Fisher syndrome and Bickerstaff brainstem encephalitis (Fisher–Bickerstaff syndrome)

Journal of Neuroimmunology 215 (2009) 1–9

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Journal of Neuroimmunology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n e u r o i m

Review article

Fisher syndrome and Bickerstaff brainstem encephalitis (Fisher–Bickerstaff syndrome) Nobuhiro Yuki ⁎ Departments of Neurology and Clinical Research, Niigata National Hospital, 3-52 Akasaka, Kashiwazaki, Niigata 945-8585, Japan

a r t i c l e

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Article history: Received 9 March 2009 Received in revised form 8 May 2009 Accepted 29 May 2009 Keywords: Anti-GQ1b antibody Bickerstaff brainstem encephalitis Campylobacter jejuni Fisher syndrome Guillain–Barré syndrome Molecular mimicry

a b s t r a c t Since identification of the autoantibodies in Fisher syndrome, remarkable progress has been made in our understanding of that syndrome and related conditions. Because of the similarities in the clinical presentations of it and Bickerstaff brainstem encephalitis, opinions differ as to whether the two are distinct or related syndromes and whether the lesions responsible for ophthalmoplegia, ataxia and areflexia are in the peripheral or central nervous system. The finding that both conditions have autoantibodies in common suggested that the autoimmune mechanism is the same in both and they are not distinct conditions. Common autoantibodies, antecedent infections, and neuroimaging and neurophysiological results from a large study offer conclusive evidence that these conditions form a continuous spectrum with variable central and peripheral nervous system involvement. A new eponymic terminology “Fisher–Bickerstaff syndrome” may be helpful for nosology. A considerable number of patients with Bickerstaff brainstem encephalitis have associated Guillain–Barré syndrome, indicative that these two disorders are closely related on a continuous spectrum. That finding is further evidence of continuity between Bickerstaff brainstem encephalitis and Fisher syndrome, a variant of Guillain–Barré syndrome. © 2009 Elsevier B.V. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . Fisher syndrome . . . . . . . . . . . . . . . . . . 2.1. Clinical profile . . . . . . . . . . . . . . . . 2.2. Autoantibobies . . . . . . . . . . . . . . . . 2.3. Responsible lesions . . . . . . . . . . . . . . 2.4. Molecular mimicry . . . . . . . . . . . . . . 2.5. Campylobacter genes . . . . . . . . . . . . . 2.6. Overlap with Guillain-Barré syndrome . . . . . 3. Bickerstaff brainstem encephalitis . . . . . . . . . . 3.1. Historical perspective . . . . . . . . . . . . . 3.2. Autoimmune etiology . . . . . . . . . . . . . 3.3. Comparison with Fisher syndrome . . . . . . . 3.3.1. Case report . . . . . . . . . . . . . 3.3.2. Diagnostic criteria . . . . . . . . . . 3.3.3. Clinical similarities . . . . . . . . . . 3.3.4. Both CNS and PNS involvement . . . . 3.3.5. Immunopathogenesis . . . . . . . . . 3.3.6. Proposal: “Fisher–Bickerstaff syndrome” 3.4. Overlap with Guillain–Barré syndrome . . . . . 3.5. Treatment . . . . . . . . . . . . . . . . . . 4. Conclusion . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . .

⁎ Tel.: +81 257 22 2126; fax: +81 257 22 7487. E-mail address: [email protected]. 0165-5728/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2009.05.020

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N. Yuki / Journal of Neuroimmunology 215 (2009) 1–9

1. Introduction Kusunoki's group identified IgG antibodies against GQ1b in patients with Fisher syndrome (FS) and proposed those autoantibodies as a diagnostic marker of FS (Chiba et al., 1992). Their landmark study, soon confirmed by other investigators (Willison et al., 1993; Yuki et al., 1993b), set the stage for new research on the pathogenesis and treatment of FS and related conditions. Willison's group clarified the role of complement and complement regulators in mediating motor nerve terminal injury in a murine FS model and proposed complement inhibitor therapy. This journal recently published that exciting research review (Willison et al., 2008a). Collaborative work by Kuwabara's group and ours has reported clinical, neurophysiological and immunological findings for FS and Bickerstaff brainstem encephalitis (BBE), as well as Guillain–Barré syndrome (GBS). This article reviews our research findings, focusing on the continuity between FS and BBE. 2. Fisher syndrome Because of confusion engendered by the mistaken notion that Miller and Fisher were two separate people, several investigators actually have used “Miller–Fisher syndrome” (Giroud et al., 1990; Kornberg et al., 1996; Nam Shin et al., 1997). I therefore use the term “Fisher syndrome” rather than “Miller Fisher syndrome”. Fisher described three cases of acute ophthalmoplegia, ataxia and areflexia subsequent to upper respiratory infectious symptoms and postulated that the disorder is a GBS variant because of cerebrospinal fluid (CSF) albuminocytological dissociation found in one patient (Fisher, 1956). 2.1. Clinical profile Three (6%) of 53 FS patients, who were seen at a hospital over 20 years, developed profound limb weakness and progressed to GBS, proving Fisher's postulation (Mori et al., 2001). In their other 50 FS patients, respiratory symptoms occurred in the month before FS onset in 76%, gastrointestinal symptoms in 4% and fever in 2%. No infectious symptoms occurred in 18%. The median interval between infection onset and development of neurological symptoms was 8 days (range 1 to 30 days). FS frequently started on the same day as diplopia (78%), ataxia (46%) or both (34%). Other initial symptoms were dysesthesia in the limbs (14%), dysphagia (2%), blepharoptosis (2%) and photophobia (2%). The median interval between the onset of diplopia and ataxia was 1 day (range 0 to 4 days). The median time to the nadir of symptoms after neurologic onset was 6 days (range 2 to 21 days). There was complete external ophthalmoplegia in 30% of the patients at nadir, and 30% could not walk independently owing to ataxia (Mori et al., 2001). Mydriasis was present in 42%, and light reflexes were sluggish in 42%. Facial palsy was found in 32%. Sensory loss, which occurred in 24%, included decreases in superficial sensations in 20% and in deep sensations in 18%. Results of the thumb localizing test, a marker for impaired proprioception in the fixed limb, were abnormal in 76%. Almost all the patients showed a decrease in ataxia, ophthalmoplegia and areflexia in that order (Mori et al., 2001). The natural recovery courses for 28 of the 50 patients who had received no immunotherapy had respective median (range) periods between neurologic onset and the beginning of recovery from ataxia and ophthalmoplegia of 12 (3 to 41) and 15 (3 to 46) days. The respective median (range) periods for the disappearance of ataxia and ophthalmoplegia were 32 (8 to 271) and 88 (29 to 165) days.

patients) (Ito et al., 2008), 96% (23/24) (Chiba et al., 1993) and 100% (9/9) (Willison and Veitch, 1994). Anti-GQ1b IgG antibody titers peak at disease onset then decrease with time (Chiba et al., 1993; Willison and Veitch, 1994; Yuki et al., 1993b). CSF albuminocytological dissociation often is present but the protein concentration raised in only 25% of FS patients during the first week (Nishimoto et al., 2004); whereas, it is increased in 71% during the second and 84% during the third week. AntiGQ1b antibody testing is much more useful than a CSF examination for diagnosing FS during the first week. Lumbar punctures are not required serially when a physician gets a positive anti-GQ1b IgG antibody result for an FS patient whose CSF protein level is normal during that week. Anti-GQ1b IgG antibodies cross-react with GT1a (Chiba et al., 1993). Biochemical analysis showed GQ1b, but no GT1a, in the human oculomotor nerve (Chiba et al., 1997). An immunochemical study, however, detected both GQ1b and GT1a in the oculomotor nerve (Koga et al., 2002). Fig. 1 shows the structure of GQ1b and the relevant gangliosides discussed in this review. Some anti-GQ1b/GT1a antibodies also cross-react with the b-series gangliosides GD3, GD2, GD1b or GT1b, and impaired deep sense is associated with anti-GQ1b antibodies that cross-react with GD1b (Susuki et al., 2001). In addition to GQ1b, clustered epitopes of ganglioside complexes that include GQ1b, appear to be the prime target antigens for serum antibodies (Kaida et al., 2006). Three different specificities of IgG antibodies against GQ1b; GQ1bspecific, anti-GQ1b/GM1-positive and anti-GQ1b/GD1a-positive, exist. Sensory disturbances were infrequent in anti-GQ1b/GM1-positive FS patients (Kanzaki et al., 2008). Antibodies specific to GQ1b were present more often in FS than in GBS with ophthalmoplegia. Whether the autoantibodies' fine specificities determine clinical features needs to be tested in studies of larger numbers of patients with FS and related conditions. 2.3. Responsible lesions The oculomotor, trochlear and abducens nerves, as well as the optic nerve, have significantly higher percentages of GQ1b than the other cranial nerves and ventral and dorsal roots of the spinal cord (Chiba et al., 1997). Immunohistochemical studies showed that GQ1b is highly expressed in extramedullary regions of the human oculomotor, trochlear and abducens nerves; whereas, no accumulation was found

2.2. Autoantibobies Anti-GQ1b IgG antibodies frequently are present in FS sera. Possibly because of differences in method and cutoff values, serological results differ somewhat among representative laboratories; 83% (387/466

Fig. 1. Gangliosides cited in this review.

N. Yuki / Journal of Neuroimmunology 215 (2009) 1–9

in other cranial nerves, including the optic nerve (Chiba et al., 1993). In contrast, some of 27 FS patients had findings suggestive of supranuclear involvement; preservation of Bell's phenomenon despite paralysis of voluntary upward gaze in two, gaze-evoked horizontal dissociated nystagmus in two, preservation of convergence despite adduction palsy with conjugate gaze in one and internuclear ophthalmoplegia in one (Mori et al., 2001). These neuro-ophthalmological findings indicate the presence of a central nervous system (CNS) lesion in some FS patients. Neuromuscular junctions (NMJs) may be particularly vulnerable to autoantibody attack as they are outside the blood–nerve barrier, are rich in gangliosides and dependent on rapid membrane turnover for normal functioning (Willison and O'Hanlon, 1999). For proteolytic action many bacterial toxins, including botulinum and tetanus ones, depend on binding to gangliosides with subsequent uptake into the NMJs. Histological analysis of NMJs demonstrated the binding of antibodies to b-series gangliosides, including GQ1b, as was the case for the specialized en grappe end-plates of polyinnervated muscle fibers within rat extraocular muscles. Monoclonal antibody against GQ1b and GT1a also bound the vast majority of motor end-plates of human oculomotor muscles (Liu et al., 2009). Anti-GQ1b antibodies cause functional and structural changes at NMJs where GQ1b is expressed in mouse nerve–muscle preparations (reviewed in Willison et al., 2008a). These findings suggest that anti-GQ1b IgG antibodies attack NMJs of oculomotor muscles, and produce ophthalmoplegia in FS patients. Limb weakness is unusual in patients with FS unless overlapped by GBS, but the possibility of subclinically impaired neuromuscular transmission in limb muscles in FS cannot be excluded. Single fiber electromyography is the most sensitive in vivo measure of neuromuscular transmission and may be abnormal despite normal muscle strength. Previous clinical studies using single fiber electromyography or repetitive nerve stimulation tests suggested abnormal neuromuscular transmission in patients with FS (Lange et al., 2006; Lo et al., 2006). Axonal-stimulating single fiber electromyography performed in the forearm muscles of seven patients with anti-GQ1b IgG antibodies, however, showed normal jitter and no blockage in all seven (Kuwabara et al., 2007). There is a paucity of a monoclonal anti-GQ1b/ GT1a antibody binding to NMJs in human limb muscles (Liu et al., 2009). These results indicate that anti-GQ1b antibodies do not affect neuromuscular transmission in human limb muscles. The lesion sites of ataxia as well as ophthalmoplegia are controversial. In his original description, Fisher considered ataxia the manifestation of an unusual peripheral neuron lesion but also reported it as the cerebellar type because it was out of proportion to sensory loss (Fisher, 1956). Some investigators found peripheral nerve dysfunction in electrophysiological studies, which supports a peripheral ataxia mechanism in FS (Jamal and Ballantyne, 1988; Ropper and Shahani, 1983). Others reported magnetic resonance imaging (MRI) abnormalities indicative of CNS lesions as responsible for ataxia (Giroud et al., 1990; Urushitani et al., 1995). Serum IgG with anti-GQ1b reactivity stains cerebellar molecular layer in humans (Kornberg et al., 1996). Upright stance in humans is maintained by feedback information from three afferent systems; proprioceptive, vestibular and visual. Postural body sway analysis, which measures other aspects of cerebellar and peripheral nerve functions, showed different patterns for lesions of the cerebellum and proprioceptive ascending systems. Nine of 10 FS patients had a distinct 1-Hz peak (Kuwabara et al., 1999). Cerebellar patients had a peak at 2.4 Hz, whereas sensory ataxia patients had a 1-Hz peak. Clinical sensory loss or abnormal sensory nerve potentials were present only in three; whereas, soleus H-reflexes were absent in all the FS patients. These findings indicate that FS patients have a dysfunctional proprioceptive afferent system and that special sensory ataxia may be caused by the selective involvement of muscle spindle afferents. Muscle spindles, proprioceptive transducers within the muscles, are an integral part of the γ reflex loop. They contain specialized muscle fibers which have motor innervation and are enriched by a

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sensory ending. The neural components and intrafusal muscle fibers of these spindles may be important targets in FS patients because they are labeled by a monoclonal antibody against b-series gangliosides, including GQ1b, in mice and rats (Willison et al., 1996) and a monoclonal anti-GQ1b/GT1a antibody in humans (Liu et al., 2009). The latter staining pattern suggests that the group 1a afferents in muscle spindles contain GQ1b. Human immunohistochemical studies using a monoclonal anti-GQ1b/GT1a antibody have shown the existence of some large neurons in dorsal root ganglia which could be group 1a neurons (Kusunoki et al., 1999). GQ1b at the NMJs of oculomotor muscles and on muscle spindles may be targets, and produce the characteristic combination of FS clinical symptoms. 2.4. Molecular mimicry A prospective case–control study was conducted for 73 Japanese patients with FS and 73 sex- and age-matched hospital controls. Serologic evidence of Campylobacter jejuni (21%) and Haemophilus influenzae (8%) infections was present in the FS patients significantly more often than in the hospital controls (Koga et al., 2005a) (Fig. 2). Epidemiological associations have been established between both bacterial infections and FS. An epidemiological study of C. jejuniisolate FS patients showed a patient age-range peak in 10- to 20-yearold patients and a male/female ratio of 2.2:1 (Takahashi et al., 2005). The median interval from diarrhea onset to neurological symptom onset was 10 days. Interestingly, H. influenzae was isolated from the sputum of one of Fisher's original patients (Fisher, 1956). That patient had had cough and fever before neurologic onset. Based on a chest X-ray, pneumonia had been diagnosed. The pathogens Streptococcus pyogenes, Staphylococcus aureus, M. pneumoniae, Coxiella burnetii, cytomegalovirus, Epstein–Barr virus, varicella-zoster virus and mumps virus are reported to be antecedent agents in FS, but no statistical associations have been shown (reviewed in Yuki, 2001). Immunochemical study results using monoclonal anti-GQ1b antibodies suggest molecular mimicry between GQ1b and the C. jejuni isolated from FS patients (Yuki et al., 1994). Lipo-oligosaccharide (LOS) is a major component of the outer membrane of C. jejuni. Mass spectrometry analysis identified a C. jejuni strain from an FS patient, which carried a GT1a-like LOS-mimicking GQ1b (Koga et al., 2005a) (Fig. 3). A GD1c-like LOS, which mimics GQ1b, also has been identified in C. jejuni isolates from FS patients (Kimoto et al., 2006; Nam Shin et al., 1997). Immunization of GQ1b/GT1a-deficient mice with GT1a-like LOS generated monoclonal IgG antibodies that reacted with GQ1b and GT1a (Koga et al., 2005a). An H. influenzae isolate from FS has a GD3-like LOS which mimics GQ1b (Houliston et al., 2007). Infections by these bacteria bearing the GQ1b epitope may induce the production of antiGQ1b IgG antibodies.

Fig. 2. Frequency of positive infectious serology in patients with Fisher syndrome and Bickerstaff brainstem encephalitis (BBE). Hospital controls were sex- and agematched (± 5 years) to each patient with Fisher syndrome. CMV, cytomegalovirus. ⁎, p b 0.01; ⁎⁎, p b 0.05.

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N. Yuki / Journal of Neuroimmunology 215 (2009) 1–9

Fig. 3. Campylobacter jejuni gene polymorphism as a determinant of clinical neuropathies after infection by that bacterium. C. jejuni carrying cst-II (Thr51) can express GM1- or GD1a-like LOS on its cell surface. Infection by such a strain may induce anti-GM1 or anti-GD1a IgG antibodies in some patients. Anti-GM1 IgG antibodies bind to GM1 or anti-GD1a IgG antibodies to GD1a. These products are expressed on motor nerves of the four limbs. Binding induces acute motor axonal neuropathy. By contrast, C. jejuni that carries cst-II (Asn51) expresses GT1a- or GD1c-like LOS on the cell surface. Infection by these C. jejuni strains may induce anti-GQ1b IgG production in some patients. Anti-GQ1b IgG antibodies bind to GQ1b expressed on oculomotor nerves and muscle spindles, inducing Fisher syndrome or related conditions. Modified from Muscle Nerve 35:691–711, Copyright ©2007, John Wiley & Sons, Inc.

2.5. Campylobacter genes Although molecular mimicry between microbial and self components exists in a number of autoimmune diseases, none has satisfied all four criteria needed to conclude that a disease is triggered by a mimic. These criteria are (i) establishment of an epidemiological association between the infectious agent and immune-mediated disease, (ii) identification of T cells or antibodies directed against the patient's target antigens, (iii) identification of microbial mimics of the target antigen and (iv) reproduction of the disease in an animal model (Ang et al., 2004). GBS currently is divided into acute inflammatory demyelinating neuropathy and acute motor axonal neuropathy (AMAN) based on pathological studies (Hafer-Macko et al., 1996a; Hafer-Macko et al., 1996b). It fulfills all the four criteria of (i) establishment of an epidemiological association between GBS and C. jejuni infection in a prospective case–control study (Rees et al., 1995), (ii) identification of autoantibodies against GM1 and GD1a gangliosides in patients with AMAN subsequent to C. jejuni enteritis

(Ho et al., 1999), (iii) identification of molecular mimicry between GM1 or GD1a and the LOS of C. jejuni isolated from AMAN sufferers (Fig. 3) (Koga et al., 2005a; Yuki et al., 1993c) and (iv) reproduction of the AMAN model by active immunization with GM1 or C. jejuni LOS (Yuki et al., 2004; Yuki et al., 2001b), and by passive transfer of anti-GD1a antibodies (Goodfellow et al., 2005). In other words, ganglioside-like LOS is a cause of GBS. Sialyltransferase Cst-II or -III, N-acetylgalactosaminyltransferase CgtA, and galactosyltransferase CgtB are essential for biosynthesis (Gilbert et al., 2002). C. jejuni isolates from GBS (96%) and FS (88%) carry the cst-II or -III, cgtA and cgtB genes which encode these enzymes significantly more often than do isolates from uncomplicated enteritis (72%) (Koga et al., 2006). Why a certain microbial infection may induce development of several autoimmune diseases has yet to be clarified. For example, the mechanism of how group A streptococcal infection induces acute rheumatic fever in some patients and acute glomerulonephritis in others is unknown. The mechanism of how C. jejuni induces GBS in

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some patients and FS in others, however, has been clarified. Cst-II sialyltransferase consists of 291 amino acids, the 51st determining its enzymatic activity (Gilbert et al., 2002). Cst-II (Thr51) has only α-2,3sialyltransferase activity (monofunctional) and produces GM1- and GD1a-like LOSs. In contrast, Cst-II (Asn51) has both α-2,3- and α-2,8sialyltransferase activities (bifunctional) and synthesizes GT1a- or GD1c-like LOSs that mimic GQ1b. Neuropathic strains more frequently were found to have cst-II, in particular cst-II (Thr51), than did enteritic ones (82% versus 52%) (Koga et al., 2005b). Strains with cst-II (Asn51) regularly expressed the GQ1b epitope, whereas those with cst-II (Thr51) had the GM1 and GD1a epitopes (Table 1). The presence of these bacterial epitopes in neuropathy patients corresponded to autoantibody reactivity. Patients infected with C. jejuni (cst-II Asn51) more often were positive for anti-GQ1b IgG antibodies and had ophthalmoparesis and ataxia. In contrast, patients who had C. jejuni (cst-II Thr51) more frequently were positive for anti-GM1 and antiGD1a IgG antibodies and had limb weakness. 2.6. Overlap with Guillain-Barré syndrome GM1 and GD1a are expressed at the nodes of Ranvier on motor nerve axons (Gong et al., 2002) and probably at the NMJs in limb muscles (Goodfellow et al., 2005; Schluep and Steck, 1988). GQ1b is expressed at the NMJs within the extraocular muscles and muscle spindles (Liu et al., 2009). Subclass of IgG antibodies to GM1 or GQ1b mainly belongs to IgG1 in patients with GBS or FS subsequent to C. jejuni enteritis (Yuki et al., 1995). Although anti-ganglioside antibodies may exert some of their paralytic effects directly (independent of complements) (Buchwald et al., 2001), tissue bound antibody of the appropriate subclass inevitably fixes complement to exacerbate injury unless complement regulation is highly active. Anti-ganglioside antibodies bind the targets, activate complements and produce nerve injury (Gong et al., 2002; Susuki et al., 2007). Briefly, the molecular pathogenesis of GBS or FS subsequent to C. jejuni enteritis is as follows (Fig. 3): C. jejuni that carries cst-II (Thr51) can express GM1- or GD1a-like LOS on its cell surface. Infection by such a C. jejuni strain may induce anti-GM1 or anti-GD1a IgG antibodies in some patients. The autoantibodies bind to the GM1 or GD1a expressed on motor nerves in the four limbs, inducing AMAN. In contrast, C. jejuni that carries cst-II (Asn51) expresses GT1a- or GD1c-like LOS on its cell surface, and infection by such a strain may induce anti-GQ1b IgG antibodies in some patients. The autoantibodies bind to the GQ1b expressed at the NMJs of oculomotor muscles and on muscle spindles inducing FS. In other words, cst-II polymorphism (Thr/Asn51) determines whether GBS or FS develops after C. jejuni enteritis. Some patients with FS overlapped by GBS (FS/GBS overlap) carry IgG antibodies against GM1 and GD1a as well as against GQ1b, which findings are reasonable (Kimoto et al., 2006). For example, a GT1a-like LOS is synthesized by Cst-II (Asn51) via GM1- and GD1a-like LOSs, and

Table 1 Association of cst-II polymorphism of C. jejuni isolates from patients with their autoantibodies and neurological sings. cst-II (Asn51) Serum IgG antibodies to GQ1b GM1 GD1a Neurological signs Ophthalmoparesis Ataxia Limb weakness

cst-II (Thr51)

Present

Absent

p value Present

n = 32 18 (56%) 7 (22%) 7 (22%) n = 33 21 (64%) 14 (42%) 22 (67%)

n = 62 5 (8%) b0.001 51 (82%) 0.03 29 (47%) b0.001 n = 64 8 (13%) b0.001 7 (11%) 0.001 60 (94%) 0.001

n = 48 2 (4%) 42 (88%) 25 (52%) n = 48 4 (8%) 3 (6%) 47 (98%)

Absent n = 46 21 (46%) 16 (35%) 11 (24%) n = 49 25 (51%) 18 (37%) 35 (71%)

p value b0.001 b0.001 0.006 b0.001 b0.001 b0.001

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an FS isolate carries GM1- and GD1a-like LOSs as well as a GT1a-like LOS. C. jejuni strains bearing cst-II (Asn51) induce the synthesis of anti-GM1 or anti-GD1a IgG antibodies, as well as anti-GQ1b IgG antibodies, and FS/GBS overlap develops in some patients. Rather than bacterial, host genetic factors may determine the autoantibodies produced and whether the clinical presentation is an FS or FS/GBS overlap. Patients with the FS/GBS overlap needed mechanical ventilation significantly more often than those with GBS (24% versus 10%) (Funakoshi et al., 2009). Such patients who show titubation and descending tetraparesis need to be carefully monitored as the illness progresses because those clinical features are of use as predictors of respiratory failure. 3. Bickerstaff brainstem encephalitis 3.1. Historical perspective Bickerstaff and Cloake published a report of three cases they called “mesencephalitis and rhombencephalitis” (Bickerstaff and Cloake, 1951). Later, Bickerstaff added five more cases to the original study and named the condition “brain stem encephalitis” (Bickerstaff, 1957). Seven of those eight patients had symmetrical ophthalmoplegia, ataxia and impaired consciousness. Although all eight patients' conditions were severe, seven had benign outcomes. The etiology of this condition was speculated to be similar to that of GBS because of evidence of prodromal upper respiratory infection, areflexia and CSF albuminocytological dissociation. Bickerstaff's group subsequently reported 18 other patients who had “brainstem encephalitis and the syndrome of Miller Fisher” and argued for a central origin (Al-Din et al., 1982). All 18 suffered ophthalmoplegia and ataxia. Eleven experienced drowsiness, and one became comatose. Muscle stretch reflexes were absent in 11, normal in three and brisk in four. Four had Babinski's sign, and two long-tract sensory disturbance. Based on radiological (three patients) and pathological (one patient) changes in the brainstem, as well as abnormal electroencephalographic (EEG) findings (12 patients), the authors insisted that the responsible lesion in the 18 patients was localized in the CNS and that the condition represents a clinical entity distinct from GBS. An investigator who criticized their report considered six of the 18 cases typical FS and the other 12 obscure brainstem lesions without peripheral polyneuropathy (Ropper, 1983). Najim Al-Din described two cases in which there were an altered state of consciousness and motor nerve dysfunction in addition to the FS triad and reviewed similar cases (Najim Al-Din, 1987). He proposed a “spectrum hypothesis” in which both FS and BBE, although clinically and pathologically distinct, represent opposite ends of a broad spectrum. He regarded his reported cases as being in the middle of the spectrum. One of the three patients originally described by Fisher experienced drowsiness (Fisher, 1956). Because of the apparent similarities in the clinical presentation of FS and BBE, opinions have differed as to whether the two conditions are distinct or related and whether the lesions responsible for ophthalmoplegia, ataxia and areflexia are in the peripheral nervous system (PNS) or CNS. As described below, the autoimmune etiology of BBE has been established, providing evidence that both FS and BBE are part of a continuous spectrum (Yuki et al., 1993a). Moreover, clinical analysis of 581 cases of acute ophthalmoplegia and ataxia found that both conditions represent a spectrum with variable PNS and CNS involvement (Ito et al., 2008). In other words, a modified “spectrum hypothesis” has been proved. 3.2. Autoimmune etiology While studying sera from FS patients in order to confirm the results of Chiba et al. (Chiba et al., 1992), our attention was brought to a BBE patient treated previously. That patient (Patient 2 in Yuki et al., 1993a)

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became comatose in addition to suffering acute ophthalmoplegia, ataxia and areflexia. These neurological signs disappeared 2 months after onset. At that time we thought that BBE was distinct from FS and that anti-GQ1b antibody testing could differentiate between them. Unexpectedly, the patient had anti-GQ1b IgG antibodies. We therefore investigated whether two other BBE patients had those antibodies and showed that all three BBE patients had high anti-GQ1b IgG antibody titers which decreased with their clinical improvement. Anti-GQ1b IgG antibodies from patients with BBE, as well as from those with FS, were absorbed by GT1a, evidence that the fine specificity of anti-GQ1b IgG antibodies is the same as in FS and BBE (Susuki et al., 2001). Anti-GM1b or anti-GalNAc-GD1a antibodies, but not anti-GQ1b antibodies, were detected in some patients with FS and BBE (Tatsumoto et al., 2006). Such patients may express GM1b or GalNAc-GD1a in their ocular motor nerves and muscle spindles but not in the spinal motor nerves. The finding that BBE and FS have autoantibodies in common suggested that the autoimmune mechanism is common to both, and they are not distinct conditions. 3.3. Comparison with Fisher syndrome 3.3.1. Case report A patient was reported who had the clinical triad of FS (ophthalmoplegia, ataxia and areflexia), impaired consciousness and hemisensory loss (Ogawara et al., 2002). Her serum was positive for anti-GQ1b IgG antibodies. EEG findings (diffuse slow activity), median somatosensory evoked potentials (SEPs) (absence of cortical N20 with normal cervical N13) and blink reflex studies (absent R2) suggested central dysfunction, whereas results of facial nerve conduction studies (low amplitudes of compound muscle action potentials), F-wave and H-reflex studies (absence of F-waves and soleus H-reflexes) and brainstem auditory evoked potentials (prolongation of wave I latency) indicated peripheral abnormalities. These findings support FS and BBE being a single autoimmune disease that usually involves the PNS and occasionally the CNS. 3.3.2. Diagnostic criteria Whether BBE and FS are part of a continuous spectrum has remained unclear because of the lack of studies of large numbers of patients with BBE or FS. We therefore reviewed medical records of 581 patients who suffered acute ophthalmoplegia and ataxia but showed no significant limb weakness (Ito et al., 2008). Based on Fisher's and Bickerstaff's findings, “progressive, relatively symmetric external ophthalmoplegia and ataxia by four weeks” would be the clinical features necessary for the diagnoses of both BBE and FS (Bickerstaff, 1957; Fisher, 1956). Whereas “hypo- or areflexia” and clear consciousness were required for the diagnosis of FS, “impaired consciousness” was required for that of BBE. Hypo- or areflexia was not an exclusion criterion for the diagnosis of BBE because half of the original patients had hypo- or areflexia. In our study, “severe limb weakness” of 3 or less on the Medical Research Council (MRC) scale was an exclusion criterion for both conditions, although there was gross flaccid limb weakness in one of his original patients (Bickerstaff, 1957). In contrast, limb weakness of 4 on the MRC scale was an inclusion criterion for either condition because there was mild limb weakness in Fisher's original case (Fisher, 1956). For the diagnosis of either condition the following must be excluded; vascular disease involving the brainstem, Wernicke encephalopathy, botulism, myasthenia gravis, brainstem tumor, pituitary apoplexy, acute disseminated encephalomyelitis (disorders described by Al-Din et al., 1982; Bickerstaff, 1957; Bickerstaff and Cloake, 1951; Fisher, 1956), multiple sclerosis, neuroBehçet disease, vasculitis, malignant lymphoma and Creutzfeldt– Jakob disease (our addition). Based on GBS criteria (Asbury and Cornblath, 1990), extensor plantar reflexes do not exclude an FS diagnosis if the other clinical features are typical.

3.3.3. Clinical similarities Our 581 selected patients were divided into three groups; 53 with typical BBE who had impaired consciousness, 466 with typical FS who had alert consciousness and hypo- or areflexia and 62 unclassified patients who had clear consciousness and preserved muscle stretch reflexes during their illnesses (Ito et al., 2008). The findings of our large study provided significant information about the clinical features of BBE and FS and convincing evidence of their clinical similarity. In both, males predominated (male/female ratio, 2.3:1 versus 1.5:1), and age distribution showed two peaks ([20–29 and 40–49 years] versus [30–39 and 50–59 years]). Blepharoptosis (34% versus 37%) and internal ophthalmoplegia (55% versus 35%) were frequent during illness. Deep sensation (2% versus 17%) was relatively unimpaired despite profound ataxia. Two (4%) of the BBE patients died, whereas none of the FS patients did. In BBE and FS, CSF albuminocytological dissociation occurred during the first week of illness (25% versus 37%, Table 2) and increased in the second week (46% versus 76%) (Ito et al., 2008). Although each BBE frequency was lower than in that for FS, the presence of CSF albuminocytological dissociation in BBE, as well as in FS, suggests a common etiology. In addition, 32% of the BBE patients had CSF pleocytosis compared to 4% of the FS patients. These findings show that CSF studies alone cannot discriminate BBE from FS. Breakdown of the blood–CSF barrier may be more severe in BBE, producing CSF pleocytosis more often than in FS. 3.3.4. Both CNS and PNS involvement Although the presence of brainstem lesions in BBE was doubted (Ropper, 1983), postmortem examinations of three BBE patients found definite inflammatory changes in the brainstem (Al-Din et al., 1982; Bickerstaff, 1957; Odaka et al., 2003). Fifty-three BBE patients also had definite CNS involvement because all had impaired consciousness (Ito et al., 2008). Table 2 presents abnormal MRI and EEG findings. On T2-weighted images 11% of BBE patients had high intensity abnormalities in the pons (n = 4), thalamus (n = 2), cerebellum (n = 1), medulla oblongata (n = 1), midbrain (n = 1), superior cerebellar peduncle (n = 1) or corpus callosum (n = 1). One percent of FS patients had MRI abnormalities in the midbrain (n = 1), cerebellum (n = 1) or middle cerebellar peduncle (n = 1). Seven percent of 54 unclassified patients had abnormalities in the pons (n = 3), medulla oblongata (n = 2) or middle cerebellar peduncle (n = 1). EEG recordings showed diffuse slow activities in the θ or δ range in 57% of BBE and in 25% of 32 FS patients who were fully conscious. These observations indicate that central components occasionally are associated with FS. In nerve conduction and H-reflex studies the most frequent abnormality was the absence of soleus H-reflexes in 75% of four BBE and 74% of 28 FS patients, whereas routine motor and sensory nerve conduction study results were normal for both groups (Ito et al., 2008). SEPs rarely were abnormal, but one of three BBE patients had Table 2 Serology, CSF, MRI and EEG findings in patients with Bickerstaff brainstem encephalitis and Fisher syndrome.

Serum Anti-GQ1b IgG antibodies: n (%) Anti-GT1a IgG antibodies: n (%) CSF Albuminocytological dissociation: n (%) Cell count (cells/μl): median (range) Pleocytosis: n (%) MRI Abnormal findings: n (%) EEG Abnormal findings: n (%)

Bickerstaff brainstem encephalitis

Fisher syndrome

n = 53 36 (68%) 32 (60%) n = 44 11 (25%) 4 (0–668) 14 (32%) n = 47 5 (11%) n = 30 17 (57%)

n = 466 387 (83%) 364 (78%) n = 375 139 (37%) 1 (0–105) 15 (4%) n = 353 4 (1%) n = 32 8 (25%)

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no cortical potentials (median N20, tibial P37) despite having normal spinal/peripheral potentials (median N13, tibial N20). Similarly, abnormal SEP frequencies were low in FS patients; 23% of 13 had them in median SEPs and 15% in tibial SEPs. Body sway analyses showed a power spectrum peak at 1 Hz, indicative of proprioceptive afferent system dysfunction, in 67% of three BBE and 72% of 18 FS patients. These findings showed that BBE patients also had this peak, indicative that ataxia is caused by a mechanism, dysfunction of the proprioceptive afferent system, common to FS and BBE. The coexistence of central and peripheral components refutes the idea of a simple relationship between BBE and purely central involvement, as well as between FS and a simple peripheral neuropathy.

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autoimmune disease that variably involves the PNS or CNS. Clinical findings, anatomical lesions and immunological findings for our unclassified condition group were similar to those for BBE and FS. A nosological position is needed for unclassified conditions, therefore we have proposed the new eponymic terminology “Fisher–Bickerstaff syndrome” which includes unclassified conditions as well as FS and BBE (Ito et al., 2008). This terminology may be useful for understanding the clinical continuity among FS, BBE and unclassified conditions, and diagnosing the unclassified patients. Based on the historical points of view, however, FS or BBE rather than Fisher–Bickerstaff syndrome should be used at usual clinical setting. 3.4. Overlap with Guillain–Barré syndrome

3.3.5. Immunopathogenesis Anti-GQ1b IgG antibodies were positive in 68% of BBE patients and in 83% of FS (Table 2) (Ito et al., 2008). Most patients also had antiGT1a IgG antibody. Serological evidence of recent C. jejuni (23%) or H. influenzae (6%) infection was more common in 34 BBE patients (as well as in FS patients) than in the hospital control participants (Fig. 2). Anti-H. influenzae antibody-positive patients had antecedent symptoms of upper respiratory infections. In BBE and FS a history of preceding diarrhea (29% versus 25%) was less common than one of the preceding upper respiratory infection symptoms (60% versus 76%), as reported in GBS (Yuki, 2001). The presence of common antecedent infectious agents such as C. jejuni and H. influenzae in both conditions supports the hypothesis that BBE and FS have similar etiologies, as is the case for GBS and FS. C. jejuni was the most frequent microbial agent identified in FS and BBE and was isolated from both groups of patients. Characteristics of a C. jejuni isolate from a BBE patient were those of FS not of GBS (Kimoto et al., 2006). That isolate had cst-II (Asn51) and the GQ1b epitope on LOS, evidence that BBE and FS are part of a continuous spectrum. Rather than bacterial factors, host factors such as antibody accessibility, may determine whether the clinical presentation is FS or BBE. Twenty-eight patients developed C. jejuni enteritis after eating raw chicken, but only one patient, who carried anti-GQ1b IgG antibodies, developed BBE (Mori et al., 2008). None of the others had those autoantibodies. C. jejuni was cultured from the stool samples of five patients who had enteritis alone. All the isolates had the same genotype, cst-II (Asn51), characteristic of strains isolated from BBE (Kimoto et al., 2006). These findings suggest that host susceptibility has a role in inducing production of anti-ganglioside antibodies and the development of BBE. Patients with mild BBE show drowsiness but are easily roused by stimulation, suggesting that the brainstem reticular formation is involved in BBE. The blood–brain barrier (BBB) protects the brain from deleterious effects of large molecules circulating in the blood, but in several areas the BBB is deficient. Studies on the permeability (Faraci et al., 1989) and ultrastructure (van Breemen and Clemente, 1955) of the area postrema have demonstrated that the BBB in this region is relatively permeable, allowing large molecules to penetrate the brainstem parenchyma at this site. It is possible that in BBE the antiGQ1b antibodies reach the brainstem via this route and attack the brainstem reticular formation, but this has yet to be demonstrated experimentally. The probable sequence of events in the pathogenesis of BBE and FS therefore is as follows: Infection by a microorganism bearing the GQ1b epitope induces production of anti-GQ1b IgG antibodies in certain patients. The anti-GQ1b antibodies bind to GQ1b expressed on the oculomotor nerves and muscle spindles, inducing FS. In some cases anti-GQ1b antibodies also enters the brainstem in areas where the BBB is deficient, e.g. the area postrema, and binds to GQ1b which may be expressed on the brainstem reticular formation, inducing BBE. 3.3.6. Proposal: “Fisher–Bickerstaff syndrome” As clarified above, BBE is not distinct from FS clinically, anatomically or etiologically. These two conditions therefore represent a single

Whereas Bickerstaff speculated that the etiology of BBE is similar to that of GBS (Bickerstaff, 1957), his group insisted that it is distinct (Al-Din et al., 1982). In other words, the nosological relationship of BBE to GBS has remained unknown. We undertook a study to clarify the clinical, electrophysiological, neuroimaging and immunological features of 62 BBE patients (Odaka et al., 2003). “Progressive, relatively symmetric external ophthalmoplegia and ataxia by four weeks” and “impaired consciousness or hyperreflexia” were required clinical features for the diagnosis of BBE. One patient in Bickerstaff's original report had flaccid limb weakness (Bickerstaff, 1957), thus our BBE cases were divided into “BBE without limb weakness” and “BBE with limb weakness”. Muscle weakness was symmetric and flaccid in 37 patients who had “BBE with limb weakness” (Odaka et al., 2003). Twenty-five of them met the GBS criterion of a limb weakness of “4” on the MRC scale, the other 12 had scores of “3 or less”. There was no significant difference in the clinical profiles of the two subgroups. Upper respiratory infection was the most frequent antecedent illness, and diplopia (51%) or gait disturbance (41%) the most frequent initial neurological symptom. Dysesthesia was present in 27%, limb weakness in 19% and dysarthria in 16%. Consciousness was disturbed in 81% (drowsiness, 43%; stupor or coma, 38%). All those without altered consciousness had hyperreflexia. Muscle stretch reflexes were absent or decreased in 67%, normal in 3% and brisk in 30%. Babinski's sign was present in 49%. All the patients had ataxia, but only 22% deep sense impairment. Facial weakness (57%), bulbar palsy and superficial sense impairment (43%), internal ophthalmoplegia (38%), blepharoptosis (27%) and nystagmus (16%) were relatively common. Except for limb weakness, there was no significant difference in the clinical profiles of the subgroups of BBE without weakness and BBE with overlapping GBS (BBE/GBS overlap). Assisted ventilation was required for 24% of the 37 patients with BBE with limb weakness. Six months after onset, 51% of the 35 patients for whom outcome data were available showed complete remission with no residual symptoms. Limb weakness persisted in 23%. Abnormal MRI findings were detected in 23% of 31 BBE/GBS overlap patients and abnormal EEG findings in 70% of 20 patients with BBE/GBS overlap (Odaka et al., 2003). Abnormal motor nerve conduction findings were found for 58% of 24 BBE/GBS (axonal degeneration 50%, demyelination 8%) patients, suggestive of predominant axonal involvement. Needle electromyography showed positive sharp waves or fibrillation potentials in three patients on days 21 to 53. CSF protein concentration was increased in 56% during the first 4 weeks. CSF albuminocytological dissociation was present in 29%, and the frequencies increased from 15% in the first week to 55% in the third and fourth weeks. Anti-GQ1b IgG antibodies were present in 70%, and anti-GM1, anti-GD1a or anti-GalNAc-GD1a IgG antibodies, serological markers of AMAN (Ogawara et al., 2000) were present in 24% of the 37 BBE/GBS overlap patients and in 50% of the 12 patients who had a score of “3 or less”. These results suggested that elements of the autoimmune mechanism are common to BBE and GBS. Clinical and electrophysiological findings as well as immunological ones showed

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that BBE is closely related to GBS and that they form a continuous spectrum, further support of continuity between BBE and FS, a variant of GBS. Serological evidence of recent C. jejuni infection was present in 22% of 36 patients (Odaka et al., 2003). C. jejuni was isolated from two patients with BBE/GBS overlap, and both isolates had cst-II (Asn51) and the GQ1b epitope on LOS (Kimoto et al., 2006). GD1c-like LOS was identified in one of the isolates. A number of GBS patients have been reported to experience coma, for whom BBE/GBS overlap should be the diagnosis. C. jejuni (OH 4384) bearing a GT1a-like LOS was isolated from one of them (Aspinall et al., 1994; Yuki and Tsujino, 1995). Host genetic rather than bacterial factors may determine which autoantibodies are produced and whether the clinical presentation is BBE or BBE/GBS overlap. 3.5. Treatment Because randomized controlled trials have established the efficacy of plasma exchange and intravenous immunoglobulin (IVIG) for GBS (Hughes et al., 2007), either treatment should be given to patients with FS/GBS or BBE/GBS overlap. Their efficacy for treating Fisher–Bickerstaff syndrome, however, has yet to be shown as there have been no randomized controlled trials (Overell et al., 2007). Retrospective analysis of 92 consecutive FS cases found that IVIG somewhat lessened ophthalmoplegia and ataxia but had no effect on outcomes, presumably because of good natural recoveries (Mori et al., 2007). Although generally BBE outcomes are good, several patients have died (Al-Din et al., 1982; Bickerstaff, 1957; Odaka et al., 2003). At present, therefore, patients who have BBE but not FS should be treated with IVIG or plasmapheresis. Tryptophan-immobilized columns are used clinically to adsorb anti-GQ1b IgG antibodies (Yuki, 1996b), but synthetic disialylgalactose immunosorbents, which selectively deplete anti-GQ1b antibodies, may provide a new type of plasmapheresis for Fisher–Bickerstaff syndrome (Willison et al., 2004). Complement activation is an important nerve injury mechanism for producing anti-ganglioside antibody-mediated neuropathy (Willison et al., 2008b). A more rational treatment uses complement inhibitors such as eculizumab and nafamostat mesilate (Halstead et al., 2008; Phongsisay et al., 2008) although IVIG does have anti-complement activity (Zhang et al., 2004). Both inhibitors are used clinically to treat other conditions and are suitable candidates for trials on GBS, FS/GBS and BBE. 4. Conclusion Since the identification of anti-GQ1b antibodies in FS, remarkable progress has been made in our understanding of FS and BBE. As discussed, the autoimmune etiology of BBE and the nosological relationship between FS and BBE have been established. My coworkers and I have proposed the new term “anti-GQ1b IgG antibody syndrome” for FS and related conditions because it is useful for understanding the etiological relationships among those illnesses (Odaka et al., 2001; Yuki, 1996a). This new syndrome terminology includes not only FS and BBE, but GBS, ataxic GBS (Yuki et al., 2000), acute ophthalmoparesis without ataxia (Yuki et al., 2001a), isolated internal ophthalmoplegia (Yuki et al., 2001a), acute oropharyngeal palsy (O'Leary et al., 1996) and pharyngeal–cervical–brachial weakness (Nagashima et al., 2007) as well. In addition to clinical similarities and overlappings, the presence of common autoantibodies is evidence that these conditions form a continuous spectrum. The pioneering contributions of Chiba and Kusunoki have substantially enhanced our understanding of the anti-GQ1b antibody syndrome. Acknowledgements I greatly appreciate the critical reading of this review by Drs. Masahiro Mori, Atsuro Chiba, Satoshi Kuwabara and Susumu Kusunoki,

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