Elsevier

The Lancet Neurology

Volume 12, Issue 12, December 2013, Pages 1180-1188
The Lancet Neurology

Review
Axonal Guillain-Barré syndrome: concepts and controversies

https://doi.org/10.1016/S1474-4422(13)70215-1Get rights and content

Summary

Acute motor axonal neuropathy (AMAN) is a pure motor axonal subtype of Guillain-Barré syndrome (GBS) that was identified in the late 1990s. In Asia and Central and South America, it is the major subtype of GBS, seen in 30–65% of patients. AMAN progresses more rapidly and has an earlier peak than demyelinating GBS; tendon reflexes are relatively preserved or even exaggerated, and autonomic dysfunction is rare. One of the main causes is molecular mimicry of human gangliosides by Campylobacter jejuni lipo-oligosaccharides. In addition to axonal degeneration, electrophysiology shows rapidly reversible nerve conduction blockade or slowing, presumably due to pathological changes at the nodes or paranodes. Autoantibodies that bind to GM1 or GD1a gangliosides at the nodes of Ranvier activate complement and disrupt sodium-channel clusters and axoglial junctions, which leads to nerve conduction failure and muscle weakness. Improved understanding of the disease mechanism and pathophysiology might lead to new treatment options and improve the outlook for patients with AMAN.

Introduction

Guillain-Barré syndrome (GBS) is an immune-mediated polyneuropathy and an important cause of acute neuromuscular paralysis. Since the first description of this disorder in France in 1916, GBS has been regarded as demyelinating neuropathy, but has also been used to describe acute inflammatory demyelinating polyneuropathy (AIDP). The concept of GBS, however, changed substantially in the 1990s because an axonal subtype, acute motor axonal neuropathy (AMAN), was identified in a clinical and neurophysiological study done in northern China,1 and has since been reported in other countries.2, 3, 4, 5 AMAN and AIDP are the two main subtypes of GBS. Each subtype of GBS has an independent immunopathogenesis, and is characterised by specific clinical features; therefore, each subtype might have different responses to treatment.

Over the past two decades, major advances have been made in understanding the immunopathogenesis and pathophysiology of AMAN. One of the main underlying mechanisms of the disease is molecular mimicry of human gangliosides by Campylobacter jejuni lipo-oligosaccharide.6 Autopsy studies in patients have revealed motor axonal degeneration without demyelination,1 but electrophysiological studies have shown that this is not the only important pathophysiological feature. Additionally, rapidly and fully reversible nerve conduction blockade or slowing that develops in a few days to a few weeks is frequently seen. This time course suggests pathological changes at the nodal and paranodal axolemma rather than segmental demyelination and remyelination.7, 8, 9

Several disease-related issues remain unresolved: what the optimum electrodiagnostic criteria are; what the mechanisms are for selective involvement of motor axons and the hyper-reflexia seen in some patients; and what the best treatments are. In this Review we aim to elucidate important concepts and controversies associated with AMAN and discuss how they might lead to improved treatment and management of patients.

Section snippets

History

The first cases of axonal GBS were reported by Feasby and colleagues.10 They described five patients with acute polyneuropathy in whom motor nerve conduction studies revealed no compound muscle action potentials (inexcitability), and autopsies showed severe axonal degeneration without demyelination; axonal degeneration was proposed as the predominant pathological process. Histological assessment, however, was done in only one patient and, because inexcitability of motor nerves can be caused by

Epidemiology

The frequency of AMAN in the whole GBS population varies substantially between countries: it is rare in many European and in North American countries but particularly prevalent in east Asia and Central and South America (figure 1).3, 4, 5 Worldwide, a substantial proportion of patients with GBS have AMAN (figure 1); therefore, recognition of the disorder is clinically important.

When AMAN was initially described in China, specific electrodiagnostic criteria, different from those for AIDP, were

Clinical features

The term AMAN was initially used to describe a summer epidemic of acute ascending paralysis observed in children in northern China.1 A similar seasonal pattern has been noted in Mexico.4 In Japan20 and England19 AMAN mainly affects adults irrespective of season, and in Bangladesh patients are predominantly young men living in rural areas, with a peak in new cases seen between January and March.23 Infection with C jejuni is the most frequent antecedent in patients with AMAN and, therefore, the

Electrodiagnostic criteria

Neurophysiological studies play an important part in the classification of GBS subtypes and the understanding of pathophysiology. According to conventional electrodiagnostic criteria, patients who show slowed nerve conduction that indicates demyelination in two or more motor nerves are diagnosed as having AIDP, whereas those who have reductions in amplitude of distally evoked compound muscle action potentials without conduction slowing suggestive of demyelination are diagnosed as having AMAN (

Immunopathogenesis

Immunological, pathological, and bacteriological studies have shown carbohydrate mimicry between GM1 and GD1a gangliosides and the lipo-oligosaccharides of C jejuni. Four criteria must be satisfied to conclude that an autoimmune disease is triggered by molecular mimicry:43 establishment of an epidemiological association between the infectious agent and immune-mediated disease; identification of T cells or antibodies directed against the patient's target antigens; identification of microbial

Development of models

An animal model of AMAN was developed by immunisation of Japanese white rabbits with a bovine brain ganglioside mixture or isolated GM1.16 The rabbits were seropositive for IgG antibodies against GM1 and developed acute, monophasic flaccid limb weakness. Pathological findings of the peripheral nerves showed prominent axonal degeneration without lymphocytic infiltration and demyelination. Cauda-equine and ventral-root samples revealed IgG deposits at the nodes of Ranvier and macrophage

Controversies and unresolved questions

Although the immunopathogenesis and pathophysiology of AMAN have been established, several issues are still controversial. First, the electrodiagnostic criteria were proposed on the assumption of simple axonal degeneration in AMAN and, therefore, they do not seem to distinguish between AIDP and AMAN with certainty. Sequential electrodiagnostic studies would provide new insights into the pathophysiology and electrodiagnosis of GBS.28 Other unresolved issues include the identification of

Conclusions

AMAN is a major subtype of GBS in east Asia and Central and South America. Molecular mimicry of human gangliosides by the bacterial lipo-oligosaccharide of C jejuni (carbohydrate mimicry) has been established as the cause of AMAN. Through advances in epidemiology, immunology, and electrophysiology, understanding of the pathophysiology of this subtype is growing rapidly. Detailed studies of the molecular structure of nodal and paranodal axolemma are providing insights into the pathogenesis of

Search strategy and selection criteria

We searched PubMed, Embase, and the Cochrane Library for papers published up to July 31, 2013, with the search terms “Guillain-Barre syndrome”, “axonal Guillain-Barre syndrome” or “acute motor axonal neuropathy” in combination with “diagnosis”, “epidemiology”, “electrophysiology”, “neurophysiology”, “immunology”, “management”, and “treatment”. The final reference list was generated on the basis of originality and relevance to the topics covered in this Review. Emphasis was placed on

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