's nutritional 262 status. Carnitine supplementation may be considered. Finally, renal transplantation offers the best chance for improvement.

Medication-Induced Myopathy Many different medications cause a myopathy (Chapter 36). Most of these cause a necrotizing myopathy that presents clinically with the acute to subacute onset of generalized weakness. In severe cases, myoglobinuria occurs. Myalgias may occur. Serum CK values are usually elevated. Pathologically, there are necrosis and regeneration of muscle fibers with myophagocytosis. 3-Hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (atorvastatin, simvastatin, and other statins), fibric acid derivatives (clofibrate, gemfibrozil, and others), organophosphates, ε-aminocaproic acid, and hypervitaminosis E are all associated with a necrotizing myopathy. Any medication that lowers potassium levels, including diuretics, licorice, and laxatives, may produce a myopathy. A few medications (e.g., zidovudine) cause a mitochondrial myopathy. Once the offending medication is discontinued, most patients make a rapid and full recovery. RHABDOMYOLYSIS AND MYOGLOBINURIA Myoglobin is an oxygen-carrying protein in the sarcoplasm of muscle cells. Its functions include oxygen storage and “buffering” of oxygen to prevent mitochondrial anoxia. Any cause of muscle injury leads to an increase in serum concentration of myoglobin. If the concentration of myoglobin in the urine surpasses 250 mg/ml (normal is

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