Anti‐ganglioside antibodies in Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy in Chinese patients

Introduction: In this study we investigated the relationships between anti‐ganglioside antibodies and Guillain–Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: Samples from 48 Chinese patients diagnosed with GBS and 18 patients diagnosed with CIDP were retrospectively reviewed. Results: In the GBS patients, 62.5% were classified as having acute inflammatory demyelinating polyneuropathy (AIDP), 27.1% were found to have acute motor axonal neuropathy (AMAN), and 10.4% were unclassified. Serum IgG anti‐ganglioside antibodies were detected in 46.2% of the AMAN patients and in 6.7% of the AIDP patients (P < 0.05); 5.6% of the 18 CIDP patients were IgG antibody positive, and 27.8% were IgM antibody positive. Facial palsy and sensory impairment were significantly associated with IgM antibodies. Conclusions: These results suggest that IgG anti‐GM1 antibodies are associated with AMAN, but not with AIDP, and that IgM antibodies against GM1, GM2, and GM3 are associated with facial nerve palsy. Muscle Nerve 55 : 470–475, 2017     

Optimizing the electrodiagnostic accuracy in Guillain-Barré syndrome subtypes: Criteria sets and sparse linear discriminant analysis

ObjectiveTo optimize the electrodiagnosis of Guillain-Barré syndrome (GBS) subtypes at first study.MethodsThe reference electrodiagnosis was obtained in 53 demyelinating and 45 axonal GBS patients on the basis of two serial studies and results of anti-ganglioside antibodies assay. We retrospectively employed sparse linear discriminant analysis (LDA), two existing electrodiagnostic criteria sets (Hadden et al., 1998; Rajabally et al., 2015) and one we propose that additionally evaluates duration of motor responses, sural sparing pattern and defines reversible conduction failure (RCF) in motor and sensory nerves at second study.ResultsAt first study the misclassification error rates, compared to reference diagnoses, were: 15.3% for sparse LDA, 30% for our criteria, 45% for Rajabally’s and 48% for Hadden’s. Sparse LDA identified seven most powerful electrophysiological variables differentiating demyelinating and axonal subtypes and assigned to each patient the diagnostic probability of belonging to either subtype. At second study 46.6% of axonal GBS patients showed RCF in two motor and 8.8% in two sensory nerves.ConclusionsBased on a single study, sparse LDA showed the highest diagnostic accuracy. RCF is present in a considerable percentage of axonal patients.SignificanceSparse LDA, a supervised statistical method of classification, should be introduced in the electrodiagnostic practice.     

Increased incidence of axonal Guillain‐Barré syndrome in La Spezia area of Italy: A 13‐year follow‐up study

Guillain‐Barré syndrome (GBS) is an acute immune‐mediated polyradiculoneuropathy with a worldwide incidence of 0.81‐1.89 per 100 000 person‐years. In Europe and North America only 5% of patients with GBS have axonal subtypes, which in South America and Asia account for 30%‐47% of cases. The aim of our study is to assess the annual incidence and clinical features of GBS in La Spezia area in Italy. A retrospective (from 1 January 2003 to 31 December 2011) followed by a prospective (from 1 January 2012 to 31 December 2015) analysis was carried out on patients admitted to La Spezia hospital who fulfilled the GBS diagnostic criteria. A total of 86 patients (58 men), mean age of 62.7 years (range 21‐90), were included. The mean annual incidence rate was 3/100 000 (range: 0.9/100 000‐5.37/100 000) significantly higher than the European incidence (P < 0.001). Forty‐seven percent were classified as acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 35% as acute motor and motor‐sensory axonal neuropathy (AMAN‐AMSAN), 13% as variant forms, and 5% were not defined. AIDP was most common in “Golfo dei Poeti” (50%) and “Val di Magra” (63.2%), whereas AMAN/AMSAN prevailed in “Val di Vara” (63.6%) and “Riviera Spezzina” (62.5%) (P = 0.024). In La Spezia area GBS incidence (especially the AMAN subtype) is significantly higher than the incidence reported in Europe. AIDP predominates in the eastern area whereas AMAN/AMSAN in the western, with a significantly different incidence rate (P = 0.003). Prospective studies to assess possible predisposing environmental factors are needed.     

Electrodiagnostic criteria for Guillain-Barrè syndrome: a critical revision and the need for an update

Electrophysiology plays a determinant role in Guillain-Barré syndrome (GBS) diagnosis, classification of the subtypes and in establishing prognosis. In the last three decades, different electrodiagnostic criteria sets have been proposed for acute inflammatory demyelinating neuropathy (AIDP), acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN). Criteria sets for AIDP varied for the parameters indicative of demyelination considered, for the cut-off limits and the number of required abnormalities (all a priori established) showing different sensitivities. Criteria sets for AMAN and AMSAN were proposed on the initial assumption that these subtypes were pathologically characterised by simple axonal degeneration. However, some AMAN patients show transient conduction block/slowing in intermediate and distal nerve segments, mimicking demyelination but without the development of abnormal temporal dispersion, named reversible conduction failure (RCF). The lack of distinction between RCF and demyelinating conduction block leads to fallaciously classify AMAN patients with RCF as AIDP or AMAN with axonal degeneration. Serial electrophysiological studies are mandatory for proper diagnosis of GBS subtypes, identification of pathophysiological mechanisms and prognosis. More reliable electrodiagnostic criteria should be devised to distinguish axonal and demyelinating subtypes of GBS, taking into consideration the RCF pattern and focussing on temporal dispersion.     

Determining the Utility of the Guillain-Barré Syndrome Classification Criteria

Background and PurposeSeveral variants of Guillain-Barré syndrome (GBS) and Miller Fisher syndrome (MFS) exist, but their frequencies vary in different populations and do not always meet the inclusion criteria of the existing diagnostic criteria. However, the GBS classification criteria by Wakerley and colleagues recognize and define the clinical characteristics of each variant. We applied these criteria to a GBS and MFS cohort with the aim of determining their utility.MethodsConsecutive GBS and MFS patients presenting to our center between 2010 and 2020 were analyzed. The clinical characteristics, electrophysiological data, and antiganglioside antibody profiles of the patients were utilized in determining the clinical classification.ResultsThis study classified 132 patients with GBS and its related disorders according to the new classification criteria as follows: 64 (48.5%) as classic GBS, 2 (1.5%) as pharyngeal-cervical-brachial (PCB) variant, 7 (5.3%) as paraparetic GBS, 29 (22%) as classic MFS, 3 (2.3%) as acute ophthalmoparesis, 2 (1.5%) as acute ataxic neuropathy, 2 (1.5%) as Bickerstaff brainstem encephalitis (BBE), 17 (12.9%) as GBS/MFS overlap, 4 (3%) as GBS/BBE overlap, 1 (0.8%) as MFS/PCB overlap, and 1 (0.8%) as polyneuritis cranialis. The electrodiagnosis was demyelinating in 55% of classic GBS patients but unclassified in 79% of classic MFS patients. Anti-GM1, anti-GD1a, anti-GalNAc-GD1a, and anti-GD1b IgG ganglioside antibodies were more commonly detected in the axonal GBS subtype, whereas the anti-GQ1b and anti-GT1a IgG ganglioside antibodies were more common in classic MFS and its subtypes.ConclusionsMost of the patients in the present cohort met the criteria of either classic GBS or MFS, but variants were seen in one-third of patients. These findings support the need to recognize variants of both syndromes in order to achieve a more-complete case ascertainment in GBS.     

Association of antibodies to ganglioside complexes and conduction blocks in axonal Guillain‐Barré syndrome presenting as acute motor conduction block neuropathy

A close relationship between acute motor conduction block neuropathy and antibodies against the complex of GM1 and GalNAc‐GD1a has been reported. This study investigates the hypothesis that conduction block at the early phase of axonal Guillain‐Barré syndrome (GBS) is also associated with such ganglioside complexes. Sera were obtained from seven French patients with initial evidence of isolated conduction blocks that resolved or progressed to acute motor axonal neuropathy. Serum IgG to asialo‐GM1 and gangliosides of LM1, GM1, GM1b, GD1a, GalNAc‐GD1a, GD1b, GT1a, GT1b, and GQ1b as well as their complexes were measured. Five of seven patients progressed within the first month of disease to AMAN. One patient had IgG antibodies against the complex of asialo‐GM1 and each of the other ganglioside antigens. Another patient carried IgG antibodies against GM1 complex with GM1b, GD1a, and GT1a as well as asialo‐GM1 complex with GD1a and GT1a. None had IgG antibodies against GM1/GalNAc‐GD1a complex. Six patients had IgG against single antigens GM1, GD1a, GalNAc‐GD1a, GD1b, and asialo‐GM1. In three patients, a reduced reaction against GM1/GalNAc‐GD1a complex was observed. The presence of conduction block in axonal GBS is not always associated with anti‐GM1/GalNAc‐GD1a complex antibodies.     

Proximal conduction block in the pharyngeal–cervical–brachial variant of guillain–barrÉ syndrome

Introduction: Conduction block (CB) has been included in the Rajabally criteria for axonal Guillain–Barré syndrome (GBS). Because the nerve roots may be affected early in GBS, detection of proximal CB by the triple stimulation technique (TST) can be useful. Methods: We describe TST findings in 2 patients who presented with the pharyngeal–cervical–brachial (PCB) variant of axonal GBS. Results: In the first patient, although conventional nerve conduction studies (NCS) did not fit electrodiagnostic criteria for axonal GBS, the TST detected proximal CB in the median and ulnar nerves. In the second patient, NCS fulfilled criteria for axonal GBS, and the TST detected proximal CB in the median nerve. After plasmapheresis, NCS and TST findings were normalized, suggesting reversible conduction failure rather than demyelinating CB. Conclusion: The TST may be useful for diagnosis of PCB when NCS remain inconclusive. The technique provides additional clues for classifying PCB into the acute nodo‐paranodopathies. Muscle Nerve 52 : 1102–1106, 2015     

Pathogenesis Of Guillain-Barre Syndrome

Recent neurophysiological and pathological studies have led to a reclassification of the diseases that underlie Guillain‐Barre syndrome (GBS) into acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor and sensory axonal neuropathy (AMSAN) and acute motor axonal neuropathy (AMAN). The Fisher syndrome of ophthalmoplegia, ataxia and areflexia is the most striking of several related conditions. Significant antecedent events include Campylobacter jejuni (4–66%), cytomegalovirus (5–15%), Epstein‐Barr virus (2–10%), and Mycoplasma pneumoniae (1–5%) infections. These infections are not uniquely associated with any clinical subtype but severe axonal degeneration is more common following C.jejuni and severe sensory impairment following cytomegalovirus. Strong evidence supports an important role for antibodies to gangliosides in pathogenesis. In particular antibodies to ganglioside GM1 are present in 14–50% of patients with GBS, and are more common in cases with severe axonal degeneration associated with any subtype. Antibodies to ganglioside GQ1b are very closely associated with Fisher syndrome, its formes frustes and related syndromes. Ganglioside‐like epitopes exist in the bacterial wall of C.jejuni. Infection by this and other organisms triggers an antibody response in patients with GBS but not in those with uncomplicated enteritis. The development of GBS is likely to be a consequence of special properties of the infecting organism, since some strains such as Penner O:19 and O:41 are particularly associated with GBS but not with enteritis. It is also likely to be a consequence of the immunogenetic background of the patient since few patients develop GBS after infection even with one of these strains. Attempts to match the subtypes of CBS to the fine specificity of anti‐ganglioside antibodies and to functional effects in experimental models continue but have not yet fully explained the pathogenesis. T cells are also involved in the pathogenesis of most or perhaps all forms of GBS. T cell responses to any of three myelin proteins, PZ, PO and PMP22, are sufficient to induce experimental autoimmune neuritis. Activated T cells are present in the circulation in the acute stage, up‐regulate matrix metalloproteinases, cross the blood‐nerve barrier and encounter their cognate antigens. Identification of the specificity of these T cell responses is still at a preliminary stage. The invasion of intact myelin sheaths by activated macrophages is difficult to explain according to a purely T cell mediated mechanism. The different patterns of GBS are probably due to the diverse interplay between antibodies and T cells of differing specificities.     

Novel anti‐idiotype antibody therapy for lipooligosaccharide‐induced experimental autoimmune neuritis: Use relevant to Guillain‐Barré syndrome

Campylobacteriosis is a frequent antecedent event in Guillain‐Barré syndrome (GBS), inducing high‐titer serum antibodies for ganglioside antigens in the peripheral nervous system (PNS). Molecular mimicry between the lipooligosaccharide (LOS) component of Campylobacter jejuni and human peripheral nerve gangliosides is believed to play an important role in the pathogenesis of GBS. Conventional treatment strategies for patients with GBS include plasmapheresis, intravenous immunoglobulin (IVIG), and immunosuppression, which are invasive or relatively ineffective. In this study, we used our animal model of GBS, in which Lewis rats were immunized with GD3‐like LOS isolated from C.jejuni. The animals developed anti‐GD3 ganglioside antibodies and manifested neuromuscular dysfunction. To develop novel therapeutic strategies, we treated the animals by intraperitoneal administration of an anti‐GD3 antiidiotype monoclonal antibody (BEC2) that specifically interacts with the pathogenic antibody. The treated animals had a remarkable reduction of anti‐GD3 antibody titers and improvement of motor nerve functions. The results suggest that ganglioside mimics, such as antiidiotype antibodies, may be powerful reagents for therapeutic intervention in GBS by neutralizing specific pathogenic antiganglioside antibodies. © 2010 Wiley‐Liss, Inc.     

Ganglioside mimicry and peripheral nerve disease

Four criteria must be satisfied to conclude that a given microorganism causes Guillain-Barré (GBS) or Fisher (FS) syndrome associated with anti-ganglioside antibodies: (1) an epidemiological association between the infecting microbe and GBS or FS; (2) isolation in the acute progressive phase of illness of that microorganism from GBS or FS patients with associated anti-ganglioside IgG antibodies; (3) identification of a microbial ganglioside mimic; and (4) a GBS or FS with associated anti-ganglioside antibodies model produced by sensitization with the microbe itself or its component, as well as with ganglioside. Campylobacter jejuni is a definitive causative microorganism of acute motor axonal neuropathy and may cause FS and related conditions. Haemophilus influenzae and Mycoplasma pneumoniae are possible causative microorganisms of acute motor axonal neuropathy or FS. Acute and chronic inflammatory demyelinating polyneuropathies may be produced by mechanisms other than ganglioside mimicry.     

Electrophysiological studies in the Guillain–Barré syndrome: Distinguishing subtypes by published criteria

Guillain–Barré syndrome (GBS) is recognized clinically by the presence of acute, rapidly progressive weakness, areflexia, and albuminocytological dissociation in cerebrospinal fluid. Although GBS was initially considered to be primarily an acute inflammatory demyelinating polyneuropathy (AIDP), several other subtypes have been recognized: acute motor axonal neuropathy (AMAN), acute motor-sensory axonal neuropathy (AMSAN), and Fisher syndrome (FS). Because each of these subtypes may have an independent immunopathogenesis and, therefore, may require selective treatments in the future, recognition of these subtypes is important. When using nerve conductions to classify the subtypes, the most easily and confidently identified subtype is AIDP. Therefore, most electrodiagnostic criteria have attempted to identify demyelination in this acute setting, in which physiology is constantly changing. In a single well-defined GBS population, we compared the various published criteria for demyelination in GBS. We reviewed charts of 43 patients with GBS between 1991 and 1996. Applying six available criteria sets, the number of patients categorized as having AIDP ranged from 21% to 72%. Until investigators can agree on a single set of criteria, considerable variability will continue to exist when identifying cases of AIDP. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1275–1279, 1998.     

Antiganglioside antibodies in Guillain-Barré syndrome and its related conditions

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.     

Isolated facial diplegia in Guillain–Barré syndrome: Bifacial weakness with paresthesias

Bifacial weakness with paresthesias (BFP) is a subtype of Guillain–Barré syndrome defined by rapidly progressive bilateral facial weakness in the absence of other cranial neuropathies, ataxia, or limb weakness. Many patients also complain of distal limb paresthesias and display diminished or absent deep tendon reflexes. BFP is a localized form of Guillain–Barré syndrome and is thought to be caused exclusively by demyelinating‐ rather than axonal‐type neuropathy. Patients with BFP do not display anti‐ganglioside IgG antibodies. Since it is rare, many physicians are unfamiliar with BFP, as bilateral facial weakness is more commonly associated with sarcoidosis, Lyme disease, or meningeal pathology. Many patients diagnosed with bilateral Bell palsy may instead have BFP. In this review, we highlight the clinical features of BFP and outline diagnostic criteria. Muscle Nerve 52 : 927–932, 2015     

Paraparetic Guillain‐Barré syndrome: Nondemyelinating reversible conduction failure restricted to the lower limbs

Introduction: Paraparetic Guillain‐Barré syndrome (GBS) is a rare subtype of GBS characterized by leg weakness and areflexia in the absence of neurological involvement of the arms, cranial nerves, or respiratory muscles. Onset is characterized by lower back, buttock, or leg pain, followed by development of symmetric flaccid limb weakness in the absence of sensory disturbance. Methods: We describe an elderly woman who developed postinfectious symmetric flaccid leg weakness in the absence of sensory disturbance. Serial nerve conduction studies were carried out over 5 months. Results: Antecedent infection, a monophasic disease course, and the presence of cerebrospinal fluid albuminocytological dissociation suggested a diagnosis of paraparetic GBS. Serial nerve conduction studies demonstrated nondemyelinating reversible conduction failure, which was restricted to the legs. Axonal neuropathy was supported by the presence of anti‐GM1 IgG antibodies. Conclusions: These findings suggest that patients with paraparetic GBS have axonal neuropathy, which is restricted to the lower limbs. Muscle Nerve 55 : 281–285, 2017     

Detection of anti-ganglioside antibodies in Guillain-Barré syndrome and its variants by the agglutination assay

Sera from 40 patients with Guillain-Barré syndrome (GBS), including the subtypes acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and Miller Fisher syndrome (MFS) were examined for the presence of anti-ganglioside antibodies using the ganglioside agglutination assay, and the enzyme-linked immunosorbent assay (ELISA). In the ELISA system, sera were tested for IgM and IgG antibodies to GM1, GM2, GD1a, GD1b, GT1b, and GQ1b gangliosides. Antibodies to gangliosides were detected in 21 (53%) of the GBS patients by agglutination assay and in 17 (43%) of the patients by ELISA. Some of the sera reacted with more than one ganglioside. Antibodies were not found in the control sera that were studied. The agglutination assay may be useful for rapid screening of GBS sera for antibodies to multiple gangliosides.     

Upper leg conduction time distinguishes demyelinating neuropathies

Background: The objective of this study was to determine whether differentiation between demyelinating and axonal neuropathies could be enhanced by comparing conduction time changes in defined segments of the total peripheral nerve pathway. Methods: Compound muscle action potentials (CMAPs) were elicited by cathodal stimulation of the tibial nerve at the ankle and popliteal fossa, and by paravertebral neuromagnetic stimulation at proximal and distal cauda equina while recording from muscles of the foot, shin, and thigh. Segmental conduction times were calculated in normal subjects; in patients with lumbosacral radiculopathy, distal symmetric diabetic neuropathy, amyotrophic lateral sclerosis, acute and chronic inflammatory demyelinating polyneuropathy; and in patients with anti–myelin‐associated glycoprotein, myelomatous, and Charcot–Marie–Tooth type 1a polyneuropathies. Results: Distal cauda equina latency and CMAP duration and segmental conduction times in upper leg and cauda equina facilitated differentiation of demyelinating from axonal neuropathies, even in the presence of a range of reduced amplitude CMAPs. Conclusions: Within the demyelinating neuropathy spectrum, it was further possible to distinguish subtypes. Muscle Nerve, 2011     

Sural sparing pattern discriminates Guillain–Barré syndrome from its mimics

Introduction: Electrodiagnostic features of demyelination are essential for establishing the diagnosis in demyelinating subtypes of Guillain‐Barré syndrome (GBS), but they may also occur in disorders that mimic GBS clinically. Information about their frequency in GBS mimics is sparse. Methods: Evaluation of electrodiagnostic features from 38 patients with suspected GBS in whom the diagnosis was later refuted (GBS mimics). Their diagnostic accuracy was analyzed by comparison with nerve conduction studies (NCS) from 73 confirmed GBS patients. Results: Disorders that mimicked GBS clinically at the time of hospital admission included other inflammatory, metabolic, toxic, or infectious neuropathies and spinal cord disorders. The sural sparing pattern was the most specific electrodiagnostic feature for demyelinating GBS. Conclusions: Common electrodiagnostic abnormalities in early demyelinating GBS do not usually exclude other rare differential diagnoses. An exception to this is the sural sparing pattern described here, which strongly supports the diagnosis of demyelinating GBS. Muscle Nerve 50 : 780–784, 2014     

Guillain-Barré syndrome: An update

Guillain-Barré syndrome (GBS) is an acute polyneuropathy consisting of different subtypes. Acute inflammatory demyelinating polyradiculoneuropathy, the classic demyelinating form of GBS, accounts for 90% of all GBS cases in the Western world. Acute motor axonal neuropathy (AMAN) and acute motor and sensory axonal neuropathy (AMSAN) are axonal forms of GBS that are more prevalent in Asia, South and Central America, often preceded by infection by Campylobacter jejuni. AMAN and AMSAN may be mediated by specific anti-ganglioside antibodies that inhibit transient sodium ion (Na⁺) channels. The efficacy of plasmapheresis and intravenous immunoglobulin has been established in large international randomised trials, with corticosteroids proven ineffective. Although axonal demyelination is an established pathophysiological process in GBS, the rapid improvement of clinical deficits with treatment is consistent with Na⁺ channel blockade by antibodies or other circulating factors, such as cytokines. This review provides an update on the epidemiology, clinical features, diagnosis, pathogenesis and treatment of GBS.     

Guillain–Barré syndrome subtypes: A clinical electrophysiological study of 100 patients

Introduction

A retrospective analysis was performed to document the clinical and electrophysiological features of Guillain-Barré syndrome (GBS) subtypes using different diagnostic criteria.