Electrophysiologic study of Fisher syndrome

Case Reports

Electrophysiologic Study of Fisher Syndrome

sy exists over the differentiation between bisher and Guillain-Barr6 syndromes, We report a 6-year-old girl with Fishm syndrome as sociated with albuminocytologic dissociation of cerebrospinal fluid (CSF). We also presenl the results ol electrophysiologic studies using several evoked potentials which may help to elucidate the pathogenesis of the syndrome.

Case Report G e n U n i s h i , M D * , A k i h i r o Y a s u h a r a , MD+, A i k o Hori, M D * , T a t e o S u g i m o t o , M D * , a n d Yohnosuke Kobayashi, MD*

Electrophysiologic studies were performed on a 6-yearold girl with Fisher syndrome. We recorded several evoked potentials in this patient: visual evoked potenrials, auditory brainstem responses, auditory evoked potentials, short-latency somatosensory evoked potentials, blink reflex elicited by photic stimuli (photoevoked eyelid microvibration), blink reflex elicited by auditory stimuli (auditory evoked eyelid microvibration), and motor nerve conduction velocity. In our study, photo-evoked eyelid microvibration response was not obtainable; laterality was indicated in visual evoked potential and electroencephalographic studies, and the remaining evoked potentials demonstrated normal responses. The results obtained from the brainstem reflex (photo-evoked eyelid microvibration) suggest that the pathologic focus of Fisher syndrome is located in the midbrain, particularly in the pretectum. It is expected that the combined use of these electrophysiologic techniques may facilitate differentiation between Fisher and Guillain-Barr6 syndromes. Unishi G, Yasuhara A, Hori A, Sugimoto T, Kobayashi Y. Electrophysiologic study of Fisher syndrome. Pediatr Neurol 1988;4:296-300.

Introduction In 1956, Fisher described 3 patients with ocular muscle paralysis, ataxia, and areflexia as "an unusual variant of acute idiopathic polyneuritis" [1]. Since then, many patients presenting with these 3 cardinal symptoms have been reported under the name of Fisher syndrome; however, a number of problems still remain regarding the pathogenesis and anatomic structures responsible for the above neurologic manifestations. Furthermore, controver-

From the *Deparmaent of Pediatrics; Kansai Medical University; Moriguchi, Osaka, Japan; tDepartment of Neurology, Division of Clinical Electrophysiology; University of Iowa Hospitals and Clinics; Iowa City, Iowa.

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This 6-year-old girt was admitted with widening of the palpebral fissures and a waddling gait. Twenty days prior to admission, she had abdominal pain and vomiting for 4 days but no fever. Two days later, she developed a gait disturbance and again had the same abdominal symptoms as well as fever of 39°C. Although fever subsided m I day, the gastrointestinal manifestations lasted for 3 days. One week after the occurrence of the gait disturbance, she had wide palpebral fissures and soon thereafter complained of double visi{m. On ophthalmologic examination, decreased blinking, strabismus, and external exophthalmoplegia of the right eye were demonstrated. The patiem was referred for further neurologic evaluation on the twentieth day of the illness. On admission, the patient was alert and not in acute distress. She was able to walk, but had a waddling gait. Latent strabismus of the right eye was disclosed by a cover-uncover test. Slight bilateral plosis was present. There was no anisocoria and her pupils reacted promptly to light. Eyeball movement was not restricted, but lateral monocular horizontal nystagmus, especially of the left eye, was apparent on lateral gaze. Convergence of the left eye was disturbed. The face was symmetric and Bell's phenomenon was not evident. The tongue was normal and neither dysarthria nor dysphagia was present. Deep tendon reflexes, including biceps, triceps, patellar, and Achilles, were not elicitable: there was no sensory disturbance. Finger-to-nose, heel-to-knee, and Romberg tests were unimpaired. The thyroid gland was not palpable and there were no clinical manifestations suggestive of hyperthyroidism, The remainder of the physical examination was normal Laboratory Findings. Routine laboratory examinations, including thyroid function tests, were normal. Funduscopic examination and cranial computed tomography (CT) were negative. Visual acuity was normal. Extent of exophthalmus was 15 mm by Herter. Visual field examination revealed centripetal narrowing. One week after acknission, CSF demonstrated protein, 49 mg/dl and absence of cells, indicating albuminocytologic dissociation: lgG was slightly elevated (3,6 mg/dl), but an IgG index, expressed as: CSF lgG/sertun lgG CSF Alb/serum AIh was 0.43 which remained within the normal rangc Serum viral antibody titers (i.e., complement fixation titers; CF titersl were 1:256 for type 3 parainfluenza virus and 1:16 for adenovirus, but no elevation was demonstrated in CSF. CF titers against other relevant viruses were not elevated: mycoplasma, herpes, varicella zoster, and coxsackievirus. Clinical Course, After admission, she did not complain of double vision. The waddling gait gradually improved by the twenty-seventh day of illness and ptosis cleared 3 days later. She was discharged 46 days after onset with complete areflexia, mild lateral gaze nystagmus of the left eye, and mild impairment of convergence of the left eye. Three months after onset, there was neither gaze nystagmus nor disturbance ol

Communications should be addressed to: Dr. Yasuhara; Division of Clinical Electrophysiotogy, Department of Neurology; University of Iowa Hospitals and Clinics; Iowa City, IA 52242. Received September 25, 1987; accepted July 13, 198F,.

convergence, but areflexia persisted. Stretch reflexes appeared 2 months later but remained hypoactive. Electrophysiologic Examination. The term, multimodality evoked potentials (MEPs), refers to the recording of several evoked potentials in the same patient [2]. MEPs usually incorporate visual evoked potentials (VEPs) [3,4], auditory brainstem responses (ABRs) [5,6], and shortlatency somatosensory evoked potentials (SSEPs) [7-9]. Small lesions may be undetected when using only these 3 types of evoked potentials; therefore, other evoked potentials were recorded simultaneously: auditory evoked potentials (AEPs) [10], blink reflex elicited by photic stimuli (photo-evoked eyelid microvibration; PEMV) [11,12], blink reflex elicited by auditory stimuli (auditory evoked eyelid microvibration; AMV) [13,14], and motor nerve conduction velocities (MCVs). When possible, blink reflex was elicited by electrical or tapping stimuli. Our first recording of MEPs was during the acute phase of the disorder; we then continued to monitor those evoked potentials that demonstrated abnormalities. Visual Evoked Potentials. VEPs were obtained with an averaging computer (Nihon Koden ATAC-350) from bipolar recording (C3-Ol, C4-O2). Negative deflections at occipital sites displayed an upward recording. For light stimulation, a stroboscope with a strength of 0.6 Joules was used at the frequency of 1 Hz and 128 responses were calculated on computer. In this patient, the major peaks, (i.e., Pl, N1, P2) could be identified on the left side, but P2 and N2 were suppressed on the right (Fig IA). The laterality of the first recording disappeared 4 months after the onset (Fig 1B). Latencies of Pl and Nl were prolonged during the first recording, but returned to the normal range during the second trial. Auditory Brainstem Responses. ABRs were recorded (Fig 2) according to Yasuhara et al. [6]. The latencies of waves I, III, and V were 1.6, 3.8, and 5.3 msec, respectively. There was no laterality of the latency or amplitude. The threshold of wave V was < 25 dB HL. All of these responses were interpreted to be normal. Short-latency Somatosensory Evoked Potentials. SSEPs were studied (Fig 3) according to Cracco and Cracco [7]. The uniform recording site

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was the central region of the scalp (C4). The reference electrode was placed on the back of the hand, contralateral to the left median nerve stimulated. We simultaneously recorded the responses from Erb's point and Cz. A series of 1,012 stimuli was administered at a repetition rate of 5/sec. Sweep time was set at 20 msec. A band pass of 150-3,000 Hz was used. SSEP was recorded during the acute phase. Four positive peaks of P9, PII, PI3, and P14 were recorded, as well as 1 negative N19 peak. The latencies of these peaks were 5.1, 7.3, 8.8, 11.0, and 13.0 msec, respectively, all of which were normal. We determined the peak number according to a report by Yamada et al. [8,9] and the normal range by Tomita et al. [15]. Auditory Evoked Potentials. AEPs (Fig 4) were recorded with the bipolar method (OI-C3, O2-C4). Negative deflections at central sites displayed an upward recording; 50 responses were calculated. The responses revealed 3 negative and 3 positive peaks and the latencies in each wave were in the normal range. No lateralities were observed. Photo-evoked Eyelid Microvibration. The blink reflex elicited by photic stimulation was recorded as the microvibration of the eyelid contraction, termed PEMV. For light stimulation, a hand-triggered stroboscope with a strength of 2 Joules was used. The transducer for microvibration was applied to the central part of the upper eyelid. This gravity transducer was made of titanium-zirconic acid-lead (Nihon Koden MT47111); 1 g of the contraction vibration was converted into 100 mV. The upper graph of Figure 5A demonstrates PEMV recorded during the acute phase when no significant wave was observed; the lower graph of Figure 5A demonstrates PEMV recorded 4 months after onset. The latency was normal (60 msec). Auditory Evoked Eyelid Microvibration. Blink reflex elicited by auditory stimulation was recorded as microvibration of the eyelid, termed auditory evoked eyelid microvibration (AMV). Auditory stimuli consisted of 1,000 Hz, 10 msec tone bursts (excluding rise or fall interval), and were 109 dB SL in intensity; they were produced by a signal controller (Dana Japan DA-502A). The same transducer utilized for PEMV was used. The upper graph of Figure 5B reveals AMV responses in the acute and convalescent phases. The latencies were normal (40-45 msec). Motor Nerve Conduction Velocities. MCVs were normal; the ulnar nerve was 50 msec between the elbow and the wrist and 43 msec between the wrist and the finger. We did not observe the F wave during the acute phase. Electroencephalography. Serial electroencephalograms (EEGs) were recorded on a 12-channel model using disk electrodes applied according to the international 10-20 system. During the acute phase, the basic rhythm was 7 Hz; intermittent rhythmic activity was 4-5 Hz. Hyperventilation, however, provoked slower waves with a frequency recorded at 3.5-3.75 Hz in the parietal occipital regions and a predominantly right laterality. Two months later, the laterality was found to have disappeared.

Unishi et al: ]BEG and EMG in Fisher Syndrome

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Discussion Fisher syndrome is characterized by ophthalmoplegia, ataxia, and loss of tendon reflexes [1]. In many patients, upper respiratory or gastrointestinal symptoms precede the onset of these neurologic complaints which are frequently associated with albuminocytologic dissociation in CSE Because of these clinical manifestations, Fisher syndrome has been discussed in association with acute idiopathic polyneuritis (Guillain-Barr6 syndrome). Although Fisher originally described this syndrome as a variant of GuillainBarr6 syndrome, the anatomic locus has not been precisely demonstrated [1]. Only 1 autopsied patient with Fisher syndrome has been reported, undoubtedly because of the usual favorable outcome [ 16]. Because the pathologic locus responsible for these neurologic manifestations cannot be explained by a peripheral nerve disorder, the site of pathology in this syndrome is not clear. We attempted to locate the origin of electrophysiologic abnormality in Fisher syndrome using MEP techniques. To our knowledge, there are few reports of the combined use of such electrophysiologic methods to study this condition [17]. The abnormal findings of our patient included the laterality of EEG and VEP and the absence of PEMV. We know that the laterality of VEP originates cerebrally because EEGs indicate cerebral dysfunction. EEG abnormalities in Fisher syndrome have been previously reported; Shibaski et al. reported EEG abnormalities recorded serially in a patient with Fisher syndrome [18]. Becker et al. reported 3 patients with Fisher syndrome during childhood, all of whom demonstrated abnormalities provoked by hy-

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perventilation; VEPs also revealed a laterality on the ipsilateral side [19]. These findings suggest the involvement of both the cerebral cortex and brainstem. Conversely, abnormal EEGs have been reported in only a few patients with Guillain-Barr6 syndrome [20]. PEMV is presumed to arise when the visual inputs pass to the pretectum and facial nerve nuclei via the midbram reticular formation [9,21 ]. The absence of PEMV indicates the existence of abnormalities in this pathway. In our study, the AMV was intact; this pathway is believed to exist in the brainstem via the auditory nerve, cochlear, and supraolivary nuclei without passing through the inferior colliculi to the facial nerve nuclei [11,12]. Efferent pathways in both PEMV and AMV traverse the facial nerve: therefore, it appears that the facial nerve is intact. Furthermore. from the laterality of VEPs we believe that the optic nerve was not injured, despite dysfunction in the cerebral cortex. V,rnen both are considered, these findings imply that the PEMV abnormality originated in the pretectum of the midbrain which is the center of this reflex. In addition to these electrophysiologic studies, clinical findings, such as lateral gaze nystagmus and disturbance of convergence, also suggest a pretectal lesion [22]. Derakhshan et al. reported a patient with abnormal CT findings in the midbrain tegmentum which support the current observations [23]. In their patient, contrast-enhanced CT recorded 2 weeks after onset demonstrated an area of increased radiodensity within the midbrain tegmentum; 2 weeks later, this lesion was not visualized. In our patient, unenhanced CT recorded on the twentieth day of the illness was negative; contrast-enhanced CT was not performed. In our patient, MCVs were normal during areflexia. There were few reports of abnormal MCVs in patients with Fisher syndrome, except for 2 patients reported by Guiloff [24]. According to MacLeod, however, abnormal MCVs were demonstrated in about 90% of 114 patients with Guillain-Barl'6 syndrome [25]. It appears that this patient did not have brainstem encephalitis because some of the brainstem responses (i.e., ABR, SSEP, AMV) were normal, although PEMV was not.

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Figure 5. (A) PEMV recorded during the acute phase of the illness in the upper graph with no significant waves. PEMV recorded 120 days after the onset of the illness reveals a normal response in the lower graph. (B) AMV recorded during the acute phase of the illness and 120 days after onset. A M V latencies were within normal limits.

T h e p r e s e n t d a t a s u g g e s t t h a t the p a t h o l o g y o f o u r p a t i e n t w i t h F i s h e r s y n d r o m e is l o c a t e d in t h e m i d b r a i n , e s p e c i a l ly in the p r e t e c t u m . T h e u s e o f serial m o n i t o r i n g to f o l l o w t h e c o u r s e o f the d i s e a s e a p p e a r s to b e h e l p f u l . A l t e r e d c e r e b r a l f u n c t i o n w a s e v i d e n t in the a c u t e p h a s e o f t h e disorder. It is e x p e c t e d t h a t the c o m b i n e d use o f M E P s will n o t o n l y c o n t r i b u t e to t h e e l u c i d a t i o n o f the site o f i n v o l v e m e n t in F i s h e r s y n d r o m e b u t also will h e l p to d i f f e r e n t i a t e it f r o m Guillain-Barr6 syndrome.

This study was supported in part by the Mami Mizutani Foundation.

References

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[6] Yasuhara A, Kinoshita Y, Hori A, Sugimoto T, Iwase S, Kobayashi Y. Auditory brainstem response in neonates with asphyxia and intracranial hemorrhage. Eur J Pediatr 1986;145:347-50. [7] Cracco RQ, Cracco JB. Somatosensory evoked potential in man: Far field potential. Electroencephalogr Clin Neurophysiol 1976; 41:460-6. [8] Yamada T, Kimura J, Nitz DM. Short latency somatosensory evoked potentials following median nerve stimulation in man. Electroencephalogr Clin Neurophysiol 1980;48:367-76. [9] Yamada T, Machida M, Tippin J. Somatosensory evoked potentials. In: Owen JM, Davis H, eds. Evoked potential testing: Clinical application. Orlando: Grune and Stratton, 1985; 109-58. [10] Vaughan HG, Ritter W. The sources of auditory responses recorded from the human scalp. Electroencephalogr Clin Neurophysiol 1970;28:360-7. [11] Yasuhara A, Yamada A, Matsumura T. Photo-evoked eyelid microvibration (blink reflex elicited by flash stimuli) in newborns and children. Brain Dev 1983;5:474-7. [12] Yasuhara A, Hori A, Sugimoto T, Iwase S, Kobayashi Y. Diagnostic/prognostic significance of photo-evoked eyelid microvibration in neonates with intracranial hemorrhage. Electroencephalogr Clin Neurophysiol 1987;67:584-7. [13] Yamada A. Blink reflex elicited by auditory stimulation: Clinical study in newborn infants. Brain Dev 1984;6:45-53. [14] Yamada A, Yasuhara A, Naito H, Yasuhara M. Blink reflex elicited by auditory stimulation in the rabbit. J Neurol Sci 1986; 76:49-59. [15[ Tomita Y, Nishimura S, Tanaka T. Short latency SEPs in infants and children: Developmental changes and maturational index of SEPs. Electroencephalogr Clin Neurophysiol 1986;65:335-43. [16] Phillips MS, Stewart S, Anderson JR. Neurological findings in Miller-Fisher syndrome. J Neurol Neurosurg Psychiatry 1984;47:492-5. [17] Jamal GA, MacLeod WN. Electrophysiologic studies in MillerFisher syndrome. Neurology 1984;34:685-8. ]18] Shibasaki H, Igisu H, Kuroiwa Y. EEG abnormality in Fisher's syndrome. Folia Psychiatr Neurol Jpn 1972;26:201-7. [19] Beeker WJ, Watters GV, Humphreys E Fisher syndrome in childhood. Neurology 1981;31:555-60.

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[20] Poser CM, Fowler CW. The nosologic situation of LandryGuillain-Barr6 syndrome. Acta Neurol Scand 1963;39:187-201. [21] Itoh K, Takada M, Yasui Y, Mizuno N. A pretectofacial prqiection in the cat: A possible link in the visually-triggered blink reflex pathways. Brain Res 1983;273:332-5. [22] Cohen B, Komatsuzaki A, Bender MB. Electrooculographic syndrome in monkeys after pontine reticular formation lesions. Arch Neurol 1968; 18:78-92.

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[23] Derakhshan 1, Lotfi J. Kauflllan B. Ophthahnoplegia. ~taxia. and hyporeflexia (Fisher's syndromel with a midbram lesi~n demola strated by CT scanning. Eur Neurol 1979; 18:361-6. [24] Guiloff RJ. Peripheral nerve conduction in Miller f-l>~hel ~'~m drome. J Neurol Neurosurg Psychiatry 1t)77:40:801~7. [25] MacLeod JG. Electrophysiological studies in the (hJillain-Barre syndrome. Ann Neurol 1981 ;9(suppl):20-7.