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Guillain-Barre syndrome in Asia

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JNNP Online First, published on December 19, 2013 as 10.1136/jnnp-2013-306212
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; jsb_res@hotmail.co.kr
Received 8 July 2013
Revised 27 November 2013
Accepted 28 November 2013
To cite: Bae JS, Yuki N,
Kuwabara S, et al. J Neurol
Neurosurg Psychiatry
Published Online First:
[please include Day Month
Year] doi:10.1136/jnnp-
2013-306212
BaeCopyright Article
JS, et al. J Neurol
Neurosurg Psychiatry(or their employer)
Downloaded from jnnp.bmj.com on January 23, 2014 - Published by group.bmj.com
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
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 anti-
ganglioside 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 anti-
ganglioside 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
Guillain–Barré syndrome (GBS) is generally charac-
terised as a postinfectious, acute flaccid paralysis
with albuminocytologic dissociation: that is, high
levels of protein in the cerebrospinal fluid com-
bined 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 reflect-
ing clinicopathological aspects of the disease.
However, after the first suggestion about the exist-
ence of an axonal form of GBS by Feasby et al3 in
1986, and the subsequent definition of acute motor
author
2013;0:1–7. 2013. Produced
doi:10.1136/jnnp-2013-306212 by BMJ Publishing Group Ltd under licence.
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 con-
sequence, 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 understand-
ing may provide clues to the remaining controver-
sies of AMAN: geographic differences, molecular
mimicry with infectious agents and the unique elec-
trophysiological 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 infiltra-
tion of inflammatory cells, particularly T lympho-
cytes 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 inter-
changeable 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 patho-
logical aspects. Specifically, in AMAN, IgG and acti-
vated complement bind to the axolemma of motor
fibres at the nodes of Ranvier, followed by forma-
tion of the membrane attack complex (figure 1).6
The resulting nodal lengthening tends to be fol-
lowed by degeneration of motor axons, with neither
lymphocytic inflammation nor demyelination appear-
ing 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 improve-
ments in understanding the immunopathogenesis
of AMAN. The discovery of anti-ganglioside
1
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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 approxi-
mately 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
the Campylobacter jejuni lipo-oligosaccharide (LOS) has been
established as a trigger to the immunological pathogenesis asso-
ciated 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

2 Bae JS, et al. J Neurol Neurosurg Psychiatry 2013;0:1–7. doi:10.1136/jnnp-2013-306212

 Downloaded from jnnp.bmj.com on January 23, 2014 - Published by group.bmj.com
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 degener-
ation, 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 anti-
ganglioside antibodies were associated with the specific clinical
characteristics of GBS. However, some anti-ganglioside anti-
bodies such as anti-GM1, GM1b, GD1a and GalNAc-GD1a anti-
bodies 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 deter-
mining 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 electrodiagnos-
tic 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 electro-
diagnostic 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 differ-
entiate 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 disper-
sion 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 dis-
persion 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
Bae JS, et al. J Neurol Neurosurg Psychiatry 2013;0:1–7. doi:10.1136/jnnp-2013-306212
Neuromuscular
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 micro-
structural 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 parano-
dal adhesion molecules, such as contactin, contactin-associated
protein and neurofascin-155, indicative of impaired tight para-
nodal axo-glial junctions.27 The possibility of a non-
demyelinating, ‘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 pro-
longed, may return to normal values without the development
of excessive temporal dispersion. Such features are clearly differ-
ent from what is usually expected in AIDP patients without anti-
ganglioside 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, suggest-
ing 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
3
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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 some Asian countries. What then could cause this apparent
predominant subtype of GBS. However, AMAN was previously discrepancy?
considered a rare variant and, even now, remains the less There may be a number of explanations. First, although
common subtype in most world regions, with the exception of 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
Table 1 Relative frequencies of acute motor axonal neuropathy for long periods, characteristics that will clearly limit transmis-
(AMAN)/acute inflammatory demyelinating polyneuropathy (AIDP) sion.43 C jejuni infection occurs year-round, but with a sharp
subtypes worldwide peak in the summer and early autumn. Infection is higher when
Proportion of AMAN Proportion of air temperatures rise44 and is influenced by rainfall in tropical
to total Guillain–Barré AIDP to total Number of countries. The epidemiology of infection in developing coun-
Country syndrome (GBS) (%) GBS (%) reference tries is markedly different. Indeed, in developing countries,
North America 4 90 22 C jejuni is often isolated from healthy individuals, and infection
and Europe* is especially common in children or immunocompromised
England* 7 – 31 individuals.45 46 Thus, AMAN may be apparently more fre-
Slovenia 11 79 32 quent in countries with a higher incidence of diarrhoea and a
Israel 22 63 33 poor hygienic infrastructure.36
Pakistan 31 46 34 Climate may also underlie differences in AMAN occurrence.
Japan† 36 36 16 Most countries with higher AMAN percentages, particularly
Turkey 40 – 37 across Asia, have extremely hot and humid summer seasons,
Korea* 50 – 39 whereas Europe and North America have relatively dry summer
Northeast China 54 8 38 seasons. Thus, the vulnerability of C jejuni to dry conditions
Bangladesh* 56 22 36 may contribute to a lower incidence of infection, especially in
China* 65 24 23 the summer months across Western countries.23 35
*Study using the anti-ganglioside assay only.
A further consideration relates to factors associated with the
†Study using both serial nerve conduction studies (NCS) and anti-ganglioside assays. individual host. Given that GBS is generally considered a spor-
Bars with no marking indicate use of neither serial NCS nor anti-ganglioside antibody adic disease, an association of AMAN and AIDP with the
assays.
genetic background of the host seems unlikely. Although some

4 Bae JS, et al. J Neurol Neurosurg Psychiatry 2013;0:1–7. doi:10.1136/jnnp-2013-306212

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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 symp-
toms may inexplicably persist for several months or even years
in a few affected people.51
Finally, there remain other relatively untested theories asso-
ciated 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 rela-
tive 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 infec-
tion 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 diag-
nosis 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 anti-
bodies, potentially leading to underestimation of true AMAN
incidence. Concerning immunological aspects, a previous
Dutch–Japanese collaborative study identified a similar propor-
tion of ganglioside positivity.54 However, this comparative study
identified a different range of cross-reactivity and isotype distri-
bution 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 cul-
tures are often negative. Consequently, serology remains the
Bae JS, et al. J Neurol Neurosurg Psychiatry 2013;0:1–7. doi:10.1136/jnnp-2013-306212
Neuromuscular
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 proced-
ure 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 infec-
tion 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 differen-
tiate 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 subcli-
nically 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 electrophysio-
logical 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.
5
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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 clini-
cians will be able to better assess the clinical phenotype and
prognosis of GBS patients through detection of specific anti-
ganglioside 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 appro-
priate 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 ganglio-
side 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.
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.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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7
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Guillain−Barré syndrome in Asia

Jong Seok Bae, Nobuhiro Yuki, Satoshi Kuwabara, et al.

J Neurol Neurosurg Psychiatry published online December 19, 2013

doi: 10.1136/jnnp-2013-306212

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