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GuillainBarr syndrome: pathogenesis,


diagnosis, treatment and prognosis
Bianca van den Berg, Christa Walgaard, Judith Drenthen, Christiaan Fokke, Bart C. Jacobs
and Pieter A. van Doorn
Abstract | GuillainBarr syndrome (GBS) is a potentially life-threatening postinfectious disease characterized
by rapidly progressive, symmetrical weakness of the extremities. About 25% of patients develop respiratory
insufficiency and many show signs of autonomic dysfunction. Diagnosis can usually be made on clinical
grounds, but lumbar puncture and electrophysiological studies can help to substantiate the diagnosis and
to differentiate demyelinating from axonal subtypes of GBS. Molecular mimicry of pathogen-borne antigens,
leading to generation of crossreactive antibodies that also target gangliosides, is part of the pathogenesis
of GBS; the subtype and severity of the syndrome are partly determined by the nature of the antecedent
infection and specificity of such antibodies. Intravenous immunoglobulin and plasma exchange are proven
effective treatments but many patients have considerable residual deficits. Discrimination of patients with
treatment-related fluctuations from those with acute-onset chronic inflammatory demyelinating polyneuropathy
is important, as these conditions may require different treatments. Novel prognostic models can accurately
predict outcome and the need for artificial ventilation, which could aid the selection of patients with a poor
prognosis for more-individualized care. This Review summarizes the clinical features of and diagnostic criteria
for GBS, and discusses its pathogenesis, treatment and prognosis.
Van den Berg, B. etal. Nat. Rev. Neurol. advance online publication 15 July 2014; doi:10.1038/nrneurol.2014.121

Introduction
GuillainBarr syndrome (GBS) is a common cause of antibodies largely determine the subtype and clini-
acute flaccid paralysis, characterized by symmetrical cal course of GBS. Over the past 10years, much new
weakness of the limbs, and hyporeflexia or areflexia, information has been gathered about the role of ante-
which reaches a maximum severity within 4weeks cedent infections and antiganglioside antibodies in the
(Figure1).14 Sensory symptoms, such as paraesthesia or immunopathology of GBS. We now know that the most
numbness, usually start distally and have a symmetrical common pathogen causing the antecedent infection
pattern. The most common subtypes of GBS are acute is Campylobacter jejuni, which is associated with the
inflammatory demyelinating polyneuropathy (AIDP) AMAN subtype of GBS.
and acute motor axonal neuropathy (AMAN).1,3,58 Aless Currently, intravenous immunoglobulin (IVIg) and
common subtype is Miller Fisher syndrome (MFS), plasma exchange are proven effective treatments for
which is characterized by ophthalmoplegia, ataxia GBS.1115 However, despite these treatment options, many
andareflexia.9,10 Overall, the clinical course, severity and patients have a severe disease course, pain, and residual
Department of
outcomes of GBS are highly variable. deficits. In this Review, we summarize current data on
Neurology (B.v.d.B., GBS typically occurs after an infectious disease in the immune pathogenesis and clinical characteristics of
C.W., B.C.J., P.A.v.D.), which the immune response generates antibodies that GBS. We describe the current diagnostic criteria for GBS,
Department of Clinical
Neurophysiology (J.D.), crossreact with gangliosides at nerve membranes. This and discuss the possible additional diagnostic value of
Erasmus MC University autoimmune response results in nerve damage or func- cerebrospinal fluid (CSF) examinations and nerve con-
Medical Centre
Rotterdam,
tional blockade of nerve conduction. The type of preced- duction tests. In addition, we review treatment options
POBox2040, ing infection and the specificity of the antiganglioside and prognosis, including novel predictive models, for
3000 CA Rotterdam, patients with GBS.
Netherlands.
Department of Competing interests
Neurology, Gelre B.C.J. receives research support from the Netherlands Epidemiology
ziekenhuis lokatie Organization for Health Research and Development, Erasmus
Apeldoorn, Albert
GBS is a rare disease with an incidence of 0.811.89
MC, Prinses Beatrix Spierfonds and GuillainBarr syndrome,
Schweitzerlaan 31, chronic inflammatory demyelinating polyneuropathy (GBS-CIDP) (median 1.11) per 100,000 personyears, and is more
7334 DZ Apeldoorn, common in men than in women (ratio 3:2).1,16 Worldwide,
Foundation International, and travel support from Baxter
Netherlands (C.F.).
Biopharmaceutics. P.A.v.D. receives research support from the the incidence is variable; for example, a low rate of 0.40
Prinses Beatrix Spierfonds, the GBS-CIDP Foundation
Correspondence to: per 100,000 personyears was reported in Brazil, in con-
P.A.v.D. International, Baxter Biopharmaceutics, Griffols and Sanquin
p.a.vandoorn@ Plasma Products. B.v.d.B., C.W., J.D. and C.F. declare no trast to a high rate of 2.5 per 100,000 personyears in
erasmusmc.nl competing interests. Curaao and Bangladesh.1620 GBS seems to occur less

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Key points infection, possibly in combination with different genetic


susceptibilities due to varying genetic polymorphisms
GuillainBarr syndrome (GBS) is a heterogeneous disease characterized by
between individuals or groups of people living in dif-
rapidly progressive, symmetrical limb weakness with hyporeflexia or areflexia;
sensory disturbances and cranial nerve deficits occur in some patients ferent areas of the world.25,26 These differences may be
The clinical diagnosis of GBS can be supported by additional investigations related not only to the development of a specific GBS
(such as cerebrospinal fluid examination and nerve conduction studies), which subtype, but also to the course and severity of disease.
are especially useful in patients with atypical features or diagnostic doubt Genetic studies with a high number of patients are
Molecular mimicry, antiganglioside antibodies and, likely, complement required to investigate theserelationships.
activation are involved in the pathogenesis of GBS; a potential role for genetic
susceptibility requires further investigation
Pathogenesis
Intravenous immunoglobulin and plasma exchange are proven effective
treatments, but improved therapies are needed as ~25% of patients require
As indicated above, GBS is a postinfectious disorder.
artificial ventilation and 20% are unable to walk after 6months Two-thirds of patients report symptoms of a respira-
Pain is an important symptom that may be present before onset of weakness, tory or gastrointestinal tract infection before the onset
and can impede correct diagnosis, especially in children; other residual of GBS. In about half of patients with GBS, a specific
features (sensory disturbances and fatigue) may persist for years type of preceding infection can be identified,27 and
Prognostic models can predict patient outcomes at 4weeks, 3months and C.jejuni is responsible for at least one-third of these
6months, as well as the probability of respiratory insufficiency, even early in infections.3,24,27 Other pathogens that cause antecedent
the course of the disease
infections related to GBS are cytomegalovirus, Epstein
Barr virus, Mycoplasma pneumonia, Haemophilus influ-
enzae, and influenza A virus.3,27,28 Notably, a casecontrol
No weakness

Course of GBS study conducted in the Netherlands showed that 5% of


Infection
Antiganglioside
patients with GBS had a hepatitis E virus infection before
antibodies onset of GBS, compared with 0.5% of matched healthy
controls.29 Similarly, 10% of patients with GBS from
Bangladesh had an antecedent hepatitis E virus infec-
tion, indicating that hepatitis E virus is a worldwide
trigger of GBS.30 However, despite the strong association
between specific acute infections and GBS, the overall
risk of developing this severe postinfectious compli-
cation is very small. Only one in 1,0005,000 patients
with Campylobacter enteritis will develop GBS in the
subsequent 2months.31,32 This fact explains why GBS
Paralysis

is a sporadic disorder, although outbreaks of GBS after


C.jejuni infection have occasionally been reported.33
4 0 4 8 12 One of the critical steps in GBS pathogenesis after
Time from onset of weakness (weeks) C.jejuni infection is the generation of antibodies that
Figure 1 | The course of GBS. The majority of patients with GBS report an infection crossreact with specific gangliosides (Figure2), which
before the onset of weakness. Antiganglioside antibodies are often detected; their are not produced during uncomplicated C.jejuni gastro
levels decrease over time. Different types of antibodies are related to the enteritis.34,35 However, the production of crossreactive
preceding infection and the GBS subtype. Progressive weakness reaches its antibodies is only induced in susceptible individuals.35,36
maximum within 4weeks (often within 2weeks). The recovery phase may last Antibodies that crossreact with various gangliosides have
many weeks, months or even years. Abbreviation: GBS, GuillainBarr syndrome. been described in patients with GBS.3,3739 However, only
Reprinted from Lancet Neurology 7, van Doorn, P.A., Ruts, L. & Jacobs,B.C.
a subset of C.jejuni strains contain lipo-oligosaccharides
Clinical features, pathogenesis, and treatment of GuillainBarr syndrome,
939950 (2008), with permission from Elsevier.
that mimic the carbohydrate moiety of gangliosides that
are present in human peripheral nerves (Figure2).3 The
synthesis of these ganglioside-mimicking carbohydrate
frequently in children (0.341.34 per 100,000 person structures depends on a set of polymorphic genes and
years) than in adults,18 and its incidence increases with enzymes that vary greatly between different C.jejuni
age.16,18 The background incidence of GBS in most studies strains.40,41 The Thr51 variant of the C.jejuni cstII gene is
remains constant over time, although seasonal fluc- associated with the occurrence of GBS, while the Asn51
tuations have occasionally been found in studies from variant is associated with MFS.42
Curaao, Bangladesh and China.17,18,20,21 Some antibody specificities are associated with par-
The proportions of patients with GBS who have ticular GBS subtypes and related neurological deficits,
AIDP and AMAN vary greatly around the world. AIDP reflecting the distribution of different gangliosides in
is the predominant subtype (6080% of patients) in human peripheral nerves (Table1). 3,43 C.jejuni infec-
North America and Europe.1,2,6 By contrast, the fre- tions are predominantly, but not exclusively, related to
quency of AMAN ranges from 67% in the UK and the AMAN or pure motor subtype of GBS.44 Patients with
Spain to 3065% in Asia, Central America and South AMAN frequently have serum antibodies against GM1a,
America.6,7,2224 The geographical diversity is probably GM1b, GD1a and GalNAc-GD1a gangliosides.3,7,37,4547
attributable to differences in exposure to certain types of Patients with MFS or MFSGBS overlap syndrome

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Campylobacter with uncomplicated cytomegalovirus infections.27,50


jejuni
T cell Interestingly, as well as antibodies against single ganglio-
Immune response
sides, patients can also have antibodies against combina-
tions of epitopes from ganglioside complexes.38,5153 Such
APC complexes are located in specialized microdomains, or
Ganglioside mimicry lipid rafts, in the cell membrane.54 Antibodies that target
B cell
ganglioside complexes also crossreact with C.jejuni
lipo-oligosaccharides, and are probably induced by a
Lipid A Antibody preceding infection with C.jejuni.55 Antibodies against
production various combinations or complexes of glycolipids have
also been reported in patients with AIDP, although the
Outer membrane role of these antibodies in its pathogenesis remains to
bedetermined.53
In conjunction with the presence of antiganglioside
Crossreactive antibodies, complement activation seems to contrib-
antibodies
Ceramide ute to nerve degeneration in GBS56,57a phenomenon
that has been studied at the nodes of Ranvier and at the
Axolemma
Plasma motor nerve terminal in a mouse model of AMAN.58
cells
Sodium channel clusters, as well as paranodal axoglial
junctions, the nodal cytoskeleton, and Schwann cell
microvilli, all of which stabilize the sodium channel clus-
ters, were disrupted by complement activation in a GBS
Peripheral nerve disease model.7,59,60 Additional studies in a GBS mouse
model provided evidence that blockade of complement
activation prevents emergence of the clinical signs of
antiganglioside-mediated neuropathy.61
The development of GBS after a C.jejuni infection may
AMAN AIDP also depend on patient-related factors that influence the
Complement susceptibility to produce crossreactive, carbohydrate-
Anti-GM1 or Membrane Unknown targeted antibodies. This hypothesis is supported by the
anti-GD1a attack complex target of fact that GBS has a relapse rate of 5%, which is clearly
crossreactive antibody
antibody higher than would be expected by chance.62 The initial
pathogenhost interaction has a key role in the devel-
opment of GBS. C.jejuni lipo-oligosaccharides bind
to siglec7 (sialic acid-binding immunoglobulin-like
Node lectin7) and activate dendritic cells via Toll-like recep-
of Ranvier Macrophage Schwann cell
tor 4 and CD14. These dendritic cells produce type1
Figure 2 | Immunopathogenesis of GBS: molecular mimicry and antiganglioside interferon and tumour necrosis factor (TNF), which
antibodies. Infections with pathogens, such as Campylobacter jejuni, can trigger induce proliferation of Bcells.35,63,64 This immune acti-
humoral immune and autoimmune responses that result in nerve dysfunction and vation could be influenced by genetic polymorphisms
the symptoms of GBS. Lipo-oligosaccharides on the C.jejuni outer membrane may but, to date, genetic factors have only been studied in
elicit the production of antibodies that crossreact with gangliosides, such as GM1
small cohorts of patients. Interestingly, a meta-analysis
and GD1a on peripheral nerves. The antigens targeted in AMAN are located at or
near the node of Ranvier. The anti-GM1 and anti-GD1a antibodies bind to the nodal
identified a moderate association between GBS and a
axolemma, leading to complement activation followed by MAC formation and particular TNF polymorphism.65 In addition, an associ
disappearance of voltage-gated sodium channels. This damage can lead to ation between polymorphisms in the MBL2 gene (encod-
detachment of paranodal myelin, and nerve conduction failure. Macrophages then ing mannose-binding protein C) and the severity and
invade from the nodes into the periaxonal space, scavenging the injured axons. outcome of GBS has been confirmed.25 Future genome-
The antigens targeted in AIDP are, presumably, located on the myelin sheath. The wide association studies in large, well-described and
antibodies can activate complement, which leads to formation of the MAC on the adequately controlled cohorts are required to establish
outer surface of Schwann cells, initiation of vesicular degeneration, and invasion
the role of host factors in the pathogenesis of GBS.
ofmyelin by macrophages. Abbreviations: AIDP, acute inflammatory demyelinating
polyneuropathy; AMAN, acute motor axonal neuropathy; APC, antigen-presenting
cell; GBS, GuillainBarr syndrome; MAC, membrane attack complex. The potential role of vaccination
A few patients develop GBS shortly after receiving a
vaccination. Despite their rarity, such events cause con-
(see below) frequently have antibodies against GD1b, siderable public concern. In the vaccination campaign
GD3, GT1a and GQ1b gangliosides, which are related against influenza A (H1N1) in the USA in 1976, the
to ataxia and ophthalmoplegia.3,9,37,48,49 In a study from estimated attributable risk of vaccine-related GBS was
the Netherlands, 20% of patients with AIDP related to about one in 100,000.66 A similar association was sug-
cytomegalovirus infection had anti-GM2 antibodies, gested for the vaccination campaign against influenzaA
although these antibodies are also found in patients (H1N1) in 2009, but extensive national and international

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Table 1 | GBS subtypes, clinical features and relevant antibodies3,37,43 campaign of 20092010.72 These criteria were specifically
developed for retrospective epidemiological and vaccine
GBS subtypes Main clinical features NCS findings Antibodies*
safety studies and, consequently, are likely to combine
Acute Sensorimotor GBS, often Demyelinating Various high specificity with limited sensitivity. The Brighton
inflammatory combined with cranial polyneuropathy
demyelinating nerve deficits and frequent criteria identify GBS with four levels of diagnostic cer-
polyneuropathy autonomic dysfunction tainty, from level 1 (highest) to level 4 (lowest). Use of the
(AIDP) Brighton criteria to classify patients with suspected GBS
Acute motor Pure motor GBS; cranial Axonal polyneuropathy, GM1a, GM1b is highly dependent on completeness of the diagnostic
axonal nerves rarely affected sensory action potential GD1a data. A study from the Netherlands in 335 patients with
neuropathy normal GalNAc-GD1a GBS with complete sets of diagnostic datawhich are
(AMAN)
required for level 1 certainty according to the Brighton
Acute motor Resembles severe AMAN, Axonal polyneuropathy, GM1, GD1a
criteriaclassified 61% as level 1, 33% as level 2, none
sensory axonal but sensory fibres are sensory action potential
neuropathy affected, leading to reduced or absent as level 3 and 6% as level 4. However, patients diagnosed
(AMSAN) sensory deficits at different levels of diagnostic certainty did not differ in
Pharyngeal Prominent weakness of Normal in most patients, GT1a>GQ1b disease severity or outcome.73 In studies from Korea and
cervical oropharyngeal, facial, neck sometimes abnormalities in >>GD1a India in patients who had GBS, 24% and 14% of patients,
brachial variant and shoulder muscles arms, mostly axonal pattern respectively, were classified as level 4.74,75 The Brighton
Miller Fisher Ataxia, ophthalmoplegia, Normal in most patients; GQ1b, GT1a criteria are not, however, intended to be used for diag-
syndrome areflexia discrete changes in nostic purposes in clinical practice. Further research is
sensory conduction or
needed to develop criteria that can be used to diagnose
Hreflex may be present
GBS and its less-frequent variants in the acute phase of
*Antibodies are predominantly IgG, but IgM and IgA antibodies have also been demonstrated. Association
with GBS and role in its pathogenesis unknown. Abbreviations: GBS, GuillainBarr syndrome; NCS, nerve the disease. However, in practice, the criteria published
conduction study. in 1990 still provide a good basis for clinicians worldwide
to make a diagnosis of GBS.

studies found that vaccination was associated with only Clinical symptoms and subtypes of GBS
a small attributable risk of GBS: 1.6 excess cases of GBS GBS is characterized by a rapidly progressive, symmet-
per 1,000,000 vaccine recipients, a frequency similar rical weakness of the limbs in combination with hypo
to that for all seasonal vaccinations.67 In fact, vacci- reflexia or areflexia.2,4,73 However, GBS is highly diverse
nation might even reduce the risk of acquiring GBS, with respect to the presence, distribution and extent
as this condition can be caused by infections such as of cranial nerve deficits, sensory symptoms, weakness,
influenza. The risk of developing GBS after influenza ataxia, pain, autonomic dysfunction, and the course of
infection is estimated to be 47 times higher than after the disease. Many patients have sensory deficits, such
influenza vaccination.68 No relapses of GBS in patients as numbness and/or paraesthesias.4 About half of the
with a history of this disease have been observed after patients have cranial nerve deficits, especially bilateral
influenzavaccination.68,69 facial weakness, swallowing difficulties or (sometimes)
For these reasons, the following practical guideline extraocular motor dysfunction. 4 A high propor-
regarding vaccination of patients with a history of GBS tion (5489%) of patients with GBS experience pain,
is currently used in the Netherlands: GBS as such is not including painful paraesthesias, backache, muscle pain
an indication for influenza vaccination, and vaccina- and meningism, which may even precede the onset of
tion seems to be safe in patients who developed GBS muscle weakness in about one-third of GBS cases.2,4,76,77
>3months ago and when onset of GBS was not shortly Approximately 25% of patients develop respiratory insuf-
after vaccination.70 ficiency requiring artificial ventilation.73,7880 Autonomic
dysfunction (predominantly cardiovascular dysregula-
Diagnosis tion) is present in about two-thirds of patients, although
Diagnostic criteria its severity is highly variable.2,77,81 About one-third of
In 1978, the US National Institute of Neurological patients remain able to walk throughout the course ofthe
Disorders and Stroke (NINDS) developed case defini- disease, and are often described as mildlyaffected.
tions for GBS in the course of investigating the suspected GBS is a monophasic disease, usually reaching
association between GBS and the swine flu vaccination maximum severity (nadir) within 4weeks.1,2,4 One study
campaign of 19761977. The initial diagnostic criteria showed that 80% of patients with GBS reach the nadir
published in 1981 were modified in 1990.4,71 Though within 2weeks after onset of weakness, and 97% reach
primarily developed for research purposes, they are the nadir within 4weeks.73 A further subset ofpatients
probably still the most widely used criteria in clinical reach the nadir within 46weeks of onset of weakness.73,82
practice.4 The criteria consist of features that are required The progressive phase is usually followed by a plateau
for or strongly support the diagnosis of GBS, and features phase ranging from 2days to 6months (median duration
that cast doubt on the diagnosis (Box1). 7days) before patients start to recover(Figure1).73
In 2011, the Brighton Collaboration published new Various subtypes of GBS have been reported that
case definitions for GBS while studying a possible associ differ in their clinical, electrophysiological and histo
ation between GBS and the H1N1 swine flu vaccination logical features (Table1 and Box1). 1,3,68,23 The two

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Box 1 | Diagnostic criteria for GBS2,4,6,7 prolonged, owing to axonal degeneration. However,
some patients withAMAN recover quickly, even from
Features required for diagnosis of GBS*
Progressive weakness in legs and arms (sometimes initially only in legs)
severe weakness.83 AMAN is frequently associated with
Areflexia (or decreased tendon reflexes) in weak limbs an antecedent C.jejuniinfection.7,8,46
Acute inflammatory demyelinating polyneuropathy (AIDP) In some patients with axonal GBS, sensory as well
Additional symptoms asmotor fibres are affected. This subtype, termed acute
Progressive phase lasts days to 4weeks motor and sensory axonal neuropathy (AMSAN), can
Relative symmetry of symptoms be considered a severe variant of AMAN.1,3,7 MFS is an
Mild sensory symptoms or signs uncommon subtype of GBS characterized by the clini-
Cranial nerve involvement, especially bilateral weakness of facial muscles cal triad of ophthalmoplegia, ataxia and areflexia.9,10,49,84
Autonomic dysfunction Inmost patients, diplopia is the presenting symptom.9,10,49
Pain (often)
Patients with MFS usually have a good clinical outcome
Nerve conduction study findings but some develop limb weakness and respiratory insuf-
Features of demyelination (only assessable if distal CMAP amplitude is >10% LLN)
ficiency (termed MFSGBS overlap syndrome). A new
Prolonged distal motor latency
Decreased motor nerve conduction velocity electrophysiological technique called compound muscle
Increased Fwave latency, conduction blocks and temporal dispersion action potential (CMAP) scanning has shown that some
Acute motor axonal neuropathy (AMAN) patients with MFS also have subclinical limb motor
Additional symptoms nerve dysfunction.85 Other local variants of GBS, such
Progressive phase lasts days to 4weeks as the pharyngealcervicalbrachial variant, have also
Relative symmetry of symptoms beenreported.3,84,86
No sensory symptoms or signs
Cranial nerve involvement (rarely) Atypical GBS
Autonomic dysfunction
About 8% of patients with GBS present with para
Pain (sometimes)
paresis, which often complicates the diagnosis and
Nerve conduction study findings
requires extensive diagnostic work-up. Paraparesis may
No features of demyelination (or, one demyelinating feature in one nerve if distal
persist in about 70% of these patients during follow-up.73
CMAP amplitude is <10% LLN)
Distal CMAP amplitude is <80% LLN in at least two nerves Definite asymmetrical limb weakness, however, is very
Transient motor nerve conduction block may be present (possibly caused by uncommon in patients with GBS.73
antiganglioside antibodies) Although the 1990 GBS criteria require hyporeflexia
Features that should raise doubt about the diagnosis of GBS or areflexia for the diagnosis of GBS, in one cohort of
Increased number of mononuclear cells in cerebrospinal fluid (>50cells per l) patients with GBS, 9% had normal tendon reflexes in
orpolymorphonuclear cells in cerebrospinal fluid weak arms and 2% had normal tendon reflexes in weak
Severe pulmonary dysfunction with limited limb weakness at onset legs at presentation. 73 During follow-up, all patients
Severe sensory signs with limited weakness at onset developed hyporeflexia or areflexia in their legs, but in
Bladder or bowel dysfunction at onset
some patients, normal reflexes persisted in the arms.73 For
Fever at onset
Sharp spinal cord sensory level
an as yet unknown reason, a small proportion of patients
Slow progression with limited weakness and without respiratory involvement with GBS, especially those with the AMAN subtype, have
(consider subacute inflammatory demyelinating polyneuropathy or acute-onset well-preserved or even exaggerated tendonreflexes.7,87
chronic inflammatory demyelinating polyneuropathy)
Marked persistent asymmetry of weakness Additional investigations
Persistent bladder or bowel dysfunction Lumbar puncture
*Classification of GBS as either AIDP or AMAN is not required for diagnosis of GBS, and whether A lumbar puncture is often performed in patients with
AIDP and AMAN require different treatments is unknown. The amount of conduction slowing
required to define demyelination differs between classification systems.6,23 Abbreviations: CMAP, suspected GBS. Importantly, this procedure especially
compound muscle action potential; GBS, GuillainBarr syndrome; LLN, lower limit of normal. should be done to exclude other diagnoses rather than
to confirm GBS. A combination of elevated protein level
and normal cell counts in the CSF (termed albumino
best-known GBS subtypes are AIDP and AMAN. AIDP cytological dissociation) is considered a hallmark of GBS.
is a sensorimotor form of GBS that is often accompa- A frequent misconception, however, is that albumino
nied by cranial nerve deficits, autonomic dysfunc- cytological dissociation must always be present to
tion, and pain. This condition is characterized by a confirm the diagnosis,13,88 as only 64% of patients with
demyelinating polyneuropathy at electrophysiological GBS have this feature. Elevated CSF protein levels are
examination.1,3,8 By contrast, AMAN is a pure motor found in approximately 50% of patients in the first 3days
form of GBS, in which the axonal polyneuropathy is after onset of weakness, which increases to 80% after the
not accompanied by sensory deficits at clinical and first week.73
electrophysiol ogical examination (although 10% of CSF cell counts >50 cells per l should cast doubt on
patients with AMAN do have sensory symptoms).68,46 the diagnosis of GBS, and other differential diagnoses
Cranial nerve deficits are less frequent than in AIDP, should be considered, such as leptomeningeal malig-
but patients with AMAN may have autonomic dys- nancy, lymphoma, cytomegalovirus radiculitis, HIV
function and pain.3,7,77 Usually, disease progresses more polyneuropathy and poliomyelitis.13,73,88 If the protein
rapidly in AMAN than in AIDP, and recovery is often level in the CSF is normal, repeat lumbar punctures are

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not usually recommended because albuminocytological Since no consensus exists on which neurophysiologi-
dissociation is not necessary to diagnose GBS. In addi- cal criteria are best for confirming the diagnosis of GBS
tion, treatment with high-dose IVIg can increase both subtype, multiple classification systems are used.6,23,95
protein levels and cell counts in the CSF, likely due to Atpresent, however, subtype classification does not
transudation or to aseptic meningitis, which can confuse seem to influence treatment choices, as patients with
the diagnostic picture in patients who undergo a repeat axonal and demyelinating forms of GBS currently receive
lumbar puncture. similar treatment, at least in principle.

Muscle and nerve electrophysiology Testing for antiganglioside antibodies


Nerve conduction studies (NCS) can help to support Although antiganglioside antibodies are involved in
the clinical diagnosis of GBS and discriminate between the pathogenesis of GBS, their role in diagnosis has
axonal and demyelinating subtypes. Diagnosis of GBS not been established. In general, the frequency of each
can sometimes be difficult in the early phase of the specific antibody is low, implying that the negative pre-
disease, especially when reflexes are still present or dictive value of detection tests will also be low, and that
the weakness is not distributed according to the classic the negative test findings cannot, therefore, exclude
pattern (for instance, in patients with paraparesis). NCS GBS as a diagnosis. In addition, tests for detecting these
can demonstrate abnormalities in locations with subclin- antibodies have a limited positive predictive value, as
ical disease, such as the arms. NCS findings of periph- antiganglioside antibodies (especially those of the IgM
eral neuropathy or polyradiculopathy can also help to class) also occur in other diseases. Possible exceptions
confirm the diagnosis of GBS. to this rule might be anti-GQ1b antibodies, which are
Nerve conduction abnormalities tend to peak present in the serum of at least 90% of patients with MFS,
>2weeks after the onset of weakness.6 However, if NCS and anti-GM1 and anti-GD1a IgG antibodies, which
are required to confirm a diagnosis of suspected GBS, a are frequently found in patients with AMAN.7,9,37,4649
delay of 2weeks is often too long. Although NCS can be Detection of these specific antibodies might be diagnos-
performed earlier in the disease course, the results might tically helpful, provided that validated assays are used.96
still be normal at this stage. Often, the first-detected NCS Moreover, research into antiganglioside antibody detec-
abnormalities are prolonged or absent Fwaves, although tion methods is rapidly progressing, and more-sensitive
other conduction abnormalities become evident as the and more-specific tests may emerge in the near future.
disease progresses. To increase the diagnostic yield of
NCS, at least four motor nerves, three sensory nerves Differential diagnosis
and Fwaves should be investigated. In patients with typical features of GBS, diagnosis is
Abnormalities found on NCS depend on the GBS usually straightforward, but in patients with atypi-
subtype (AIDP, AMAN or AMSAN). In patients with cal features, GBS can sometimes be difficult to recog-
AIDP, NCS reveal features of demyelination, including nize. Even in patients with typical features, a lumbar
prolonged distal motor latency, reduced nerve conduc- puncture is recommended to rule out diagnoses other
tion velocity, prolonged Fwave latency, increased tempo- than GBS. The differential diagnosis of GBS includes
ral dispersion, and conduction block. The sural sensory infectious diseases, malignancy and disorders of the
potential is often preserved.89 Features of axonal GBS neuromuscularjunction.1,2,9799
(AMAN or AMSAN) include decreased motor and/or In patients with an elevated cell count in the CSF, dif-
sensory amplitudes, typically in the absence of demyelin ferential diagnoses such as spinal root inflammation due
ating features. Sensory-nerve studies can help to dif- to cytomegalovirus or HIV, transverse myelitis, Lyme
ferentiate between AMAN and AMSAN. In AMAN, disease, leptomeningeal malignancy, or poliomyelitis
neurophysiological findings can be very complex, as should be considered.9799 Laboratory investigations
some patients with this condition have transient conduc- can also be helpful to reveal other causes of GBS-like
tion block or slowing, which rapidly recovers during the symptoms, such as electrolyte disturbances (especially
course of the diseasea phenomenon called reversible hypokalaemia) and vitamin B1 deficiency.
conduction failure.7,9093 In patients with pure motor symptoms, differen-
Reversible conduction failure can mimic demyelin tial diagnoses of myasthenia gravis, polymyositis and
ation, and is probably caused by impaired conduction dermatomyositis, poliomyelitis, hypermagnesaemia, por-
at the node of Ranvier caused by antiganglioside anti- phyria, botulism, and lead or organophosphate poison
bodies. Besides reversible conduction failure, other ing should be considered.9799 NCS can be helpful in such
NCS features that suggest demyelination can some- individuals to differentiate between polyneuropathy,
times be observed in the acute phase of axonal GBS.94 myopathy, anterior horn cell disease (poliomyelitis), and
Patients with reversible conduction failure may be disorders of the neuromuscular junction.
falsely diagnosed as having AIDP instead of AMAN. When a diagnosis of GBS is considered in a patient
Serial NCS might be needed to reliably distinguish with paraparesis or abnormal spinal sensory level at
these two subtypes of GBS;95 for example, in an Italian neurological examination, MRI of the spinal cord, and
study, 24% of patients initially classified as having possibly also CSF examination, should be performed to
AIDP were reclassified as having AMAN when serial exclude spinal cord compression or transverse myelitis.
NCSwereperformed.92 NCS can also be helpful in these patients, especially when

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History and neurological investigation leptomeningeal malignancy should be considered.9799


compatible with GBS When the severity of respiratory failure is dispropor-
tionate to that of limb weakness, disorders such as myas-
Laboratory investigations
Sodium, potassium, phosphate, magnesium,
thenia gravis, hypermagnesaemia, hypophosphataemia,
liver enzymes, creatine kinase, white blood cell count, high cervical intramedullary lesions, p oliomyelitis and
C-reactive protein (on specific indication: thiamine,
thyroid-stimulating hormone)* botulism should be excluded.9799
Lumbar puncture especially to rule out other diagnosis
Consider nerve conduction studies when Diagnosis of GBS in children
the diagnosis of GBS is doubtful
The clinical presentation and outcome of GBS is different
Diagnosis of GBS Prevention or treatment in children compared with adults, and diagnosis of child-
of complications hood GBS can be challenging, especially in young chil-
Regular check of:
Admission to ICU/high care unit or to neurology ward|| Respiratory dysfunction
dren aged <6years.101104 Pain, difficulty with walking, or
Consider using prognostic model EGRIS155 (initially every 13 h) refusing to walk are the most frequent presenting symp-
Rapidly progressive
weakness in arms and legs toms in children, and should raise suspicion of GBS.101104
Treatment indication IVIg or PE
Facial/bulbar weakness However, only one-third of preschool children with GBS
Severely affected patients (inability to walk unaided, Autonomic dysfunction
GBS disability scale 3), especially when <2 weeks
Pain
receive a correct diagnosis at admission. 103 In young
from onset of weakness# children, GBS may initially be diagnosed as meningitis,
Mildly affected patients (GBS disability scale 12) More general complications:
surveillance for further deterioration/treatment Venous thrombosis coxitis, or malaise caused by viral infections. Moreover,
indication Decubitus the diagnosis of GBS in children is often delayed. In pre-
Respiratory tract infections
school children (aged <6years), the delay in diagnosis
Treatment-related fluctuation? Consider:
Physiotherapy can be even more than 2weeks.103 Insufficient monitor-
Secondary deterioration after initial improvement
or stabilization Rehabilitation ing of these children during this period may result in
Retreatment with IVIg: 0.4 g/kg daily for 5 days Logopaedic help emergency intubation and even death.105
(or with PE) Psychological support
Patient support group
Consider A-CIDP130 Assessment scales
If deterioration occurs three times or more Over the past few decades, the GBS Disability Scale has
and/or if deterioration occurs after more than
8 weeks, treat as CIDP (retreatment with IVIg or PE), been used as an outcome scale in the majority of clini-
or start treatment with corticosteroids cal trials in GBS. The GBS Disability Scale has six levels:
0(healthy), 1 (minor symptoms and capable of running),
If improvement or stabilization 2 (able to walk 10m without assistance but unable to run),
Consider discharge to neurology ward,
rehabilitation centre or home 3 (able to walk 10m across an open space with help),
4(bedridden or wheelchair-bound), 5 (requiring assisted
Figure 3 | Diagnosis and treatment of GBS. *If a non-GBS disorder is suspected, ventilation for at least part of the day), and 6(dead).106
target laboratory investigations accordingly. In case of cell count >50cells per l,
GBS assessment scales must be valid, sensitive, reliable,
consider spinal nerve root inflammation due to other causes. Normal cell counts and
elevated cerebrospinal fluid protein level (albuminocytological dissociation) are and able to capture subtle clinical changes over time.
indicative of GBS; however, protein level can be normal, especially in the first week.73 The Peripheral Neuropathy Measures Outcome Study

When no other diagnosis could be confirmed by laboratory investigation, lumbar (PERINOMS) accordingly investigated a large number
puncture or NCS. Consider performing NCS to subclassify GBS after 12weeks. of assessment scales.107 In a European Neuromuscular
||
Indications for intensive care unit admission are rapidly progressive weakness with Centre meeting, the PERINOMS study group reached
impaired respiration (vital capacity <20ml/kg), need for artificial ventilation, a consensus about the use of a variety of measures for
insufficient swallowing (often with severe weakness), and severe autonomic
the follow-up of patients with GBS in future trials. 107
dysfunction. Or if the treating physician decides that there is an indication for
treatment, for example, rapid progressive weakness, mild weakness with severe
They recommended using the GBS Disability Scale and
autonomic dysfunction, or severe swallowing problems. #IVIg: start within 2weeks of the Rasch-built Overall Disability Scale to measure dis-
onset: 0.4g/kg daily for 5days. PE: start 5PE with a total exchange volume of five ability, and both the Medical Research Council (MRC)
plasma volumes in 2weeks. Abbreviations: ACIDP, acute-onset chronic inflammatory sum score (ranging from 060) and the new Rasch-built
demyelinating polyneuropathy; EGRIS, Erasmus GBS Respiratory Insufficiency Score; MRCscore to measure muscle strength.106110
GBS, GuillainBarr syndrome; ICU, intensive care unit; IVIg, intravenous
immunoglobulin; NCS, nerve conduction studies; PE, plasma exchange. Treatment
Treatment of GBS usually combines multidisciplin
they reveal signs of demyelinating polyneuropathy or ary supportive medical care and immunotherapy
nerve conduction abnormalities in clinically unaffected (Figure3). Proven effective treatments for GBS are IVIg
arms, as both can be indicative of GBS. MRI findings and plasma exchange.1113 Immunotherapy is usually
of nerve root enhancement also support a diagnosis of started if patients are not able to walk 10m unaided
GBS.100 For patients with bladder or bowel dysfunction (GBS Disability Scale score 3).2,11 Plasma exchange and
at onset or who develop persistent bladder or bowel dys- IVIg have pleiotropic immunomodulatory effects, but we
function, the differential diagnoses include spinal cord have yet to establish which effects explain their thera-
or caudal compression, and t ransverse myelitis. peutic efficacy in GBS, and whether the same effects are
If a patient has asymmetric weakness, differential involved in all patients and all subtypes of GBS.
diagnoses such as vasculitic neuropathy, multiple mono IVIg treatment may inhibit Fc-mediated activation of
neuropathy, Lyme disease, diphtheria, poliomyelitis and immune cells, binding of antiganglioside antibodies to

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REVIEWS

their neural targets or local complement activation.12,111 Results from a small study, which unfortunately had
Serum IgG Fc glycosylation in patients with GBS seems some methodol ogical flaws, suggested that patients
to be associated with disease severity and could influence with AMAN might have better outcomes after treat-
the immunomodulatory effects of IVIg.112 ment withplasma exchange than after IVIg therapy, and
Plasma exchange is thought to remove neurotoxic that plasma exchange was also the most cost-effective
antibodies, complement factors and other humoral option.120 However, in countries where plasma exchange
mediators of inflammation.11,13 Plasma exchange is ben- machines are not widely available or patients cannot
eficial when performed within the first 4weeks after afford this expensive procedure, small-volume plasma
onset of weakness in patients who are unable to walk exchange or exchange transfusion can be a low-cost
unaided (GBS Disability Scale score 3), but the largest therapeutic option. 121124 Controlled studies of these
effect is seen when treatment is started within the first procedures are currently lacking.
2weeks.11,13,113,114 The usual plasma exchange regimen The combination of plasma exchange followed by
consists of five treatments administered over 2weeks, IVIg is not significantly better than either plasma
involving a total of about five plasma volumes. In mildly exchange or IVIg alone. 11,80 Oral steroids and intra
affected patients (still able to walk), however, two plasma venous methylprednisolone are not beneficial in patients
exchange sessions induced more-rapid onset of motor with GBS.11,15,79 The combination of IVIg and methyl
recovery than did no plasma exchange.115 prednisol one is no more effective than IVIg alone,
IVIg is effective in patients who are unable to walk although this combined treatment might have some
10m unaided (GBS Disability Scale score 3) and additional short-term benefits when known prognos-
when started within 2weeks of onset of weakness.11,12 tic factors are taken into account.79 Small randomized
Randomized controlled trials showed that IVIg at a placebo-controlled trials of IFN-1a and brain-derived
dose of 0.4g/kg daily for 5 consecutive days (or 1g/kg neurotrophic factor, and one trial studying a 6week
daily for 2days) was as effective as a full course of five course of mycophenolate mofetil combined with stand-
plasma exchange sessions applied over 2weeks. 80,116 ard IVIg versus IVIg alone, did not indicate beneficial
Whether rapid IVIg treatment over 2days is superior effects of these treatments.14,125
to treatment with the same total dose (2g/kg) adminis- No randomized controlled trials have been per-
tered over 5days has not been fully evaluated. However, formed in patients with MFS.126 A retrospective analysis
one trial demonstrated that children receiving treat- showed that recovery starts slightly earlier in patients
ment over 2days more frequently had treatment-related with MFS treated with IVIg than in those who were
fluctuations than did children receiving treatment treated with plasma exchange or received no immuno
over 5days.117 As IVIg therapy is widely available, does therapy. However, final outcomes were the same in
not require special equipment, and generally has only all three groups.126,127 Indeed, almost all patients with
minor adverse effects, it has replaced plasma exchange MFS recover fully, irrespective of whether they receive
as the preferred treatment for GBS in many hospi- immunotherapy.126,127 Owing to the lack of evidence of a
tals.11,12 Immunoabsorption, as an alternative to plasma beneficial effect of IVIg or plasma exchange in patients
exchange, is occasionally used as a treatment for patients with MFS, combined with the good natural recovery
with GBS, and may be equally effective. However, no seen in these patients, withholding of immunotherapy
large-scale randomized controlled trials have shown in patientswith MFS seems currently justified. However,
that treatments other than IVIg or plasma exchange patients withMFSGBS overlap syndrome can be
areeffective.11,12 severely affected, and treatment with IVIg or plasma
The choice of treatment depends on both patient- exchange remains an option for these patients. Notably,
related and socioeconomic factors. For instance, plasma no large-scale randomized controlled trials have been
exchange requires special equipment and is not always performed to determine the optimal treatment strategy
available in all hospitals. In addition, plasma exchange in children with GBS and they are, therefore, usually
can be difficult to perform in young children, and care treated in the same manner as adults with GBS.104
should be taken in patients with autonomic cardiovascu-
lar instability because of the large volume shifts involved Importance of supportive care in GBS
in the plasma exchange procedure. However, the direct A patient in the progressive phase of GBS requires hos-
costs of IVIg treatment can be more than twice those pital admission. Important questions are how to monitor
of plasma exchange, making this treatment less attrac- progression and how to avoid or treat complications
tive in low-income countries.118,119 In this respect, it is related to weakness, immobility, respiratory insuffi-
important to remember that most clinical trials of these ciency, autonomic dysfunction, and pain. Patients with
treatments were conducted in Western Europe or North GBS need multidisciplinary supportive care to prevent
America and, therefore, predominantly involved patients or to manage these diverse complications (Figure3),128
who fulfilled the most commonly used GBS diagnostic and to facilitate timely transfer to the intensive care unit
criteria.4 The results of these trials might be less applica- (ICU) when indicated.
ble in other parts of the world, especially where AMAN Care includes monitoring of respiratory function
is highly prevalent. by frequent measurement of vital capacity and other
Whether patients with AMAN should receive the clinical parameters, such as respiratory depth, res-
same treatment as those with AIDP remains uncertain. piratory frequency and cough strength. The optimal

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Table 2 | Differentiating characteristics of GBS, GBS-TRF, ACIDP and CIDP130 in patients who develop TRF.2 These patients may have
a prolonged autoimmune response that causes ongoing
Characteristic GBS GBS-TRF A-CIDP CIDP
nerve damage, or functional blockade that requires
Time to nadir <2weeks <2weeks 48weeks, followed >8weeks prolongedtreatment.
(maximum (maximum by progression with
4weeks) 4weeks) deteriorations
GBS with extended progression phase
Disease Monophasic 12 >2 deteriorations or Progressive,
course deteriorations deterioration after stepwise or Some patients experience multiple periods of deteriora-
within 8weeks 8weeks fluctuating tion or have a progression phase that exceeds 4weeks. In
Severity Highly variable Highly variable Mostly moderate Mostly these patients, the question often arises of whether the
between between moderate, patient really has GBS, or whether they have acute-onset
patients, patients, distal and chronic inflammatory demyelinating polyneuropathy
ranging from ranging from proximal
(A-CIDP).130 A diagnosis of ACIDP should be consid-
mild symptoms mild symptoms weakness
to paralysis to paralysis ered when patients who were initially diagnosed with
GBS have three or more periods of clinical deterioration,
Ventilator 2030% 2030% Almost never Almost never
dependence or when new deterioration occurs >8weeks after disease
onset (Table2).130,132 It is vitally important to recognize
Cranial nerve Often Often Sometimes Sometimes
deficits any late or additional deteriorations, because patients
with GBSTRF may improve after retreatment with
Response Good Good, with Variable Good
toIVIg fluctuations IVIg, whereas those with ACIDP often require chronic
maintenance treatment with IVIg or a therapeutic switch
EMG/NCS* Sometimes no Sometimes no Often demyelinating Demyelination
classification classification polyneuropathy at to corticosteroids.
possible at possible at first EMG/NCS
first EMG/NCS first Residual deficits
EMG/NCS
Adult patients with GBS frequently have residual defi-
Treatment IVIg or plasma Repeat IVIg IVIg or plasma IVIg, cits that greatly impair their daily activities and quality
exchange orplasma exchange, on prednisolone
exchange confirmed diagnosis or plasma
of life.133139 For example, 6months after disease onset,
of CIDP consider exchange about 20% of patients with GBS are still not able to walk
also switch to unaided.1,2,11 Most improvement occurs within the first
prednisolone year after onset, but can continue after this period.140,141
maintenance
treatment
The most common residual deficits are reduced muscle
strength, sensory signs, fatigue, and pain.77,135,138,139 Many
*AIDP or AMAN. Abbreviations: ACIDP, acute-onset CIDP; AIDP, acute inflammatory demyelinating
polyneuropathy; AMAN, acute motor axonal neuropathy; CIDP, chronic inflammatory demyelinating patients have to make changes to their lifestyle, work,
polyneuropathy; EMG, electromyography; GBS, GuillainBarr syndrome; GBS-TRF, GuillainBarr syndrome
with treatment-related fluctuation; IVIg, intravenous immunoglobulin; NCS, nerve conduction studies.
and social activities.133,135 However, even patients with a
good functional outcome (GBS Disability Scale score 1)
have a reduction in psychosocial health status.134 Some
frequency to measure these vital functions has not been evidence suggests that high-intensity, multidisciplinary
investigated, but is probably about once every 14h rehabilitation reduces disability and improves quality
depending on the rate of deterioration. The duration of life in patients with GBS.136,142,143 Children with GBS
of ventilation may be shortened by selective digestive may have better outcomes than adults, although the long-
tractdecontamination.129 term residual effects on daily life in children have not
Other issues that require attention are prophylaxis been established.102,104
against deep vein thrombosis, cardiac and haemo Long-lasting symptoms of fatigue are present in the
dynamic monitoring, pain management, management of majority of patients with GBS.138 Fatigue can be assessed
possible bladder and bowel dysfunction, physiotherapy, using the fatigue severity scale, and the Rasch-built
rehabilitation, and psychosocial support.2,128 GBS can be fatigue severity scale.144 The precise pathophysiological
a very challenging disorder for both patients and their mechanisms leading to fatigue are not well understood,
relatives, who may benefit from contacting national or but axonal loss seems to be a contributory factor. 145
international GBS-related patient organizations. Anoncontrolled, nonblinded study showed that physi-
cal training is feasible and effective in patients who have,
Deterioration after initial improvement neurologically, recovered well from GBS, but who still
About 10% of patients with GBS who have been treated have severe fatigue.136
with IVIg or plasma exchange deteriorate after initial Moderate to severe pain is very common in patients
improvement or stabilizationa phenomenon that is with GBS. A prospective follow-up study showed that
termed treatment-related fluctuation (TRF).130,131 These two-thirds of patients report pain within the first
patients usually improve after retreatment with IVIg or 3weeks after onset, and one-third still have pain after
plasma exchange, and although the efficacy of retreat- 1year.77 Up to 89% of patients experience pain at some
ment has never been demonstrated in a randomized point during their disease course,76 and pain may even
controlled trial, this approach has become common precede weakness in about one-third of patients.77 The
practice. On the basis of clinical experience, we and most common locations of pain are the extremities or
others advise retreatment with IVIg (2g/kg over 5days) the back; patients mainly report muscle pain, painful

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paraesthesias, radicular pain, arthralgia or mening- head from the bed, and increased liver enzyme levels
ism.77 Attention must be paid to pain during the entire were predictors of an increased probability of need for
disease course because although pain can be very severe, artificial ventilation.153 A second French study found that
it is often under-recognized. Pain can be treated with peroneal nerve conduction block and low vital capacity
neuropathic analgesics, but not all patients have a good correlated with a high risk of respiratory failure.154 The
response to such treatment. A Cochrane review on the third study was conducted in the Netherlands, and used
pharmacological treatment of pain in patients with GBS data from a derivation cohort of 397 patients with GBS
showed that evidence to support a pain-relieving effect to identify clinical predictors of mechanical ventilation,
of analgesics in this condition is scarce.146 The precise which were validated in an independent cohort of 191
causes of pain in GBS are probably diverse, and may vary patients with GBS.155
over the course of the disease.147 Notably, distal intra The results of the Dutch study led to development
epidermal nerve fibre density is reduced in patients with of the Erasmus GBS Respiratory Insufficiency Score
GBS, and is associated with both incidence and sever- (EGRIS).155 EGRIS is an accurate prediction model that
ity of pain (but not with autonomic dysfunction, as can be used in the emergency room to predict the prob-
discussedbelow).148,149 ability of respiratory insufficiency in the first week after
Autonomic dysfunction predominantly occurs in the admission for GBS.155,156 The model incorporates the fol-
acute phase of GBS but can also occur in the recovery lowing parameters: severity of weakness (expressed as
phase. It can be a serious problem in patients with GBS the MRC sum score), the number of days between onset
and may cause sudden death.150152 Tachycardia (38%), of weakness and admission, and facial and/or bulbar
hypertension (69%), gastrointestinal dysfunction (45%), weakness (Supplementary Figure1 online). If a patients
and bladder dysfunction (19%) have been reported in a predicted chance of developing respiratory insufficiency
series of 156 GBS patients.77 Patients with severe cardio is high, it can be advisable to admit the patient to the ICU
vascular dysfunction can have rapid changes in blood rather than to a general neurology ward.
pressure and cardiac dysrhythmia that sometimes Factors that are predictive of successful weaning
require a cardiac pacemaker. In children, autonomic from the ventilator are age <60years,157 lack of auto-
dysfunction was present in half of the mildly affected nomic dysfunction, and vital capacity >20ml/kg or an
patients and seemed not to be related to the severity of improvement in vital capacity of 4ml/kg.158 Autonomic
the disease,81 which implies that autonomic disturbances dysfunction, advanced age and pulmonary comorbid-
are common and may occur throughout the spectrum of ity are associated with a long duration of mechanical
severity of GBS. ventilation and the need for tracheostomy.158,159
Autonomic dysfunction in patients with GBS reflects
dysfunction of sympathic and/or parasympathic inner- Predictors of poor long-term outcomes
vation, but the exact immunopathological mechanisms In almost all studies, poor outcome is defined as a
remain to be elucidated. Specifically, the relationship GBS Disability Scale score 3 after either 6months or
between specific antiganglioside antibodies and auto- 12months.160163 Such a high grade on the GBS Disability
nomic dysfunction needs to be investigated in more Scale at neurological examination, diarrhoea preceding
detail. We did not observe a correlation between reduc- GBS onset,28,160,163,164 and advanced age28,78,140,141,154,160,162165
tion of intraepidermal nerve fibre density and autonomic are all predictors of poor outcome.
failure.149 The reason why some patients have severe Validated prognostic models have been developed for
autonomic dysfunction that can include light-fixed use in clinical practice to predict long-term outcome in
pupils and excessive sweating, whereas others have severe individual patients with GBS. An example is the Erasmus
cardiac dysrhythmia, is currently unknown and, unfortu- GBS Outcome Score (EGOS), which is based on three
nately, cannot be predicted from a clinical point ofview. clinical characteristics: age, GBS Disability Scale score
Careful monitoring for the presence of featuresof auto- at 2weeks after hospital admission, and preceding diar-
nomic dysfunction is indicated also after a patient is rhoea.156,163 However, the 2week delay before EGOS
discharged from the ICU. can be determined may be too long to adequately tailor
treatment according to the patients predicted outcome.
Prognosis and outcome By contrast, the modified EGOS can be used to predict
As the clinical course and outcomes of GBS are highly outcomes early in the course of GBS, before irreversible
variable, their accurate prediction is important to enable damage occurs.156,166 This model can be used at admis-
clinicians to tailor supportive care and treatment to the sion and at 1week after admission, and is based on age,
individual patients needs and to inform patients and severity of weakness (expressed as MRC sum score), and
relatives about the expected clinical course. preceding diarrhoea (Supplementary Figure2 online).

Predictors of need for ventilation Electrophysiological findings


Three large studies have been performed to predict the In addition to their diagnostic role, electrophysiological
probability of respiratory insufficiency in patients with findings might have prognostic relevance. In one NCS
GBS. A French study including 722 patients found that study, patients with features of demyelination more
time from onset to admission of <7days, inability to often required mechanical ventilation than did patients
cough, inability to stand, inability to lift the elbows or without this type of damage.154 The most consistent

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electrophysiological finding predictive of poor outcome of a second course of IVIg given shortly after the first
is low CMAPs.167 However, some studies demonstrated course in patients with GBS who have a poor progno-
that an axonal neuropathy is not necessarily a predic- sis (defined as a mEGOS score of 612 at 1week after
tor of poor outcome, since patients with AMAN can initiation of a standard 5day course of IVIg). A related
either improve very slowly and incompletely or recover international study with an observational prospective
rapidly.22,168 These observations seem inconsistent, but design (I-SID-GBS) is investigating the same approach.
rapid recovery might be caused by restoration of tran- This study is part of IGOS and is being performed by the
sient conduction block. Further studies are required to Inflammatory Neuropathy Consortium.
precisely delineate the relationships between conduc- In addition, a new randomized placebo-controlled
tion block, the presence of a ntiganglioside a ntibodies, trial of eculizumab in patients with early GBS who are
the effects of treatment, and outcome. unable to walk is about to start.172 This study is partly
based on findings in an animal model of GBS, in
Predictors of mortality which antiganglioside antibodies induce complement-
Mortality from GBS varies between 3% and 7%.140,169,170 dependent damage at the nodes of Ranvier, nerve ter-
Predictors of an increased risk of death are advanced minals, and perisynaptic Schwann cells (Figure2).59,173
age, severe disease, increased comorbidity, pulmonary Notably, these deleterious effects of complement on
and cardiac complications, mechanical ventilation, and nerve terminals in mice can be blocked by the admin-
systemic infection.140,160,169171 Death can occur in all istration of eculizumab, a humanized monoclonal
phases of the disease; however, in two studies, a large antibody that binds with high affinity to complement
proportion of the deaths occurred >30days from onset, factor C5 and prevents its cleavage to C5a and the pro-
and a subsequent study showed that the majority of inflammatory, cytolytic C5b9 complex.61 Many other
patients who died were in the recovery phase.160,170,171 studies, such as those investigating pain treatment,
Consequently, severely affected patients in the recov- nerve regeneration, and other factors that may improve
ery phase of GBS and after discharge from the ICU still the outcomes of patients with GBS, are eagerly awaited.
require good observation and supportive care.170 The
most common causes of death are respiratory insuffi- Conclusions
ciency, pulmonary infection, autonomic dysfunction, GBS is a heterogeneous and often severe diso rder.
and cardiacarrest.78,160,170,171 Although nonspecific immunotherapy is available
and effective in most patients, a need remains for
Ongoing research improved treatment and patient care throughout the
Nearly a century after it was first described, GBS is still a disease course. Optimal supportive medical care is
life-threatening disorder that results in a poor outcome also essential to prevent or treat disease-related com-
in at least 20% of patients and has persistent residual plications. Novel prognostic models have been devel-
effects in the majority. Further research is urgently oped and might enable treatment to be tailored to each
required to improve this situation. From a clinical per- patientsrequirements.
spective, the following are the most challenging needs: Although a large amount of information on the
to develop improved diagnostic criteria for use in daily immunopathogenesis of the various subtypes of GBS
clinical practice, trials and vaccine safety studies; to has been collected, further research is still needed. In
determine the burden of disease caused by GBS world- the past few years, new large-scale clinical studies based
wide; to develop new and better GBS outcome measures; on worldwide collaborations have been started and will
to establish the precipitating events and patient-related help us to further define this syndrome and to optimize
factors that lead to GBS; to define biological and clinical the care of affected patients.
predictors of the clinical course and outcome in indi-
vidual patients; and, most importantly, to develop more-
effective and specific treatments, as well as protocols for Review criteria
supportive care. PubMed was searched for articles published between
These aims can probably only be achieved by large- January 1990 and March 2014. MeSH search terms were
scale international and multidisciplinary collabora- GuillainBarr syndrome alone and in combination with
tions, such as the International GBS Outcome Study epidemiology, immunology, genetics, therapy,
(IGOS), which was launched in 2012. Tissue samples and drug therapy or mortality. Non-MeSH search terms
were GuillainBarr syndrome, acute inflammatory
detailed, standardized clinical data are being collected
demyelinating polyneuropathy, acute motor axonal
during a follow-up period of 13years with the inten-
polyneuropathy and Guillain-Barr syndrome combined
tion of including at least 1,000 patients with GBS from all with epidemiology, diagnosis, diagnostic criteria,
over the world. At present, centres from 17 countries infection, antibodies, immunology, nerve
Argentina, Australia, Bangladesh, Belgium, Canada, conduction studies, electrophysiology, treatment,
Denmark, France, Germany, Italy, Japan, Malaysia, genetics, vaccination, autonomic dysfunction or
Netherlands, Spain, South Africa, Taiwan, UK and the pain. Only papers in English were reviewed. Articles
USAare recruiting patients. In addition, a randomized were selected for their relevance, with a preference for
new papers. Some other relevant papers known by the
controlled trial, the SID-GBS study, is being conducted
authors were also included.
in the Netherlands. This trial is investigating the effect

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REVIEWS

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