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Neuromuscular
REVIEW
Guillain–Barré syndrome in Asia Jong Seok Bae,1,2 Nobuhiro Yuki,3 Satoshi Kuwabara,4 Jong Kuk Kim,5 Steve Vucic,2,6 Cindy S Lin,2 Matthew C Kiernan7 1
Department of Neurology, College of Medicine, Hallym University, Seoul, Korea 2 Neuroscience Research Australia, Sydney, Australia 3 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 4 Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan 5 Department of Neurology, College of Medicine, Dong-A University, Busan, Korea 6 Department of Neurology, Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia 7 Bushell Chair of Neurology, Brain & Mind Research Institute, University of Sydney, Sydney, New South Wales, Australia Correspondence to Dr Jong Seok Bae, Department of Neurology, College of Medicine, Hallym University, Seoul, Korea, Kangdong Sacred Heart Hospital, 150 Seongan-ro, Gangdong-gu, Seoul 134-701, Korea; [email protected] Received 8 July 2013 Revised 27 November 2013 Accepted 28 November 2013 Published Online First 19 December 2013
ABSTRACT Over the past 20 years, the most notable advance in understanding Guillain–Barré syndrome (GBS) has been the identification of an axonal variant. This advance arose chiefly through studies undertaken in East Asian countries and comprised two major aspects: first, the immunopathogenesis of axonal GBS related to antiganglioside antibodies and molecular mimicry of Campylobacter jejuni; and second, the observation that distinct electrophysiological patterns of axonal GBS existed, reflecting reversible conduction failure (RCF). As a consequence, the pathophysiology of acute motor axonal neuropathy (AMAN) has perhaps become better understood than acute inflammatory demyelinating polyneuropathy. Despite these more recent advances, a critical issue remains largely unresolved: whether axonal GBS is more common in Asia than in Europe or North America. If it is more common in Asia, then causative factors must be more critically considered, including geographical differences, issues of genetic susceptibility, the role of antecedent infections and other potential triggering factors. It has become apparent that the optimal diagnosis of AMAN requires serial electrophysiological testing, to better delineate RCF, combined with assessment for the presence of antiganglioside antibodies. Recent collaborative approaches between Europe and Asia have suggested that both the electrophysiological pattern of AMAN and the seropositivity for anti-ganglioside antibodies develop similarly. Separately, however, current electrodiagnostic criteria for AMAN limited to a single assessment appear inadequate to identify the majority of cases. As such, diagnostic criteria will need to be revised to improve the diagnostic sensitivity for AMAN.
INTRODUCTION
To cite: Bae JS, Yuki N, Kuwabara S, et al. J Neurol Neurosurg Psychiatry 2014;85:905–911.
Guillain–Barré syndrome (GBS) is generally characterised as a postinfectious, acute flaccid paralysis with albuminocytologic dissociation: that is, high levels of protein in the cerebrospinal fluid combined with a normal cell count.1 Worldwide, GBS is now considered the most common cause of acute flaccid paralysis and constitutes significant chronic morbidity.1 Since the first description by Guillain et al2 in 1916, GBS has been classically linked to the inflammatory destruction of the myelin sheath in peripheral nerves and roots, termed acute inflammatory demyelinating polyneuropathy (AIDP).1 In fact, for an extended period, AIDP became a synonym of GBS, with this term reflecting clinicopathological aspects of the disease. However, after the first suggestion about the existence of an axonal form of GBS by Feasby et al3 in 1986, and the subsequent definition of acute motor
Bae JS, et al. J Neurol Neurosurg Psychiatry 2014;85:905–911. doi:10.1136/jnnp-2013-306212
axonal neuropathy (AMAN) in the 1990s, general understanding of the syndrome has transformed. AMAN was first reported from the East Asia region, particularly China and Japan,4 5 with subsequent neurophysiological, pathological and immunological evidence to suggest that GBS could be divided into two major subtypes, AIDP and AMAN.6 7 As a consequence, AIDP is no longer considered a synonym of GBS, but rather solely reflects a subtype of the condition. From this perspective, understanding the clinical features, pathophysiology and diagnosis of AMAN remain essential for the overall conceptualisation of GBS. In turn, development of a greater understanding may provide clues to the remaining controversies of AMAN: geographic differences, molecular mimicry with infectious agents and the unique electrophysiological patterns. As such, the present review will focus on what is known about AMAN and what remains to be established.
CAMPYLOBACTER JEJUNI, GANGLIOSIDE ANTIBODIES AND MOLECULAR MIMICRY Originally, GBS was defined immunologically based on the inflammatory demyelinating polyneuritis linked to a cell-mediated immune response against unknown myelin protein antigens, considered similar to experimental allergic neuritis.8 Relevant pathological findings in GBS relate to the infiltration of inflammatory cells, particularly T lymphocytes and macrophages, with areas of segmental demyelination, often associated with secondary axonal degeneration, detectable in the spinal roots or peripheral nerves. These features were, for an extended period, considered to be consistent across all GBS presentations. As a consequence, in terms of terminology, AIDP was a term considered interchangeable with GBS, both in clinical and research communities. However, it has subsequently been demonstrated that AMAN was substantially different from AIDP, particularly in relation to immunological and pathological aspects. Specifically, in AMAN, IgG and activated complement bind to the axolemma of motor fibres at the nodes of Ranvier, followed by formation of the membrane attack complex (figure 1).6 The resulting nodal lengthening tends to be followed by degeneration of motor axons, with neither lymphocytic inflammation nor demyelination appearing as prominent features.5 9 Perhaps it could be argued that over the past 20 years, the most notable advances across the inflammatory neuropathies have been improvements in understanding the immunopathogenesis of AMAN. The discovery of anti-ganglioside 905
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Neuromuscular
Figure 1 Immunopathogenesis of acute motor axonal neuropathy. Molecular mimicry exists between gangliosides(GM1 and GD1a) and Campylobacter jejuni lipo-oligosaccharides (LOSs). Infection by C jejuni bearing GM1-like or GD1a-like LOSs may induce the production of IgG anti-GM1 or GD1a antibodies in certain patients, The autoantibodies bind to the nodes of Ranvier, where GM1 and GD1a are strongly expressed, and activate complement. Membrane attack complex is formed at the nodal axolemma, resulting in the disappearance of voltage-gated sodium (Nav) channels and the detachment of paranodal myelin. These pathological changes may lead to conduction failure and consequent muscle weakness. Subsequently, Wallerian-like degeneration may ensue, with macrophages penetrating the periaxonal space at the nodal area, scavenging the injured axons. In acute inflammatory demyelinating polyneuropathy, unknown autoantibodies may bind to the outer surface of Schwann cells and activate complement-related immunological mechanisms.
antibodies and their relationship with AMAN disclosed the immunogenic target: gangliosides present in the axolemma. Previously serological investigations revealed that approximately 60% of the acute-phase GBS sera had anti-ganglioside antibodies, predominantly IgG class, against at least one ganglioside.10 Molecular mimicry of human gangliosides by 906
the Campylobacter jejuni lipo-oligosaccharide (LOS) has been established as a trigger to the immunological pathogenesis associated with this disorder (figure 1).11 This critical understanding explained both the development of AMAN after antecedent infections, mostly gastrointestinal, and the seasonal variability of GBS and AMAN, probably according to seasonal epidemics of
Bae JS, et al. J Neurol Neurosurg Psychiatry 2014;85:905–911. doi:10.1136/jnnp-2013-306212
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Neuromuscular infectious pathogens.5 12 This seasonal pattern has also been reported in other countries, even those with a low incidence of AMAN.13 Theories of pathogenesis have been further explored using animal models of AMAN, including the sensitisation of Japanese white rabbits with a bovine brain ganglioside mixture or isolated GM1.14 In these landmark studies, rabbit models developed IgG anti-GM1 antibodies associated with acute monophasic flaccid limb weakness. Pathological findings in the peripheral nerve established prominent Wallerian-like degeneration, without lymphocytic infiltration or demyelination. Cauda equina and ventral root specimens revealed IgG deposits at the nodes of Ranvier and macrophage infiltration in the periaxonal space,15 similar to the situation identified in AMAN autopsy cases. Immunisation of animals with C jejuni LOS also produced AMAN,11 further supporting the molecular mimicry mechanism in this autoimmune disease process. Until recently, there was no clear evidence as to which antiganglioside antibodies were associated with the specific clinical characteristics of GBS. However, some anti-ganglioside antibodies such as anti-GM1, GM1b, GD1a and GalNAc-GD1a antibodies appeared in high frequencies in GBS from Asian countries as representative markers of AMAN.16 17 More recently, these antibodies were identified as important in determining the unusual electrophysiological characteristics.18 Additionally, although not the case in typical GBS, which is accompanied by limb weakness, unusual presentations such as ataxia may be attributed to the various differences across the spectrum of anti-ganglioside antibodies.19
AMAN AND REVERSIBLE CONDUCTION FAILURE Across the spectrum of peripheral neuropathies, an important utility of conventional nerve conduction studies (NCS) relates to the differentiation of axonal loss from apparent demyelination. When AIDP was used as a synonym of GBS, the electrodiagnostic criteria for demyelinating neuropathy were identical to those for GBS. Several electrophysiological criteria primarily used parameters associated with conduction velocity and evoked amplitude based on a single electrodiagnostic assessment.20–23 However, development of an understanding of AMAN as a distinct entity leads in turn to the need to determine new electrodiagnostic criteria to delineate the axonal variant of GBS. For the first AMAN diagnostic criteria, a slightly modified version of the Albers criteria20 was introduced by Ho and colleagues to differentiate between AIDP and AMAN in a Chinese population.23 In the Ho criteria set, ‘unequivocal’ temporal dispersion, but not conduction block (CB), was considered important. Hadden and colleagues further modified diagnostic criteria, not considering temporal dispersion, but reintroducing CB, defined as >50% reduction in proximal compound muscle action potential (CMAP) amplitude compared with distal CMAP.22 Currently, the Ho and Hadden criteria remain the most widely used in clinical practice to delineate AIDP from AMAN. In some series, in an attempt to overcome discrepancy, unequivocal temporal dispersion was set at >30% increased duration of proximal CMAP compared with distal CMAP.24 25 This seemingly arbitrary cut-off was established to distinguish between the effects of temporal dispersion due to demyelination when compared with axonal loss.26 The initial diagnostic criteria sets were based on an initial assumption that AMAN was characterised simply by axonal degeneration. However, previous electrophysiological studies revealed that some AMAN patients exhibited transient CB and slowing in intermediate and distal nerve segments, mimicking demyelination, although without features of abnormal temporal
dispersion, a process termed reversible conduction failure (RCF).18 This rapidly reversible block, which typically resolves within days to weeks, is frequently encountered in AMAN patients. Such a time course may suggest functional or microstructural changes at the node of Ranvier, rather than segmental demyelination and subsequent remyelination. As such, serial NCS are required to identify this important feature. Such a finding remains consistent with animal models of AMAN that established the presence of microstructural changes at or near the node of Ranvier, specifically disruption of nodal sodium channel clusters, and detachment of paranodal terminal myelin loops, mimicking paranodal demyelination, before macrophage invasion and resultant axonal degeneration ensued.27 28 The immune attack may in turn lead to the disappearance of paranodal adhesion molecules, such as contactin, contactin-associated protein and neurofascin-155, indicative of impaired tight paranodal axo-glial junctions.27 The possibility of a nondemyelinating, ‘physiological’ CB in AMAN has also been raised by autopsy studies that showed minimal structural changes at the node of Ranvier in patients with severe muscle weakness, leading to death from respiratory failure.9
PROBLEMS WITH EXISTING ELECTRODIAGNOSTIC CRITERIA The lack of distinction between RCF and demyelinating CB from a single NCS may lead to the incorrect classification of AMAN as AIDP.18 In these AMAN patients, CB in intermediate nerve segments may promptly resolve, distal CMAP amplitudes may rapidly increase and distal motor latencies, when prolonged, may return to normal values without the development of excessive temporal dispersion. Such features are clearly different from what is usually expected in AIDP patients without antiganglioside antibodies (figure 2). It is now accepted that some AMAN patients, as distinct from the classical axonal degeneration pattern, may exhibit transient CB and conduction slowing, thereby mimicking demyelination, but without components characteristic of remyelination, suggesting impaired conduction at the node of Ranvier, presumably related to the effects of anti-ganglioside antibodies. Until now, there have been no electrodiagnostic criteria based on results obtained from serial NCS. Clearly, serial electrophysiological studies remain essential for the diagnosis of GBS subtypes, the identification of pathophysiological mechanisms and assessment of prognosis. As such, more reliable electrodiagnostic criteria need to be devised to distinguish axonal from demyelinating subtypes of GBS, taking into consideration the RCF pattern and focusing on temporal dispersion.29
IS AMAN MORE COMMON IN ASIA? Although there are only slight differences in the total worldwide incidence and prevalence of GBS,30 the incidence of AMAN appears to vary considerably between countries. Across Europe and North America, AIDP is the dominant subtype of GBS31 32 and represents up to 90% of total GBS.22 However, there is discrepancy of such incidence in Western and Central Asian countries33 34 and perhaps even Central America.35 Specifically, reports of AMAN are relatively common in Asian countries,16 23 36–39 especially Eastern Asia, where the frequency of AMAN is high, perhaps even higher than AIDP (table 1)23 36 38and also in Central and South America, where the frequency ranges from 40% to 65%.23 25 35 36 40 Given that C jejuni is the most common antecedent infection of GBS worldwide41 and the suggestion from molecular mimicry studies that C jejuni infection may be expected to
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Figure 2 Serial recordings of the motor nerve conduction studies in various Guillain–Barré syndrome subtypes. Superimposed compound motor action potential (CMAP) recordings over the abductor pollicis brevis muscle, following stimulation of the median nerve at the wrist and elbow. The procedure was performed by Dr N. Kokubun (Dokkyo Medical University, Japan). Acute inflammatory demyelinating polyneuropathy (A). Although clinical nadir was reached at day 10, progressive prolongation of distal motor latency (DML) and decrease in CMAP amplitude with excessive temporal dispersion were seen by week 6, indicating that the conduction slowing is primarily a sign of remyelination. CMAP amplitudes began to show gradual improvement by week 11, but slight prolongation of DML remained at week 47. Acute motor axonal neuropathy (B). A rapid, progressive decrease in CMAP amplitudes was present in the early stage of the disease. Clinical nadir was reached by day 10. As well as clinical recovery, CMAPs were seen to improve gradually without prolongation of the DMLs, conduction slowing or excessive temporal dispersion. Acute motor-conduction-block neuropathy (C). On day 5, conduction blocks (CBs) were present at the forearm and upper arm segments of the median nerve. The CBs rapidly resolved, with no remyelination features, such as excessive temporal dispersion or conduction slowing, by day 14. Clinical nadir was reached at day 3, and complete recovery was seen by week 14. The result of the normal nerve conduction study at week 14 is shown (modified from Yuki and Hartung1 with permission from Massachusetts Medical Society).
invariably induce AMAN, AMAN may be expected to be the predominant subtype of GBS. However, AMAN was previously considered a rare variant and, even now, remains the less common subtype in most world regions, with the exception of
Table 1 Relative frequencies of acute motor axonal neuropathy (AMAN)/acute inflammatory demyelinating polyneuropathy (AIDP) subtypes worldwide
Country North America and Europe* England* Slovenia Israel Pakistan Japan† Turkey Korea* Northeast China Bangladesh* China*
Proportion of AMAN to total Guillain–Barré syndrome (GBS) (%)
Proportion of AIDP to total GBS (%)
Number of reference
4
90
22
7 11 22 31 36 40 50 54 56 65
– 79 63 46 36 – – 8 22 24
31 32 33 34 16 37 39 38 36 23
*Study using the anti-ganglioside assay only. †Study using both serial nerve conduction studies (NCS) and anti-ganglioside assays. Bars with no marking indicate use of neither serial NCS nor anti-ganglioside antibody assays.
908
some Asian countries. What then could cause this apparent discrepancy? There may be a number of explanations. First, although C jejuni is a common enteric human pathogen, epidemiological differences in C jejuni infection across world regions must be considered.42 For instance, although C jejuni grows best at 42°C, it cannot be pathologically active at freezing temperatures for long periods, characteristics that will clearly limit transmission.43 C jejuni infection occurs year-round, but with a sharp peak in the summer and early autumn. Infection is higher when air temperatures rise44 and is influenced by rainfall in tropical countries. The epidemiology of infection in developing countries is markedly different. Indeed, in developing countries, C jejuni is often isolated from healthy individuals, and infection is especially common in children or immunocompromised individuals.45 46 Thus, AMAN may be apparently more frequent in countries with a higher incidence of diarrhoea and a poor hygienic infrastructure.36 Climate may also underlie differences in AMAN occurrence. Most countries with higher AMAN percentages, particularly across Asia, have extremely hot and humid summer seasons, whereas Europe and North America have relatively dry summer seasons. Thus, the vulnerability of C jejuni to dry conditions may contribute to a lower incidence of infection, especially in the summer months across Western countries.23 35 A further consideration relates to factors associated with the individual host. Given that GBS is generally considered a sporadic disease, an association of AMAN and AIDP with the genetic background of the host seems unlikely. Although some
Bae JS, et al. J Neurol Neurosurg Psychiatry 2014;85:905–911. doi:10.1136/jnnp-2013-306212
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Neuromuscular cases of familial GBS have been described,47 48 there is no strong human leukocyte antigen (HLA) linkage,49 although one study suggested a link with a CD1 polymorphism.50 Recurrence of pure GBS also remains rare. However, some peculiar features of the sequelae of C jejuni infection may suggest a possible role for host factors, probably via immunological processes. After recovery from C jejuni infection, reactive arthritis or Reiter’s syndrome may develop in some hosts, related to genetic factors (eg, HLA-B27-positive patients), as seen in other gastrointestinal infections, such as with Yersinia, Salmonella and Shigella species. On the other hand, non-specific rheumatologic symptoms may inexplicably persist for several months or even years in a few affected people.51 Finally, there remain other relatively untested theories associated with host factors: C jejuni strains with C jejuni sialyl transferase (Cst-II) (Thr51) express GM1-like and GD1a-like LOS, whereas strains with Cst-II (Asn51) expressed GT1a-like and GD1c-like LOS.52As such, Cst-II (Thr51) strain also induce IgG anti-GQ1b antibodies. In such cases, GBS may also overlap with Fisher syndrome. If geographical differences in genetic polymorphisms of C jejuni strains exist, such ‘bacterial’ factors may make differences in the phenotype or subtype of GBS across different regions of the world. However, host factors are also important, in that infections by the aforementioned strains do not always induce GBS. As such, it would be helpful to resolve these issues about host factors and to determine the relative proportion of AMAN or Fisher syndrome that may develop in Asian immigrants living in Western countries.
IS AMAN UNDERESTIMATED IN WESTERN COUNTRIES OR OVERESTIMATED IN ASIA? To explain the apparent discrepancy of frequent C jejuni infection and less frequent axonal GBS in Western countries, it remains plausible that 1. AMAN could be underestimated; 2. C jejuni infection could be overestimated or 3. C jejuni infection may lead to both AIDP and AMAN.53 The first hypothesis is closely related to a false-negative diagnosis of AMAN. As discussed in previous sections, the present electrodiagnostic criteria for AMAN leave a high likelihood of misdiagnosing AMAN as AIDP. Additionally, many previous studies of AMAN did not use assays for anti-ganglioside antibodies, potentially leading to underestimation of true AMAN incidence. Concerning immunological aspects, a previous Dutch–Japanese collaborative study identified a similar proportion of ganglioside positivity.54 However, this comparative study identified a different range of cross-reactivity and isotype distribution among various anti-ganglioside antibodies. This study revealed a different reaction between antecedent infection and antibody formation in relation to the different geographic factors. From an electrophysiological perspective, an Italian group determined that sequential NCS resulted in a significant increase in the frequency of AMAN, from 18% to 38%.13 This group subsequently reported their findings in a collaborative study with Japanese colleagues using the same procedures, incorporating anti-ganglioside assays and a serial NCS protocol.55 Interestingly, approximately 30% of both Japanese and Italian patients with a positive ganglioside antibody demonstrated an AIDP pattern at their first NCS, whereas sequential studies determined that most ultimately developed AMAN. With regard to the second hypothesis, the gold standard for C jejuni infection remains a positive stool culture, but because of the delay in GBS onset from a preceding infection, such cultures are often negative. Consequently, serology remains the
method of choice for diagnosing a recent C jejuni infection. Although the sensitivity and specificity of serological assays vary between laboratories, Dutch–Japanese collaborative studies have suggested that the incidence of antecedent C jejuni infection in Japanese GBS was no higher than Dutch GBS.56 Few trials have investigated the third hypothesis, although one study suggested that C jejuni infection occasionally induced AIDP,57 using serological assays from both a Dutch laboratory and also from a Japanese laboratory. This was the same procedure used in a previous Japanese study that reported an exclusive relationship between C jejuni and AMAN.58 However, these comparative studies showed three probable demyelinating GBS cases tested positive by the Dutch assay, of which only one was positive by both the Dutch and Japanese assays. Overall, it seems unlikely that C jejuni infection elicits typical AIDP, but the possibility that C jejuni infection may induce unique myelin damage cannot be excluded.53 Separately, the development of AMAN without C jejuni infection has been suggested. Specifically, despite the lack of a precise pathophysiology and specific categorisation of its clinical laboratory features, some reports have described the development of AMAN after infection with other agents, such as mycoplasma or Haemophilus influenzae. Thus, a certain proportion of AMAN patients may be related to antecedent infections by organisms other than C jejuni.59 60
OTHER GBS SUBTYPES IN ASIA At present there is little information concerning the incidence of acute motor sensory axonal neuropathy (AMSAN) across Asia, although it appears to represent up to 4% of GBS in Japan,61 62 6% in India25 and 11% in Bangladesh.36 It has been suggested that patients with AMAN and AMSAN may share serological markers.61 Indeed, AMSAN has the same immunological markers, IgG anti-GM1 and anti-GD1a antibodies that differentiate AMAN from AIDP. This common immunological profile supports the notion that AMAN and AMSAN may arise as a result of the same immune response against the axon, rather than two separate disease entities. Perhaps of relevance, serial sensory NCS have identified that sensory fibres are often subclinically involved in AMAN63 and that RCF occurs in sensory and motor fibres in AMAN and AMSAN. As such, AMSAN may be considered an extreme sensory-predominant form of AMAN. It was previously proposed that acute motor conduction block neuropathy (AMCBN) was an axonal variant of GBS.64 However, AMCBN and AMAN may share antecedent C jejuni enteritis and IgG anti-GM1 and anti-GD1a antibodies in common. Furthermore, AMCBN patients may demonstrate the RCF pattern described in some nerves of AMAN patients (figure 2). As a consequence, it has been hypothesised that AMCBN represented an ‘arrested’ form of AMAN, in which anti-ganglioside antibodies bound to the nodal axolemma to thereby induce RCF, although nerves do not progress to more severe axonal degeneration.64
CONCLUSIONS Recognition of AMAN and the development of meaningful animal models have facilitated an understanding concerning the immunopathogenesis associated with ganglioside antibodies and also C jejuni infection. Identification of different electrophysiological profiles of AMAN, particularly by means of serial NCS testing, has resulted in the establishment of a new concept of conduction failure due to nodal pathology, the so-called RCF.
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Neuromuscular As a consequence, clinicians can now diagnose AMAN using these combined serological and electrophysiological approaches. With further research, it seems likely that the sensitivity for a diagnosis of AMAN will further increase with time and clinicians will be able to better assess the clinical phenotype and prognosis of GBS patients through detection of specific antiganglioside antibodies. Furthermore, immunological profiles may prove useful in predicting the clinical phenotype. For instance, identification of antibodies to specific components of the ganglioside complex, such as antibodies against GD1a/GD1b and GD1b/GT1b complexes, appears to be associated with more severe presentations of GBS, requiring artificial ventilation.65 However, as it currently stands, the incidence of axonal GBS appears underestimated in Western countries, and more appropriate diagnostic criteria for AMAN will ideally need to be developed and incorporated into a practical algorithm. To achieve this goal, an international consensus will need to be reached concerning the electrodiagnostic criteria for AMAN. Second, large, prospective studies that systematically incorporate ‘serial’ electrodiagnostic studies, C jejuni serology and ganglioside antibody measurements will be required. In this respect, the International Guillain–Barré syndrome Outcome Study, which will recruit 1000 patients, has recently commenced, with support from the Peripheral Nerve Society, Inflammatory Neuropathy Consortium, and through such approaches many of the controversial issues outlined in the present review may yet be resolved.
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Contributors JSB, MCK, NY and SK conceived the review and JSB wrote the initial draft. All authors contributed to subsequent drafting and critically revising the content.
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Competing interests None.
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Provenance and peer review Commissioned; externally peer reviewed.
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Ogawara K, Kuwabara S, Mori M, et al. Axonal Guillain-Barré syndrome: relation to anti-ganglioside antibodies and Campylobacter jejuni infection in Japan. Ann Neurol 2000;48:624–31. Ogawara K, Kuwabara S, Koga M, et al. Anti-GM1b IgG antibody is associated with acute motor axonal neuropathy and Campylobacter jejuni infection. J Neurol Sci 2003;210:41–5. Kuwabara S, Yuki N, Koga M, et al. IgG anti-GM1 antibody is associated with reversible conduction failure and axonal degeneration in Guillain-Barré syndrome. Ann Neurol 1998;44:202–8. Yuki N, Susuki K, Hirata K. Ataxic Guillain-Barré syndrome with anti-GQ1b antibody: relation to Miller Fisher syndrome. Neurology 2000;54:1851–3. Albers JW, Donofrio PD, McGonagle TK. Sequential electrodiagnostic abnormalities in acute inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve 1985;8:528–39. Cornblath DR. Electrophysiology in Guillain-Barré syndrome. Ann Neurol 1990;27 (Suppl):S17–20. Hadden RDM, Cornblath DR, Hughes RAC, et al. Electrophysiological classification of Guillain-Barré syndrome: clinical associations and outcome. Ann Neurol 1998;44:780–8. Ho TW, Mishu B, Li CY, et al. Guillain-Barré syndrome in northern China. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain 1995;118:597–605. Alam TA, Chaudhry V, Cornblath DR. Electrophysiological studies in the Guillain-Barré syndrome: distinguishing subtypes by published criteria. Muscle Nerve 1998;21:1275–9. Kalita J, Misra UK, Das M. Neurophysiological criteria in the diagnosis of different clinical types of Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry 2008;79:289–93. van Asseldonk JT, van den Berg LH, Kalmijn S, et al. Criteria for demyelination based on the maximum slowing due to axonal degeneration, determined after warming in water at 37°C: diagnostic yield in chronic inflammatory demyelinating polyneuropathy. Brain 2005;128:880–91. Susuki K, Rasband MN, Tohyama K, et al. Anti-GM1 antibodies cause complement-mediated disruption of sodium channel clusters in peripheral motor nerve fibers. J Neurosci 2007;27:3956–67. Vucic S, Kiernan MC, Cornblath DR. Guillain-Barré syndrome: an update. J Clin Neurosci 2009;16:733–41. Uncini A, Kuwabara S. Electrodiagnostic criteria for Guillain-Barré syndrome: a critical revision and the need for an update. Clin Neurophysiol 2012;123:1487–95. McGrogan A, Madle GC, Seaman HE, et al. The epidemiology of Guillain-Barré syndrome worldwide: a systematic literature review. Neuroepidemiology 2009;32:150–63. Rees JH, Gregson NA, Hughes RA. Anti-ganglioside GM1 antibodies in Guillain-Barré syndrome and their relationship to Campylobacter jejuni infection. Ann Neurol 1995;38:809–16. Omejec G, Podnar S. Retrospective analysis of Slovenian patients with Guillain-Barré syndrome. J Peripher Nerv Syst 2012;17:217–19. Kushnir M, Klein C, Pollak L, et al. Evolving pattern of Guillain-Barré syndrome in a community hospital in Israel. Acta Neurol Scand 2008;117:347–50. Shafqat S, Khealani BA, Awan F, et al. Guillain-Barré syndrome in Pakistan: similarity of demyelinating and axonal variants. Eur J Neurol 2006;13:662–5. Nachamkin I, Arzarte Barbosa P, Ung H, et al. Patterns of Guillain-Barré syndrome in children: results from a Mexican population. Neurology 2007;69:1665–71. Islam Z, Jacobs BC, van Belkum A, et al. Axonal variant of Guillain-Barré syndrome associated with Campylobacter infection in Bangladesh. Neurology 2010;74:581–7. Sayin R, Tombul T, Gulec TC, et al. Acute motor axonal neuropathy cases in Van region. Bratisl Lek Listy 2011;112:269–72. Ye Y, Zhu D, Wang K, et al. Clinical and electrophysiological features of the 2007 Guillain-Barré syndrome epidemic in northeast China. Muscle Nerve 2010;42:311–14. Kim JK, Bae JS, Kim DS, et al. Prevalence of anti-ganglioside antibodies and their clinical correlates with Guillain–Barré syndrome in Korea: nationwide multicenter study. J Clin Neurol (Accepted). Paradiso G, Tripoli J, Galicchio S, et al. Epidemiological, clinical, and electrodiagnostic findings in childhood Guillain-Barré syndrome: a reappraisal. Ann Neurol 1999;46:701–7. Poropatich KO, Walker CL, Black RE. Quantifying the association between Campylobacter infection and Guillain-Barré syndrome: a systematic review. J Health Popul Nutr 2010;28:545–52. Allos BM, Blaser MJ. Campylobacter jejuni and related species. In: Mandel GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th edn. Philadelphia: Churchill Livingstone Elsevier, 2010:2793–802. Blaser MJ, Taylor DN, Feldman RA. Epidemiology of Campylobacter jejuni infections. Epidemiol Rev 1983;5:157–76. Louis VR, Gillespie IA, O’Brien SJ, et al. Temperature-driven Campylobacter seasonality in England and Wales. Appl Environ Microbiol 2005;71:85–92. Glass RI, Stoll BJ, Huq MI, et al. Epidemiologic and clinical features of endemic Campylobacter jejuni infection in Bangladesh. J Infect Dis 1983;148:292–6.
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Calva JJ, Ruiz-Palacios GM, Lopez-Vidal AB, et al. Cohort study of intestinal infection with campylobacter in Mexican children. Lancet 1988;1:503–6. Geleijns K, Brouwer BA, Jacobs BC, et al. The occurrence of Guillain-Barré syndrome within families. Neurology 2004;63:1747–50. Saunders M, Rake M. Familial Guillain-Barré syndrome. Lancet 1965;2:1106–7. Hughes RA, Rees JH. Clinical and epidemiologic features of Guillain-Barré syndrome. J Infect Dis 1997;176(Suppl 2):S92–8. Caporale CM, Papola F, Fioroni MA, et al. Susceptibility to Guillain-Barré syndrome is associated to polymorphisms of CD1 genes. J Neuroimmunol 2006;177:112–18. Bremell T, Bjelle A, Svedhem A. Rheumatic symptoms following an outbreak of campylobacter enteritis: a five year follow up. Ann Rheum Dis 1991;50: 934–8. Koga M, Takahashi M, Masuda M, et al. Campylobacter gene polymorphism as a determinant of clinical features of Guillain-Barré syndrome. Neurology 2005;65:1376–81. Kuwabara S. Does Campylobacter jejuni infection elicit axonal or demyelinating Guillain-Barré syndrome, or both? J Neurol Neurosurg Psychiatry 2011;82:238. Ang CW, Koga M, Jacobs BC, et al. Differential immune response to gangliosides in Guillain-Barré syndrome patients from Japan and The Netherlands. J Neuroimmunol 2001;121:83–7. Sekiguchi Y, Uncini A, Yuki N, et al. Antiganglioside antibodies are associated with axonal Guillain-Barré syndrome: a Japanese-Italian collaborative study. J Neurol Neurosurg Psychiatry 2012;83:23–8.
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Koga M, Ang CW, Yuki N, et al. Comparative study of preceding Campylobacter jejuni infection in Guillain-Barré syndrome in Japan and The Netherlands. J Neurol Neurosurg Psychiatry 2001;70:693–5. Drenthen J, Yuki N, Meulstee J, et al. Guillain-Barré syndrome subtypes related to Campylobacter infection. J Neurol Neurosurg Psychiatry 2011;82:300–5. Kuwabara S, Ogawara K, Misawa S, et al. Does Campylobacter jejuni infection elicit "demyelinating" Guillain-Barré syndrome? Neurology 2004;63:529–33. Mori M, Kuwabara S, Miyake M, et al. Haemophilus influenzae infection and Guillain-Barré syndrome. Brain 2000;123:2171–8. Susuki K, Odaka M, Mori M, et al. Acute motor axonal neuropathy after Mycoplasma infection: evidence of molecular mimicry. Neurology 2004;62:949–56. Yuki N, Kuwabara S, Koga M, et al. Acute motor axonal neuropathy and acute motor-sensory axonal neuropathy share a common immunological profile. J Neurol Sci 1999;168:121–6. Kuwabara S. Guillain-Barré syndrome. Curr Neurol Neurosci Rep 2007;7:57–62. Capasso M, Notturno F, Manzoli C, et al. Involvement of sensory fibres in axonal subtypes of Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry 2011;82:664–70. Capasso M, Caporale CM, Pomilio F, et al. Acute motor conduction block neuropathy another Guillain-Barré syndrome variant. Neurology 2003;61:617–22. Kaida K, Morita D, Kanzaki M, et al. Anti-ganglioside complex antibodies associated with severe disability in GBS. J Neuroimmunol 2007;182:212–18.
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Guillain−Barré syndrome in Asia Jong Seok Bae, Nobuhiro Yuki, Satoshi Kuwabara, Jong Kuk Kim, Steve Vucic, Cindy S Lin and Matthew C Kiernan J Neurol Neurosurg Psychiatry 2014 85: 907-913 originally published online December 19, 2013
doi: 10.1136/jnnp-2013-306212 Updated information and services can be found at: http://jnnp.bmj.com/content/85/8/907
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Neuromuscular
REVIEW
Guillain–Barré syndrome in Asia Jong Seok Bae,1,2 Nobuhiro Yuki,3 Satoshi Kuwabara,4 Jong Kuk Kim,5 Steve Vucic,2,6 Cindy S Lin,2 Matthew C Kiernan7 1
Department of Neurology, College of Medicine, Hallym University, Seoul, Korea 2 Neuroscience Research Australia, Sydney, Australia 3 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 4 Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan 5 Department of Neurology, College of Medicine, Dong-A University, Busan, Korea 6 Department of Neurology, Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia 7 Bushell Chair of Neurology, Brain & Mind Research Institute, University of Sydney, Sydney, New South Wales, Australia Correspondence to Dr Jong Seok Bae, Department of Neurology, College of Medicine, Hallym University, Seoul, Korea, Kangdong Sacred Heart Hospital, 150 Seongan-ro, Gangdong-gu, Seoul 134-701, Korea; [email protected] Received 8 July 2013 Revised 27 November 2013 Accepted 28 November 2013 Published Online First 19 December 2013
ABSTRACT Over the past 20 years, the most notable advance in understanding Guillain–Barré syndrome (GBS) has been the identification of an axonal variant. This advance arose chiefly through studies undertaken in East Asian countries and comprised two major aspects: first, the immunopathogenesis of axonal GBS related to antiganglioside antibodies and molecular mimicry of Campylobacter jejuni; and second, the observation that distinct electrophysiological patterns of axonal GBS existed, reflecting reversible conduction failure (RCF). As a consequence, the pathophysiology of acute motor axonal neuropathy (AMAN) has perhaps become better understood than acute inflammatory demyelinating polyneuropathy. Despite these more recent advances, a critical issue remains largely unresolved: whether axonal GBS is more common in Asia than in Europe or North America. If it is more common in Asia, then causative factors must be more critically considered, including geographical differences, issues of genetic susceptibility, the role of antecedent infections and other potential triggering factors. It has become apparent that the optimal diagnosis of AMAN requires serial electrophysiological testing, to better delineate RCF, combined with assessment for the presence of antiganglioside antibodies. Recent collaborative approaches between Europe and Asia have suggested that both the electrophysiological pattern of AMAN and the seropositivity for anti-ganglioside antibodies develop similarly. Separately, however, current electrodiagnostic criteria for AMAN limited to a single assessment appear inadequate to identify the majority of cases. As such, diagnostic criteria will need to be revised to improve the diagnostic sensitivity for AMAN.
INTRODUCTION
To cite: Bae JS, Yuki N, Kuwabara S, et al. J Neurol Neurosurg Psychiatry 2014;85:905–911.
Guillain–Barré syndrome (GBS) is generally characterised as a postinfectious, acute flaccid paralysis with albuminocytologic dissociation: that is, high levels of protein in the cerebrospinal fluid combined with a normal cell count.1 Worldwide, GBS is now considered the most common cause of acute flaccid paralysis and constitutes significant chronic morbidity.1 Since the first description by Guillain et al2 in 1916, GBS has been classically linked to the inflammatory destruction of the myelin sheath in peripheral nerves and roots, termed acute inflammatory demyelinating polyneuropathy (AIDP).1 In fact, for an extended period, AIDP became a synonym of GBS, with this term reflecting clinicopathological aspects of the disease. However, after the first suggestion about the existence of an axonal form of GBS by Feasby et al3 in 1986, and the subsequent definition of acute motor
Bae JS, et al. J Neurol Neurosurg Psychiatry 2014;85:905–911. doi:10.1136/jnnp-2013-306212
axonal neuropathy (AMAN) in the 1990s, general understanding of the syndrome has transformed. AMAN was first reported from the East Asia region, particularly China and Japan,4 5 with subsequent neurophysiological, pathological and immunological evidence to suggest that GBS could be divided into two major subtypes, AIDP and AMAN.6 7 As a consequence, AIDP is no longer considered a synonym of GBS, but rather solely reflects a subtype of the condition. From this perspective, understanding the clinical features, pathophysiology and diagnosis of AMAN remain essential for the overall conceptualisation of GBS. In turn, development of a greater understanding may provide clues to the remaining controversies of AMAN: geographic differences, molecular mimicry with infectious agents and the unique electrophysiological patterns. As such, the present review will focus on what is known about AMAN and what remains to be established.
CAMPYLOBACTER JEJUNI, GANGLIOSIDE ANTIBODIES AND MOLECULAR MIMICRY Originally, GBS was defined immunologically based on the inflammatory demyelinating polyneuritis linked to a cell-mediated immune response against unknown myelin protein antigens, considered similar to experimental allergic neuritis.8 Relevant pathological findings in GBS relate to the infiltration of inflammatory cells, particularly T lymphocytes and macrophages, with areas of segmental demyelination, often associated with secondary axonal degeneration, detectable in the spinal roots or peripheral nerves. These features were, for an extended period, considered to be consistent across all GBS presentations. As a consequence, in terms of terminology, AIDP was a term considered interchangeable with GBS, both in clinical and research communities. However, it has subsequently been demonstrated that AMAN was substantially different from AIDP, particularly in relation to immunological and pathological aspects. Specifically, in AMAN, IgG and activated complement bind to the axolemma of motor fibres at the nodes of Ranvier, followed by formation of the membrane attack complex (figure 1).6 The resulting nodal lengthening tends to be followed by degeneration of motor axons, with neither lymphocytic inflammation nor demyelination appearing as prominent features.5 9 Perhaps it could be argued that over the past 20 years, the most notable advances across the inflammatory neuropathies have been improvements in understanding the immunopathogenesis of AMAN. The discovery of anti-ganglioside 905
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Neuromuscular
Figure 1 Immunopathogenesis of acute motor axonal neuropathy. Molecular mimicry exists between gangliosides(GM1 and GD1a) and Campylobacter jejuni lipo-oligosaccharides (LOSs). Infection by C jejuni bearing GM1-like or GD1a-like LOSs may induce the production of IgG anti-GM1 or GD1a antibodies in certain patients, The autoantibodies bind to the nodes of Ranvier, where GM1 and GD1a are strongly expressed, and activate complement. Membrane attack complex is formed at the nodal axolemma, resulting in the disappearance of voltage-gated sodium (Nav) channels and the detachment of paranodal myelin. These pathological changes may lead to conduction failure and consequent muscle weakness. Subsequently, Wallerian-like degeneration may ensue, with macrophages penetrating the periaxonal space at the nodal area, scavenging the injured axons. In acute inflammatory demyelinating polyneuropathy, unknown autoantibodies may bind to the outer surface of Schwann cells and activate complement-related immunological mechanisms.
antibodies and their relationship with AMAN disclosed the immunogenic target: gangliosides present in the axolemma. Previously serological investigations revealed that approximately 60% of the acute-phase GBS sera had anti-ganglioside antibodies, predominantly IgG class, against at least one ganglioside.10 Molecular mimicry of human gangliosides by 906
the Campylobacter jejuni lipo-oligosaccharide (LOS) has been established as a trigger to the immunological pathogenesis associated with this disorder (figure 1).11 This critical understanding explained both the development of AMAN after antecedent infections, mostly gastrointestinal, and the seasonal variability of GBS and AMAN, probably according to seasonal epidemics of
Bae JS, et al. J Neurol Neurosurg Psychiatry 2014;85:905–911. doi:10.1136/jnnp-2013-306212
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Neuromuscular infectious pathogens.5 12 This seasonal pattern has also been reported in other countries, even those with a low incidence of AMAN.13 Theories of pathogenesis have been further explored using animal models of AMAN, including the sensitisation of Japanese white rabbits with a bovine brain ganglioside mixture or isolated GM1.14 In these landmark studies, rabbit models developed IgG anti-GM1 antibodies associated with acute monophasic flaccid limb weakness. Pathological findings in the peripheral nerve established prominent Wallerian-like degeneration, without lymphocytic infiltration or demyelination. Cauda equina and ventral root specimens revealed IgG deposits at the nodes of Ranvier and macrophage infiltration in the periaxonal space,15 similar to the situation identified in AMAN autopsy cases. Immunisation of animals with C jejuni LOS also produced AMAN,11 further supporting the molecular mimicry mechanism in this autoimmune disease process. Until recently, there was no clear evidence as to which antiganglioside antibodies were associated with the specific clinical characteristics of GBS. However, some anti-ganglioside antibodies such as anti-GM1, GM1b, GD1a and GalNAc-GD1a antibodies appeared in high frequencies in GBS from Asian countries as representative markers of AMAN.16 17 More recently, these antibodies were identified as important in determining the unusual electrophysiological characteristics.18 Additionally, although not the case in typical GBS, which is accompanied by limb weakness, unusual presentations such as ataxia may be attributed to the various differences across the spectrum of anti-ganglioside antibodies.19
AMAN AND REVERSIBLE CONDUCTION FAILURE Across the spectrum of peripheral neuropathies, an important utility of conventional nerve conduction studies (NCS) relates to the differentiation of axonal loss from apparent demyelination. When AIDP was used as a synonym of GBS, the electrodiagnostic criteria for demyelinating neuropathy were identical to those for GBS. Several electrophysiological criteria primarily used parameters associated with conduction velocity and evoked amplitude based on a single electrodiagnostic assessment.20–23 However, development of an understanding of AMAN as a distinct entity leads in turn to the need to determine new electrodiagnostic criteria to delineate the axonal variant of GBS. For the first AMAN diagnostic criteria, a slightly modified version of the Albers criteria20 was introduced by Ho and colleagues to differentiate between AIDP and AMAN in a Chinese population.23 In the Ho criteria set, ‘unequivocal’ temporal dispersion, but not conduction block (CB), was considered important. Hadden and colleagues further modified diagnostic criteria, not considering temporal dispersion, but reintroducing CB, defined as >50% reduction in proximal compound muscle action potential (CMAP) amplitude compared with distal CMAP.22 Currently, the Ho and Hadden criteria remain the most widely used in clinical practice to delineate AIDP from AMAN. In some series, in an attempt to overcome discrepancy, unequivocal temporal dispersion was set at >30% increased duration of proximal CMAP compared with distal CMAP.24 25 This seemingly arbitrary cut-off was established to distinguish between the effects of temporal dispersion due to demyelination when compared with axonal loss.26 The initial diagnostic criteria sets were based on an initial assumption that AMAN was characterised simply by axonal degeneration. However, previous electrophysiological studies revealed that some AMAN patients exhibited transient CB and slowing in intermediate and distal nerve segments, mimicking demyelination, although without features of abnormal temporal
dispersion, a process termed reversible conduction failure (RCF).18 This rapidly reversible block, which typically resolves within days to weeks, is frequently encountered in AMAN patients. Such a time course may suggest functional or microstructural changes at the node of Ranvier, rather than segmental demyelination and subsequent remyelination. As such, serial NCS are required to identify this important feature. Such a finding remains consistent with animal models of AMAN that established the presence of microstructural changes at or near the node of Ranvier, specifically disruption of nodal sodium channel clusters, and detachment of paranodal terminal myelin loops, mimicking paranodal demyelination, before macrophage invasion and resultant axonal degeneration ensued.27 28 The immune attack may in turn lead to the disappearance of paranodal adhesion molecules, such as contactin, contactin-associated protein and neurofascin-155, indicative of impaired tight paranodal axo-glial junctions.27 The possibility of a nondemyelinating, ‘physiological’ CB in AMAN has also been raised by autopsy studies that showed minimal structural changes at the node of Ranvier in patients with severe muscle weakness, leading to death from respiratory failure.9
PROBLEMS WITH EXISTING ELECTRODIAGNOSTIC CRITERIA The lack of distinction between RCF and demyelinating CB from a single NCS may lead to the incorrect classification of AMAN as AIDP.18 In these AMAN patients, CB in intermediate nerve segments may promptly resolve, distal CMAP amplitudes may rapidly increase and distal motor latencies, when prolonged, may return to normal values without the development of excessive temporal dispersion. Such features are clearly different from what is usually expected in AIDP patients without antiganglioside antibodies (figure 2). It is now accepted that some AMAN patients, as distinct from the classical axonal degeneration pattern, may exhibit transient CB and conduction slowing, thereby mimicking demyelination, but without components characteristic of remyelination, suggesting impaired conduction at the node of Ranvier, presumably related to the effects of anti-ganglioside antibodies. Until now, there have been no electrodiagnostic criteria based on results obtained from serial NCS. Clearly, serial electrophysiological studies remain essential for the diagnosis of GBS subtypes, the identification of pathophysiological mechanisms and assessment of prognosis. As such, more reliable electrodiagnostic criteria need to be devised to distinguish axonal from demyelinating subtypes of GBS, taking into consideration the RCF pattern and focusing on temporal dispersion.29
IS AMAN MORE COMMON IN ASIA? Although there are only slight differences in the total worldwide incidence and prevalence of GBS,30 the incidence of AMAN appears to vary considerably between countries. Across Europe and North America, AIDP is the dominant subtype of GBS31 32 and represents up to 90% of total GBS.22 However, there is discrepancy of such incidence in Western and Central Asian countries33 34 and perhaps even Central America.35 Specifically, reports of AMAN are relatively common in Asian countries,16 23 36–39 especially Eastern Asia, where the frequency of AMAN is high, perhaps even higher than AIDP (table 1)23 36 38and also in Central and South America, where the frequency ranges from 40% to 65%.23 25 35 36 40 Given that C jejuni is the most common antecedent infection of GBS worldwide41 and the suggestion from molecular mimicry studies that C jejuni infection may be expected to
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Neuromuscular
Figure 2 Serial recordings of the motor nerve conduction studies in various Guillain–Barré syndrome subtypes. Superimposed compound motor action potential (CMAP) recordings over the abductor pollicis brevis muscle, following stimulation of the median nerve at the wrist and elbow. The procedure was performed by Dr N. Kokubun (Dokkyo Medical University, Japan). Acute inflammatory demyelinating polyneuropathy (A). Although clinical nadir was reached at day 10, progressive prolongation of distal motor latency (DML) and decrease in CMAP amplitude with excessive temporal dispersion were seen by week 6, indicating that the conduction slowing is primarily a sign of remyelination. CMAP amplitudes began to show gradual improvement by week 11, but slight prolongation of DML remained at week 47. Acute motor axonal neuropathy (B). A rapid, progressive decrease in CMAP amplitudes was present in the early stage of the disease. Clinical nadir was reached by day 10. As well as clinical recovery, CMAPs were seen to improve gradually without prolongation of the DMLs, conduction slowing or excessive temporal dispersion. Acute motor-conduction-block neuropathy (C). On day 5, conduction blocks (CBs) were present at the forearm and upper arm segments of the median nerve. The CBs rapidly resolved, with no remyelination features, such as excessive temporal dispersion or conduction slowing, by day 14. Clinical nadir was reached at day 3, and complete recovery was seen by week 14. The result of the normal nerve conduction study at week 14 is shown (modified from Yuki and Hartung1 with permission from Massachusetts Medical Society).
invariably induce AMAN, AMAN may be expected to be the predominant subtype of GBS. However, AMAN was previously considered a rare variant and, even now, remains the less common subtype in most world regions, with the exception of
Table 1 Relative frequencies of acute motor axonal neuropathy (AMAN)/acute inflammatory demyelinating polyneuropathy (AIDP) subtypes worldwide
Country North America and Europe* England* Slovenia Israel Pakistan Japan† Turkey Korea* Northeast China Bangladesh* China*
Proportion of AMAN to total Guillain–Barré syndrome (GBS) (%)
Proportion of AIDP to total GBS (%)
Number of reference
4
90
22
7 11 22 31 36 40 50 54 56 65
– 79 63 46 36 – – 8 22 24
31 32 33 34 16 37 39 38 36 23
*Study using the anti-ganglioside assay only. †Study using both serial nerve conduction studies (NCS) and anti-ganglioside assays. Bars with no marking indicate use of neither serial NCS nor anti-ganglioside antibody assays.
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some Asian countries. What then could cause this apparent discrepancy? There may be a number of explanations. First, although C jejuni is a common enteric human pathogen, epidemiological differences in C jejuni infection across world regions must be considered.42 For instance, although C jejuni grows best at 42°C, it cannot be pathologically active at freezing temperatures for long periods, characteristics that will clearly limit transmission.43 C jejuni infection occurs year-round, but with a sharp peak in the summer and early autumn. Infection is higher when air temperatures rise44 and is influenced by rainfall in tropical countries. The epidemiology of infection in developing countries is markedly different. Indeed, in developing countries, C jejuni is often isolated from healthy individuals, and infection is especially common in children or immunocompromised individuals.45 46 Thus, AMAN may be apparently more frequent in countries with a higher incidence of diarrhoea and a poor hygienic infrastructure.36 Climate may also underlie differences in AMAN occurrence. Most countries with higher AMAN percentages, particularly across Asia, have extremely hot and humid summer seasons, whereas Europe and North America have relatively dry summer seasons. Thus, the vulnerability of C jejuni to dry conditions may contribute to a lower incidence of infection, especially in the summer months across Western countries.23 35 A further consideration relates to factors associated with the individual host. Given that GBS is generally considered a sporadic disease, an association of AMAN and AIDP with the genetic background of the host seems unlikely. Although some
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Neuromuscular cases of familial GBS have been described,47 48 there is no strong human leukocyte antigen (HLA) linkage,49 although one study suggested a link with a CD1 polymorphism.50 Recurrence of pure GBS also remains rare. However, some peculiar features of the sequelae of C jejuni infection may suggest a possible role for host factors, probably via immunological processes. After recovery from C jejuni infection, reactive arthritis or Reiter’s syndrome may develop in some hosts, related to genetic factors (eg, HLA-B27-positive patients), as seen in other gastrointestinal infections, such as with Yersinia, Salmonella and Shigella species. On the other hand, non-specific rheumatologic symptoms may inexplicably persist for several months or even years in a few affected people.51 Finally, there remain other relatively untested theories associated with host factors: C jejuni strains with C jejuni sialyl transferase (Cst-II) (Thr51) express GM1-like and GD1a-like LOS, whereas strains with Cst-II (Asn51) expressed GT1a-like and GD1c-like LOS.52As such, Cst-II (Thr51) strain also induce IgG anti-GQ1b antibodies. In such cases, GBS may also overlap with Fisher syndrome. If geographical differences in genetic polymorphisms of C jejuni strains exist, such ‘bacterial’ factors may make differences in the phenotype or subtype of GBS across different regions of the world. However, host factors are also important, in that infections by the aforementioned strains do not always induce GBS. As such, it would be helpful to resolve these issues about host factors and to determine the relative proportion of AMAN or Fisher syndrome that may develop in Asian immigrants living in Western countries.
IS AMAN UNDERESTIMATED IN WESTERN COUNTRIES OR OVERESTIMATED IN ASIA? To explain the apparent discrepancy of frequent C jejuni infection and less frequent axonal GBS in Western countries, it remains plausible that 1. AMAN could be underestimated; 2. C jejuni infection could be overestimated or 3. C jejuni infection may lead to both AIDP and AMAN.53 The first hypothesis is closely related to a false-negative diagnosis of AMAN. As discussed in previous sections, the present electrodiagnostic criteria for AMAN leave a high likelihood of misdiagnosing AMAN as AIDP. Additionally, many previous studies of AMAN did not use assays for anti-ganglioside antibodies, potentially leading to underestimation of true AMAN incidence. Concerning immunological aspects, a previous Dutch–Japanese collaborative study identified a similar proportion of ganglioside positivity.54 However, this comparative study identified a different range of cross-reactivity and isotype distribution among various anti-ganglioside antibodies. This study revealed a different reaction between antecedent infection and antibody formation in relation to the different geographic factors. From an electrophysiological perspective, an Italian group determined that sequential NCS resulted in a significant increase in the frequency of AMAN, from 18% to 38%.13 This group subsequently reported their findings in a collaborative study with Japanese colleagues using the same procedures, incorporating anti-ganglioside assays and a serial NCS protocol.55 Interestingly, approximately 30% of both Japanese and Italian patients with a positive ganglioside antibody demonstrated an AIDP pattern at their first NCS, whereas sequential studies determined that most ultimately developed AMAN. With regard to the second hypothesis, the gold standard for C jejuni infection remains a positive stool culture, but because of the delay in GBS onset from a preceding infection, such cultures are often negative. Consequently, serology remains the
method of choice for diagnosing a recent C jejuni infection. Although the sensitivity and specificity of serological assays vary between laboratories, Dutch–Japanese collaborative studies have suggested that the incidence of antecedent C jejuni infection in Japanese GBS was no higher than Dutch GBS.56 Few trials have investigated the third hypothesis, although one study suggested that C jejuni infection occasionally induced AIDP,57 using serological assays from both a Dutch laboratory and also from a Japanese laboratory. This was the same procedure used in a previous Japanese study that reported an exclusive relationship between C jejuni and AMAN.58 However, these comparative studies showed three probable demyelinating GBS cases tested positive by the Dutch assay, of which only one was positive by both the Dutch and Japanese assays. Overall, it seems unlikely that C jejuni infection elicits typical AIDP, but the possibility that C jejuni infection may induce unique myelin damage cannot be excluded.53 Separately, the development of AMAN without C jejuni infection has been suggested. Specifically, despite the lack of a precise pathophysiology and specific categorisation of its clinical laboratory features, some reports have described the development of AMAN after infection with other agents, such as mycoplasma or Haemophilus influenzae. Thus, a certain proportion of AMAN patients may be related to antecedent infections by organisms other than C jejuni.59 60
OTHER GBS SUBTYPES IN ASIA At present there is little information concerning the incidence of acute motor sensory axonal neuropathy (AMSAN) across Asia, although it appears to represent up to 4% of GBS in Japan,61 62 6% in India25 and 11% in Bangladesh.36 It has been suggested that patients with AMAN and AMSAN may share serological markers.61 Indeed, AMSAN has the same immunological markers, IgG anti-GM1 and anti-GD1a antibodies that differentiate AMAN from AIDP. This common immunological profile supports the notion that AMAN and AMSAN may arise as a result of the same immune response against the axon, rather than two separate disease entities. Perhaps of relevance, serial sensory NCS have identified that sensory fibres are often subclinically involved in AMAN63 and that RCF occurs in sensory and motor fibres in AMAN and AMSAN. As such, AMSAN may be considered an extreme sensory-predominant form of AMAN. It was previously proposed that acute motor conduction block neuropathy (AMCBN) was an axonal variant of GBS.64 However, AMCBN and AMAN may share antecedent C jejuni enteritis and IgG anti-GM1 and anti-GD1a antibodies in common. Furthermore, AMCBN patients may demonstrate the RCF pattern described in some nerves of AMAN patients (figure 2). As a consequence, it has been hypothesised that AMCBN represented an ‘arrested’ form of AMAN, in which anti-ganglioside antibodies bound to the nodal axolemma to thereby induce RCF, although nerves do not progress to more severe axonal degeneration.64
CONCLUSIONS Recognition of AMAN and the development of meaningful animal models have facilitated an understanding concerning the immunopathogenesis associated with ganglioside antibodies and also C jejuni infection. Identification of different electrophysiological profiles of AMAN, particularly by means of serial NCS testing, has resulted in the establishment of a new concept of conduction failure due to nodal pathology, the so-called RCF.
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Neuromuscular As a consequence, clinicians can now diagnose AMAN using these combined serological and electrophysiological approaches. With further research, it seems likely that the sensitivity for a diagnosis of AMAN will further increase with time and clinicians will be able to better assess the clinical phenotype and prognosis of GBS patients through detection of specific antiganglioside antibodies. Furthermore, immunological profiles may prove useful in predicting the clinical phenotype. For instance, identification of antibodies to specific components of the ganglioside complex, such as antibodies against GD1a/GD1b and GD1b/GT1b complexes, appears to be associated with more severe presentations of GBS, requiring artificial ventilation.65 However, as it currently stands, the incidence of axonal GBS appears underestimated in Western countries, and more appropriate diagnostic criteria for AMAN will ideally need to be developed and incorporated into a practical algorithm. To achieve this goal, an international consensus will need to be reached concerning the electrodiagnostic criteria for AMAN. Second, large, prospective studies that systematically incorporate ‘serial’ electrodiagnostic studies, C jejuni serology and ganglioside antibody measurements will be required. In this respect, the International Guillain–Barré syndrome Outcome Study, which will recruit 1000 patients, has recently commenced, with support from the Peripheral Nerve Society, Inflammatory Neuropathy Consortium, and through such approaches many of the controversial issues outlined in the present review may yet be resolved.
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Contributors JSB, MCK, NY and SK conceived the review and JSB wrote the initial draft. All authors contributed to subsequent drafting and critically revising the content.
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Competing interests None.
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Provenance and peer review Commissioned; externally peer reviewed.
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Guillain−Barré syndrome in Asia Jong Seok Bae, Nobuhiro Yuki, Satoshi Kuwabara, Jong Kuk Kim, Steve Vucic, Cindy S Lin and Matthew C Kiernan J Neurol Neurosurg Psychiatry 2014 85: 907-913 originally published online December 19, 2013
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