Miller Fisher syndrome: brief overview and update with a focus on electrophysiological findings

Miller Fisher syndrome (MFS), a variant of the Guillain–Barré syndrome (GBS), is characterized by ophthalmoplegia, ataxia, and areflexia. The annual incidence is around one patient per one million population. The antiganglioside anti‐GQ1b IgG antibody has a role in the pathogenesis of the syndrome, especially of ophthalmoplegia. The presence of this antibody in the serum can be identified in over 80% of the patients, peaking in the first week, whereas albuminocytological dissociation in the cerebrospinal fluid (CSF) appears later. The most consistent electrophysiological findings in MFS are reduced sensory nerve action potentials and absent H reflexes. More variability is seen with F waves and various investigations involving cranial structures. Although there are usually no abnormalities in MFS by routine neuroimaging, in a few cases, contrast enhancement of nerve roots and signs of central nervous system involvement were described supporting the hypothesis of an anti‐GQ1b‐syndrome, a continuum involving GBS, MFS, and Bickerstaff’s brainstem encephalitis. Owing to the lack of randomized trials, treatments used for GBS (intravenous immunoglobulin and plasmapheresis) are usually applied, although from retrospective analyses, the outcome was similar between treated and untreated subjects. The outcome of MFS is usually good with case fatality of < 5%. In the few autopsy cases, macroscopic abnormalities were generally not seen in the nervous system. Microscopic examination of the peripheral nervous system (including cranial nerves) showed segmental demyelination with minimal perivascular infiltration with normal spinal cord and brain stem.     

Acute onset of a bilateral areflexical mydriasis in Miller-Fisher syndrome: a rare neuro-ophthalmologic disease.

Miller-Fisher syndrome (MFS) is characterized by variable ophthalmoplegia, ataxia, and tendon areflexia. It seems to be a variant of Guillain-Barré syndrome (GBS), but unlike in GBS, there is a primitive involvement of the ocular motor nerves, and in some cases there is brainstem or cerebellum direct damage. The unusual case of MFS in the current study started with a bilateral areflexical mydriasis and a slight failure of accommodative-convergence. Ocular-movement abnormalities developed progressively with a palsy of the upward gaze and a bilateral internuclear ophthalmoplegia to a complete ophthalmoplegia. In the serum of this patient, high titers of an IgG anti-GQ1b ganglioside and IgG anti-cerebellum. anti-Purkinje cells in particular, were found. The former autoantibody has been connected to cases of MFS, of GBS with associated ophthalmoplegia, and with other acute ocular nerve palsies. The anti-cerebellum autoantibody could explain central nervous system involvement in MFS. The role of these findings and clinical implications in MFS and in other neuro-ophthalmologic diseases are discussed.     

重症吉兰-巴雷综合征的预测因素分析

目的分析轻症与重症吉兰-巴雷综合征(Guillain-Barrésyndrome,GBS)患者临床及神经电生理检查特点,筛选出重症患者的预测因素。方法回顾性分析2006年1月至2015年11月在本院住院治疗的GBS患者101例。根据疾病高峰期Hughes评分划分为轻症组(0~2分)和重症组(3~6分)。分别统计两组患者发病年龄、性别、前驱感染史、首发症状、是否有延髓功能障碍、是否累及颅神经和自主神经、有无轴索损害等指标,分析两组之间差异,并筛选出重症患者的预测因素。结果以非感觉异常为首发症状(P0.001)、有延髓功能障碍(P0.001)、颅神经受累(P=0.025)、自主神经系统受累(P=0.018)、运动系统受累(P=0.004)以及轴索损害(P0.001)的患者容易发展为重型患者。多因素Logistic回归分析发现轴索损害(P=0.008,OR=4.632)、延髓受累(P=0.010,OR=10.420)、颅神经受累(P=0.047,OR=0.076)是发展为重型的独立危险因素。结论轴索损害、延髓受累和颅神经受累可能是GBS患者发展至重型的有意义的预测因素。     

Prediction of disease progression in Miller Fisher and overlap syndromes

Patients with Miller Fisher syndrome (MFS) may have a relatively mild clinical course or progress to Guillain‐Barré syndrome (GBS) with limb weakness (MFS‐GBS overlap syndrome). Other variants in this spectrum are GBS with ophthalmoparesis and Bickerstaff's Brainstem encephalitis (BBE). To compare the clinical course of MFS and overlap syndromes and to identify predictors of disease progression. In a prospective study of 170 patients with GBS and variant forms, 37 (22%) had a MFS, MFS‐GBS overlap syndrome, ophthalmoplegic GBS or BBE. The clinical, serological, and electrophysiological features were compared. Twenty‐three patients presented with MFS, of which 10 (43%) developed limb weakness (MFS‐GBS overlap syndrome). All these transitions occurred in the first week after onset of symptoms. There were no differences in the clinical, electrophysiological and serological features at entry between MFS and MFS‐GBS. Twelve patients had ophthalmoplegic GBS and the disease severity at nadir and outcome was worse than in the patients with a MFS‐GBS overlap syndrome. No early predictors for progression from MFS to MFS‐GBS overlap syndrome were found. All transitions occurred in the first week. This finding implicates that all patients with MFS need careful monitoring for at least 1 week.     

Clinical characteristics and outcomes of patients with Guillain–Barré and acquired CNS demyelinating overlap syndrome: a cohort study based on a literature review

Abstract

Background:

Some patients with Guillain–Barré syndrome (GBS) also have acquired demyelination of the central nervous system (CNS) (i.e. acquired demyelinating syndrome, ADS). Often, the overlap of GBS and ADS is overlooked. Therefore, we evaluated case reports of GBS/ADS overlap syndrome.

Methods:

We mainly performed website-based research based on articles in cases presented with GBS/ADS overlap syndrome. A total of 66 cases were included. Clinical and prognosis data were analyzed.

Results:

A total of 85% of patients with simultaneous or consecutive occurrence of GBS and ADS were identified within 4 weeks of the initial diagnosis. Transverse myelitis (TM) (32%) was the most common ADS found in GBS/ADS. Patients with Miller Fisher syndrome (MFS)/ADS overlap syndrome had greater female predominance, mean age, frequency of onset at the same time period, or within a short period, and percentage of sole involvement of the subtentorial region. The outcome was favorable based on the functional status in 74% of patients. The sensory level (OR = 0·182, 95% CI = 0·055–0·598; P = 0·005) was the best predictor of a poor outcome, while visual deficit (OR = 4·667, 95% CI = 1·187–18·352; P = 0·027) predicted a favorable outcome.

Conclusion:

The ADS in GBS are diverse, CNS demyelinating may occur at any time, but early in the GBS course (and vice versa). MFS/ADS overlap syndromes is more common. The prognosis is generally good, but patients with sensory level deficit are likely to have a poor prognosis. The features of MFS/other CIS may better reflect involvement of the brainstem in MFS itself, rather than ADS in autoimmune peripheral neuropathies.     

Involvement of the central nervous system in Miller Fisher syndrome: a case report

Miller Fisher syndrome (MFS) is characterised by ophthalmoplegia, ataxia and areflexia. Reports on cerebellar ataxia and supranuclear oculomotor derangement in MFS suggested an additional involvement of the central nervous system (CNS), resembling Bickerstaff's brainstem encephalitis (BBE). In the present report, a patient with a monophasic acute illness, early recovery and specific clinical-laboratory findings suggested both intrinsic brainstem and peripheral nerve disease (MFS and BBE). In pons and medulla oblangata, blurred to discrete T2-lesions were revealed by cranial MRI, while involvement of peripheral nerves was detected with EMG. The CSF showed no increase in protein or cell content, such as occurs in brainstem encephalitis.     

Visual impairment in anti-GQ1b positive Miller Fisher syndrome

Autoimmune neuropathies such as the Guillain-Barré syndrome (GBS), the Miller Fisher syndrome (MFS), and chronic inflammatory demyelinating neuropathy (CIDP) have conventionally been considered diseases exclusively of the peripheral nervous system. In the last decades, however, several reports of CNS involvement in peripheral neuropathy have challenged this view. We describe a patient with anti-GQ1b positive MFS who--apart from the classical features--also presented with reversible loss of visual acuity suggesting CNS involvement.     

Miller-Fisher综合征临床特点及亚型诊断(附27例报告)

目的分析Miller-Fisher综合征(MFS)的临床特点,并对其进行亚型诊断,以加深对其认识,提高诊治水平。方法回顾性分析27例诊断为MFS患者的发病诱因、临床表现、实验室检查、治疗及预后等临床资料,并依据2014年GBS分类专家组制定的Guillain-Barré综合征(GBS)和MFS的新分类和诊断标准进行亚型诊断。所有患者接受脑脊液、肌电图及血清抗GQ-1b抗体检测。结果27例患者平均患病年龄为(41.0±22.6)岁,14例患者有前驱感染史,主要临床表现为复视、步态不稳,主要体征为眼外肌麻痹、共济失调、腱反射减弱或消失等。18例患者出现蛋白细胞分离现象;17例患者血清抗GQ-1b抗体阳性;26例患者出现不同程度的神经根及周围神经受损表现。亚型诊断:典型MFS患者19例,MFS与GBS重叠型(MFS/GBS)5例,急性眼睑下垂(AP)1例,急性瞳孔散大(AM)1例,急性共济失调性神经病(AAN)1例。除1例患者仅接受营养神经等治疗外,余26例患者分别接受了免疫球蛋白和(或)激素冲击治疗,所有患者出院时症状好转。结论 MFS的诊断需要结合患者临床表现、脑脊液检查、神经电生理检查和血清抗GQ-1b抗体等,患者予以免疫球蛋白和(或)激素冲击治疗预后良好。     

Anti-LM1 antibodies in the sera of patients with Guillain-Barré syndrome, Miller Fisher syndrome, and motor neuron disease

This study is designed to establish whether sialosylneolactotetraosylceramide (LM1), a major component of human peripheral nerve ganglioside, is a potential target antigen for the development of peripheral autoimmune neuropathies such as Guillain-Barré syndrome (GBS) and Miller Fisher syndrome (MFS). Serum antibodies against LM1 in 116 patients with GBS, 56 patients with MFS, 88 patients with motor neuron disease (MND) and 60 normal control subjects were quantified using enzyme-linked immunosorbent assay (ELISA). The presence of anti-LM1 antibodies were confirmed using an immunostaining method on high-performance thin-layer chromatographic plates (HPTLC). Anti-LM1 IgG antibodies were detected in 22% (25/116) of patients with GBS. The ratio of the demyelination type to the axonal type of GBS was approximately 3:1. Among the 25 anti-LM1-positive GBS patients, additional anti-GM1 IgG antibodies were detected in 7 patients, 4 of whom possessed the axonal form of GBS. Anti-LM1 antibodies were also detected in a significant portion of patients with MFS (20%, 11/56). In contrast, anti-LM1 antibodies were detected in only 2% (2/88) of patients with MND, and 7% (4/60) of normal control subjects. The results of this study suggest that serum antibodies against LM1 may have a pathogenic role in the development of GBS and MFS.     

Proximal nerve lesions in early Guillain–Barré syndrome: implications for pathogenesis and disease classification

Guillain–Barré syndrome (GBS) is an acute-onset, immune-mediated disorder of the peripheral nervous system. In early GBS, arbitrarily established up to 10 days of disease onset, patients could exhibit selective manifestations due to involvement of the proximal nerves, including nerve roots, spinal nerves and plexuses. Such manifestations are proximal weakness, inaugural nerve trunk pain, and atypical electrophysiological patterns, which may lead to delayed diagnosis. The aim of this paper was to analyze the nosology of early GBS reviewing electrophysiological, autopsy and imaging studies, both in acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor/motor-sensory axonal neuropathy (AMAN/AMSAN). Early electrophysiology showed either well-defined demyelinating or axonal patterns, or a non-diagnostic pattern with abnormal late responses; there may be attenuated M responses upon lumbar root stimulation as the only finding. Pathological changes predominated in proximal nerves, in some studies, most prominent at the sides where the spinal roots unite to form the spinal nerves; on very early GBS endoneurial inflammatory edema was the outstanding feature. In the far majority of cases, spinal magnetic resonance imaging showed contrast enhancement of cauda equina, selectively involving anterior roots in AMAN. Both in AIDP and AMAN/AMSAN, ultrasonography has demonstrated frequent enlargement of ventral rami of C5–C7 nerves with blurred boundaries, whereas sonograms of upper and lower extremity peripheral nerves exhibited variable and less frequent abnormalities. We provide new insights into the pathogenesis and classification of early GBS.     

Ophthalmoplegic Guillain-Barré syndrome: An independent entity or a transitional spectrum?

Ophthalmoplegia can occur in both Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) with typical limb involvement. However, ophthalmoplegic GBS (OGBS) has been poorly defined. We aimed to characterize OGBS and clarify the pathophysiological implications across the overall GBS spectrum. Twenty GBS and seven MFS patients from three university based teaching hospitals in Korea were enrolled and analyzed. Six GBS patients who were classified as OGBS commonly also had facial diplegia (50%) and bulbar palsy (50%), while only a small portion of non-ophthalmoplegic GBS (NOGBS) patients had facial diplegia (21%). None of the patients had bulbar palsy in the NOGBS or MFS groups. The most frequent anti-ganglioside antibody in OGBS was the IgG anti-GT1a antibody (50%). The IgG anti-GM1 antibody was found mainly in NOGBS (57%) with high concordance with the pure motor type classification on electrophysiology. IgG anti-GQ1b antibody was positive uniquely in MFS (100%), although some patients were also positive for anti-GT1a antibody (71%). OGBS had distinct clinical features, including bulbar palsy, as well as ophthalmoplegia and limb weakness for both GBS and MFS. Relevant immunological factors were anti-GT1a antibody. Whether OGBS is an independent entity or a transitional spectrum remains to be established and further study will be needed.     

Detection of serum anticerebellar antibodies in patients with Miller Fisher syndrome

We performed Western blot analysis to detect anticerebellar antibodies in the serum of patients with Miller Fisher syndrome (MFS). We studied 7 MFS patients, 6 Guillain-Barré syndrome (GBS) patients and 10 normal healthy persons as controls. Six MFS patients (86%) had IgG antibodies against mouse cerebellar protein, whereas 3 GBS patients (50%) and 4 healthy controls (40%) had antibodies. The mean number of antibodies in the serum of patient with MFS was 2.43, which was significantly more than that of GBS patients (mean 0.67) and healthy control (mean 0.70). This finding suggests variability and complexity of target in nervous systems that suffer aberrant immunity in MFS, and may also reflect the variability and heterogeneity of the pathogenesis of this syndrome.     

Autoimmune thyroiditis and acquired demyelinating polyradiculoneuropathy

Guillain-Barrè syndrome (GBS) and Miller-Fisher syndrome (MFS) are variant forms of acquired demyelinating polyradiculoneuropathy. Their concurrence with immune disorders of the thyroid is infrequent. We report on a 7.5-year-old girl in whom a subclinical thyroiditis was concurrently detected to GBS and a 70-year-old woman with Hashimoto's thyroiditis (HT) who had recurrent MFS. Even though autoimmune thyroiditis is associated with many autoimmune disorders more often than would be expected by chance alone, its concurrence with immune disorders of the peripheral nerve is less frequently reported. The calculated coincidental concurrence of acquired demyelinating polyradiculoneuropathy (in both variants, MFS and GBS) and autoimmune thyroiditis (as in the present cases) was extremely low (0.0004%), thus suggesting common pathogenic mediators.     

Neuro-ophthalmology and the anti-GQ1b antibody syndromes

The discovery of the association of the anti-GQ1b IgG antibody with the postinfectious clinical syndromes of ophthalmoplegia, ataxia, and areflexia helped house the phenotypes of the Miller Fisher syndrome (MFS), atypical MFS, Guillain-Barr’e syndrome with ophthalmoplegia, and Bickerstaff’s brainstem encephalitis under one roof. The neuro-ophthalmologic signs classically predominate and may vary from case to case, but they maintain clinically recognizable patterns that assist with the diagnosis. The identification of a common lipopolysaccharide on the plasma membrane in human cranial and peripheral nerves at the GQ1b epitope and on infectious particles of bacteria and viruses (ie, Campylobacter jejuni) demonstrates molecular mimicry. The high frequency of oculomotor dysfunction is partially explained by the tissue ganglioside concentration and distribution and the attraction of antibody-stimulating complement activation. Current experimental treatment targets antibody removal and neutralization and prevents membrane attack complex formation through deactivation of complement. This article aims to bring together the historically disparate opinions on the origins of these syndromes as either a purely peripheral nervous system or central nervous system dysfunction, highlight the clinical neuro-ophthalmologic signs, discuss some of the biology of the anti-GQ1b antibody, and review imaging abnormalities and treatment of this fascinating disorder.     

Detection of MCP-1 and IL-8 in the serum and cerebrospinal fluid of a child with Miller Fisher syndrome

We describe an 11-year-old female patient who presented with a 7-day history of diplopia and difficulty walking. On examination she had ataxia, areflexia and ophthalmoplegia, and a diagnosis of Miller Fisher syndrome (MFS) was made after the exclusion of other conditions. Monocyte chemotactic protein-1 (MCP-1) and interleukin (IL)-8 chemokine levels in the cerebrospinal fluid (CSF) were significantly increased in the acute phase. We believe MFS in this patient was due to both peripheral nervous system dysfunction, and central nervous system (CNS) involvement. The cause of MFS in this patient was suggested by the localized chemokine production in the CSF. The high expression of MCP-1 and IL-8 chemokines suggest that macrophages and T cells may stimulate inflammation of the CNS in MFS.     

The treatment of experimental allergic neuritis by plasma exchange

Experimental allergic neuritis (EAN) is a demyelinating disease of the peripheral nervous system that can be induced in laboratory animals. This disorder has been considered to show many similarities to acute inflammatory polyneuropathy (Guillain-Barré syndrome, GBS). Reports that plasma exchange may benefit patients with GBS prompted the investigation of the effect of plasma exchange in EAN. A controlled study was performed on New Zealand White rabbits. Sixteen animals were allocated to control or treatment groups at the onset of the disease. Clinical assessment on days 7 and 14 showed that treated animals were less severely affected neurologically (P = 0.05, day 7; P < 0.001 day 14), with a commensurate reduction in the severity of the histological lesions in peripheral nerves.     

Clinical and immunological spectrum of the Miller Fisher syndrome

The Miller Fisher syndrome (MFS), characterized by ataxia, areflexia, and ophthalmoplegia, was first recognized as a distinct clinical entity in 1956. MFS is mostly an acute, self-limiting condition, but there is anecdotal evidence of benefit with immunotherapy. Pathological data remain scarce. MFS can be associated with infectious, autoimmune, and neoplastic disorders. Radiological findings have suggested both central and peripheral involvement. The anti-GQ1b IgG antibody titer is most commonly elevated in MFS, but may also be increased in Guillain-Barré syndrome (GBS) and Bickerstaff's brainstem encephalitis (BBE). Molecular mimicry, particularly in relation to antecedent Campylobacter jejuni and Hemophilus influenzae infections, is likely the predominant pathogenic mechanism, but the roles of other biological factors remain to be established. Recent studies have demonstrated the presence of neuromuscular transmission defects in association with anti-GQ1b IgG antibody, both in vitro and in vivo. Collective findings from clinical, radiological, immunological, and electrophysiological techniques have helped to define MFS, GBS, and BBE as major disorders within the proposed spectrum of anti-GQ1b IgG antibody syndrome.     

Central motor conduction in patients with anti-ganglioside antibody associated neuropathy syndromes and hyperreflexia

OBJECTIVES: Several serum antibodies against gangliosides are diagnostically important, particularly in Guillain-Barré syndrome (GBS), Miller Fisher syndrome (MFS), and multifocal motor neuropathy (MMN). Although hyperreflexia is an atypical symptom in these disorders, it has been found in some patients with GBS, MFS, and MMN. The aim of the study was to determine whether hyperreflexia corresponds to corticospinal tract dysfunction in these patients. METHODS: The study examined central and peripheral motor conduction in patients with hyperreflexia who exhibited acute paralysis (group 1, n=5), acute ataxia and ophthalmoplegia (group 2, n=7), or chronic paralysis with conduction block (group 3, n=2). The clinical symptoms are similar to those in patients with GBS, MFS, and MMN, respectively, and serum anti-ganglioside antibodies were found to be positive in all patients. Using magnetic and electrical stimulation techniques, central and peripheral motor conduction were compared in patients in groups 1, 2, and 3 and patients with GBS (n=7), MFS (n=8), and MMN (n=6). RESULTS: Central motor conduction times (CMCTs) in patients in groups 1, 2, and 3 were significantly delayed compared with those in patients with GBS, MFS, and MMN (p<0.01, p<0.05, p<0.05, respectively), and the delayed CMCTs significantly improved in the recovery periods (p<0.01, p<0.01, p<0.05, respectively). However, motor conduction velocity, compound muscle action potential, and F wave conduction velocity were not significantly different between the patients. CONCLUSION: These findings indicate that corticospinal tract is functionally involved in patients with anti-ganglioside antibody associated neuropathy syndromes and hyperreflexia     

Miller–Fisher syndrome mimicking intracranial hypertension following head trauma

Introduction Miller-Fisher syndrome (MFS) is a polyneuropathy with benign outcome characterized by ophthalmoplegia, limb ataxia and tendon areflexia. Impaired consciousness level and intracranial hypertension are very rare symptoms in MFS.Case report We describe the case of a 5-year-old girl who showed intracranial hypertension, transient coma and respiratory failure after mild head injury; moreover the patient showed mild ataxia, areflexia, ophthalmoplegia and autonomic disturbancies. These symptoms were suggestive of MFS. Electrophysiologic studies and laboratory tests confirmed the diagnosis and immunoglobulins and steroids were given. The child showed a progressive clinical improvement and the final outcome was good.Conclusion This case, initially managed as trauma injury due to the presence of suggestive signs and clinical history, maskered an atypical presentation of Miller-Fisher syndrome, a rare disorder of central nervous system.     

Anti-GQ1b IgG antibody syndrome: clinical and immunological range

OBJECTIVES: To clarify the nosological relation among Miller Fisher syndrome (MFS), Guillain-Barré syndrome (GBS) with ophthalmoplegia, Bickerstaff's brain stem encephalitis (BBE), and acute ophthalmoparesis without ataxia. Serum samples from patients with each condition often have anti-GQ1b IgG antibody. METHODS: Information on antecedent illness, initial symptoms, neurological signs during the illness, and CSF findings were reviewed in 194 patients with anti-GQ1b IgG. It was determined whether overlapping MFS and GBS (MFS/GBS), as well as overlapping BBE and GBS (BBE/GBS), is explained by the combined action of anti-GQ1b IgG and anti-GM1 or anti-GD1a IgG, serological markers of GBS. RESULTS: Based on the diagnostic criteria, all the patients with acute ophthalmoparesis, MFS, MFS/GBS, BBE/GBS, and BBE had external ophthalmoplegia; all the patients with MFS, MFS/GBS, or GBS had hyporeflexia or areflexia; and all those with MFS and BBE showed ataxia. Tendon reflexes were decreased or absent in 91% of those with BBE/GBS, 67% of those with BBE, and 53% of those with acute ophthalmoparesis. Ataxia was present in 68% of the patients with MFS/GBS and 45% of those with BBE/GBS. Antecedent illness caused by upper respiratory tract infection had occurred in 60% to 80% of these patients, and CSF albuminocytological dissociation in 25% to 75%. Anti-GM1 or anti-GD1a IgG was present in 50% of those with GBS, 35% of those with MFS/GBS, 27% of those with BBE/GBS, 16% of those with MFS, and 8% of those with BBE. CONCLUSIONS: These findings together with the common autoantibody (anti-GQ1b IgG) suggest that a common autoimmune mechanism functions in the pathogenesis of these illnesses. In a larger study, it was confirmed clinically that MFS, GBS, BBE, and acute ophthalmoparesis are closely related, forming a continuous range. This is supported by the immunological findings. The term "anti-GQ1b IgG antibody syndrome" is not intended to be used as a clinical diagnosis, but recognition of this syndrome is useful for understanding the aetiological relation among the various illnesses and for introducing the established treatments of GBS for use with other conditions.