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2.-Seminario Lancet 2016
2.-Seminario Lancet 2016
Guillain-Barr syndrome
Hugh J Willison, Bart C Jacobs, Pieter A van Doorn
Guillain-Barr syndrome is the most common and most severe acute paralytic neuropathy, with about 100 000 people Lancet 2016; 388: 71727
developing the disorder every year worldwide. Under the umbrella term of Guillain-Barr syndrome are several Published Online
recognisable variants with distinct clinical and pathological features. The severe, generalised manifestation of February 29, 2016
http://dx.doi.org/10.1016/
Guillain-Barr syndrome with respiratory failure aects 2030% of cases. Treatment with intravenous immunoglobulin
S0140-6736(16)00339-1
or plasma exchange is the optimal management approach, alongside supportive care. Understanding of the infectious
Institute of Infection,
triggers and immunological and pathological mechanisms has advanced substantially in the past 10 years, and is Immunity and Inflammation,
guiding clinical trials investigating new treatments. Investigators of large, worldwide, collaborative studies of the College of Medical, Veterinary
spectrum of Guillain-Barr syndrome are accruing data for clinical and biological databases to inform the development and Life Sciences, University of
Glasgow, Glasgow, UK
of outcome predictors and disease biomarkers. Such studies are transforming the clinical and scientic landscape of
(Prof H J Willison MBBS); and
acute autoimmune neuropathies. Department of Neurology
(Prof B C Jacobs MD,
Introduction immunoglobulins (IVIg) or plasma exchange is of proven Prof P A van Doorn MD) and
Department of Immunology
The clinical journey through Guillain-Barr syndrome benet and crucial, especially in patients with rapidly
(Prof B C Jacobs), Erasmus MC,
follows a typical pattern that can be readily divided into progressive weakness.12 Because a quarter of patients need University Medical Center,
its constituent phases and components (gure 1).1 articial ventilation and many develop autonomic Rotterdam, Netherlands
Demyelinating and axonal forms of the syndrome occur in disturbances, many patients need admission in the high or Correspondence to:
varying proportions across dierent geographical regions, intensive care setting. Symptoms peak within 4 weeks, Prof Hugh J Willison, Glasgow
Biomedical Research Centre,
and clinical variants, such as Miller Fisher syndrome, are followed by a recovery period that can last months or years,
120 University Place, University of
readily denable.2 Within the typical disease course are as the immune response decays and the peripheral nerve Glasgow, Glasgow, G12 8TA, UK
many less well understood biological variations, which are undergoes an endogenous repair process. Hugh.Willison@glasgow.ac.uk
considered chronologically in this Seminar. Eorts focus on the measurement and prediction of
First, Guillain-Barr syndrome is usually preceded by clinical course and outcome to improve the care and
infection or other immune stimulation that induces an treatment of individual patients.13 Good prognostic
aberrant autoimmune response targeting peripheral models have been developed, but additional studies are
nerves and their spinal roots.3,4 Molecular mimicry needed to investigate whether these prognostic factors
between microbial and nerve antigens is clearly a major dier between dierent disease subgroups and areas in
driving force behind the development of the disorder, at the world. In parallel, prognostic biomarkers now need
least in the case of Campylobacter jejuni infection. to be developed to better predict outcomes and guide
However, the interplay between microbial and host action, such as personalised treatment renements in
factors that dictates if and how the immune response is acute management.14 Finally, the impact of Guillain-Barr
shifted towards unwanted autoreactivity is still not well syndrome on individuals and as a global health issue is
understood.5 Furthermore, genetic and environmental discussed alongside eorts to create evidence-based
factors that aect an individuals susceptibility to develop uniformity in the management of aected patients in
the disease are unknown.6 Unwanted autoimmunity dierent health-care settings.
does not arise in most individuals (>99%) exposed to an
immune stimulus as a result of Guillain-Barr syndrome- Epidemiology and preceding infections
associated infections such as C jejuni.7 Most studies that estimate incidence rates of Guillain-
The acute progression of limb weakness, often with Barr syndrome were done in Europe and North America,
sensory and cranial nerve involvement 12 weeks after and showed a similar range of 0819 (median 11) cases
immune stimulation, proceeds to its peak clinical decit in per 100 000 people per year.15 The annual incidence rate of
24 weeks.8 When patients present with rapidly progressive
paralysis, the diagnosis of Guillain-Barr syndrome needs
to be made as soon as possible. Although establishment of Search strategy and selection criteria
the diagnosis in typical cases is usually straightforward, We searched the entire Cochrane Library, MEDLINE, and
there are many clinical and investigative components to PubMed using the search term Guillain-Barr syndrome.
consider, especially in atypical cases. The diagnosis is We mainly selected publications from the past 5 years, but
largely based on clinical patterns, because diagnostic did not exclude commonly referenced and highly regarded
biomarkers are not available for most variants of the older publications. We also searched the reference lists of
syndrome. Identication of biomarkers and establishment articles identied by this search strategy and selected those
of their pathophysiological roles, if any, in experimental papers we judged relevant. Review articles are cited to
models has been a major research challenge.9,10 All patients provide readers with more details and references than can
with Guillain-Barr syndrome need meticulous monitoring be provided in this Seminar.
and supportive care.11 Early initiation of intravenous
infection. Two possible reasons could account for the low An intriguing, new area for exploration that originally
number of people who develop acute motor axonal emerged from Japanese Guillain-Barr syndrome studies
neuropathy. First, only a small proportion of C jejuni has highlighted the notion that glycolipid domains,
strains have ganglioside mimics on their LOSmost composed of multiple glycolipid and lipid components,
strains bear other glycans.47 Second, most individuals who can associate to form neoantigens that are not present in
have been exposed to C jejuni maintain immunological any single molecule.55 These so-called anti-complex
tolerance to the self-glycans on LOS, and instead mount a antibodies only bind heteromeric or multimeric lipid
projective immune response against other components complexes and are dicult to detect. In addition to being
of the bacterial surface. Why certain individuals break found in some cases of acute motor axonal neuropathy,
tolerance and enter an autoreactive state is not known at they might be widely present, but as yet, undiscovered in
present. Unlike T-cell tolerance, the mechanisms acute inammatory demyelinating polyneuropathy.
underlying B-cell tolerance to T-cell-independent Studies investigating these antibodies are continuing
antigens, including gangliosides, are not well studied.5 and involve the development of both technical platforms
By contrast with acute motor axonal neuropathy, the and study design.56,57
immunological cascade involved in acute inammatory Although the distinction between acute motor axonal
demyelinating polyneuropathy is less well understood neuropathy and acute inammatory demyelinating
for various reasons. First, a wider range of immune polyneuropathy is conceptually clear, the margins might
stimulants cause acute inammatory demyelinating be more blurred than originally thought.58 Electro-
polyneuropathy compared with acute motor axonal physiological methods are the mainstay of clinical
neuropathy, which includes bacterial and viral infections, investigation. A substantial proportion of acutely
and vaccines. Second, specic antibody biomarkers have diagnosed patients with Guillain-Barr syndrome cannot
yet to be characterised, despite widespread screening be classied into a category, either because the tractable
eorts to identify the putative nerve antigens. At present, nerves (ie, the upper and lower limb nerves that can be
a wider range of anti-nerve autoantibodies directed at readily accessed by surface electrodes used in clinical
both proteins and glycolipids could be responsible for electrophysiology) are so severely aected that they are
acute inammatory demyelinating polyneuropathy inexcitable, or are physiologically normal; both states are
immunopathology than is the case for acute motor uninformative for classication as acute motor axonal
axonal neuropathy or Miller Fisher syndrome. neuropathy or acute inammatory demyelinating
Alternatively, nerve specic T cells, directed against as polyneuropathy. Furthermore, electrophysiological re-
yet unknown antigens might play a greater part in acute cordings are ambiguous, change during the clinical
inammatory demyelinating polyneuropathy than is course in any one individual, and yield an acute
known at present. Historically, few studies have shown inammatory demyelinating polyneuropathy pattern
T-cell and B-cell responses to compact myelin proteins, early on and an acute motor axonal neuropathy pattern
including P0, P2, and PMP22, although these responses later (reversible conduction block).59,60 Thus, inammatory
have been found in small numbers of cases.48 Antibodies injury of either glial or axonal membranes (or both
against proteins in the specialised domains at the node of simultaneously) in the nodal complex might result in
Ranvier, including gliomedin, contactin, TAG-1, moesin, very similar electrophysiological features of reversible
and neurofascin have been identied.49 For example, a conduction failure.
high proportion of antibodies against moesin, a The molecular architecture of the nodal complex, which
component of the ezrinradixinmoesin cytoplasmic consists of specialised nodal, paranodal, and juxta-
complex in Schwann-cell microvilli that surround the paranodal domains that mediate glialaxonal interactions,
nodal axolemma, have been reported in cases of acute has been well characterised and provides a foundation for
inammatory demyelinating polyneuropathy triggered the study of the ne details of Guillain-Barr syndrome
by CMV infection,50 although this result has not been pathogenesis from a nodal perspective.61 Although yet to
replicated.51 Nerve glycolipids expressed in glial be established, immune responses focused on the nodal
membranes, including myelin, are prime candidates as complex probably underlie much of the pathogenic
important antigens in acute inammatory demyelinating cascade that takes place in Guillain-Barr syndrome, and
polyneuropathy.52 Antibodies against the glycolipid LM1, the term nodo-paranodopathy has been coined to
sulphoglucuronosyl paragloboside, galactocerebroside, emphasise the focus on this site.62 As noted previously, the
and sulfatide are found in a small proportion of patients nodal area is richly decorated with potential antigens,
with acute inammatory demyelinating polyneuropathy.53 including proteins and glycolipids, and is functionally
In addition to being present in axonal membranes, some very sensitive to pathological perturbations induced
gangliosides (including GM1 and GQ1b) are expressed in by antibody deposits, complement activation, and
glial membranes at the node of Ranvier, where they macrophage recruitment. Nodal conduction block, of glial
might mediate paranodal demyelination that causes the or axonal origin, can arise quickly, but functionality can be
pathophysiological features of acute inammatory restored in equally short time periods through local repair
demyelinating polyneuropathy.54 of injured membranes. Conversely, complete axonal
transaction (which is always followed by Wallerian could follow a protracted course and result in severe,
degeneration of the distal stump),63 especially if proximally permanent disability. During the acute phase, the stable
located in the nerve roots at a long distance from the phase, or even during recovery, patients might have signs
innervation target, will be a permanent irreparable injury or symptoms of autonomic dysfunction like cardiac
because regeneration cannot eectively occur over long arrhythmia that occasionally necessitates a pacemaker,
distances. Although these considerations have clinical excessive sweating, blood pressure instability, or ileus.4
relevance, prediction of how they might aect outcome in Guillain-Barr syndrome is a clinical diagnosis, but
individual cases is dicult, and there are no specic additional investigations can be helpful or even needed
therapeutic implications at present. for conrmation. Examination of the cerebrospinal uid
Clinical classication and diagnosis Panel 1: Diagnostic criteria for Guillain-Barr syndrome1
In typical Guillain-Barr syndrome, rapidly progressive
bilateral weakness is the key presenting symptom in most Features needed for diagnosis of Guillain-Barr syndrome in clinical practice
patients (panel 1).1,8,65,66 Weakness is classically described Progressive weakness in legs and arms (sometimes initially only in legs).
as ascending, and usually starts in the distal lower Areexia (or decreased tendon reexes) in weak limbs.
extremities, but can start more proximally in the legs or
Additional symptoms
arms. The latter pattern can give the false clinical
Progressive phase lasts days to 4 weeks (often 2 weeks).
impression of a pyramidal lesion (ie, at the level of the
Relative symmetry.
spinal cord or above), but can be easily explained by focal
Mild sensory symptoms or signs (not present in acute motor axonal neuropathy).
conduction block at the level of the lumbar and cervical
Cranial nerve involvement, especially bilateral weakness of facial muscles.
nerve roots, rather than along the length of the nerve
Autonomic dysfunction.
bre. A small number of patients present with
Pain (common).
paraparesis, which can remain during the course of the
disease.67 Others might present with cranial nerve Features that should raise doubt about the diagnosis of Guillain-Barr syndrome
involvement resulting in facial, oculomotor, or bulbar CSF: increased number of mononuclear cells or polymorphonuclear cells (>50 cells per L).
weakness, as in Miller Fisher syndrome, which might Severe pulmonary dysfunction with little or no limb weakness at onset.
then extend to involve the limbs. In addition to weakness, Severe sensory signs with little or no weakness at onset.
patients might initially have sensory signs, ataxia, and Bladder or bowel dysfunction at onset.
features of autonomic dysfunction. Muscle pain or Fever at onset.
radicular pain, often but not always in the spinal region, Sharp spinal cord sensory level.
is another frequent initial sign, which can complicate the Marked, persistent asymmetry of weakness.
diagnosis because pain can precede weakness in about a Persistent bladder or bowel dysfunction.
third of patients.68 Symptoms of preceding infection Slow progression of weakness and without respiratory involvement (consider
might be too vague to add to the clinical presentation, but subacute inammatory demyelinating polyneuropathy or acute onset chronic
could be more informative, especially in the case of orid inammatory demyelinating polyneuropathy).
gastroenteritis. Most patients have, or develop, reduced
Nerve conduction studies
tendon reexes in the aected limbs. Reexes can initially
Can be helpful in clinical practice, but are generally not required to diagnose
be normal especially in pure motor and axonal forms of
Guillain-Barr syndrome.
the disorder or in a few cases, even be hyper-reexic.69
Needed to meet all Brighton criteria for Guillain-Barr syndrome.8
According to various diagnostic criteria for Guillain-Barr
Essential for classication of Guillain-Barr syndrome in acute inammatory
syndrome, patients can have progression of weakness
demyelinating polyneuropathy or acute motor axonal neuropathy.
within 4 weeks. Most patients, however, reach the nadir
Acute inammatory demyelinating polyneuropathy: features of demyelination
within 2 weeks.8 Progression can last up to 6 weeks after
(decreased motor nerve conduction velocity, prolonged distal motor latency,
onset (subacute Guillain-Barr syndrome) in some rare
increased F-wave latency, conduction blocks, and temporal dispersion).58
cases.70 During the progressive phase, 2030% of patients
Acute motor axonal neuropathy: no features of demyelination (one demyelinating
develop respiratory failure and need ventilation at an
feature in one nerve, if distal CMAP amplitude is less than 10% LLN, can be found;
intensive care unit (ICU).8 The clinical condition of at
distal CMAP amplitude less than 80% LLN in at least two nerves.58 Transient motor
least 25% of patients deteriorates during or shortly after
nerve conduction block might be present.64
treatment with IVIg or plasma exchangethe inference
of which is that they would be worse without therapy, Classication of Guillain-Barr syndrome as either acute inammatory demyelinating
rather than an indication of complete treatment polyneuropathy or acute motor axonal neuropathy is not required for diagnosis of
resistance.12 The severity and duration of disease is highly Guillain-Barr syndrome, whether acute inammatory demyelinating polyneuropathy
diverse in patients and can range from mild weakness, and acute motor axonal neuropathy require dierent treatments is unknown. The
from which patients recover spontaneously, to patients amount of conduction slowing required to dene demyelination diers between
becoming quadriplegic and ventilator-dependent without classication systems.
signs of recovery for several months or longer. Eventually, CSF=cerebrospinal uid. CMAP=compound muscle action potential. LLN=lower limit of normal.
however, all patients start improving, although recovery
(CSF) is important especially to exclude other causes of considered a variant of Guillain-Barr syndrome is
weakness associated with an increase in CSF cell count.4 unclear. Miller Fisher syndrome is a variant of
The disorder is classically known for its cytoalbumino- Guillain-Barr syndrome accounting for 5% of cases in
logical dissociationthe combination of a normal cell western Europe, although prevalence might be higher in
count and increased protein level. However, normal other areas, such as Taiwan and Japan.73 Miller Fisher
protein level (especially when determined in the rst syndrome is characterised by the triad of ophthal-
week after onset of disease) does not make the diagnosis moplegia, ataxia, and areexia. In practice, Miller Fisher
unlikely or even exclude Guillain-Barr syndrome.71 syndrome is frequently accompanied by other cranial
Additionally, 15% of patients with the disease have a mild nerve involvement and can progress to weakness of the
increase in CSF cell count (550 cells per L).8 limbs (Miller Fisher-Guillain-Barr overlap syndrome).74
Equally, Miller Fisher syndrome, as dened by the
Variants, formes frustes, and paediatric presence of anti-GQ1b antibody, can present solely as an
presentations isolated, ocular nerve palsy. Another regional form is the
Guillain-Barr syndrome is a remarkably clinically so-called pharyngeal-brachial variant of Guillain-Barr
diverse disorder and includes several clinically distinctive syndrome. A typical forme fruste is the paraparetic
variants, formes frustes, and atypical cases. The variant of the disease in which the paresis is restricted to
frequency of these variant forms in part relates to the the legs, but most patients later develop involvement of
geographical area in which the disease is reported. the arms shown by sensory signs, low or absent reexes,
Guillain-Barr syndrome can be restricted to specic or electrophysiological changes in these nerves.67
nerve bres, as 15% of patients with a pure motor form Guillain-Barr syndrome can be dicult to diagnose in
do not have any sensory decits.4 Pure motor children, especially preschool children, because they
Guillain-Barr syndrome can occur both in patients with present their complaints atypically and neurological
acute motor axonal neuropathy or acute inammatory examination is more challenging.75,76 Thus, although the
demyelinating polyneuropathy. Acute pure sensory diagnosis of Guillain-Barr syndrome is usually
neuropathies are well recognised, but do not meet straightforward, it can be challenging especially in
existing diagnostic criteria of Guillain-Barr syndrome.72 young children, atypical cases, patients with severe pain
Whether or not acute pure sensory neuropathies can be preceding weakness, or in low-income countries with
poor diagnostic facilities and a broader dierential
diagnosis. A widespread, dierential diagnosis of
Panel 2: Dierential diagnosis of rapidly progressive limb weakness (with or without Guillain-Barr syndrome exists, which depends on the
respiratory failure) clinical presentation, age, and country of origin of the
CNS patients (panel 2).
Encephalitis, acute disseminated encephalomyelitis, transverse myelitis, brainstem or
myelum compression, leptomeningeal malignancy Electrophysiological classication: current
considerations
Motor neurons Guillain-Barr syndrome is a clinically diagnosed
Poliomyelitis, West Nile virus anterior myelitis, amyotrophic lateral sclerosis, progressive disorder, but nerve conduction studies (NCS) can help to
spinal muscular atrophy support the diagnosis, to discriminate between axonal
Plexus and demyelinating subtypes, and could relate to
Neuralgic amyotrophia, diabetes mellitus prognosis. Nerve conduction abnormalities are most
pronounced 2 weeks after start of weakness.58
Nerve roots NCS ndings can be normal especially early in the course
Guillain-Barr syndrome, acute onset chronic inammatory demyelinating neuropathy, of disease. To increase the diagnostic yield, at least four
Lyme disease, cytomegalovirus-related radiculitis, HIV-related radiculitis, leptomeningeal motor nerves, three sensory nerves, F-waves, and
malignancy H-reexes, should be examined. NCS enables clinicians
Peripheral nerves to divide Guillain-Barr syndrome into acute
Guillain-Barr syndrome, acute onset chronic inammatory demyelinating neuropathy, inammatory demyelinating polyneuropathy, acute
iatrogenic, toxic, critical illness myopathy-neuropathy, vasculitis, diphtheria, porphyria, motor axonal neuropathy, or acute motor and sensory
thiamine deciency, porphyria, Lyme disease, metabolic or electrolyte disorders axonal neuropathy.77 NCS in patients with acute
(hypokalaemia, phosphataemia or magnesaemia, hypoglycaemia) inammatory demyelinating polyneuropathy show
features of demyelination, including prolonged distal
Neuromuscular junction motor latency, reduced nerve conduction velocity,
Myasthenia gravis, botulism, intoxication prolonged F-wave latency, increased temporal dispersion,
Muscles and conduction blocks. The sural sensory potential is
Critical illness myopathy-neuropathy, mitochondrial disease, acute rhabdomyolysis, often preserved.78 Features of axonal Guillain-Barr
polymyositis, dermatomyositis syndrome (acute motor axonal neuropathy or acute
motor and sensory axonal neuropathy) are decreased
Although IVIg and plasma exchange have proved many centres to do so.66 Patients with Guillain-Barr
eective, many patients with Guillain-Barr syndrome syndrome with a TRF are likely to have a prolonged
still develop severe weakness and have a long disease immune response that causes sustained nerve damage
course, often with incomplete recovery, pain, and or functional blockade, which needs more prolonged
fatigue. A better treatment is therefore needed. Rather treatment than standard care.
surprisingly, both oral steroids and intravenous Some patients initially diagnosed with Guillain-Barr
methylprednisolone are not benecial in the disorder.86 syndrome can have several episodes of deterioration.
The combination of IVIg and methylprednisolone is not Others initially have a rapidly progressive course like
more eective than IVIg alone, although there might be Guillain-Barr syndrome, but subsequently have further
some additional short-term eect after correction for progression exceeding 4 weeks. In these patients, the
known prognostic factors.87 Combination of plasma question often arises as to whether the diagnosis is still
exchange followed by IVIg is not signicantly better consistent with Guillain-Barr syndrome, or the patient
than plasma exchange or IVIg alone.88 No evidence has chronic inammatory demyelinating polyneuropathy
exists that shows a second course of IVIg is eective in with acute onset. In a prospective study series, about 5%
patients with Guillain-Barr syndrome who continue to of patients initially diagnosed with Guillain-Barr
deteriorate. Researchers in the Netherlands are syndrome were eventually found to have acute onset
investigating whether patients with Guillain-Barr chronic inammatory demyelinating neuropathy.89,93
syndrome with a poor prognosis, dened using the The diagnosis of acute onset chronic inammatory
modied Erasmus GBS outcome scale (mEGOS), might demyelinating neuropathy should especially be
benet from a second IVIg course when given shortly considered in patients initially diagnosed with Guillain-
after the rst IVIg course (SID-GBS RCT trial).14,89 Barr syndrome who have three or more periods with
Investigators of an international variant of the SID-GBS clinical deterioration, or when there is a new deterioration
trial (I-SID-GBS) are studying this eect using an after 8 weeks from onset of weakness. These secondary
observational, prospective open study design. The deteriorations should be recognised because patients
I-SID-GBS study is being done as part of the with Guillain-Barr syndrome with a TRF might improve
For more on the International International Guillain-Barr syndrome Outcome Study after re-treatment, and patients with acute onset chronic
Guillain-Barr syndrome (IGOS), supported by the Inammatory Neuropathy inammatory demyelinating neuropathy usually need
Outcome Study (IGOS) see
https://www.gbsstudies.org/
Consortium, which aims to contribute to a broader chronic maintenance treatment with IVIg or a switch to
understanding of the major causal factors in the disease. corticosteroid treatment.
A completely new approach is being investigated in an
RCT of the drug, eculizumaba humanised monoclonal Outcome and prediction of outcome
antibody that binds with high anity to the complement Guillain-Barr syndrome is still a life-threatening
factor C5 and prevents its cleavage to C5a and the disorder with frequent morbidities, even with the best
proinammatory, cytolytic C5b-9 complex.90,91 Yet, at treatment available. Mortality rates in Europe and North
present only IVIg and plasma exchange are proven America vary between 3% and 7%, and more widely in
eective treatments for Guillain-Barr syndrome. other countries where data are available.23,9496 Patients
Because IVIg is more convenient to give, widely can die in the acute progressive stage, most probably
available, and generally has only minor side-eects, it because of ventilatory insuciency or pulmonary
has replaced plasma exchange as the preferred treatment complications, or from autonomic dysfunction
in many centres. A disadvantage of IVIg is the high including arrhythmia. However, death can occur at a
costa major reason why some centres still use plasma late stage when a patient is discharged from an ICU to a
exchange. In low-income countries, both IVIg and general neurology ward, which further shows the
standard plasma exchange treatment might be too importance of prolonged accurate monitoring and
expensive for a large proportion of patients. New studies general care.57,96 Emergency situations can occur after
to improve the course and outcome of Guillain-Barr delayed diagnosis, especially in young children.76
syndrome are still urgently needed. Patients who survive Guillain-Barr syndrome
frequently have residual complaints and decits, which
TRFs and acute onset chronic inammatory can have a substantial eect on daily activities and
demyelinating neuropathy quality of life.97 About 20% of patients with Guillain-
About 10% of patients treated with IVIg or plasma Barr syndrome cannot walk unaided 6 months after
exchange will deteriorate after initial improvement or onset. Most patients have residual pain and fatigue,
stabilisationie, they will have a TRF.12,92 These TRFs which can in part be attributed to persistent axonal
usually occur within the rst 8 weeks after start of loss.98,99 Many patients have to change their work and
treatment. Repeated treatment (2 g IVIg/kg in 25 days) daily activities, even after reaching a good functional
has been observed to be benecial in these patients. level.75,100 Most improvement happens in the rst year,
Although no RCTs have shown that re-treatment is but patients might show further recovery even after 3 or
benecial in case of a TRF, it is common practice in more years.
26 Geurtsvankessel CH, Islam Z, Mohammad QD, Jacobs BC, 51 Miyaji K, Shahrizaila N, Umapathi T, Chan YC, Hirata K, Yuki N.
Endtz HP, Osterhaus AD. Hepatitis E and Guillain-Barre syndrome. Are ERM (ezrin/radixin/moesin) proteins targets for autoantibodies
Clin Infect Dis 2013; 57: 136970. in demyelinating neuropathies? Hum Immunol 2014; 75: 108991.
27 van den Berg B, van der Eijk AA, Pas SD, et al. Guillain-Barr 52 Samukawa M, Hamada Y, Kuwahara M, et al, for the Japanese GBS
syndrome associated with preceding hepatitis E virus infection. Study Group. Clinical features in Guillain-Barr syndrome with
Neurology 2014; 82: 49197. anti-Gal-C antibody. J Neurol Sci 2014; 337: 5560.
28 Musso D, Cao-Lormeau VM, Gubler DJ. Zika virus: following the 53 Kaida K, Kusunoki S. Immune-mediated neuropathy and
path of dengue and chikungunya? Lancet 2015; 386: 24344. anti-glycolipid antibodies. Brain Nerve 2013; 65: 41323 (in Japanese).
29 Ho TW, Willison HJ, Nachamkin I, et al. Anti-GD1a antibody is 54 Chiba A, Kusunoki S, Obata H, Machinami R, Kanazawa I.
associated with axonal but not demyelinating forms of Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia
Guillain-Barr syndrome. Ann Neurol 1999; 45: 16873. in Miller Fisher syndrome and Guillain-Barr syndrome: clinical and
30 Jacobs BC, van Doorn PA, Schmitz PI, et al. Campylobacter jejuni immunohistochemical studies. Neurology 1993; 43: 191117.
infections and anti-GM1 antibodies in Guillain-Barr syndrome. 55 Kaida K, Morita D, Kanzaki M, et al. Ganglioside complexes as new
Ann Neurol 1996; 40: 18187. target antigens in Guillain-Barr syndrome. Ann Neurol 2004;
31 Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, et al. 56: 56771.
Guillain-Barre syndrome following vaccination in the National 56 Rinaldi S, Brennan KM, Kalna G, et al. Antibodies to heteromeric
Inuenza Immunization Program, United States, 19761977. glycolipid complexes in Guillain-Barr syndrome. PLoS One 2013;
Am J Epidemiol 1979; 110: 10523. 8: e82337.
32 Lehmann HC, Hartung HP, Kieseier BC, Hughes RA. 57 Galban-Horcajo F, Halstead SK, McGonigal R, Willison HJ.
Guillain-Barr syndrome after exposure to inuenza virus. The application of glycosphingolipid arrays to autoantibody
Lancet Infect Dis 2010; 10: 64351. detection in neuroimmunological disorders. Curr Opin Chem Biol
33 Salmon DA, Proschan M, Forshee R, et al, for the H1N1 GBS 2014; 18: 7886.
Meta-Analysis Working Group. Association between Guillain-Barr 58 Hadden RD, Cornblath DR, Hughes RA, et al, for the Plasma
syndrome and inuenza A (H1N1) 2009 monovalent inactivated Exchange/Sandoglobulin Guillain-Barr Syndrome Trial Group.
vaccines in the USA: a meta-analysis. Lancet 2013; 381: 146168. Electrophysiological classication of Guillain-Barr syndrome:
34 Guillain-Barr syndrome common concerns. http://www.cdc.gov/ clinical associations and outcome. Ann Neurol 1998; 44: 78088.
vaccinesafety/Concerns/gbs.html (accessed Feb 1, 2016). 59 Umapathi T, Tan EY, Kokubun N, Verma K, Yuki N.
35 Kuitwaard K, Bos-Eyssen ME, Blomkwist-Markens PH, Non-demyelinating, reversible conduction failure in Fisher
van Doorn PA. Recurrences, vaccinations and long-term symptoms syndrome and related disorders. J Neurol Neurosurg Psychiatry 2012;
in GBS and CIDP. J Peripher Nerv Syst 2009; 14: 31015. 83: 94148.
36 Willison HJ. The immunobiology of Guillain-Barr syndromes. 60 Uncini A. A common mechanism and a new categorization for
J Peripher Nerv Syst 2005; 10: 94112. anti-ganglioside antibody-mediated neuropathies. Exp Neurol 2012;
37 Feasby TE, Hahn AF, Brown WF, Bolton CF, Gilbert JJ, 235: 51316.
Koopman WJ. Severe axonal degeneration in acute Guillain-Barr 61 Stathopoulos P, Alexopoulos H, Dalakas MC. Autoimmune
syndrome: evidence of two dierent mechanisms? J Neurol Sci 1993; antigenic targets at the node of Ranvier in demyelinating disorders.
116: 18592. Nat Rev Neurol 2015; 11: 14356.
38 Willison HJ, Yuki N. Peripheral neuropathies and anti-glycolipid 62 Uncini A, Susuki K, Yuki N. Nodo-paranodopathy: beyond the
antibodies. Brain 2002; 125: 2591625. demyelinating and axonal classication in anti-ganglioside
39 Koga M, Ang CW, Yuki N, et al. Comparative study of preceding antibody-mediated neuropathies. Clin Neurophysiol 2013;
Campylobacter jejuni infection in Guillain-Barr syndrome in Japan 124: 192834.
and The Netherlands. J Neurol Neurosurg Psychiatry 2001; 70: 69395. 63 Cashman CR, Hke A. Mechanisms of distal axonal degeneration
40 Soliven B. Animal models of autoimmune neuropathy. ILAR J 2014; in peripheral neuropathies. Neurosci Lett 2015; 596: 3350.
54: 28290. 64 Kokubun N, Nishibayashi M, Uncini A, Odaka M, Hirata K, Yuki N.
41 Susuki K, Yuki N, Schafer DP, et al. Dysfunction of nodes of Conduction block in acute motor axonal neuropathy. Brain 2010;
Ranvier: a mechanism for anti-ganglioside antibody-mediated 133: 2897908.
neuropathies. Exp Neurol 2012; 233: 53442. 65 Sejvar JJ, Kohl KS, Gidudu J, et al, for the Brighton Collaboration
42 Willison HJ. The translation of the pathological ndings described GBS Working Group. Guillain-Barr syndrome and Fisher
in humans to experimental models of acute motor axonal syndrome: case denitions and guidelines for collection, analysis,
neuropathy. J Peripher Nerv Syst 2012; 17 (suppl 3): 38. and presentation of immunization safety data. Vaccine 2011;
29: 599612.
43 Jacobs BC, Koga M, van Rijs W, et al. Subclass IgG to motor
gangliosides related to infection and clinical course in 66 van Doorn PA. Diagnosis, treatment and prognosis of
Guillain-Barr syndrome. J Neuroimmunol 2008; 194: 18190. Guillain-Barr syndrome (GBS). Presse Med 2013; 42: e193201.
44 McGonigal R, Rowan EG, Greenshields KN, et al. Anti-GD1a 67 van den Berg B, Fokke C, Drenthen J, van Doorn PA, Jacobs BC.
antibodies activate complement and calpain to injure distal motor Paraparetic Guillain-Barr syndrome. Neurology 2014; 82: 198489.
nodes of Ranvier in mice. Brain 2010; 133: 194460. 68 Ruts L, Drenthen J, Jongen JL, et al, for the Dutch GBS Study
45 Plomp JJ, Willison HJ. Pathophysiological actions of Group. Pain in Guillain-Barre syndrome: a long-term follow-up
neuropathy-related anti-ganglioside antibodies at the study. Neurology 2010; 75: 143947.
neuromuscular junction. J Physiol 2009; 587: 397999. 69 Yuki N, Kokubun N, Kuwabara S, et al. Guillain-Barr syndrome
46 Liu JX, Willison HJ, Pedrosa-Domellf F. Immunolocalization of associated with normal or exaggerated tendon reexes. J Neurol
GQ1b and related gangliosides in human extraocular 2012; 259: 118190.
neuromuscular junctions and muscle spindles. 70 Oh SJ, Kurokawa K, de Almeida DF, Ryan HF Jr, Claussen GC.
Invest Ophthalmol Vis Sci 2009; 50: 322632. Subacute inammatory demyelinating polyneuropathy. Neurology
47 Nachamkin I, Liu J, Li M, et al. Campylobacter jejuni from patients 2003; 61: 150712.
with Guillain-Barr syndrome preferentially expresses a GD(1a)-like 71 Wong AH, Umapathi T, Nishimoto Y, Wang YZ, Chan YC, Yuki N.
epitope. Infect Immun 2002; 70: 5299303. Cytoalbuminologic dissociation in Asian patients with
48 Makowska A, Pritchard J, Sanvito L, et al. Immune responses to Guillain-Barr and Miller Fisher syndromes. J Peripher Nerv Syst
myelin proteins in Guillain-Barr syndrome. 2015; 20: 4751.
J Neurol Neurosurg Psychiatry 2008; 79: 66471. 72 Yang J, Huan M, Jiang H, Song C, Zhong L, Liang Z. Pure sensory
49 Willison H, Scherer SS. Ranvier revisited: novel nodal antigens Guillain-Barr syndrome: a case report and review of the literature.
stimulate interest in GBS pathogenesis. Neurology 2014; 83: 10608. Exp Ther Med 2014; 8: 1397401.
50 Sawai S, Satoh M, Mori M, et al. Moesin is a possible target 73 Lyu RK, Tang LM, Cheng SY, Hsu WC, Chen ST.
molecule for cytomegalovirus-related Guillain-Barr syndrome. Guillain-Barr syndrome in Taiwan: a clinical study of 167 patients.
Neurology 2014; 83: 11317. J Neurol Neurosurg Psychiatry 1997; 63: 494500.
74 Funakoshi K, Kuwabara S, Odaka M, Hirata K, Yuki N. 89 Ruts L, Drenthen J, Jacobs BC, van Doorn PA, for the Dutch GBS
Clinical predictors of mechanical ventilation in Fisher/ Study Group. Distinguishing acute-onset CIDP from uctuating
Guillain-Barr overlap syndrome. J Neurol Neurosurg Psychiatry Guillain-Barre syndrome: a prospective study. Neurology 2010;
2009; 80: 6064. 74: 168086.
75 Roodbol J, de Wit MC, Aarsen FK, Catsman-Berrevoets CE, 90 Fitzpatrick AM, Mann CA, Barry S, Brennan K, Overell JR,
Jacobs BC. Long-term outcome of Guillain-Barr syndrome in Willison HJ. An open label clinical trial of complement inhibition
children. J Peripher Nerv Syst 2014; 19: 12126. in multifocal motor neuropathy. J Peripher Nerv Syst 2011; 16: 8491.
76 Roodbol J, de Wit MC, Walgaard C, de Hoog M, 91 Halstead SK, Zitman FM, Humphreys PD, et al. Eculizumab
Catsman-Berrevoets CE, Jacobs BC. Recognizing Guillain-Barre prevents anti-ganglioside antibody-mediated neuropathy in a
syndrome in preschool children. Neurology 2011; 76: 80710. murine model. Brain 2008; 131: 1197208.
77 Ho TW, Mishu B, Li CY, et al. Guillain-Barr syndrome in northern 92 Kleyweg RP, van der Mech FG. Treatment related uctuations in
China. Relationship to Campylobacter jejuni infection and Guillain-Barr syndrome after high-dose immunoglobulins or
anti-glycolipid antibodies. Brain 1995; 118: 597605. plasma-exchange. J Neurol Neurosurg Psychiatry 1991; 54: 95760.
78 Vucic S, Cairns KD, Black KR, Chong PS, Cros D. 93 Dionne A, Nicolle MW, Hahn AF. Clinical and electrophysiological
Neurophysiologic ndings in early acute inammatory demyelinating parameters distinguishing acute-onset chronic inammatory
polyradiculoneuropathy. Clin Neurophysiol 2004; 115: 232935. demyelinating polyneuropathy from acute inammatory
79 Kokubun N, Shahrizaila N, Hirata K, Yuki N. Reversible conduction demyelinating polyneuropathy. Muscle Nerve 2010; 41: 20207.
failure is distinct from neurophysiological patterns of recovery in 94 Netto AB, Taly AB, Kulkarni GB, Rao UG, Rao S. Mortality in
mild demyelinating Guillain-Barr syndrome. J Neurol Sci 2013; mechanically ventilated patients of Guillain Barr Syndrome.
326: 11114. Ann Indian Acad Neurol 2011; 14: 26266.
80 Uncini A, Zappasodi F, Notturno F. Electrodiagnosis of GBS 95 Benamer HT, Bredan A. Guillain-Barr syndrome in Arab
subtypes by a single study: not yet the squaring of the circle. countries: a systematic review. J Neurol Sci 2014; 343: 22123.
J Neurol Neurosurg Psychiatry 2015; 86: 58. 96 van den Berg B, Bunschoten C, van Doorn PA, Jacobs BC.
81 Walgaard C, Lingsma HF, Ruts L, et al. Prediction of respiratory Mortality in Guillain-Barre syndrome. Neurology 2013; 80: 165054.
insuciency in Guillain-Barr syndrome. Ann Neurol 2010; 97 Darweesh SK, Polinder S, Mulder MJ, et al. Health-related quality of
67: 78187. life in Guillain-Barr syndrome patients: a systematic review.
82 Liu J, Wang LN, McNicol ED. Pharmacological treatment for pain J Peripher Nerv Syst 2014; 19: 2435.
in Guillain-Barr syndrome. Cochrane Database Syst Rev 2015; 98 Drenthen J, Jacobs BC, Maathuis EM, van Doorn PA, Visser GH,
4: CD009950. Blok JH. Residual fatigue in Guillain-Barre syndrome is related to
83 Raphal JC, Chevret S, Hughes RA, Annane D. Plasma exchange axonal loss. Neurology 2013; 81: 182731.
for Guillain-Barr syndrome. Cochrane Database Syst Rev 2012; 99 Merkies IS, Faber CG. Fatigue in immune-mediated neuropathies.
7: CD001798. Neuromuscul Disord 2012; 22 (suppl 3): S20307.
84 Hughes RA, Swan AV, Raphael JC, Annane D, van Koningsveld R, 100 Bernsen RA, de Jager AE, Schmitz PI, van der Mech FG.
van Doorn PA. Immunotherapy for Guillain-Barr syndrome: Residual physical outcome and daily living 3 to 6 years after
a systematic review. Brain 2007; 130: 224557. Guillain-Barr syndrome. Neurology 1999; 53: 40910.
85 Korinthenberg R, Schessl J, Kirschner J, Mnting JS. Intravenously 101 Vanhoutte EK, Faber CG, Merkies IS, for the PeriNomS study
administered immunoglobulin in the treatment of childhood group. 196th ENMC international workshop: outcome measures in
Guillain-Barr syndrome: a randomized trial. Pediatrics 2005; inammatory peripheral neuropathies 810 February 2013,
116: 814. Naarden, The Netherlands. Neuromuscul Disord 2013; 23: 92433.
86 Hughes RA, van Doorn PA. Corticosteroids for Guillain-Barr 102 van Koningsveld R, Steyerberg EW, Hughes RA, Swan AV,
syndrome. Cochrane Database Syst Rev 2012; 8: CD001446. van Doorn PA, Jacobs BC. A clinical prognostic scoring system for
87 van Koningsveld R, Schmitz PI, Mech FG, Visser LH, Meulstee J, Guillain-Barr syndrome. Lancet Neurol 2007; 6: 58994.
van Doorn PA, for the Dutch GBS study group. Eect of 103 Yuki N, Hartung HP. Guillain-Barr syndrome. N Engl J Med 2012;
methylprednisolone when added to standard treatment with 366: 2294304.
intravenous immunoglobulin for Guillain-Barr syndrome:
randomised trial. Lancet 2004; 363: 19296.
88 Plasma Exchange/Sandoglobulin Guillain-Barr Syndrome Trial
Group. Randomised trial of plasma exchange, intravenous
immunoglobulin, and combined treatments in Guillain-Barr
syndrome. Lancet 1997; 349: 22530.