Central ocular motor disorders,including gaze palsy and nystagmus

An impairment of eye movements, or nystagmus, is seen in many diseases of the central nervous system, in particular those affecting the brainstem and cerebellum, as well as in those of the vestibular system. The key to diagnosis is a systematic clinical examination of the different types of eye movements, including: eye position, range of eye movements, smooth pursuit, saccades, gaze-holding function and optokinetic nystagmus, as well as testing for the different types of nystagmus (e.g., central fixation nystagmus or peripheral vestibular nystagmus). Depending on the time course of the signs and symptoms, eye movements often indicate a specific underlying cause (e.g., stroke or neurodegenerative or metabolic disorders). A detailed knowledge of the anatomy and physiology of eye movements enables the physician to localize the disturbance to a specific area in the brainstem (midbrain, pons or medulla) or cerebellum (in particular the flocculus). For example, isolated dysfunction of vertical eye movements is due to a midbrain lesion affecting the rostral interstitial nucleus of the medial longitudinal fascicle, with impaired vertical saccades only, the interstitial nucleus of Cajal or the posterior commissure; common causes with an acute onset are an infarction or bleeding in the upper midbrain or in patients with chronic progressive supranuclear palsy (PSP) and Niemann–Pick type C (NP-C). Isolated dysfunction of horizontal saccades is due to a pontine lesion affecting the paramedian pontine reticular formation due, for instance, to brainstem bleeding, glioma or Gaucher disease type 3; an impairment of horizontal and vertical saccades is found in later stages of PSP, NP-C and Gaucher disease type 3. Gaze-evoked nystagmus (GEN) in all directions indicates a cerebellar dysfunction and can have multiple causes such as drugs, in particular antiepileptics, chronic alcohol abuse, neurodegenerative cerebellar disorders or cerebellar ataxias; purely vertical GEN is due to a midbrain lesion, while purely horizontal GEN is due to a pontomedullary lesion. The pathognomonic clinical sign of internuclear ophthalmoplegia is an impaired adduction while testing horizontal saccades on the side of the lesion in the ipsilateral medial longitudinal fascicule. The most common pathological types of central nystagmus are downbeat nystagmus (DBN) and upbeat nystagmus (UBN). DBN is generally due to cerebellar dysfunction affecting the flocculus bilaterally (e.g., due to a neurodegenerative disease). Treatment options exist for a few disorders: miglustat for NP-C and aminopyridines for DBN and UBN. It is therefore particularly important to identify treatable cases with these conditions.     

Paresis of lateral gaze alternating with so-called posterior internuclear ophthalmoplegia. A partial paramedian pontine reticular formation-abducens nucleus syndrome

Summary A patient with multiple myeloma developed gaze paresis to the left with slowed saccades and gaze-paretic nystagmus, which alternated with abduction palsy in the left eye (with preserved oculocephalic deviation) and dissociated adducting nystagmus in the right eye, suggesting so-called posterior internuclear ophthalmoplegia. At autopsy multiple small infarcts were found with partial destruction of the left paramedian pontine reticula formation (PPRF) extending towards the abducens nucleus, which was involved only in its inferior pole. The medial longitudinal fasciculus and other oculomotor structures were spared. It is suggested that slowing of all ipsilateral saccades with gaze-paretic nystagmus corresponded to partial destruction of the PPRF, and that intermitted abduction palsy in the ipsilateral eye with adduction nystagmus in the fellow eye was due to intermittant dysfunction of the abducens nucleus. Involvement of voluntary saccades, pursuit movements and vestibulo-ocular responses may be dissociated in partial lesions of the abducens nucleus.     

Selective saccadic palsy caused by pontine lesions: clinical, physiological, and pathological correlations

Two patients suffered a selective deficit of voluntary saccades and quick phases of nystagmus after hypoxic-ischemic insults during open-heart surgery. All voluntary saccades, in both horizontal and vertical planes, were slow, and quick phases of vestibular and optokinetic nystagmus were absent. Smooth pursuit, the vestibuloocular reflex, the ability to hold steady eccentric gaze, and vergence eye movements were all preserved. Pathological studies in 1 patient confirmed neuronal necrosis and gliosis, consistent with ischemic lesions involving the median and paramedian pontine reticular formation and median basis pontis but sparing the rostral mesencephalon and rostral interstitial nucleus of the medial longitudinal fasciculus. These findings, taken with data from experimental studies, support the hypothesis that each functionally defined class of horizontal eye movements is controlled by a separate neural substrate that projects independently to the abducens nuclei. In addition, these data suggest that the rostral interstitial nucleus of the medial longitudinal fasciculus is dependent on inputs from the paramedian pontine reticular formation for the programming of normal vertical saccades.     

Anatomical and physiological characteristics of vestibular neurons mediating the horizontal vestibulo-ocular reflex of the squirrel monkey

The anatomical characteristics of vestibular neurons, which are involved in controlling the horizontal vestibulo-ocular reflex, were studied by injecting horseradish peroxidase (HRP) into neurons whose response during spontaneous eye movements had been characterized in alert squirrel monkeys. Most of the vestibular neurons injected with HRP that had axons projecting to the abducens nucleus or the medial rectus subdivision of the oculomotor nucleus had discharge rates related to eye position and eye velocity. Three morphological types of cells were injected whose firing rates were related to horizontal eye movements. Two of the cell types were located in the ventral lateral vestibular nucleus and the ventral part of the medial vestibular nucleus (MV). These vestibular neurons could be activated at monosynaptic latencies following electrical stimulation of the vestibular nerve; increased their firing rate when the eye moved in the direction contralateral to the soma; had tonic firing rates that increased when the eye was held in contralateral positions; and had a pause in their firing rate during saccadic eye movements in the ipsilateral or vertical directions. Eleven of the above cells had axons that arborized exclusively on the contralateral side of the brainstem, terminating in the contralateral abducens nucleus, the dorsal paramedian pontine reticular formation, the prepositus nucleus, medial vestibular nucleus, dorsal medullary reticular formation, caudal interstitial nucleus of the medial longitudinal fasciculus, and raphé obscurus. Eight of the cells had axons that projected rostrally in the ascending tract of Deiters and arborized exclusively on the ipsilateral side of the brainstem, terminating in the ipsilateral medial rectus subdivision of the oculomotor nucleus and, in some cases, the dorsal paramedian pontine reticular formation or the caudal interstitial nucleus of the medial longitudinal fasciculus. Two MV neurons were injected that had discharge rates related to ipsilateral eye position, generated bursts of spikes during saccades in the ipsilateral direction, and paused during saccades in the contralateral direction. The axons of those cells arborized ipsilaterally, and terminated in the ipsilateral abducens nucleus, MV, prepositus nucleus, and the dorsal medullary reticular formation. The morphology of vestibular neurons that projected to the abducens nucleus whose discharge rate was not related to eye movements, or was related primarily to vertical eye movements, is also briefly presented.     

Paresis of contralateral smooth pursuit and normal vestibular smooth eye movements after unilateral brainstem lesions.

Pursuit and vestibular smooth eye movements were measured in patients with lesions of the caudal brainstem tegmentum identified by magnetic resonance imaging (MRI) and computed tomography (CT), with neuropathological correlation in 1 patient. Contralateral smooth pursuit gain was significantly lower than ipsilateral gain in each patient. Ipsilateral smooth pursuit gain was also subnormal in patients with unilateral pontine damage that caused slowing of ipsilateral saccades. Horizontal vestibulo-ocular reflex gain and phase were normal. These quantitative correlations indicate that lesions of the pontine tegmentum that paralyze ipsilateral saccades can spare the vestibulo-ocular reflex, and that smooth pursuit movement and the vestibulo-ocular reflex can be impaired independently by pontine or medullary lesions. In contrast to lesions at other sites, unilateral lesions of the pontine or medullary tegmentum impair contralateral smooth pursuit more than ipsilateral pursuit movements. These findings provide evidence that a double decussating pathway mediates smooth pursuit; the first decussation is from the pons to the cerebellum, and the second decussation is from the vestibular nucleus to the contralateral abducens nucleus.     

Central oculomotor circuits

Recent data and hypotheses concerning the central oculomotor pathways are reviewed. Lateral and vertical eye movements are discussed successively, beginning in each case with the final common pathway and then progressing step by step along the main supranuclear tracts selectively involved in the 3 types of eye movements: vestibular movements, saccades and smooth pursuit. It is now established that the final common pathway of lateral eye movements in frontal-eyed species is the abducens nucleus, which controls not only the ipsilateral lateral rectus, but also, through the internuclear neurons, almost all the conjugate lateral activity of the opposite medial rectus. The ascending tract of Deiters, providing direct excitatory vestibular signals to the medial rectus motoneurons, could either have totally regressed in man or would play only a minor functional role. Likewise, a direct inhibition of the medial rectus motoneurons now seems unlikely or ineffective, the relaxation of this muscle resulting essentially from the disfacilitation mediated by the abducens internuclear neurons. This particular mechanism could be explained by the fact that the medial rectus motoneurons also receive messages of convergence, a slow disjunctive movement independent of lateral eye movements. Convergence is performed by excitatory reticular neurons near the oculomotor nucleus and by inhibitory pathways projecting onto the abducens motoneurons, perhaps passing through the internuclear neurons of the oculomotor nucleus. The premotor relay of horizontal reflex eye movements is the medial vestibular nucleus (M.V.N.) which contains excitatory and inhibitory neurons projecting onto the contralateral and ipsilateral abducens nuclei respectively. Afferences of the M.V.N. arise from: the labyrinth, through the vestibular nerve (vestibulo-ocular reflex); the neck, through the dorsal part of the medullary tegmentum (cervico-ocular reflex); the peripheral retina and the visual pathways (for the vestibular contribution of optokinetic nystagmus), perhaps via the pretectum, the nucleus reticularis tegmenti pontis (N.R.T.P.) and/or the nucleus prepositus hypoglossi (N.P.H.) (visuo-ocular reflex). The premotor relay for all ipsilateral saccades is the paramedian pontine reticular formation (P.R.F.) which excites the ipsilateral abducens nucleus and inhibits the contralateral abducens nucleus, via the burst inhibitory neurons located ventrally to the ipsilateral abducens nucleus.(ABSTRACT TRUNCATED AT 400 WORDS)     

A case of non-paralytic pontine exotropia due to pontine tegmentum lesion confirmed by magnetic resonance imaging and electronystagmography

A case with non-paralytic pontine exotropia (NPPE) due to brainstem infarction is reported. A 77-year-old hypertensive man suddenly developed dizziness, double vision, dysarthria, and right ataxic hemiparesis. Oculomotor findings on admission consisted of: (1) full right exotropia in the primary position; (2) complete adductive paralysis of the left eye with slight preservation of convergence; (3) tonic deviation of the right eye to the full abducting position with right-beating nystagmus after an immediate forward gaze. The leftward saccades showed multiple saccades with slow velocity on electronystagmography (ENG). The right exotropia disappeared and the slight adductive paresis of the left eye remained with right monocular nystagmus seven weeks after the onset. Magnetic resonance imaging (MRI), which was performed nine weeks after the onset, disclosed a small lesion with high intensity involving the left medial longitudinal fasciculus (MLF) on T2-weighted spin echo image. The leftward saccades showed multiple saccades with normal velocity eleven weeks after the onset. The hypofunction of unilateral PPRF with ipsilateral MLF lesion probably causes the contralateral NPPE.     

An electrooculographic study of internuclear ophthalmoplegia

The eye movements of 25 patients with internuclear ophthalmoplegia were recorded by electrooculography. The velocity of adducting saccades was markedly less than normal. The velocity of abducting sacades was within the normal range, but statistically there was a wider distribution. Recordings were made in 2 patients several months after the onset of internuclear ophthalmoplegia, at which time the adducting eye velocity was greater than the abducting eye velocity. A patient with a unilateral medial fasciculus lesion showed marked overshoot of the abducting eye on contralateral saccades and overshoot of both eyes toward the side of the lesion. Optokinetic and postcaloric nystagmus were recorded, and the slow phase showed increasing velocity exponential waveform for the abducting eye. The recordings also showed decreasing velocity exponential waveform for the abducting eye. Downbeat nystagmus was as common as upbeat nystagmus in our patients. The findings appear to confirm the theoretical analysis of the eye movement disorder in internuclear ophthalmoplegia provided by Pola and Robinson as modified by recent experimental work in primates.     

A case of hemi-hyperhidrosis and non-paralytic pontine exotropia due to brainstem infarction]

A case of hemihyperhidrosis and non-paralytic pontine exotropia due to brainstem infarction is reported. A 55-year-old hypertensive man developed right hemiparesis with slight dysarthria and nausea upon awaking. The right side of his face and right upper limb and trunk to the level of the Th8-9 territory showed hyperhidrosis, which disappeared in a week. Ocular motor examination revealed that during forward gaze with the left eye fixing, the right eye deviated outward. The patient was able to adduct the right eye to midposition with the right eye fixing. Rightward gaze elicited full abduction and right-beating nystagmus of the right eye, but the left eye did not adduct. When he attempted to gaze leftward, both eyes made the full excursion, but saccades were slow in that direction. Convergence was intact. Vertical gaze was full, and he did not show Horner's sign. This ocular sign, non-paralytic pontine exotropia, disappeared three days later. T2-weighted spin echo magnetic resonance imaging disclosed a small lesion with high intensity in the inner side of the left middle pons. This hyperhidrosis was thought to be caused by destruction of inhibitory fibers thermoregulating sweating. These findings suggest that at the level of the middle pons inhibitory fibers descend along the inner side of facilitatory fibers thermoregulating sweating, which are speculated to descend the dorso-lateral part of the pontine tegmentum. These findings also suggest that lesions of non-paralytic pontine exotropia may be located in the paramedian pontine reticular formation rostral to the abducens nucleus with ipsilateral medial longitudinal fasciculus lesion, but further investigation is necessary.     

Neurology of eye movements]

Eye movements are necessary for clear and stable vision, for which images of the world should be brought to the fovea and be held steady on the retina. The main types of eye movements consist of saccadic eye movements, vergence, vestibular eye movements, smooth pursuit eye movements and eye movements for visual stabilization. Saccades are fast eye movements and have consistent relationship between their peak velocity and the size of the movements. The burst neurons in the brainstem are the generator of saccades and receive projections from the frontal eye field, supplementary eye field, parietal eye field, basal ganglia, superior colliculus and cerebellum. Saccades are evaluated by a speed and accuracy of the size. There are different types of saccade, such as visually triggered saccades, antisaccades, memory-guided saccade and predictive saccades. The specific test paradigms of saccades may show the localization and the type of diseases. Opsoclonus, flatter-like oscillation, ocular myoclonus, square-wave jerks are characteristic involuntary eye movements. Syndromes of the paramedic pontine reticular formation, medial longitudinal fascicules and one-and-a-half syndrome are caused by disease of the pons.     

Eye movement related neurons in the cat pontine reticular formation: projection to the flocculus

This study examines projection to the cerebellar flocculus of eye movement-related neurons in the median and paramedian part of the cat pontine tegmentum between the trochlear and the abducens nucleus. They were identified by rhythmic activity related to horizontal vestibular nystagmus induced by sinusoidal rotation. These neurons were classified into several groups by their discharge patterns during nystagmus, using criteria of earlier studies on saccadic eye movements and vestibular nystagmus in the monkey. Electrical stimulation of the ipsilateral flocculus elicited antidromic spike responses in a number of burst-tonic neurons and long-lead and medium-lead burst neurons. These neurons were located in and around the medial longitudinal fasciculus, the nucleus raphe pontis and the nucleus reticularis tegmenti pontis. A few neurons tested were also activated antidromically by stimulation of the contralateral flocculus. In contrast, no pauser neurons were activated from the ipsi-lateral flocculus. It is concluded that eye movement-related neurons in the medial pontine tegmentum, except for pauser neurons, directly project to the flocculus and may convey information about eye movements of visual and vestibular origins to the flocculus.     

Primary Position Upbeat Nystagmus during an Acute Attack of Multiple Sclerosis

Background and Purpose

Ocular manifestation is one of the frequent signs of an acute attack in multiple sclerosis (MS), although primary position upbeat nystagmus (PPUN) is rare. The purpose of this study is to determine the incidence of PPUN in MS and to determine the lesions that are responsible for this sign.

Methods

The medical records of 120 MS patients with acute brain lesions were reviewed over a consecutive period of 9 years; of these, 6 patients were found to have PPUN. Other ocular motor abnormalities were analyzed in combination with upbeat nystagmus, video-oculographic findings, and lesions detected on brain MRI.

Results

Lesions in the pontine tegmentum involving the medial longitudinal fasciculus (MLF) and ventral tegmental tract (VTT) were the most common, being observed in three of the six patients with PPUN. One patient exhibited caudal medullary lesions bilaterally affecting the paramedian portion of the posterior tegmentum, and two patients exhibited multiple lesions involving the pons with the cerebral peduncle or medulla. In five patients, other ocular motor dysfunctions, such as gaze-evoked nystagmus (n=3) and internuclear ophthalmoplegia (n=1), were found in combination with upbeat nystagmus.

Conclusions

PPUN is an infrequent, ocular manifestation noted during an acute attack of MS, and was observed in 5% of the present cases. Brainstem lesions in these cases primarily involved the pontine tegmentum and the caudal medulla. These findings support the theory that upbeat nystagmus is attributable to damage to the upward vestibulo-ocular reflex pathway related to the vestibular nucleus, VTT, and interconnecting pathways.     

Primary position upbeat nystagmus

Primary position upbeat nystagmus is a rare clinical finding. We report a patient with clinically isolated syndrome suggestive of multiple sclerosis who presented with primary position upbeat nystagmus. MRI revealed a demyelinating lesion in the lower medulla, which affected the nucleus intercalatus; this type of lesion inhibits the flocculovestibular inhibitory pathway, thereby causing upbeat nystagmus. Nystagmus still persisted after pulsed corticosteroid therapy. This could be due to a loss of central adaptation of the vestibulo-ocular system in our patient, because of more diffuse brainstem damage, shown on vestibular-evoked myogenic potentials as delayed latencies on both sternocleidomastoid muscles and a conduction block for the left extraocular muscles.     

Behavioral and morphological effects of oculomotor nucleus lesion on abducens internuclear neurons in the cat

The activity of identified control and injured abducens internuclear neurons was recorded during spontaneous eye movements in the alert cat. From 2 days following the electrocoagulation of the contralateral oculomotor nucleus, abducens internuclear neurons showed a quick fatigability during eye fixations not observed in controls. Discharge rate during saccades started after the beginning of the eye movement and showed a fast exponential-like decay. These abnormal responses were not further recorded from 20 days following the lesion. Morphological studies indicated that 90% of the abducens internuclear neuron population disappeared 2 months following the lesion and showed no sign of recovery one year later.     

Smooth pursuit eye movement deficits after pontine nuclei lesions in humans.

Eye movements were recorded electroculographically in four patients with basal pontine lesions, demonstrated by MRI. The most prominent eye movement abnormality observed was mild to severe impairment of smooth pursuit and optokinetic nystagmus, mainly ipsilateral to the lesion. This abnormality is thought to result from damage to the pontine nuclei, which form a crucial relay between the cerebral cortex and the cerebellum controlling smooth pursuit. Abnormalities of saccades and the vestibulo-ocular reflex in one patient are also discussed.     

Geotropic ocular deviation with skew and absence of saccade in Creutzfelt-Jakob disease.

Three patients with Creutzfelt-Jakob disease (CJD) showed characteristic ocular manifestations. The head was turned left or right with the eyes deviated downward and skewed. When the head was turned to one side, the eyes very slowly deviated to that side. In addition, spontaneous ocular movements were very slow with no saccadic component early in the apathetic stage. Caloric stimulation produced tonic deviation to the appropriate side without nystagmus. At autopsy one patient showed lesions compatible with the panencephalopathic type of CJD. Although bilateral pretectal areas had marked gliosis, other nuclei and structures associated with oculomotor system in the brainstem, including the oculomotor, trochlear, abducens, vestibular and perihypoglossal nuclei, medial longitudinal fasciculus and para-median pontine reticular formation were preserved. These patients had a supranuclear disorder, probably caused by combined disruption of the direct and indirect frontal eye field to the brainstem pathways plus impairment of the superior colliculus-mediated saccade pathways.     

Internuclear ophthalmoplegia of abduction: clinical and electrophysiological data on the existence of an abduction paresis of prenuclear origin.

Three patients showed unilateral and five bilateral abduction paresis. Five had associated adduction nystagmus of the contralateral eye. Electrophysiological testing of masseter and blink reflexes indicated an ipsilateral rostral pontine or mesencephalic lesion, and excluded a lesion of the infranuclear portion of the abducens nerve. Abduction paresis was attributed to impaired inhibition of the tonic resting activity of the antagonistic medial rectus muscle. The prenuclear origin of the disorder is based on morphological and neurophysiological evidence of an ipsilateral inhibitory connection between the paramedian pontine reticular formation and the oculomotor nucleus running close to but separated from the medial longitudinal fasciculus.     

Frontal eye field efferents in the macaque monkey: II. Topography of terminal fields in midbrain and pons

Frontal eye field (FEF) projections to the midbrain and pons were studied in nine macaque monkeys that were used to study FEF projections to the striatum and thalamus (Stanton et al.: J. Comp. Neurol. 271:473-492, '88). Injections of tritiated amino acids or WGA-HRP were made into FEF cortical locations where low-level microstimulation (less than or equal to 50 microA) elicited saccadic eye movements, and anterograde axonal labeling was mapped. The injections were made into the anterior bank of the arcuate sulcus from dorsomedial sites where large saccades were evoked (lFEF) to ventrolateral sites where small saccades were evoked (sFEF). The largest terminal fields of FEF fibers were located in the ipsilateral superior colliculus (SC). Projections to SC were topographically organized: lFEF sites projected to intermediate and deep layers of caudal SC, sFEF sites projected to intermediate and superficial layers of rostral SC, and FEF sites between these extremes projected to intermediate locations in SC. Patches of terminal labeling were located ipsilaterally in the lateral mesencephalic reticular formation near the parabigeminal nucleus and the ventrolateral pontine reticular formation. These patches were larger from lFEF injections. Small, dense terminal patches were seen in the ipsilateral pontine gray, mostly along the medial and dorsal borders of these nuclei but occasionally in central and dorsolateral regions. Patches of label like those in the pontine nuclei were located ipsilaterally in the reticularis tegmenti pontis nucleus in lFEF cases and bilaterally in sFEF cases. Small terminal patches were found in the nucleus of Darkschewitsch and dorsal and medial parts of the parvicellular red nucleus in most FEF cases. In the pretectal region, labeled terminal patches were consistently found in the nucleus limitans of the posterior thalamus, but we could not determine if label in the nucleus of the pretectal area and dorsal parts of the nucleus of the posterior commissure marked axon terminals or fibers of passage. We found small, lightly labeled terminal patches in the pontine raphe between the rootlets of the abducens nerve (three cases) or in the adjacent paramedian pontine reticular formation (one case). Omnipauser cells in this region are important in initiating saccades. In one sFEF case, very small patches of label were located in the supragenual nuclei anterior to the abducens nuclei and in the ipsilateral nucleus prepositus hypoglossi posterior to the abducens nucleus. Presaccadic burster neurons in the periabducens region are known to fire immediately before horizontal saccades.(ABSTRACT TRUNCATED AT 400 WORDS)     

Primary position upbeat nystagmus. A clinicopathologic study

Eye movements were studied with electro-oculography in a patient with primary position, large amplitude, upbeat nystagmus. The upbeat nystagmus increased in amplitude on upward gaze, decreased on downward gaze, and was not altered by loss of fixation. The patient could not produce smooth pursuit movements upward or to the left, but had normal saccadic and vestibular induced eye movements in all directions. At necropsy, a low grade glioma was found involving primarily the medulla and caudal pons. The inferior olives and prepositus hypoglossal nuclei were diffusely infiltrated with tumor. These results suggest (1) primary position upbeat nystagmus is due to a defect in the upward smooth pursuit system, (2) the lower brain stem at the level of the inferior olives and nucleus prepositus hypoglossi is important in the mediation of vertical pursuit, and (3) primary position upbeat nystagmus can result from damage to several nuclei and interconnecting pathways in the caudal brain stem and midline cerebellum involved in control of vertical smooth pursuit.     

The one-and-a-half syndrome--a unilateral disorder of the pontine tegmentum: a study of 20 cases and review of the literature

The one-and-a-half syndrome is a clinical disorder of extraocular movements characterized by a conjugate horizontal gaze palsy in one direction plus an internuclear ophthalmoplegia in the other. The syndrome is usually due to a single unilateral lesion of the paramedian pontine reticular formation or the abducens nucleus on one side (causing the conjugate gaze palsy), with interruption of internuclear fibers of the ipsilateral medial longitudinal fasciculus after it has crossed the midline from its site of origin in the contralateral abducens nucleus (causing failure of adduction of the ipsilateral eye). Twenty cases are reported; 14 had multiple sclerosis.