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Bickerstaff brainstem encephalitis and Fisher syndrome: anti-GQ1b antibody syndrome

Shahrizaila N, Yuki N

J Neurol Neurosurg Psychiatry, 2013 May;84(5):576-83.

PMID: 22984203 DOI: 10.1136/jnnp-2012-302824

In the 1950s, Bickerstaff and Fisher independently described cases with a unique presentation of ophthalmoplegia and ataxia. The neurological features were typically preceded by an antecedent infection and the majority of patients made a spontaneous recovery. In the cases with Bickerstaff brainstem encephalitis, there was associated altered consciousness and in some, hyperreflexia, in support of a central pathology whereas in Fisher syndrome, patients were areflexic in keeping with a peripheral aetiology. However, both authors recognised certain similarities to Guillain-Barré syndrome such as the presence of peripheral neuropathy and cerebrospinal fluid albuminocytological dissociation. The discovery of immunoglobulin G anti-GQ1b antibodies in patients with Fisher syndrome and later in Bickerstaff brainstem encephalitis was crucial in providing the necessary evidence to conclude that both conditions were in fact part of the same spectrum of disease by virtue of their common clinical and immunological profiles. Following this, other neurological presentations that share anti-GQ1b antibodies emerged in the literature. These include acute ophthalmoparesis and acute ataxic neuropathy, which represent the less extensive spectrum of the disease whereas pharyngeal-cervical-brachial weakness and Fisher syndrome overlap with Guillain-Barré syndrome represent the more extensive end of the spectrum. The conditions can be referred to as the 'anti-GQ1b antibody syndrome'. In this review, we look back at the historical descriptions and describe how our understanding of Fisher syndrome and Bickerstaff brainstem encephalitis has evolved from their initial descriptions more than half a century ago.

Antiganglioside antibodies in Guillain-Barré syndrome and its related conditions

Shahrizaila N, Yuki N

Expert Rev Neurother, 2011 Sep;11(9):1305-13.

PMID: 21864076 DOI: 10.1586/ern.11.114

Guillain-Barré syndrome (GBS) is typically classified into two major subtypes: acute inflammatory demyelinating neuropathy and acute motor axonal neuropathy. Its most recognizable variant is Fisher syndrome. The last two decades have seen considerable advances in our understanding of GBS. Of note, various autoantibodies against ganglioside antigens have been identified and found to have significant associations with the axonal forms of GBS and Fisher syndrome. In this article, we discuss the different clinical presentations in GBS and the role of antiganglioside antibodies in their underlying pathogenesis. We also discuss the impact that antiganglioside antibodies have had in the development of experimental models and treatment modalities in GBS.

The role of immunotherapy in Guillain-Barré syndrome: understanding the mechanism of action

Shahrizaila N, Yuki N

Expert Opin Pharmacother, 2011 Jul;12(10):1551-60.

PMID: 21473704 DOI: 10.1517/14656566.2011.564160

Guillain-Barré syndrome (GBS) is the most frequent cause of acute flaccid paralysis and, despite treatment, there continues to be an associated mortality and severe disability ranging from 9 to 17%. This article reviews the rationale behind the existing immunotherapy in GBS and discusses the future direction that work in this area should follow.

Fulltext Guillain-barré syndrome animal model: the first proof of molecular mimicry in human autoimmune disorder

Shahrizaila N, Yuki N

J Biomed Biotechnol, 2011;2011:829129.

PMID: 21197269 DOI: 10.1155/2011/829129

Molecular mimicry between self and microbial components has been proposed as the pathogenic mechanism of autoimmune diseases, and this hypothesis is proven in Guillain-Barré syndrome. Guillain-Barré syndrome, the most frequent cause of acute neuromuscular paralysis, sometimes occurs after Campylobacter jejuni enteritis. Gangliosides are predominantly cell-surface glycolipids highly expressed in nervous tissue, whilst lipo-oligosaccharides are major components of the Gram-negative bacterium C. jejuni outer membrane. IgG autoantibodies to GM1 ganglioside were found in the sera from patients with Guillain-Barré syndrome. Molecular mimicry was demonstrated between GM1 and lipo-oligosaccharide of C. jejuni isolated from the patients. Disease models by sensitization of rabbits with GM1 and C. jejuni lipo-oligosaccharide were established. Guillain-Barré syndrome provided the first verification that an autoimmune disease is triggered by molecular mimicry. Its disease models are helpful to further understand the molecular pathogenesis as well as to develop new treatments in Guillain-Barré syndrome.

Fulltext Biomarkers of 'acute-onset' chronic inflammatory demyelinating polyneuropathy

Miura Y, Shahrizaila N, Yuki N

Brain, 2015 Mar;138(Pt 3):e335.

PMID: 25183714 DOI: 10.1093/brain/awu252

[A case of Guillain-Barré syndrome after the travel in southeast Asia--isolation of Campylobacter jejuni PEN 5 serotype]

Koide T, Yamazaki M, Onishi Y, Saito K, Yuki N

Rinsho Shinkeigaku, 1997 Jan;37(1):41-3.

PMID: 9146072

A 57-year-old man, while on travel in Malaysia, suffered from diarrhea after he ate fruits. He developed limbs weakness without sensory disturbance after his return to Japan. Serum from the patient had high IgG anti-GM1 antibody titer. Campylobacter jejuni was isolated from his stool. The serotype belonged to PEN 5. The patient received double-filtration plasmapheresis 7 times during from days 6 to 17. Muscle strength began to recover gradually on day 10, and returned to normal 5 months after the onset of neurologic symptoms. Repeated neurophysiologic studies indicated that the axonal degeneration of motor nerves was predominant process. This case suggests that Guillain-Barré syndrome is a complication of traveler's diarrhea.

Delayed facial palsy in Miller Fisher syndrome

Tan CY, Yuki N, Shahrizaila N

J Neurol Sci, 2015 Nov 15;358(1-2):409-12.

PMID: 26277343 DOI: 10.1016/j.jns.2015.08.009

Miller Fisher syndrome is characterised by the triad of ophthalmoplegia, ataxia and areflexia. However, facial palsy can occur during the course of the illness although development of facial palsy when other cardinal signs of Miller Fisher syndrome have reached nadir or improving, is unusual. This delayed appearance of facial palsy can be easily overlooked by the treating clinician. Here, we report four patients with Miller Fisher syndrome and delayed-onset facial palsy. We discuss the possible underlying reasons behind the delay in facial palsy.

Acute flaccid paralysis with chronic cough

Chai CH, Yuki N, Nor HM, Goh KJ, Shahrizaila N

Pract Neurol, 2012 Oct;12(5):328-31.

PMID: 22976064 DOI: 10.1136/practneurol-2011-000205

Serial nerve conduction studies provide insight into the pathophysiology of Guillain-Barré and Fisher syndromes

Shahrizaila N, Goh KJ, Kokubun N, Abdullah S, Yuki N

J Neurol Sci, 2011 Oct 15;309(1-2):26-30.

PMID: 21849173 DOI: 10.1016/j.jns.2011.07.042

The electrodiagnosis of Guillain-Barré syndrome (GBS) can be broadly divided into acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Fisher syndrome (FS) is a variant of GBS, although the underlying neuropathy of FS has yet to be established. Serial nerve conduction studies (NCS) can provide further insight into the likely pathophysiology by further subtyping of GBS and FS. We present a patient with an initial diagnosis of AIDP in whom repeated NCS revealed the AMAN variant. This led us to investigate serial NCS in five patients with GBS, FS and FS/GBS overlap presenting over a period of a year. Three patients with AIDP showed a gradual increase in distal motor latencies during the acute phase of illness. NCS of two patients with FS and FS/GBS overlap showed no demyelinating features suggesting underlying axonal neuropathy in this group of patients. The importance of serial NCS in establishing the underlying pattern of neuropathy in GBS and FS is further emphasized in this study. Larger studies incorporating serial NCS are required to confirm the observations seen in our case series especially when pathological studies are often not justified in this group of patients.

Two sets of nerve conduction studies may suffice in reaching a reliable electrodiagnosis in Guillain-Barré syndrome

Shahrizaila N, Goh KJ, Abdullah S, Kuppusamy R, Yuki N

Clin Neurophysiol, 2013 Jul;124(7):1456-9.

PMID: 23395599 DOI: 10.1016/j.clinph.2012.12.047

Recent studies have advocated the use of serial nerve conduction studies (NCS) in the electrodiagnosis of Guillain-Barré syndrome (GBS). The current study aims to elucidate when and how frequent NCS can be performed to reflect the disease pathophysiology.

Anti-GQ1b antibody syndrome: anti-ganglioside complex reactivity determines clinical spectrum

Fukami Y, Wong AH, Funakoshi K, Safri AY, Shahrizaila N, Yuki N

Eur J Neurol, 2016 Feb;23(2):320-6.

PMID: 26176883 DOI: 10.1111/ene.12769

Anti-GQ1b antibodies have been found in patients with Miller Fisher syndrome as well as its related conditions. Our aim was to identify the mechanism by which autoantibodies produce various clinical presentations in 'anti-GQ1b antibody syndrome'.

Intravenous immunoglobulin may reduce relapse frequency in neuromyelitis optica

Viswanathan S, Wong AH, Quek AM, Yuki N

J Neuroimmunol, 2015 May 15;282:92-6.

PMID: 25903734 DOI: 10.1016/j.jneuroim.2015.03.021

To evaluate the use of intravenous immunoglobulin (IVIG) in preventing relapses in patients with neuromyelitis optica (NMO) and its spectrum disorders (NMOSDs).

Complement regulatory proteins (CD46, 55 and 59) expressed on Schwann cells: immune targets in demyelinating neuropathies?

Miyaji K, Paul F, Shahrizaila N, Umapathi T, Yuki N

J Neuroimmunol, 2014 Nov 15;276(1-2):172-4.

PMID: 25156074 DOI: 10.1016/j.jneuroim.2014.08.004

Given their localization and important role in regulating complement, complement regulatory proteins may act as target antigens and their antibodies as biomarkers in demyelinating neuropathies. We investigated the binding of autoantibodies to complement regulatory proteins (CD46, 55 and 59) in demyelinating diseases. In 42 acute inflammatory demyelinating polyneuropathy, 23 chronic inflammatory demyelinating polyneuropathy, 13 acute motor axonal neuropathy, 71 multiple sclerosis, and 19 neuromyelitis optica patients as well as 55 healthy controls, we were unable to detect significant titers of antibodies to CD46, CD55 and CD59. These autoantibodies are unlikely to be biomarkers in acute and chronic inflammatory demyelinating polyneuropathies.

Autoantibodies to tetraspanins (CD9, CD81 and CD82) in demyelinating diseases

Miyaji K, Paul F, Shahrizaila N, Umapathi T, Yuki N

J Neuroimmunol, 2016 Feb 15;291:78-81.

PMID: 26857499 DOI: 10.1016/j.jneuroim.2015.12.012

Tetraspanin family proteins, CD9, CD81 and CD82 are expressed in the oligodendrocytes and Schwann cells. We investigated autoantibodies to tetraspanin proteins in patients with demyelinating diseases. Sera were collected from 119 multiple sclerosis patients, 19 neuromyelitis optica, 42 acute inflammatory demyelinating polyneuropathy, 23 chronic inflammatory demyelinating polyneuropathy and 13 acute motor axonal neuropathy as well as 55 healthy controls. Few multiple sclerosis and acute inflammatory demyelinating polyneuropathy patients had autoantibodies that were weakly reactive to CD9 or CD81 but the significance is unclear. It is unlikely that these autoantibodies are pathogenic or serve as potential biomarkers in demyelinating diseases.

Are ERM (ezrin/radixin/moesin) proteins targets for autoantibodies in demyelinating neuropathies?

Miyaji K, Shahrizaila N, Umapathi T, Chan YC, Hirata K, Yuki N

Hum Immunol, 2014 Nov;75(11):1089-91.

PMID: 25286001 DOI: 10.1016/j.humimm.2014.09.010

Ezrin, radixin and moesin, which are strongly expressed in the Schwann cell microvilli, are putative targets for autoantibodies in acute or chronic inflammatory demyelinating polyneuropathy (AIDP or CIDP). An association between anti-moesin IgG antibodies and cytomegalovirus-related AIDP has been postulated. None of 41 AIDP patients, including 8 cytomegalovirus-related AIDP patients, and 23 CIDP had IgG or IgM antibodies to ezrin, radixin and moesin; whereas, one patient with cytomegalovirus-related AIDP had anti-ezrin IgM antibodies. Ezrin, radixin and moesin are unlikely targets for autoantibodies in AIDP and CIDP, and the association of anti-moesin antibodies with cytomegalovirus-related AIDP was not confirmed.

Fulltext Different IVIG glycoforms affect in vitro inhibition of anti-ganglioside antibody-mediated complement deposition

Sudo M, Yamaguchi Y, Späth PJ, Matsumoto-Morita K, Ong BK, Shahrizaila N, et al.

PLoS One, 2014;9(9):e107772.

PMID: 25259950 DOI: 10.1371/journal.pone.0107772

Intravenous immunoglobulin (IVIG) is the first line treatment for Guillain-Barré syndrome and multifocal motor neuropathy, which are caused by anti-ganglioside antibody-mediated complement-dependent cytotoxicity. IVIG has many potential mechanisms of action, and sialylation of the IgG Fc portion reportedly has an anti-inflammatory effect in antibody-dependent cell-mediated cytotoxicity models. We investigated the effects of different IVIG glycoforms on the inhibition of antibody-mediated complement-dependent cytotoxicity. Deglycosylated, degalactosylated, galactosylated and sialylated IgG were prepared from IVIG following treatment with glycosidases and glycosyltransferases. Sera from patients with Guillain-Barré syndrome, Miller Fisher syndrome and multifocal motor neuropathy associated with anti-ganglioside antibodies were used. Inhibition of complement deposition subsequent to IgG or IgM autoantibody binding to ganglioside, GM1 or GQ1b was assessed on microtiter plates. Sialylated and galactosylated IVIGs more effectively inhibited C3 deposition than original IVIG or enzyme-treated IVIGs (agalactosylated and deglycosylated IVIGs). Therefore, sialylated and galactosylated IVIGs may be more effective than conventional IVIG in the treatment of complement-dependent autoimmune diseases.

The value of comparing mortality of Guillain-Barré syndrome across different regions

Wong AH, Umapathi T, Shahrizaila N, Chan YC, Kokubun N, Fong MK, et al.

J Neurol Sci, 2014 Sep 15;344(1-2):60-2.

PMID: 24993467 DOI: 10.1016/j.jns.2014.06.021

To study the clinical profile of Guillain-Barré syndrome (GBS) patients who died in 4 Asian countries in order to understand factors underlying any variation in mortality.

Fulltext Antibodies to single glycolipids and glycolipid complexes in Guillain-Barré syndrome subtypes

Shahrizaila N, Kokubun N, Sawai S, Umapathi T, Chan YC, Kuwabara S, et al.

Neurology, 2014 Jul 8;83(2):118-24.

PMID: 24920848 DOI: 10.1212/WNL.0000000000000577

To comprehensively investigate the relationship between antibodies to single glycolipids and their complexes and Guillain-Barré syndrome subtypes and clinical features.

Sensory nerves are frequently involved in the spectrum of fisher syndrome

Shahrizaila N, Goh KJ, Kokubun N, Tan AH, Tan CY, Yuki N

Muscle Nerve, 2014 Apr;49(4):558-63.

PMID: 23893512 DOI: 10.1002/mus.23973

Differing patterns of neurophysiological abnormalities have been reported in patients with Fisher syndrome. Fisher syndrome is rare, and few series have incorporated prospective serial studies to define the natural history of nerve conduction studies in Guillain-Barré syndrome.

Serial peripheral nerve ultrasound in Guillain-Barré syndrome

Razali SNO, Arumugam T, Yuki N, Rozalli FI, Goh KJ, Shahrizaila N

Clin Neurophysiol, 2016 Feb;127(2):1652-1656.

PMID: 26228791 DOI: 10.1016/j.clinph.2015.06.030

OBJECTIVE: To assess the longitudinal changes of nerve ultrasound in Guillain-Barré syndrome (GBS) patients.

METHODS: We prospectively recruited 17 GBS patients and 17 age and gender-matched controls. Serial studies of their nerve conduction parameters and nerve ultrasound, documenting the cross-sectional areas (CSA), were performed at admission and repeated at several time points throughout disease course.

RESULTS: Serial nerve ultrasound revealed significantly enlarged CSA in median, ulnar and sural nerves within the first 3 weeks of disease onset. Longitudinal evaluation revealed an improvement in the nerve CSA with time, reaching significance in the ulnar and sural nerves after 12 weeks. There was no significant difference between the demyelinating and axonal subtypes. There was also no significant correlation found between nerve CSA and neurophysiological parameters or changes in nerve CSA and muscle strength.

CONCLUSION: In GBS, serial studies of peripheral nerve ultrasound CSA are helpful to detect a gradual improvement in the nerve size.

SIGNIFICANCE: Serial nerve ultrasound studies could serve as a useful tool in demonstrating nerve recovery in GBS.

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