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Show STATE OF THE ART The Fisher Variant of Guillain- Barre ´ Syndrome ( Fisher Syndrome) Lee A. Snyder, MD, Vivian Rismondo, MD, and Neil R. Miller, MD Abstract: Fisher syndrome ( FS) is an acute poly-neuropathy typically characterized by the triad of ataxia, areflexia, and ophthalmoplegia, although it may present with 2 or even just 1 of these clinical findings. Similarities between FS and other acute polyneuropathies such as Guillain- Barre ´ syndrome ( GBS) and Bickerstaff brainstem encephalitis ( BBE) suggest that FS is part of a spectrum of autoimmune disorders that may affect the peripheral and/ or central nervous system. Anti- GQ1b antibody is present in the serum of more than 85% of patients with FS, but it is not specific to FS. Why some patients develop FS and others develop typical GBS or one of its other variants is still largely unknown. ( J Neuro- Ophthalmol 2009; 29: 312- 324) T he clinical triad of ataxia, areflexia, and ophthalmo-plegiawas first described by Collier in 1932 as a variant of the Guillain- Barre ´ syndrome ( GBS) ( 1). In 1956, Charles Miller Fisher reported 3 patients with this disorder, postulated that it represented a distinct clinical variant of GBS with a good prognosis ( 2), and pointed out that more invasive techniques such as cerebral angiography, pre-viously used in evaluating such patients, were not necessary ( 3). The disorder became known as the Miller Fisher syndrome or simply ‘‘ Fisher's syndrome'' in 1957, when Smith and Walsh ( 4) used the term in describing 2 additional patients with facial weakness and paresthesias. ( Because Miller is Fisher's middle name, we will follow their lead in this review and refer to the condition as Fisher syndrome [ FS]). Although most published reviews define FS strictly as an acute monophasic illness featuring the clinical triad of ophthalmoplegia, ataxia, and areflexia, it can present with 2 or even 1 of these features. It can also present with features that overlap Bickerstaff brainstem encephalitis ( BBE), a syndrome characterized by ophthalmoplegia, ataxia, im-paired consciousness, and hyperreflexia ( 5), and with features typical of GBS, in which limb weakness is the most prominent finding, sometimes accompanied by sensory loss and nonocular motor cranial neuropathies ( 6). These disorders can all develop after an antecedent infection and share a characteristic elevation of cerebrospinal fluid ( CSF) protein. The identification of the GQ1b autoantibody, present in most patients with FS, has further transformed thinking about the nosologic position of this syndrome. FS is now widely regarded as belonging to a spectrum of acute inflammatory polyneuropathies that includes BBE, anti- GQ1b- positive acute ophthalmoparesis without ataxia ( AO), ataxic GBS, and GBS with ophthalmoplegia ( 7,8) ( Table 1). The ability to test for the presence of the anti- GQ1b antibody has made the diagnosis of FS more consistent and has allowed for a greater appreciation of FS-related disorders. The marked variability in the clinical presentation of FS has blurred the lines between FS in its purest form and related clinical syndromes that defy classification ( Table 2). In this article we review the demographics as well as the neuro- ophthalmic and systemic symptoms and signs, ancillary tests, natural history, and treatment options for disorders that can together be grouped as the Fisher variant of GBS. INCIDENCE AND DEMOGRAPHICS The worldwide incidence of GBS is 1- 2 per 100,000 per year ( 9), with FS as a percentage of such cases varying depending on geography. Whereas FS has been reported at a rate of 1%- 7% of GBS in countries in the Western hemisphere ( 10- 15), it is much more common in Asia, comprising 18%- 19% of cases of GBS studied in Taiwan ( 16,17) and 25% of GBS in Japan ( 18). Men are somewhat more often affected than women, making up 60% and 68% of those with FS in 2 large series ( 18,19). Male predominance is also found in related disorders such as AO Wilmer Eye Institute ( LAS), Johns Hopkins Hospital, Owings Mills, Maryland; Greater Baltimore Medical Center ( VR), Department of Ophthalmology, University of Maryland, and Wilmer Eye Institute, Baltimore, Maryland; and Wilmer Eye Institute ( NRM), Johns Hopkins Hospital, Baltimore, Maryland. Address correspondence to Lee A. Snyder, MD, 23 Crossroads Drive, Suite 310, Owings Mills, MD 21117; E- mail: leeasnyder@ yahoo. com 312 J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 and BBE ( 19- 21). FS has been described in people of all ages, including infants ( 22), although it is less common in children than in adults ( 23). A retrospective study of 466 patients with FS reported a median age of onset of 44 years with a bimodal age distribution peaking between 30 and 39 years and 50 and 59 years ( 19). There is dispute about a seasonal predilection for FS, with studies showing a rise in new cases in the spring ( 20,24- 27), winter ( 17), summer, and fall ( 20). ANTECEDENT INFECTIONS The variability in seasonal occurrence of FS may be related to the typically postinfectious nature of this dis-order. Prodromal upper respiratory symptoms are experi-enced more commonly than gastrointestinal symptoms ( 18,28). The median time from onset of prodromal to neurologic manifestations was 8 days in 1 large series ( 18). Campylobacter jejuni is the most commonly iden-tified agent causing antecedent infection in patients with acute FS and those with GBS and related disorders, followed by Haemophilus influenzae. However, in most patients, no definite infectious association has been detected ( 29). In 1 large study, 21% of patients with FS had positive titers for C. jejuni, 8% for H. influenzae, 4% for cytomegalovirus, and 3% for Mycoplasma pneumoniae ( 19). Less common antecedent infectious agents associated with FS are Epstein- Barr virus ( 30), group A streptococcus ( 31), Coxiella burnetii ( 32), Pasteurella multocida ( 33), Helicobacter pylori ( 34), Aspergillus species ( 35), and varicella zoster ( 36). FS also has been reported after inoculation with the influenza vaccine ( 37) and after vaccination with Pneumovax ( 38). An association does not allow a causal relationship to be inferred ( 39,40). A common infectious etiology links FS with related disorders. In one study of 21 patients with AO, 81% experienced symptoms of antecedent infection, with 57% having symptoms of an upper respiratory tract infection ( 41). C. jejuni was isolated from 1 of those patients ( 41). In another series, 96% of 53 patients with BBE reported prior infectious symptoms, again mostly respiratory ( 19). Kimoto et al ( 42) reported on the spectrum of neurologic disorders that occurs subsequent to C. jejuni enteritis, including, in descending order of frequency, GBS, FS, muscle stretch reflex- preserved GBS, FS/ GBS overlap, acute oropharyngeal palsy, BBE, BBE/ GBS overlap, AO, and ataxic GBS. They correlated these groups with genotypic variations and proposed that the conditions were on a continuum. CLINICAL ASSOCIATIONS FS occasionally develops spontaneously in patients with various autoimmune, neoplastic, or infectious diseases such as myasthenia gravis ( 43- 45), systemic lupus erythematosus ( 46,47), Still disease ( 48), thyroid disease ( 49,50), Hodgkin disease ( 51), lung cancer ( 52), leptome-ningeal signet- ring cell carcinomatosis ( 53), Burkitt lymphoma ( 54), chronic lymphocytic leukemia ( 55), and AIDS ( 56). It has also been reported in patients after treatment with several medications, including tacrolimus ( 57), the antiretroviral agent stavudine ( 24,58), and tumor necrosis factor antagonists ( 59,60). These associations may be fortuitous. CLINICAL FEATURES In its purest form, FS is a triad of acute ophthalmoplegia, ataxia, and areflexia, although even the initial descriptions of the condition include patients with TABLE 1. Clinical syndromes associated with the anti- GQ1b antibody Fisher Syndrome Acute Ophthalmoparesis Bickerstaff Brainstem Encephalitis Guillain- Barre ´ Syndrome Clinical characteristics Ophthalmoplegia, ataxia, hyporeflexia or areflexia ( 2) Ophthalmoplegia ( 41, 68) Ophthalmoplegia, ataxia, impaired consciousness, hyperreflexia ( 5) Weakness, sensory loss, cranial neuropathy, areflexia ( 89) Rate of anti- GQ1b positivity Up to 95% ( 24, 67) Unknown ( 100% is required for diagnosis of ‘‘ anti- GQ1b- positive acute ophthalmoparesis without ataxia'') Up to 68% ( 19) Up to 83% in patients with ophthalmoplegia ( 67); more strongly correlated with other anti- ganglioside antibodies ( 196) Other clinical features common to the syndromes listed above include antecedent infection within the last 4 weeks and CSF albuminocytologic dissociation ( 8). 313 Fisher Syndrome J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 TABLE 2. Clinical findings in Fisher syndrome and related disorders Clinical Features Ito et al, 2008 ( 19) Mori et al, 2001 ( 18): FS Lyu et al, 1997 ( 16): FS Yuki et al, FS * Unclassified 2001 ( 41): AO No. of patients 466 62 50 32 21 Demographics Male 60% 45% 68% - 52% Female 40% 55% 32% - 48% Median age ( years) 44 42 40 45 ( mean) 32 Age range ( years) 2- 86 ( peaks 30- 39, 50- 59) 8- 88 ( peaks 30- 39, 50- 59) 13- 78 ( peaks 30- 39, 50- 59) 10- 69 Antecedent illness 90% - - - 81% Respiratory symptoms 76% 67% 76% 56% 57% Gastrointestinal symptoms 25% 26% 4% 0% 24% Respiratory and gastrointestinal symptoms 12% - - - 5% Serologic testing† 73 patients tested 44 patients tested - - - Campylobacter jejuni 21% 18% - - - Haemophilus influenzae 8% 2% - - - Cytomegalovirus 4% 0 - - - Mycobacterium pneumoniae 3% 0 - - - Initial symptom Diplopia 65% 38% 78% - 86% Gait disturbance 32% 24% 46% 28% 0% Diplopia and ataxia - - 34% - - Dysesthesias 14% 21% 14% 16% 19% Consciousness disturbance 0% 0% - - - Blepharoptosis 4% 2% 2% 9% - Limb weakness 2% 2% - 6% - Bulbar dysfunction - - - 19% - Dysphagia - - 2% - - Photophobia - - 2% - - Dizziness - - - 28% - Blurred vision - - - 34% - Headache - - - 13% - Facial weakness - - - 3% - Neurologic signs during illness External ophthalmoplegia 100% 100% 100% 100% 100% Complete - - 30% - - Binocular - - - - 76% Horizontal and vertical - - - - 48% Horizontal only - - - - 52% 314 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Snyder et al TABLE 2. Continued Clinical Features Ito et al, 2008 ( 19) Mori et al, 2001 ( 18): FS Lyu et al, 1997 ( 16): FS Yuki et al, FS * Unclassified 2001 ( 41): AO Vertical only - - - - 0% Pupillary dysfunction 35% 32% 42% - 0% Ataxia 100% 100% 100% 100% 0% Deep tendon reflexes absent or decreased 100% 0% 100% 100% 52% Deep tendon reflexes normal or brisk 0% 100% - - 48% Limb weakness 25% 24% 20% 25% 0% Blepharoptosis 37% 32% 58% 59% 33% Facial weakness 22% 16% 32% 50% 19% Bulbar palsy 17% 8% 26% 59% 10% Babinski sign 2% 15% - - 0% Trigeminal dysfunction - - - 16% - Sensory disturbance 52% 42% - 59% - Dysesthesia 45% 40% 24% - 38% Superficial sense impairment 7% 8% 20% - - Deep sense impairment 17% 13% 18% - 0% Sinus tachycardia - - - 3% - Micturition disturbance - - 16% 3% - Laboratory tests - - - - - Cerebrospinal fluid cytoalbuminous dissociation‡ - - - - 14% Within 1 week 37% 30 - - - Within 2 weeks 76% 54 - - - Anti- GQ1b- positive 83% 58 89% of 36 patients tested - 100% Anti- GT1a- positive 78% 66 - - - Neuroimaging § MRI Abnormality 1% 7% - - 5% Outcomes Median time to nadir ( days) 4% - 6 5.5 - Assisted ventilation 1% 0 - - - * Unclassified patients exhibited ophthalmoplegia and ataxia but not areflexia. -, data not reported. † A subgroup of patients underwent serologic testing. ‡ The majority of patients in the Ito et al study underwent CSF testing. § The majority of patients in the Ito et al study underwent MRI testing. FS, Fisher syndrome; AO, acute ophthalmoparesis without ataxia. 315 Fisher Syndrome J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 additional findings such as mild limb weakness or drowsiness ( 2). Symptoms The initial symptom in FS is typically diplopia ( 65%), followed by gait disturbance ( 32%) ( 19). These symptoms were described as occurring simultaneously in 14% of patients with FS ( 19). Dysesthesias are also commonly reported, occurring in 14% of patients with FS in 2 large studies ( 18,19). Less common presenting symptoms are blepharoptosis, mild limb weakness ( 19), dysphagia, photophobia ( 18), blurred vision, dizziness, headache, and facial weakness ( 16). One man with FS and positive serum anti- GQ1b autoantibodies presented with a severe and persistent headache that the authors postulated was due to antibody- mediated effects on the trigeminovas-cular pain pathway ( 61). Ophthalmoplegia Ophthalmoplegia seems to be the most prevalent and consistent finding in FS and related disorders during the acute phase of the illness ( 19) and can manifest as various combinations of deficits ( 21) ( Fig. 1). Ophthalmoplegia is closely tied to the presence of anti- GQ1b antibodies, although these antibodies also can be found in patients with no eye movement abnormalities ( 8,62). Most patients with FS exhibit bilateral, relatively symmetrical ophthalmople-gia, but the condition also can be unilateral ( 41,63- 65). Up to one third of patients have complete external ophthalmo-plegia ( 18). A review of 31 patients with complete bilateral ophthalmoplegia during a 34- year period ( 66) revealed that FS was the most common cause and, together with GBS, was responsible for 58% of such cases. The ophthalmoplegia seen in FS is similar to that described in AO ( 21). A study that compared the findings in 11 anti- GQ1b antibody- positive patients with AO to the findings in 20 anti- GQ1b antibody- positive patients with other disorders including FS concluded that the patterns of ophthalmoplegia were similar in these groups. Abduction deficit was the most common finding, occurring in 73% ( 21). The association of acute ophthalmoparesis with the anti- GQ1b antibody was identified in 1993, when Chiba et al ( 67) described 5 patients with isolated ophthalmopa-resis, 4 of whom had had a common cold as a prodrome, the fifth having had diarrhea. All had evidence of mild bilateral sixth cranial nerve palsy, and the condition was designated ‘‘ atypical FS.'' Interestingly, 2 patients in that study who were negative for anti- GQ1b antibody ( 1 with typical FS and 1 with GBS with ophthalmoplegia) had isolated com-plete unilateral sixth cranial nerve palsy, suggesting that FIG. 1. Bilateral mydriasis, pupillary areflexia, and impaired supraduction in Fisher syndrome. A 17- year- old college student developed photophobia, diplopia, and paresthesias 1 month after a febrile illness. Blood tests were positive for IgG and IgM antibodies against Epstein- Barr viral antigens and showed elevated levels of GQ1b autoantibodies. Her pupils did not constrict to direct light or a near target. 316 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Snyder et al a different mechanism and pattern of ophthalmoplegia might be present in anti- GQ1b antibody- negative patients ( 67). Yuki et al ( 68) described 8 anti- GQ1b antibody-positive patients with ophthalmoplegia and no ataxia and termed the condition simply ‘‘ acute ophthalmoparesis.'' Two had horizontal and vertical gaze palsies; the other 6 had bilateral sixth cranial nerve palsies. Yuki et al ( 41) subsequently summarized the findings in 21 other patients with AO, most of whom had bilateral, horizontal, mostly abduction deficits. In this group, gaze deficits were bilateral in 76%. Both horizontal and vertical movements were affected in 48%, and 52% had gaze deficits limited to the horizontal plane. Bilateral abduction deficit was the most common pattern, occurring in 33% of patients. Other case series have confirmed that the most characteristic pattern of AO is an initial bilateral sixth cranial nerve palsy followed by third cranial nerve palsy with internal ophthalmoplegia ( 8,69), a pattern present in 48% of the 21 patients reported by Yuki et al ( 41). No studies have determined definitively the frequency of the anti- GQ1b antibody in patients with isolated ophthalmoparesis. However, in a study of 100 patients with isolated sixth cranial nerve palsies, when traditional etiologies such as diabetes mellitus, vascular disorders, trauma, or tumor were excluded, the anti- GQ1b antibody was present in the sera of 25%, indicating that some cases may be related to FS ( 70). ‘‘ Brainstem'' Ocular Motor Deficits Clinical findings suggestive of brainstem ocular motor deficits have been described in some patients with otherwise typical FS, suggesting the possibility of central nervous system ( CNS) involvement ( 71,72). In a study of 50 patients with typical FS ( 18), 2 exhibited preservation of the Bell phenomenon despite paralysis of voluntary upgaze; 2 had gaze- evoked, horizontal, dissociated nys-tagmus; 1 showed preservation of convergence despite adduction palsy; and 1 had an internuclear ophthalmople-gia. Other forms of apparently CNS ocular motor dysfunction reported in patients with otherwise typical FS include dorsal midbrain syndrome with eyelid retraction ( 2), convergence spasm, divergence paralysis ( 73,74), saccadic dysmetria ( 75), defective vestibulo- ocular reflex despite recovery of upgaze, central vestibular nystagmus, and relative preservation of optokinetic nystagmus and preservation of the vestibulo- ocular reflex despite an otherwise complete ophthalmoplegia ( 76). Internal Ophthalmoplegia Internal ophthalmoplegia is quite common in FS and related syndromes, with the pupillary constriction to light and near stimulation ranging from slow to absent ( 21,77). Light- near dissociation may be present ( 78- 80). All 3 patients initially reported by Fisher exhibited a sluggish pupillary constriction to light ( 2), and in the series of 50 patients with FS reported by Mori et al ( 18), mydriasis was present in 42%- about half of whom had anisocoria- and the pupillary constriction to light was sluggish in 42%. Of 11 patients with FS in a study linking FS to anti- GQ1b antibody positivity, 64% had absent or sluggish pupillary reflexes ( 81). Most of these findings were bilateral. With regard to disorders that share the anti- GQ1B antibody, the incidence of internal ophthalmoplegia is highest in patients with FS exhibiting limb weakness ( 52%), followed by BBE ( 42%) and typical FS ( 37%) ( 8). Pupillary abnormalities seem to occur less commonly in patients with AO, as evidenced by the lack of pupillary defects in the study by Yuki et al ( 68) of 21 patients with AO and 7% involvement in the series of 15 patients reported by Odaka et al ( 8). Nevertheless, in 1 study of 11 patients with AO, about half had internal ophthalmoplegia ( 21). Patients with anti- GQ1b antibody positivity have also been reported to have internal ophthalmoplegia as the prominent feature with little or no external ophthalmople-gia ( 79,82,83). Many of these patients demonstrate dener-vation supersensitivity to cholinergic agents, suggesting ciliary ganglion or short ciliary nerve involvement ( 78,79). Ataxia Ataxia is often the initial presenting symptom in FS and can be quite severe, causing a gait disturbance so profound that, in 1 large series, 30% of affected persons could not walk independently ( 18). Ataxia in FS is asso-ciated with the anti- GQ1b antibody. This autoantibody also can be found in patients who have a variant of ataxia without ophthalmoplegia ( 84,85). One study showed that anti- GQ1b antibody- positive patients had more cerebellar-type severe ataxia than patients with FS who were antibody-negative ( 81). The autoantibodies seen in the ataxic forms of GBS also exhibit the same fine specificity patterns for other gangliosides as those seen in FS, further evidence that the 2 disorders are related ( 86). The pathogenesis of the ataxia in FS is not completely understood. Both peripheral and central mechanisms have been implicated. Early studies showed a correlation between abnormalities in muscle fiber afferents and severity of ataxia, suggesting impaired proprioception as the mecha-nism ( 87,88). Indeed, postural sway analysis reveals selective dysfunction of proprioception in patients with FS ( 85,89) and BBE ( 19). Thus, dysfunction of muscle spindle afferent fibers may be responsible for the ataxia, at least in some patients ( 18,89,90). However, the presence of anti- cerebellar antibodies in the sera of patients with FS has led other investigators to suggest that the ataxia in such patients is cerebellar in origin ( 91,92). Additional research is needed to elucidate fully the pathophysiology of ataxia in FS and related syndromes. 317 Fisher Syndrome J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Areflexia Deep tendon areflexia is part of the classically described FS triad, although it is also part of typical GBS ( 6). The loss of reflexes was initially thought to be present in almost all patients with FS. However, reflexes are intact more often than originally believed ( 93). For example, in a series of 581 patients with FS and BBE who presented with acute ophthalmoplegia and ataxia, Ito et al ( 19) found that of the 528 patients with intact consciousness, 12% had normal or even accentuated deep tendon reflexes ( 19). In a review of 13 Korean patients with ophthalmoplegia and ataxia and anti- GQ1b antibody- positivity, 4 ( 31%) had nor-mal reflexes ( 21). A 1992 review of the published reports of FS ( 23) concluded that 18.4% of patients had intact reflexes. Electrophysiologic studies support peripheral nerve dysfunc-tion as the cause of reduced deep tendon reflexes ( 94,95). Other Manifestations Other findings often reported in patients with FS and related syndromes include various patterns of blepharop-tosis, occurring in up to 58% of patients ( 18,23,41), and eyelid nystagmus ( 96). Dysesthesias can occur in 45% of patients during the acute phase of illness ( 19). Facial and bulbar palsies were described in 32% and 26%, re-spectively, in 1 large study ( 18). Limb weakness is a prominent and distinguishing feature of GBS as opposed to FS, but a mild decrease in muscle strength is commonly seen in FS ( 18). Several case reports have described bilateral and, less commonly, unilateral optic neuritis in FS ( 97- 102). Headache is reported in FS and was present in 2 of Fisher's original patients ( 2). Pain in FS can occur periocularly and in the back and extremities ( 103,104). In a study by Koga et al ( 103), pain was described by 22% of 27 patients, half of whom localized the discomfort to the periocular region, and was more common in children and young adults. Micturition disturbances were present in 16% of patients with FS in 1 large case series ( 18), and urinary retention also has been reported ( 17,105). Angle- closure glaucoma developed in a patient with FS in whom pupillary dysfunction occurred in the setting of a congenitally narrow anterior chamber angle ( 106). One patient with FS had unilateral absence of corneal sensation ( 107). Autonomic neuropathy can occur in FS but is less severe and less frequent than in GBS or BBE ( 105). In 1 study of cardio-vascular autonomic function ( 108), subclinical autonomic dysfunction was identified in most patients with FS. LABORATORY FINDINGS CSF Protein A rise in protein concentration in the cerebrospinal fluid ( CSF) in 1 of Fisher's original patients was the key piece of evidence that led the author to believe that the condition bore a close relationship to a ‘‘ GBS type of polyneuropathy'' ( 2). Elevation of CSF protein with minimal or no cellular reaction or ‘‘ cytoalbuminous dissociation,'' may be absent at the time of initial symptoms, becoming prominent over the next weeks ( 109). It seems to occur more frequently in the overlap syndrome of BBE/ GBS than in FS and occurs even less frequently in AO ( 8,41). However, it is difficult to compare CSF findings among these variants because the finding of elevated CSF protein depends on when in the course of the disease the specimen is collected, information that is not consistently reported. Anti- GQ1b Antibody The discovery of the frequent presence of the anti- GQ1b antibody in the acute- phase sera of patients with FS has helped clinicians understand the broader spectrum of FS and related disorders ( 7). This antibody was first reported in FS in 1992 by Chiba et al ( 7), who described 6 patients. This report and subsequent studies ( 109) have affirmed that this antibody, which cross- reacts with the GT1a ganglioside, is present in more than 85% of patients with FS. It is absent in normal control subjects and is found less often in patients with GBS without ophthalmoplegia ( 67,81,110,111). This autoantibody is also found in FS-related diseases such as GBS with ophthalmoplegia ( 67), AO ( 68), BBE ( 21,112), and ataxic GBS without ophthal-moplegia ( 86). Clinically, the presence of the anti- GQ1b antibody correlates with the presence of ophthalmoplegia ( 41) and ataxia ( 84) but has been reported in the absence of both ( 62). Odaka et al ( 8) described clinical similarities and variations among the diseases that constitute the ‘‘ anti- GQ1b syndrome'' and proposed this as further evidence that that they are part of a clinically continuous range of illnesses. The GQ1b ganglioside is a cell surface component that is concentrated in the paranodal regions of the human third, fourth, and sixth cranial nerves. It contains poly-saccharides identical to the lipopolysaccharides ( LPS) contained in the outer membranes of certain bacteria and may thus be the target of an immune response initiated against epitopes shared by these nerve fibers and various infectious agents ( 41). In 1994, Yuki et al ( 113) found that monoclonal antibodies to the GQ1b ganglioside reacted to LPS fractions from C. jejuni isolated from patients with FS. These investigators proposed that, through the mechanism of molecular mimicry, they were not only a marker for the disease, but actually played a role in its pathophysiology. Anti- GQ1b/ GT1a antibodies also bind to LPS from FS- related H. influenzae strains, suggesting a common pathogenesis ( 29). The finding of these antibodies in the sera of patients with isolated internal ophthalmoplegia suggests that these epitopes may also be present in the ciliary ganglia ( 41,67,79,114). 318 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Snyder et al Anti- GQ1b antibodies affect the neuromuscular junction, inducing axon and Schwann cell degeneration through complement- mediated pathways ( 115- 119). Gan-glioside complexes containing GQ1b have also been investigated as other possible targets for autoantibodies ( 120,121) whose specificity may be associated with the clinical features of GBS and FS ( 90). In addition, reactivity to minor gangliosides has been shown to be present in FS and related disorders and may prove to be helpful in their diagnosis and treatment ( 122). In comparing the prevalence of CSF protein elevation with that of serum anti- GQ1b antibodies in the diagnosis of FS, Nishimoto et al ( 109) demonstrated that in the 1st week after onset of symptoms, anti- GQ1b antibodies were almost always present, whereas elevated CSF protein was found in only 25% of patients. They concluded that CSF findings are not as sensitive as the anti- GQ1b antibody assay in diag-nosing FS in the early stage of the disorder. In addition, anti- GQlb antibody titers have been shown to correlate with clinical severity of the disease, particularly ophthalmoplegia ( 123) and also demonstrate a relationship to disease course because they decline with clinical recovery ( 81,109). NEUROIMAGING AND PATHOLOGIC STUDIES Results of neuroimaging are usually unremarkable in patients with FS. However, in 1 large study ( 19), 1% of patients with FS had MRI abnormalities in the midbrain, cerebellum, or middle cerebellar peduncle. Other individual case reports have described MRI lesions in the brainstem ( 124- 127); fourth ( 128), sixth ( 129), and seventh cranial nerves ( 130,131); spinocerebellar tracts in the region of the lower medulla ( 132); lumbosacral roots ( 131); cauda equina ( 133); and posterior columns ( 134) of patients with FS. In general, lesions seen on MRI in patients with FS appear as hyperintense abnormalities on T2 images or, more commonly, as enhancing areas on postcontrast T1 images ( 127,130,135- 138). Similar imaging abnormalities have been described in patients with GBS, although much less frequently ( 24). A small number of necropsy studies have shown inflammatory brainstem lesions ( 23,139- 141) as well as demyelination of peripheral nerves ( 142). In 1 patient with recurrent FS, demyelination and axonal impairment of the intra- axial portion of the third cranial nerve were present and associated with mild retrograde degeneration in the third, fifth, sixth, and seventh cranial nerve nuclei ( 143). CLINICAL COURSE Most patients with FS recover spontaneously and completely within 2- 3 months of disease onset. In 1 study ( 18), the median time from onset of neurologic symptoms to beginning of recovery in 28 untreated patients was 12 days for ataxia and 15 days for ophthalmoplegia. The median time to full recovery was 1 month for ataxia and 3 months for ophthalmoplegia. At 6 months after illness onset, no patients had substantial disability. The recovery rate was unrelated to patient age, sex, evidence of prior infection, disability at illness peak, or latency to peak ( 18). Although FS is typically regarded as a monophasic illness, recurrences have been reported ( 99,144- 158). Patients may present differently during subsequent episodes ( 150). Chronic ophthalmoplegia associated with persis-tently high titers of anti- GQ1b antibody has been reported ( 159). Rarely, the disease can progress, and patients develop features similar to GBS, requiring more significant supportive care and mechanical ventilation ( 22,160- 166). In a recent series, 1% of patients with FS required assisted ventilation compared with 34% of those with BBE ( 19). However, patients with FS who develop quadriparesis, often considered to have a ‘‘ FS/ GBS overlap,'' are more likely to require mechanical ventilation than patients with typical GBS ( 167). Other serious complications in FS include coma ( 168), ballism ( 164,169), cardiomyopathy from dysautonomia ( 170), lactic acidosis ( 58), cortico-bulbar dysfunction ( 24,171), and life- threatening hypona-tremia from inappropriate secretion of antidiuretic hormone ( SIADH) ( 172). Death in FS is rare ( 142). TREATMENT Although no randomized, controlled clinical trials of treatment for FS have been performed ( 173), a retrospective analysis of 92 consecutive patients showed that treatment with intravenous immune globulin ( IVIg) had no effect on overall outcome, presumably because patients with FS typically show good spontaneous recovery ( 174). Plasma-pheresis has also been used in selected patients with FS but without definite clinical benefit ( 175- 185). As in all conditions in which spontaneous resolution is the rule, the risks of treatment in patients with FS must be balanced with the high likelihood of spontaneous recovery ( 186- 190). OVERVIEW FS seems to represent a collection of manifestations derived from a spectrum of disorders that include GBS, BBE, and AO. The factors that determine which patients develop FS and which develop the related disorders remain unknown. The anti- GQ1b antibody is much more com-monly associated with FS than with its related disorders, although patients with each of the disorders may have no serologic evidence of the antibody. When an infectious process caused by C. jejuni precedes the development of 1 of these conditions, the serotype of the responsible strain seems to influence the clinical presentation and the severity of the condition ( 29,191) 319 Fisher Syndrome J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Host susceptibility probably also plays a role in phenotypic expression ( 192). Because the GQ1b antibody is found in sites unaffected by FS, its location in the body cannot be the only reason certain tissues are preferentially affected ( 114,115,193). For example, the antibody may have more access to certain structures through a compro-mised blood- brain barrier, perhaps leading to conditions more consistent with the CNS manifestations seen in BBE ( 85,89). Other factors may include the degree to which these gangliosides play a role in neural functioning or the ‘‘ level of immunologic tolerance to microbial glycans that mimic self gangliosides'' ( 119). Although the full immunologic cascade leading to FS has yet to be elucidated, the frequent finding of the GQ1b autoantibody is of great diagnostic value. Research into the molecular targets involved in the development of FS has already led to rational therapeutic studies in which mono-clonal antibodies have shown success in treating murine models of the disorder ( 194,195). These investigations may ultimately clarify our understanding of the pathogenesis of FS and related disorders and lead to insights that will aid in treating more severe and generalized neuropathies. REFERENCES 1. Collier J. Peripheral neuritis. Edinb Med J 1932; 39: 601- 618. 2. Fisher M. An unusual variant of acute idiopathic polyneuritis ( syndrome of ophthalmoplegia, ataxia and areflexia). N Engl J Med 1956; 255: 57- 65. 3. Fisher MC, Miller C. Fisher: the master of clinicopathologic correlation. Interview by Jonathan D. Trobe. J Neuroophthalmol 2004; 24: 68- 80. 4. Smith JL, Walsh FB. Syndrome of external ophthalmoplegia, ataxia and areflexia ( Fisher). AMA Arch Ophthalmol 1957; 58: 109- 114. 5. Odaka M, Yuki N, Yamada M, et al. Bickerstaff ' s brainstem encephalitis: clinical features of 62 cases and a subgroup associated with Guillain- Barre ´ syndrome. Brain 2003; 126: 2279- 2290. 6. Van der Meche FG, Van Doorn PA, Meulstee J, et al. Diagnostic and classification criteria for the Guillain- Barre ´ syndrome. Eur Neurol 2001; 45: 133- 139. 7. Chiba A, Kusunoki S, Shimizu T, et al. Serum IgG antibody to ganglioside GQ1b is a possible marker of Miller Fisher syndrome. Ann Neurol 1992; 31: 677- 679. 8. Odaka M, Yuki N, Hirata K. Anti- GQ1b IgG antibody syndrome: clinical and immunological range. J Neurol Neurosurg Psychiatry 2001; 70: 50- 55. 9. Hughes RA, Rees JH. Clinical and epidemiologic features of Guillain- Barre ´ syndrome. J Infect Dis 1997; 176( Suppl 2): S92- S98. 10. Bogliun G, Beghi E, Italian GBS Registry Study Group. Incidence and clinical features of acute inflammatory polyradiculoneuropathy in Lombardy, Italy, 1996. Acta Neurol Scand 2004; 110: 100- 106. 11. Ropper AH. Unusual clinical variants and signs in Guillain- Barre ´ syndrome. Arch Neurol 1986; 43: 1150- 1152. 12. Sedano MJ, Calleja J, Canga E, et al. Guillain- Barre ´ syndrome in Cantabria, Spain: an epidemiological and clinical study. Acta Neurol Scand 1994; 89: 287- 292. 13. Guillain- Barre ´ syndrome variants in Emilia- Romagna, Italy: 1992- 3: incidence, clinical features, and prognosis: Emilia- Romagna Study Group on Clinical and Epidemiological Problems in Neurology. J Neurol Neurosurg Psychiatry 1998; 65: 218- 224. 14. Rees JH, Soudain SE, Gregson NA, et al. Campylobacter jejuni infection and Guillain- Barre ´ syndrome. N Engl J Med 1995; 333: 1374- 1379. 15. Govoni V, Granieri E, Tola MR, et al. The frequency of clinical variants of Guillain- Barre ´ syndrome in Ferrara, Italy. J Neurol 1999; 246: 1010- 1014. 16. Lyu RK, Tang LM, Cheng SY, et al. Guillain- Barre ´ syndrome in Taiwan: a clinical study of 167 patients. J Neurol Neurosurg Psychiatry 1997; 63: 494- 500. 17. Yuan CL, Wang YJ, Tsai CP. Miller Fisher syndrome: a hospital-based retrospective study. Eur Neurol 2000; 44: 79- 85. 18. Mori M, Kuwabara S, Fukutake T, et al. Clinical features and prog-nosis of Miller Fisher syndrome. Neurology 2001; 56: 1104- 1106. 19. Ito M, Kuwabara S, Odaka M, et al. Bickerstaff ' s brainstem encephalitis and Fisher syndrome form a continuous spectrum: clinical analysis of 581 cases. J Neurol 2008; 255: 674- 682. 20. Lee JH, Sung IY, Rew IS. Clinical presentation and prognosis of childhood Guillain- Barre ´ syndrome. J Paediatr Child Health 2008; 44: 449- 454. 21. Lee SH, Lim GH, Kim JS, et al. Acute ophthalmoplegia ( without ataxia) associated with anti- GQ1b antibody. Neurology 2008; 71: 426- 429. 22. Benito- Leon J, Bravo J, Mateos F, et al. Miller Fisher syndrome in infancy. Childs Nerv Syst 1996; 12: 559- 561. 23. Berlit P, Rakicky J. The Miller Fisher syndrome: review of the literature. J Clin Neuroophthalmol 1992; 12: 57- 63. 24. Lo YL. Clinical and immunological spectrum of the Miller Fisher syndrome. Muscle Nerve 2007; 36: 615- 627. 25. Garrett J, Ryan P. A child with Miller Fisher syndrome. J Paediatr Child Health 2002; 38: 414- 416. 26. Hung PL, Chang WN, Huang LT, et al. A clinical and electrophysiologic survey of childhood Guillain- Barre ´ syndrome. Pediatr Neurol 2004; 30: 86- 91. 27. Cheng BC, Chang WN, Chang CS, et al. Guillain- Barre ´ syndrome in southern Taiwan: clinical features, prognostic factors and therapeutic outcomes. Eur J Neurol 2003; 10: 655- 662. 28. Yuki N. Infectious origins of, and molecular mimicry in, Guillain- Barre ´ and Fisher syndromes. Lancet Infect Dis 2001; 1: 29- 37. 29. Koga M, Gilbert M, Li J, et al. Antecedent infections in Fisher syndrome: a common pathogenesis of molecular mimicry. Neurology 2005; 64: 1605- 1611. 30. Schnorf H, Rathgeb JP, Kohler A. Anti- GQ1b- positive Miller Fisher syndrome in a patient with acute Epstein- Barr virus infection and negative Campylobacter serology. Eur Neurol 1998; 40: 177. 31. Yuki N, Hirata K. Fisher's syndrome and group A streptococcal infection. J Neurol Sci 1998; 160: 64- 66. 32. Diaz Ortuno A, Maeztu C, Munoz JA, et al. Miller Fisher syndrome associated with Q fever. J Neurol Neurosurg Psychiatry 1990; 53: 615- 626. 33. Bennetto LP, Lyons P. Miller Fisher syndrome associated with Pasteurella multocida infection. J Neurol Neurosurg Psychiatry 2004; 75: 1786- 1797. 34. Chiba S, Sugiyama T, Yonekura K, et al. An antibody to VacA of Helicobacter pylori in the CSF of patients with Miller- Fisher syndrome. Neurology 2004; 63: 2184- 2186. 35. Finsterer J, Niedermayr A, Weigl PG, et al. Anti- GQ1b- negative Miller- Fisher syndrome with lower cranial nerve involvement from parasinusoidal aspergilloma. J Infect 2006; 52: e81- e85. 36. Takano H, Yuki N. Fisher's syndrome associated with chickenpox and anti- GQ1b antibody. J Neurol 1995; 242: 255- 266. 37. Blanco- Marchite CI, Buznego- Suarez L, Fagundez- Vargas MA, et al. Miller Fisher syndrome, internal and external ophthalmoplegia after flu vaccination. Arch Soc Esp Oftalmol 2008; 83: 433- 435. 38. Thaler A. Miller Fisher syndrome in a 66- year- old female after flu and Pneumovax vaccinations. J Am Med Dir Assoc 2008; 9: 283- 294. 39. Funakoshi K, Koga M, Takahashi M, et al. Campylobacter coli enteritis and Guillain- Barre ´ syndrome: no evidence of molecular mimicry and serological relationship. J Neurol Sci 2006; 246: 163- 168. 40. Koga M, Koike S, Hirata K, et al. Ambiguous value of Haemophilus influenzae isolation in Guillain- Barre ´ and Fisher syndromes. J Neurol Neurosurg Psychiatry 2005; 76: 1736- 1738. 320 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Snyder et al 41. Yuki N, Odaka M, Hirata K. Acute ophthalmoparesis ( without ataxia) associated with anti- GQ1b IgG antibody: clinical features. Ophthalmology 2001; 108: 196- 200. 42. Kimoto K, Koga M, Odaka M, et al. Relationship of bacterial strains to clinical syndromes of Campylobacter- associated neuropathies. Neurology 2006; 67: 1837- 1843. 43. Lau KK, Goh KJ, Lee HC, et al. The co- occurrence of serologically proven myasthenia gravis and Miller Fisher/ Guillain Barre ´ overlap syndrome- a case report. J Neurol Sci 2008; 276: 187- 198. 44. Mak W, Chan KH, Ho SL. A case of ocular myasthenia gravis and Miller- Fisher syndrome. Hosp Med 2005; 66: 116- 127. 45. Newsom- Davis J. Myasthenia gravis and the Miller- Fisher variant of Guillain- Barre ´ syndrome. Curr Opin Neurol 1997; 10: 18- 21. 46. Bingisser R, Speich R, Fontana A, et al. Lupus erythematosus and Miller- Fisher syndrome. Arch Neurol 1994; 51: 828- 830. 47. Hess DC, Awad E, Posas H, et al. Miller Fisher syndrome in systemic lupus erythematosus. J Rheumatol 1990; 17: 1520- 1522. 48. Desai SS, Allen E, Deodhar A. Miller Fisher syndrome in adult onset Still's disease: case report and review of the literature of other neurological manifestations. Rheumatology ( Oxford) 2002; 41: 216- 222. 49. Vetsch G, Pato U, Fischli S, et al. A combined presentation of Graves' disease and Miller- Fisher syndrome. Lancet 2008; 371: 1886. 50. Polizzi A, Ruggieri M, Vecchio I, et al. Autoimmune thyroiditis and acquired demyelinating polyradiculoneuropathy. Clin Neurol Neu-rosurg 2001; 103: 151- 154. 51. Rubio- Nazabal E, Marey- Lopez J, Torres- Carrete JP et al. Miller- Fisher syndrome and Hodgkin's disease. J Neurol Neurosurg Psychiatry 2002; 73: 344. 52. Csepany T, Boczan J, Magyar MT, et al. Miller Fisher syndrome- a presenting clinical manifestation of lung cancer in a previously apparently healthy individual. J Neurol 2004; 251: 898- 900. 53. Nakatsuji Y, Sadahiro S, Watanabe S, et al. Leptomeningeal signet-ring cell carcinomatosis presenting with ophthalmoplegia, areflexia and ataxia. Clin Neuropathol 2001; 20: 272- 275. 54. Gentile S, Messina M, Rainero I, et al. Miller Fisher syndrome associated with Burkitt's lymphoma. Eur J Neurol 2006; 13: 430. 55. Aki Z, Aksoy O, Sucak G, et al. Miller- Fisher syndrome associated with chronic lymphocytic leukemia. Neurol India 2008; 56: 198- 200. 56. Hiraga A, Kuwabara S, Nakamura A, et al. Fisher/ Gullain- Barre ´ overlap syndrome in advanced AIDS. J Neurol Sci 2007; 258: 148- 150. 57. Kaushik P, Cohen AJ, Zuckerman SJ, et al. Miller Fisher variant of Guillain- Barre ´ syndrome requiring a cardiac pacemaker in a patient on tacrolimus after liver transplantation. Ann Pharmacother 2005; 39: 1124- 1127. 58. Shah SS, Rodriguez T, McGowan JP. Miller Fisher variant of Guillain- Barre ´ syndrome associated with lactic acidosis and stavudine therapy. Clin Infect Dis 2003; 36: e131- e133. 59. Kurmann PT, Van Linthoudt D, So AK. Miller- Fisher syndrome in a patient with rheumatoid arthritis treated with adalimumab. Clin Rheumatol 2009; 28: 93- 104. 60. Stubgen JP. Tumor necrosis factor- antagonists and neuropathy. Muscle Nerve 2008; 37: 281- 292. 61. Friedman DI, Potts E. Headache associated with Miller Fisher syndrome. Headache 2007; 47: 1347- 1358. 62. Maddison P. Anti- GQ1b IgG antibody syndrome without oph-thalmoplegia: clinical and immunological features. J Neurol Neurosurg Psychiatry 2001; 71: 282- 293. 63. Smith J, Clarke L, Severn P, et al. Unilateral external ophthalmo-plegia in Miller Fisher syndrome: case report. BMC Ophthalmol 2007; 7: 7. 64. Ichikawa H, Kamiya Y, Susuki K, et al. Unilateral oculomotor nerve palsy associated with anti- GQ1b IgG antibody. Neurology 2002; 59: 957- 968. 65. Susuki K, Yuki N, Muramatsu M, et al. Unilateral ophthalmoparesis and limb ataxia associated with anti- GQ1b IgG antibody. J Neurol 2000; 247: 652- 663. 66. Keane JR. Bilateral ocular paralysis: analysis of 31 inpatients. Arch Neurol 2007; 64: 178- 180. 67. Chiba A, Kusunoki S, Obata H, et al. Serum anti- GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain- Barre ´ syndrome: clinical and immunohis-tochemical studies. Neurology 1993; 43: 1911- 1917. 68. Yuki N. Acute paresis of extraocular muscles associated with IgG anti- GQ1b antibody. Ann Neurol 1996; 39: 668- 672. 69. Sakurai Y, Mannen T, Kusunoki S. Acute isolated ophthalmoplegia as a variant of Miller- Fisher syndrome. Muscle Nerve 1998; 21: 1107. 70. Tatsumoto M, Odaka M, Hirata K, et al. Isolated abducens nerve palsy as a regional variant of Guillain- Barre ´ syndrome. J Neurol Sci 2006; 243: 35- 38. 71. Meienberg O, Ryffel E. Supranuclear eye movement disorders in Fisher's syndrome of ophthalmoplegia, ataxia, and areflexia: report of a case and literature review. Arch Neurol 1983; 40: 402- 405. 72. Najim al- Din AS, Anderson M, Eeg- Olofsson O, et al. Neuro-ophthalmic manifestations of the syndrome of ophthalmoplegia, ataxia and areflexia: observations on 20 patients. Acta Neurol Scand 1994; 89: 87- 94. 73. Oguro H, Yamaguchi S, Abe S, et al. Acute divergence paralysis in the Miller Fisher syndrome. Rinsho Shinkeigaku 2005; 45: 524- 526. 74. Pinchoff BS, Slavin ML, Rosenstein D, et al. Divergence paralysis as the initial sign in the Miller Fisher syndrome. Am J Ophthalmol 1986; 101: 741- 752. 75. Minoda R, Uno K, Toriya T, et al. Neurologic and otologic findings in Fisher's syndrome. Auris Nasus Larynx 1999; 26: 153- 158. 76. al- Din SN, Anderson M, Eeg- Olofsson O et al. Neuro- ophthalmic manifestations of the syndrome of ophthalmoplegia, ataxia and areflexia: a review. Acta Neurol Scand 1994; 89: 157- 163. 77. Caccavale A, Mignemi L. Acute onset of a bilateral areflexical mydriasis in Miller- Fisher syndrome: a rare neuro- ophthalmologic disease. J Neuroophthalmol 2000; 20: 61- 72. 78. Nitta T, Kase M, Shinmei Y, et al. Mydriasis with light- near disso-ciation in Fisher's syndrome. Jpn J Ophthalmol 2007; 51: 224- 227. 79. Radziwill AJ, Steck AJ, Borruat FX, et al. Isolated internal ophthalmoplegia associated with IgG anti- GQ1b antibody. Neurology 1998; 50: 307. 80. Igarashi Y, Takeda M, Maekawa H, et al. Fisher's syndrome without total ophthalmoplegia. Ophthalmologica 1992; 205: 163- 167. 81. Yuki N, Sato S, Tsuji S, et al. Frequent presence of anti- GQ1b antibody in Fisher's syndrome. Neurology 1993; 43: 414- 417. 82. Yuki N, Koga M, Hirata K. Isolated internal ophthalmoplegia associated with immunoglobulin G anti- GQ1b antibody. Neurology 1998; 51: 1515- 1526. 83. Sugita A, Yanagisawa T, Kamo T, et al. Internal ophthalmoplegia with anti- GQ1b IgG antibody. J Neurol 2002; 249: 1475- 1486. 84. Kusunoki S, Chiba A, Kanazawa I. Anti- GQ1b IgG antibody is associated with ataxia as well as ophthalmoplegia. Muscle Nerve 1999; 22: 1071- 1074. 85. Mori M, Kuwabara S, Koga M, et al. IgG anti- GQ1b positive acute ataxia without ophthalmoplegia. J Neurol Neurosurg Psychiatry 1999; 67: 668- 670. 86. Yuki N, Susuki K, Hirata K. Ataxic Guillain- Barre ´ syndrome with anti- GQ1b antibody: relation to Miller Fisher syndrome. Neurology 2000; 54: 1851- 1853. 87. Weiss JA, White JC. Correlation of 1a afferent conduction with the ataxia of Fisher syndrome. Muscle Nerve 1986; 9: 327- 332. 88. Ropper AH, Shahani B. Proposed mechanism of ataxia in Fisher's syndrome. Arch Neurol 1983; 40: 537- 548. 89. Kuwabara S, Asahina M, Nakajima M, et al. Special sensory ataxia in Miller Fisher syndrome detected by postural body sway analysis. Ann Neurol 1999; 45: 533- 536. 90. Kanzaki M, Kaida KI, Ueda M, et al. Ganglioside complexes containing GQ1b as targets in Miller Fisher and Guillain- Barre ´ syndromes. J Neurol Neurosurg Psychiatry 2008; 79: 1148- 1152. 91. Inoue A, Koh C, Iwahashi T. Detection of serum anticerebellar antibodies in patients with Miller Fisher syndrome. Eur Neurol 1999; 42: 230- 234. 92. Kornberg AJ, Pestronk A, Blume GM, et al. Selective staining of the cerebellar molecular layer by serum IgG in Miller- Fisher and related syndromes. Neurology 1996; 47: 1317- 1320. 321 Fisher Syndrome J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 93. Paine MA, Keir G, Plant GT. Atypical Miller Fisher syndrome with GQ1b antibodies. J Clin Neurosci 1996; 3: 268- 271. 94. Jamal GA, MacLeod WN. Electrophysiologic studies in Miller Fisher syndrome. Neurology 1984; 34: 685- 688. 95. Jamal GA, Ballantyne JP. The localization of the lesion in patients with acute ophthalmoplegia, ataxia and areflexia ( Miller Fisher syndrome): a serial multimodal neurophysiological study. Brain 1988; 111( Pt 1): 95- 114. 96. Abdul- Rahman AM, Raj R. Eyelid nystagmus in Miller Fisher syndrome. Br J Ophthalmol 2008; 92: 1576. 97. Carvalho AA, Galvao MD, Rocha MS, et al. Miller Fisher syndrome and optic neuritis: case report. Arq Neuropsiquiatr 2000; 58: 1115- 1117. 98. Ouhabi H, Bourazza A, Rouimi A, et al. Bilateral optic neuritis and ponto- mesencephalic involvement shown by MRI in Miller- Fisher syndrome. Rev Neurol ( Paris) 1998; 154: 780- 782. 99. Chan JW. Optic neuritis in anti- GQ1b positive recurrent Miller Fisher syndrome. Br J Ophthalmol 2003; 87: 1185- 1196. 100. Colding- Jorgensen E, Vissing J. Visual impairment in anti- GQ1b positive Miller Fisher syndrome. Acta Neurol Scand 2001; 103: 259- 60. 101. Toshniwal P. Demyelinating optic neuropathy with Miller- Fisher syndrome: the case for overlap syndromes with central and peripheral demyelination. J Neurol 1987; 234: 353- 358. 102. Lolekha P, Phanthumchinda K. Optic neuritis in a patient with Miller- Fisher syndrome. J Med Assoc Thai 2008; 91: 1909- 1913. 103. Koga M, Yuki N, Hirata K. Pain in Miller Fisher syndrome. J Neurol 2000; 247: 720- 731. 104. Minguez M, Reus S, Pascual E. Dorso- lumbar pain as the first manifestation of Miller Fisher syndrome. Clin Exp Rheumatol 1998; 16: 509. 105. Kordouni M, Jibrini M, Siddiqui MA. Long- term transvenous temporary pacing with active fixation bipolar lead in the management of severe autonomic dysfunction in Miller- Fisher syndrome: a case report. Int J Cardiol 2007; 117: e10- e12. 106. Brittain CJ, Lake D. Acute angle closure in Miller Fisher syndrome. Eye 2006; 20: 739- 40. 107. Farah S, Khuraibet AJ, Montaser MA, et al. Miller Fisher syndrome: unique involvement of ophthalmic division of trigeminal nerve. Clin Neurol Neurosurg 1995; 97: 328- 331. 108. Lyu RK, Tang LM, Hsu WC, et al. Quantitative cardiovascular autonomic function study in Fisher syndrome. J Neurol Neurosurg Psychiatry 2002; 73: 333- 335. 109. Nishimoto Y, Odaka M, Hirata K, et al. Usefulness of anti- GQ1b IgG antibody testing in Fisher syndrome compared with cerebro-spinal fluid examination. J Neuroimmunol 2004; 148: 200- 205. 110. Willison HJ, Veitch J, Paterson G, et al. Miller Fisher syndrome is associated with serum antibodies to GQ1b ganglioside. J Neurol Neurosurg Psychiatry 1993; 56: 204- 206. 111. Tagawa Y, Matsumoto Y, Yuki N. Clinical utility of measurement for anti- GM1 and anti- GQ1b antibodies. No To Shinkei 1998; 50: 849- 853. 112. Yuki N, Sato S, Tsuji S, et al. An immunologic abnormality common to Bickerstaff ' s brain stem encephalitis and Fisher's syndrome. J Neurol Sci 1993; 118: 83- 87. 113. Yuki N, Taki T, Takahashi M, et al. Molecular mimicry between GQ1b ganglioside and lipopolysaccharides of Campylobacter jejuni isolated from patients with Fisher's syndrome. Ann Neurol 1994; 36: 791- 793. 114. Chiba A, Kusunoki S, Obata H, et al. Ganglioside composition of the human cranial nerves, with special reference to pathophysiology of Miller Fisher syndrome. Brain Res 1997; 745: 32- 36. 115. Goodyear CS, O'Hanlon GM, Plomp JJ, et al. Monoclonal antibodies raised against Guillain- Barre ´ syndrome- associated Campylobacter jejuni lipopolysaccharides react with neuronal gangliosides and paralyze muscle- nerve preparations. J Clin Invest 1999; 104: 697- 708. 116. O'Hanlon GM, Plomp JJ, Chakrabarti M, et al. Anti- GQ1b ganglioside antibodies mediate complement- dependent destruction of the motor nerve terminal. Brain 2001; 124: 893- 906. 117. O'Hanlon GM, Bullens RW, Plomp JJ, et al. Complex gangliosides as autoantibody targets at the neuromuscular junction in Miller Fisher syndrome: a current perspective. Neurochem Res 2002; 27: 697- 709. 118. Halstead SK, Morrison I, O'Hanlon GM et al. Anti- disialosyl antibodies mediate selective neuronal or Schwann cell injury at mouse neuromuscular junctions. Glia 2005; 52: 177- 189. 119. Willison HJ, Plomp JJ. Anti- ganglioside antibodies and the presynaptic motor nerve terminal. Ann N Y Acad Sci 2008; 1132: 114- 123. 120. Kaida K, Kanzaki M, Morita D, et al. Anti- ganglioside complex antibodies in Miller Fisher syndrome. J Neurol Neurosurg Psychiatry 2006; 77: 1043- 1046. 121. Kusunoki S, Kaida K, Ueda M. Antibodies against gangliosides and ganglioside complexes in Guillain- Barre ´ syndrome: new aspects of research. Biochim Biophys Acta 2008; 1780: 441- 444. 122. Tatsumoto M, Koga M, Gilbert M, et al. Spectrum of neurological diseases associated with antibodies to minor gangliosides GM1b and GalNAc- GD1a. J Neuroimmunol 2006; 177: 201- 208. 123. Mizoguchi K. Anti- GQ1b IgG antibody activities related to the severity of Miller Fisher syndrome. Neurol Res 1998; 20: 617- 624. 124. Chikakiyo H, Kunishige M, Yoshino H, et al. Delayed motor and sensory neuropathy in a patient with brainstem encephalitis. J Neurol Sci 2005; 234: 105- 108. 125. Giroud M, Mousson C, Chalopin JM, et al. Miller- Fisher syndrome and pontine abnormalities on MRI: a case report. J Neurol 1990; 237: 489- 90. 126. Taphoorn MJ, Uitdehaag BM, Lanting P. A brain- stem lesion in the Miller Fisher syndrome demonstrated by CT and MRI. J Neurol 1991; 238: 243. 127. Hatanaka T, Higashino H, Yasuhara A, et al. Miller Fisher syndrome: etiological significance of serial blink reflexes and MRI study. Electromyogr Clin Neurophysiol 1992; 32: 317- 319. 128. Tanaka H, Yuki N, Hirata K. Trochlear nerve enhancement on three-dimensional magnetic resonance imaging in Fisher syndrome. Am J Ophthalmol 1998; 126: 322- 324. 129. Hosoya T, Adachi M, Yamaguchi K, et al. Abducens nerve enhancement demonstrated by multiplanar reconstruction of contrast- enhanced three- dimensional MRI. Neuroradiology 2001; 43: 295- 301. 130. Garcia- Rivera CA, Rozen TD, Zhou D, et al. Miller Fisher syndrome: MRI findings. Neurology 2001; 57: 1755. 131. Pedotti R, Carpo M, Lucchi S, et al. Lumbosacral root and facial nerve enhancement in Miller Fisher syndrome. J Neurol 1998; 245: 753- 764. 132. Urushitani M, Udaka F, Kameyama M. Miller Fisher- Guillain- Barre ´ overlap syndrome with enhancing lesions in the spinocerebellar tracts. J Neurol Neurosurg Psychiatry 1995; 58: 241- 243. 133. Hattori M, Takada K, Yamada K, et al. A case of Miller Fisher syndrome with gadolinium- enhancing lesions in the cranial nerves and the cauda equina on magnetic resonance imaging. Rinsho Shinkeigaku 1999; 39: 1054- 1058. 134. Inoue N, Ichimura H, Goto S, et al. MR imaging findings of spinal posterior column involvement in a case of Miller Fisher syndrome. AJNR Am J Neuroradiol 2004; 25: 645- 648. 135. Nagaoka U, Kato T, Kurita K, et al. Cranial nerve enhancement on three- dimensional MRI in Miller Fisher syndrome. Neurology 1996; 47: 1601- 1612. 136. Shibata A, Hosoya T, Kato T, et al. Abducens nerve enhancement in acute ophthalmoparesis. Radiat Med 1998; 16: 375- 387. 137. Hsieh DT, Singh R, Zecavati N, et al. Teaching Video NeuroImage: near complete ophthalmoplegia in GQ1b antibody- positive Miller Fisher: video and MRI correlation. Neurology 2008; 71: e31. 138. Petty RK, Duncan R, Jamal GA, et al. Brainstem encephalitis and the Miller Fisher syndrome. J Neurol Neurosurg Psychiatry 1993; 56: 201- 203. 139. Al- Din AN, Anderson M, Bickerstaff ER, et al. Brainstem encephalitis and the syndrome of Miller Fisher: a clinical study. Brain 1982; 105( Pt 3): 481- 495. 322 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Snyder et al 140. Bignami A, Servim M. Acute internal and external ophthalmoplegia with muscle weakness. Lancet 1963; 1: 1110. 141. Bickerstaffer ER. Brain- stem encephalitis further observations on a grave syndrome with benign prognosis. Br Med J 1957; 1: 1384- 1387. 142. Phillips MS, Stewart S, Anderson JR. Neuropathological findings in Miller Fisher syndrome. J Neurol Neurosurg Psychiatry 1984; 47: 492- 495. 143. Barontini F, Di Lollo S, Maurri S, et al. Localization of the pathological process in Miller Fisher syndrome. Ital J Neurol Sci 1992; 13: 221- 225. 144. Tomcik J, Dufek M, Hromada J, et al. Recurrent Miller Fisher syndrome with abnormal terminal axon dysfunction: a case report. Acta Neurol Belg 2007; 107: 112- 114. 145. Dorr J, Dieste FJ, Klaasen van Husen D, et al. A case of recurrent Miller Fisher syndrome mimicking botulism. Neurol Sci 2006; 27: 424- 435. 146. Sharma V, Chan YC, Ong et al. Bickerstaff ' s brainstem encephalitis: can it recur? J Clin Neurosci 2006; 13: 277- 279. 147. Madhavan S, Geetha, Bhargavan PV. Recurrent Miller Fisher syndrome. J Assoc Physicians India 2004; 52: 582- 584. 148. Orr CF, Storey CE. Recurrent Miller- Fisher syndrome. J Clin Neurosci 2004; 11: 307- 309. 149. Derakhshan I. Recurrent Miller Fisher syndrome. Neurol India 2003; 51: 283. 150. Hamaguchi T, Yamaguchi K, Komai K, et al. Recurrent anti- GQ1b IgG antibody syndrome showing different phenotypes in different periods. J Neurol Neurosurg Psychiatry 2003; 74: 1350. 151. Kitamura H, Honda T, Uchida T, et al. Recurrent Fisher syndrome. Nippon Naika Gakkai Zasshi 2002; 91: 474- 476. 152. Sitajayalakshmi S, Borgohain R, Mani J, et al. Recurrent Miller Fisher syndrome: a case report. Neurol India 2002; 50: 365- 367. 153. Chida K, Nomura H, Konno H, et al. Recurrent Miller Fisher syndrome: clinical and laboratory features and HLA antigens. J Neurol Sci 1999; 165: 139- 143. 154. Riche G, Caudie C, Vial C, et al. Recurrent Miller Fisher syndrome and anti- GQ1b antibodies. Rev Med Interne 1998; 19: 192- 195. 155. Dewarrat A, Regli F, Steck A, et al. Recurrent Miller Fisher syndrome. Significance of anti- GQ1B antibodies. Schweiz Arch Neurol Psychiatr 1995; 146: 180- 184. 156. Vinals M, Anciones B, Cruz Martinez A, et al. Recurrent Miller- Fisher syndrome associated with brachial neuritis. Neurologia 1989; 4: 61- 65. 157. Sawyer CN, Naik RB. A case of recurrent Miller- Fisher syndrome. Br J Hosp Med 1987; 38: 566. 158. Yip PK, Tsai SY, Chen RC. The syndrome of ophthalmoplegia, ataxia and areflexia ( Fisher's syndrome): clinical analysis of 9 cases. Zhonghua Yi Xue Za Zhi ( Taipei) 1991; 47: 126- 132. 159. Reddel SW, Barnett MH, Yan WX, et al. Chronic ophthalmoplegia with anti- GQ1b antibody. Neurology 2000; 54: 1000- 1002. 160. Arakawa Y, Yoshimura M, Kobayashi S, et al. The use of intravenous immunoglobulin in Miller Fisher syndrome. Brain Dev 1993; 15: 231- 233. 161. Pulitano S, Viola L, Genovese O, et al. Miller- Fisher syndrome mimicking intracranial hypertension following head trauma. Childs Nerv Syst 2005; 21: 473- 476. 162. Eggenberger ER, Coker S, Menezes M. Pediatric Miller Fisher syndrome requiring intubation: a case report. Clin Pediatr ( Phila) 1993; 32: 372- 375. 163. Gerard V, Ossemann M, Dive A. Miller Fisher variant syndrome, an unusual and severe clinical presentation: a case report. Eur J Emerg Med 2007; 14: 239- 40. 164. Odaka M, Yuki N, Hirata K. Bilateral ballism in a patient with overlapping Fisher's and Guillain- Barre ´ syndromes. J Neurol Neurosurg Psychiatry 1999; 67: 206- 208. 165. Blau I, Casson I, Lieberman A, et al. The not- so- benign Miller Fisher syndrome: a variant of the Guillain- Barre ´ syndrome. Arch Neurol 1980; 37: 384- 395. 166. Arai M, Odaka M, Yuki N, et al. A patient with overlapping Bickerstaff ' s brainstem encephalitis, Miller Fisher syndrome and Guillain- Barre ´ syndrome during the clinical course. Eur J Neurol 2002; 9: 115- 126. 167. Funakoshi K, Kuwabara S, Odaka M, et al. Clinical predictors of mechanical ventilation in Fisher/ Guillain- Barre ´ overlap syndrome. J Neurol Neurosurg Psychiatry 2009; 80: 60- 64. 168. Matsumoto H, Kobayashi O, Tamura K, et al. Miller Fisher syndrome with transient coma: comparison with Bickerstaff brainstem encephalitis. Brain Dev 2002; 24: 98- 101. 169. Odaka M, Yuki N, Arai M, et al. A case of Guillain- Barre ´ syndrome associated with bilateral ballism: an overlap between Fisher's syndrome and Guillain- Barre ´ syndrome. Rinsho Shinkeigaku 1998; 38: 745- 749. 170. Oomura M, Yamawaki T, Oe H, et al. Association of cardiomy-opathy caused by autonomic nervous system impairment with the Miller Fisher syndrome. J Neurol Neurosurg Psychiatry 2003; 74: 689- 90. 171. Lo YL, Ratnagopal P. Corticobulbar dysfunction in the Miller Fisher syndrome. Clin Neurol Neurosurg 2003; 105: 156- 158. 172. Ramaprasad ST, Poretsky L. Life- threatening hyponatremia due to the syndrome of inappropriate secretion of antidiuretic hormone ( SIADH) in a patient with the Miller Fisher syndrome. Endocr Pract 1995; 1: 163- 165. 173. Overell JR, Hsieh ST, Odaka M, et al. Treatment for Fisher syndrome, Bickerstaff ' s brainstem encephalitis and related disor-ders. Cochrane Database Syst Rev 2007; 1: CD004781. 174. Mori M, Kuwabara S, Fukutake T, et al. Intravenous immunoglob-ulin therapy for Miller Fisher syndrome. Neurology 2007; 68: 1144- 1146. 175. Kawasaki S, Kodama T, Mizoue S, et al. Effectiveness of plasma exchange in Miller Fisher syndrome- a case report. Nippon Ganka Gakkai Zasshi 2005; 109: 148- 152. 176. Kambara C, Matsuo H, Fukudome T, et al. Miller Fisher syndrome and plasmapheresis. Ther Apher 2002; 6: 450- 453. 177. Yeh JH, Chen WH, Chen JR, et al. Miller Fisher syndrome with central involvement: successful treatment with plasmapheresis. Ther Apher 1999; 3: 69- 71. 178. Nishikage H, Saito A, Nakano Y, et al. Case of Fisher syndrome with pemphigus treated by immuno- adsorption plasmapheresis. Nippon Naika Gakkai Zasshi 1996; 85: 274- 285. 179. Cher LM, Merory JM. Miller Fisher syndrome mimicking stroke in immunosuppressed patient with rheumatoid arthritis responding to plasma exchange. J Clin Neuroophthalmol 1993; 13: 138- 140. 180. Littlewood R, Bajada S. Successful plasmapheresis in the Miller- Fisher syndrome. Br Med J ( Clin Res Ed) 1981; 282: 778. 181. Maisey DN, Olczak SA. Successful plasmapheresis in the Miller- Fisher syndrome. Br Med J ( Clin Res Ed) 1981; 282: 1159. 182. Odaka M, Yuki N, Hirata K. Comparison of the adsorption ability between tryptophan and modified tryptophan columns. Ther Apher 1997; 1: 353- 355. 183. Yuki N. Tryptophan- immobilized column adsorbs immunoglobulin G anti- GQ1b antibody from Fisher's syndrome: a new approach to treatment. Neurology 1996; 46: 1644- 1651. 184. Ohtsuka K, Nakamura Y, Hashimoto M, et al. Fisher syndrome associated with IgG anti- GQ1b antibody following infection by a specific serotype of Campylobacter jejuni. Ophthalmology 1998; 105: 1281- 1285. 185. Ohtsuka K, Nakamura Y, Tagawa Y, et al. Immunoadsorption therapy for Fisher syndrome associated with IgG anti- GQ1b antibody. Am J Ophthalmol 1998; 125: 403- 406. 186. Wittstock M, Benecke R, Zettl UK. Therapy with intravenous immunoglobulins: complications and side- effects. Eur Neurol 2003; 50: 172- 175. 187. Turner B, Wills AJ. Cerebral infarction complicating intravenous immunoglobulin therapy in a patient with Miller Fisher syndrome. J Neurol Neurosurg Psychiatry 2000; 68: 790- 801. 188. Nakajima M. Posterior reversible encephalopathy complicating intravenous immunoglobulins in a patient with Miller- Fisher syndrome. Eur Neurol 2005; 54: 58- 60. 189. Kimoto K, Odaka M, Yuki N, et al. Complications with plasma exchange. Rinsho Shinkeigaku 2000; 40: 1044- 1046. 323 Fisher Syndrome J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 190. Chida K, Takase S, Itoyama Y. Development of facial palsy during immunoadsorption plasmapheresis in Miller Fisher syndrome: a clinical report of two cases. J Neurol Neurosurg Psychiatry 1998; 64: 399- 401. 191. Takahashi M, Koga M, Yokoyama K, et al. Epidemiology of Campylobacter jejuni isolated from patients with Guillain- Barre ´ and Fisher syndromes in Japan. J Clin Microbiol 2005; 43: 335- 339. 192. Sheikh KA, Nachamkin I, Ho TW, et al. Campylobacter jejuni lipopolysaccharides in Guillain- Barre ´ syndrome: molecular mim-icry and host susceptibility. Neurology 1998; 51: 371- 378. 193. Paparounas K. Anti- GQ1b ganglioside antibody in peripheral nervous system disorders: pathophysiologic role and clinical relevance. Arch Neurol 2004; 61: 1013- 1016. 194. Halstead SK, Zitman FM, Humphreys PD, et al. Eculizumab prevents anti- ganglioside antibody- mediated neuropathy in a murine model. Brain 2008; 131: 1197- 1208. 195. Lehmann HC, Hartung HP. Complementing the therapeutic armamentarium for Miller Fisher syndrome and related immune neuropathies. Brain 2008; 131: 1168- 1170. 196. Winer JB. Guillain Barre ´ syndrome. Mol Pathol 2001; 54: 381- 385. 324 q 2009 North American Neuro- Ophthalmology Society J Neuro- Ophthalmol, Vol. 29, No. 4, 2009 Snyder et al |
