Received: 26 March 2024 | Accepted: 13 May 2024

DOI: 10.1111/ene.16365

REVIEW ARTICLE

Guillain-­Barré syndrome: A comprehensive review

Roberto Bellanti | Simon Rinaldi

Nuffield Department of Clinical Abstract

Neurosciences, University of Oxford,
Oxford, UK Guillain-­Barré syndrome (GBS) is a potentially devastating yet treatable disorder. A clas-
sically postinfectious, immune-­mediated, monophasic polyradiculoneuropathy, it is the
Correspondence
Simon Rinaldi, Nuffield Department of leading global cause of acquired neuromuscular paralysis. In most cases, the immuno-
Clinical Neurosciences, University of pathological process driving nerve injury is ill-­defined. Diagnosis of GBS relies on clinical
Oxford, Oxford, UK.
Email: [email protected] features, supported by laboratory findings and electrophysiology. Although previously
divided into primary demyelinating or axonal variants, this dichotomy is increasingly
challenged, and is not endorsed by the recent European Academy of Neurology (EAN)/
Peripheral Nerve Society (PNS) guidelines. Intravenous immunoglobulin and plasma ex-
change remain the primary modalities of treatment, regardless of the electrophysiological
subtype. Most patients recover, but approximately one-­third require mechanical ven-
tilation, and 5% die. Disease activity and treatment response are currently monitored
through interval neurological examination and outcome measures, and the potential role
of fluid biomarkers is under ongoing scrutiny. Novel potential therapies for GBS are being
explored but none have yet modified clinical practice. This review provides a comprehen-
sive update on the pathological and clinical aspects of GBS for clinicians and scientists.

KEYWORDS
diagnosis, Guillain-­Barré syndrome, immunopathology, prognosis, treatment

I NTRO D U C TI O N GBS develop a severe, generalised neuropathy, and ultimately require

mechanical ventilation due to respiratory failure. One in 20 patients
Guillain-­Barré syndrome (GBS) is the most common cause of acute die. Increased understanding of GBS has not been paralleled by prog-
neuromuscular paralysis worldwide. It can be a severe and life-­ ress in therapeutics, and the mainstay of treatment remains intrave-
threatening condition, and early treatment is essential for a better nous immunoglobulin (IVIg) or plasma exchange (PLEX). Outcome
prognosis. Over 100 years after it was first described [1], GBS is now measures and interval neurological examination are used to monitor
one of the best understood neuroinflammatory diseases, providing disease activity and response to treatment, whilst the potential role
valuable insights into the mechanisms of peripheral nerve inflam- of fluid biomarkers of neuropathy remains under evaluation. Novel
mation. However, many aspects of its nature continue to elude our therapies are also being explored and may soon contribute to clinical
comprehension, and the full scope of GBS remains a puzzle yet to be management. In light of the new European Academy of Neurology
fully deciphered. We know that GBS is a postinfectious, monopha- (EAN) and Peripheral Nerve Society (PNS) guidelines on diagnosis
sic, immune-­mediated polyradiculoneuropathy, and its diagnosis is and treatment of GBS [2], this review summarises current knowledge
largely based on clinical patterns with or without the support of labo- and best available evidence, to inform clinicians and scientists as they
ratory findings and electrophysiology. About a third of patients with navigate the journey through Guillain-­Barré syndrome.

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,
provided the original work is properly cited.
© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.

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https://doi.org/10.1111/ene.16365
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2 of 15 BELLANTI and RINALDI

E PI D E M I O LO G Y Disease initiation

There are 100,000 new cases of GBS every year [3]. Estimates of Prodromal infections
yearly incidence (per 100,000 people) are lowest in Japan (0.44)
[4], China (0.67) [5], Tanzania (0.83) [6], and Finland (0.84) [7], In most cases, GBS is a postinfectious disease, and two-­thirds of pa-
and highest in Chile (2.12) [8] and Bangladesh (3.25) [9], likely tients report prodromal gastrointestinal or respiratory symptoms.
due to differences in exposure to infectious organisms. Seasonal Campylobacter jejuni, the most commonly identified pathogenic trigger,
variations are described [10], and spikes of GBS have been re- leads to GBS in approximately 1 out of every 1000 cases, through mo-
ported following infectious outbreaks, most notably in relation lecular mimicry between its surface lipo-­oligosaccharide (LOS) and host
to Campylobacter jejuni [11] and Zika virus (ZIKV) [12, 13]. Older peripheral nerve gangliosides (Figure 1). This triggers the production of
people are more commonly affected (peak incidence of GBS is cross-­reactive antibodies targeting gangliosides like GM1, GD1a, and
between 50 and 70 years of age) and the male:female ratio is 1.5:1 GQ1b, resulting in axoglial damage. Other pathogens associated with
[3, 14, 15]. GBS include Epstein–Barr virus (EBV), cytomegalovirus (CMV), hepatitis
E virus (HEV), Mycoplasma pneumoniae, Haemophilus influenzae, influ-
enza A virus, and Zika virus. Mycoplasma pneumoniae is associated with
PATH O PH YS I O LO G Y O F G B S anti-­galactocerebroside antibodies of the IgG isotype, more frequently
in children [16, 17]. The mechanistic association between most of these
The pathophysiology of GBS can be delineated into two pivotal pathogens and axoglial damage remains unclear, and molecular mimicry
stages: initiation by an immunological trigger and immune-­mediated between C. jejuni and peripheral nerve glycans is still the best explained
disruption of axons and/or myelin. Based on electrophysiology, GBS postinfectious link in GBS, although how patients break tolerance to self-­
has been traditionally divided into two forms: acute inflammatory glycans following C. jejuni infection has not been clarified.
demyelinating polyradiculoneuropathy (AIDP) and acute motor ax-
onal neuropathy (AMAN). The notion that this neurophysiological
dichotomy reflects a true underlying pathological difference be- Vaccines associated with GBS
tween primarily demyelinating versus axonal GBS is currently being
challenged, and the new EAN/PNS guidelines no longer support the Epidemiological evidence links some vaccines with a subsequent di-
distinction between AIDP and AMAN. agnosis of GBS. These include the vaccine for the ‘swine flu’ (A/New

F I G U R E 1 Lipo-­oligosaccharide (LOS) on the outer membrane of Campylobacter jejuni induces cross-­reactive antibodies which, through
molecular mimicry, bind to the structurally identical glycans (areas in green) present on peripheral nerve gangliosides (GM1 and GQ1b in the
example above), resulting in damage to axons and Schwann cells.
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GUILLAIN-­BARRÉ SYNDROME: A REVIEW 3 of 15

Jersey/76 influenza), the recombinant zoster vaccine (RZV), and the antibody-­mediated primary Schwann cell damage occurs, and the
adenovirus-­
vector SARS-­
CoV-­
2 vaccines. The ‘swine flu’ vaccine potential contribution of T cells to B cell activation, remains to be
campaign in the USA was associated with 4.9–5.9 GBS cases per definitively established.
million vaccinations [18]. Though initial concerns were raised about Animal models [33–38] using active immunisation or passive
the H1N1 influenza A vaccination in 2009, subsequent surveillance transfer have shown that axoglial damage can be mediated by gan-
reported only 1–1.6 cases per million doses [19–21]. Similarly, her- glioside antibodies. In these models, autoantibodies target axonal
pes zoster vaccination with RZV showed a marginally increased risk or glial antigens and cause damage through complement activation
of GBS, with approximately 3 excess cases per million vaccinations and formation of the membrane attack complex (MAC) or induce
[22]. Adenovirus-­vectored SARS-­CoV-­2 vaccines, such as ChAdOx1 non-­complement-­mediated effects on myelin and axonal regen-
and Janssen COVID-­19 vaccines, have been linked to around 5.7 ex- eration. Complement-­
dependent membrane disruption leads to
cess GBS cases per million first doses [23–25]. The 2023 EAN/PNS aberrant influx of calcium into the axon, calpain activation, and ulti-
GBS guidelines conclude that the advantages of vaccination (reduc- mately damage to the node of Ranvier, the paranode, and the motor
tion in morbidity and mortality related to infection and infection-­ nerve terminals (Figure 2a) [35, 36, 39, 40]. Ganglioside antibody
associated GBS) significantly outweigh any marginal elevation in the binding also leads to displacement of voltage-­gated sodium chan-
risk of post-­vaccine GBS [2]. It remains uncertain whether repeat or nels, cytoskeletal anchoring proteins, and cell adhesion molecules
future vaccination is safe following presumed vaccine-­associated within the nodal and paranodal regions [38]. In transgenic mice
GBS, and certain individuals may be more susceptible to autoinflam- where GM1 is only expressed by Schwann cells and not axons, GM1
mation due to genetic predisposition. The risk of post-­vaccine GBS antibodies cause primary glial injury. However, following Schwann
should be acknowledged and balanced against the benefits of vac- cell/myelin dehiscence, axonal nanoruptures are formed, ultimately
cination overall. resulting in a convergence of the pathological process with influx
of calcium, calpain activation within the axon, and cleavage of cy-
toskeletal and transmembrane proteins [41]. Such findings suggest
Other proposed or established causal associations that regardless of whether the initial injury is axonal or glial, there
is a common final pathway which leads to axonal disruption and
The risk of developing GBS may be higher during the first 6 weeks functional failure.
after surgery [26], most significantly orthopaedic or gastrointestinal Ultimately, nerve conduction failure and the related spectrum of
[27], and particularly in the context of active malignancy [28]. Cases neurological symptoms seen in patients with GBS are due to dam-
of GBS in stem cell transplant patients immunosuppressed with tac- age to neurons (node, paranode, juxtaparanode, terminal axons) or
rolimus for graft versus host disease (GVHD) prophylaxis have been glia (myelin, Schwann cells) or both. These alterations then lead to
reported [29], as well as in patients treated with immune checkpoint reversible conduction failure with the potential for rapid recovery,
inhibitors [30]; however, the actual risk has not been ascertained in demyelination with slower recovery, or axonal degeneration with
controlled studies. protracted and more often incomplete recovery, or a combination of
all three within the same nerve [38].
At least 40% of GBS patients do not have identifiable serum or
Immune-­mediated axoglial disruption CSF autoantibodies. This may be because the full range of relevant
antigenic targets have yet to be found. Glycolipid domains can as-
The inflammatory nature of GBS was first acknowledged in the late sociate to form complex hetero-­dimeric clusters, and around half
1940s, when prominent lymphocyte infiltration was found in post-­ of GBS patients have antibodies targeting these complexes but not
mortem nerve biopsies [31]. It is now clear that both innate and cel- their individual components in isolation [42, 43]. Furthermore, the
lular immune mechanisms are implicated in GBS, and T cells, B cells, pathogenic potential of certain antibodies is determined by local in-
NK cells, dendritic cells, and macrophages are all likely to contribute teraction of glycolipids with neighbouring gangliosides, which can
to axonal damage and demyelination. prevent binding of autoantibodies.
A recent study investigating autoreactive T cell immunity in pa- Genetic factors might also play a role in the immunobiology of
tients with GBS [32] found that patients with AIDP had CD4+ and GBS. A metanalysis found a moderate association between GBS and
CD8+ T cells in their blood, cerebrospinal fluid (CSF) and nerve tis- a tumour necrosis factor (TNF) gene polymorphism [44]. An associa-
sue reactive to myelin protein 0 (P0), myelin protein 2 (P2), or periph- tion has also been found between GBS severity and polymorphism of
eral myelin protein 22 (PMP22) (Figure 2b). Autoreactive memory the mannose-­binding lectin (MBL) gene [45], which contributes to the
CD4+ T cells showed a proinflammatory cytotoxic TH1-­like pheno- activation of the complement system and to the clearance of apop-
type and expressed genes with a known autoimmunity association. totic cells by macrophages and dendritic cells. Genetic studies on large
A similar T cell autoreactivity was not found in patients with AMAN, GBS cohorts have yet to be conducted, and genome-­wide association
suggesting that patients with demyelinating and axonal GBS may studies in large, deeply phenotyped cohorts are needed to determine
actually have distinct immunopathological mechanisms. Whether whether and to what extent GBS is also genetically determined.
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4 of 15 BELLANTI and RINALDI

F I G U R E 2 (a) T cells reactive to peripheral nerve myelin antigens. A humoral mechanism underlying primary glial damage has long been
hypothesised, but anti-­myelin antibodies have yet to be identified. It remains unclear whether T cells are activated by macrophages (or other
antigen-­presenting cells [APCs]), or by the Schwann cells themselves. (b) Ganglioside antibody binding leads to complement activation,
membrane attack complex (MAC) formation, calcium influx into the axon, calpain-­mediated cytoskeletal disruption, and ultimately damage
to the node of Ranvier, the paranode, and the motor nerve terminals. Dendritic cells, macrophages, and other phagocytes are also typically
found within the nerve in patients with Guillain-­Barré syndrome.
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GUILLAIN-­BARRÉ SYNDROME: A REVIEW 5 of 15

C LI N I C A L FE AT U R E S O F G B S A N D GBS. In the latter case, length-­dependent involvement may produce

D I AG N OS TI C C R ITE R I A an anterior “level” that is not reproduced posteriorly. Finally, recur-
rent clinical worsening after initial improvement or stabilisation,
Clinical features known as treatment-­related fluctuations (TRF), may occur in some
patients with GBS if duration of the disease outlasts duration of ac-
GBS presents with acute, rapidly progressive flaccid paralysis tion of therapy. However, three or more TRFs and/or fluctuations
of arms and legs, and absent or decreased deep tendon reflexes after 8 weeks suggest that the diagnosis is not GBS, and alternative
(Table 1). Sensory disturbance may or may not be present. Large inflammatory neuropathies such as chronic inflammatory demyeli-
studies have shown that, typically, patients reach nadir of disability nating polyradiculoneuropathy (CIDP) or an autoimmune nodopathy
within 10–14 days, and symptoms rarely progress beyond 4 weeks (AIN) should be considered. The phenotypical spectrum of GBS is
[15, 46, 47]. CSF albuminocytological dissociation, with high protein summarised in Table 2.
level and normal white cell count (WCC), is a hallmark of GBS and,
together with raised CSF/serum albumin quotient (Qalb), indicates
disruption of the blood–nerve barrier in the affected nerve roots, Ganglioside antibodies and laboratory testing
whereby proteins exude into the subarachnoid space through the
leaky vessels. Normal CSF protein is common during the first week Ganglioside autoantibodies target peripheral nervous system gly-
of the disease and does not exclude GBS, and may be normal or cosphingolipids containing sialic acid. Both the IgG and IgM iso-
only mildly elevated in the second week after onset of symptoms. types are associated with GBS, whereas persistent IgM without IgG
Higher WCC should raise suspicion for infections (HIV, Lyme), hae- is typically found in chronic immune-­mediated neuropathies. Their
matological malignancy, or granulomatous inflammatory disorders presence supports a diagnosis of inflammatory (autoimmune) neu-
such as sarcoidosis. Crucially, CSF should be sampled prior to treat- ropathy, but their absence does not exclude GBS [48], does not im-
ment with IVIg, which typically raises both CSF protein and WCC. pact on clinical management, and has no monitoring or prognostic
Nerve conduction studies and electromyography may be normal utility. Amongst all ganglioside antibodies, anti-­GQ1b have the high-
during the first days, or show inexcitable nerves, indicating severe est specificity (Table 3) and should be tested for in patients with sus-
nerve damage, but are almost never normal weeks after disease pected Miller Fisher syndrome (MFS) or GBS/MFS overlap. Patients
onset. Similarly, initial hyperreflexia and sphincter disturbance (blad- with poor response to treatment and/or treatment-­related fluctua-
der and/or bowel dysfunction), though unusual and raising the sus- tions should be tested for nodal and paranodal antibodies, targeting
picion of an alternative diagnosis, do not exclude GBS (Figure 3). NF155, NF186/NF140, CNTN-­1, or Caspr-­1, which, if positive, would
Encephalopathy or altered level of consciousness may suggest have diagnostic, prognostic, and therapeutic implications.
Bickerstaff brainstem encephalitis (BBE), and a sensory level likely
favours a myelopathy. However, involvement of the thoracic roots or
intercostal nerves may occasionally produce a pseudo-­spinal level in Electrophysiology

Traditionally, slowing of conduction velocity (CV), conduction block,

TA B L E 1 Guillain-­Barré syndrome GBS diagnostic criteria (2023
temporal dispersion, prolonged distal motor latencies, and delayed
European Academy of Neurology [EAN]/Peripheral Nerve Society
[PNS] guidelines). F waves have been associated with the acute inflammatory demy-
elinating polyradiculoneuropathy (AIDP) form of GBS. Conversely,
Essential criteria
patients with predominantly axonal features, namely substantially
Progressive weakness of upper and lower limbs
reduced compound muscle action potentials (CMAP) with relatively
Absent or decreased deep tendon reflexes
less pronounced conduction slowing have been classified as having
Progression of clinical worsening not beyond 4 weeks the acute motor (and sensory) axonal neuropathy (AM[S]AN) forms
Clinical features supportive of GBS of GBS. However, the new guidelines do not endorse any specific
Symmetrical neuropathy diagnostic criteria for these two entities. This is because the distinc-
Mild or absent sensory symptoms (compared to motor) tion between AIDP and AMAN/AMSAN does not impact on clinical
Cranial nerve involvement (especially bilateral facial palsy) management, and there is no gold standard to select among the vari-
Respiratory failure ous published criteria [2]. In general, in patients with suspected GBS,

Autonomic dysfunction in the first week within onset of symptoms, reduced sensory nerve
action potentials (SNAP) and/or CMAP would support a diagnosis
Recent gastrointestinal or respiratory infection (<6 weeks)
of peripheral neuropathy, and the finding of absent H-­reflexes may
Back pain (interscapular or radicular)
suggest a radiculopathy. H-­reflexes are the electrophysiological cor-
Other supportive findings
relate of reflex muscle activation after electrical stimulation of affer-
Cerebrospinal fluid albuminocytological dissociation
ent sensory fibres; their absence is highly sensitive (95%–100%) [49,
Electrophysiology confirming peripheral neuropathy
50] for GBS and their presence makes a diagnosis of GBS unlikely
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6 of 15 BELLANTI and RINALDI

F I G U R E 3 Clinical features that support or refute a diagnosis of Guillain-­Barré syndrome (GBS). CNS, central nervous system; CSF,
cerebrospinal fluid.

[51, 52]. The finding of a sural-­sparing sensory pattern also facili- inflammatory, and monophasic. Mimics include peripheral and cen-
tates early diagnosis of GBS and aids differential diagnosis with mim- tral nervous system disorders, and in some cases only time will
ics [53, 54]. confirm or refute a diagnosis of GBS. Figure 4 summarises the dif-
ferential diagnosis of GBS based on localisation.

Imaging
Peripheral nerve mimics of GBS
Magnetic resonance imaging (MRI) and ultrasound (USS) are not
used as routine tests for the diagnosis of GBS in typical presenta- CIDP may have a GBS-­like acute presentation with sensory-­motor
tions but may be considered in cases where the diagnosis is uncer- disturbance (acute CIDP or A-­CIDP). Similarly, autoimmune nodopa-
tain. For example, MRI of the spinal cord might help distinguish a thies (AIN) can be acute and monophasic, but often have additional
peripheral neuropathy from a myelopathy or might localise the pa- features. In particular, patients with NF186 or pan-­
neurofascin
thology to the nerve roots. It should be noted, however, that diffuse antibodies (against NF155, NF140, and NF186) often have a se-
nerve thickening on MRI is non-­specific and can indicate a wide dif- vere, GBS-­like neuropathy with cranio-­respiratory and autonomic
ferential of neuropathies including inflammatory, infective, infiltra- involvement. Three or more TRFs, progression or (re)deterioration
tive, and genetic. over 8 weeks from onset, or substantial sensory disturbance (in-
cluding sensory ataxia) make A-­CIDP or an autoimmune nodopathy
more likely. Slow disease onset (defined as >2 weeks from onset to
D I FFE R E NTI A L D I AG N OS I S O F G B S nadir) [2] and/or significant early reduction in motor CV may also
suggest an alternative diagnosis. It is important to distinguish GBS
An inflammatory neuropathy is likely if onset and progression are from CIDP as the latter can respond to corticosteroids, often re-
acute or subacute (over days or weeks), along with elevated CSF quires long-­term or repeated treatment, and might be responsive to
protein and improvement of symptoms upon immunosuppression or steroid-­sparing immunosuppression. On the contrary, autoimmune
immunomodulation. GBS is most likely if the neuropathy is acute, nodopathies respond poorly to conventional therapies (IVIg, PLEX,
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GUILLAIN-­BARRÉ SYNDROME: A REVIEW 7 of 15

TA B L E 2 The Guillain-­Barré syndrome Typical GBS Purely motor or sensory-­motor GBS, with symmetrical
spectrum. weakness of arms and legs and reduced/absent deep
tendon reflexes
GBS variants
Pharyngeal-­cervical-­brachial Bilateral facial weakness ± bilateral arm
paraesthesias ± weakness of the arms (no involvement of
lower limbs or cranial nerves)
Paraparetic Isolated involvement of both lower limbs
Pure sensory Sensory symptoms and reduced/absent reflexes but no
weakness
MFS spectrum (GQ1b antibody syndromes)
MFS Ataxia, ophthalmoplegia, areflexia – the full triad is present
90% of patients have anti-­GQ1b antibodies
Partial MFS Two or one out of the three clinical features of MFS
Anti-­GQ1b antibodies found in similar percentage to MFS
GBS/MFS overlap syndrome Features of both GBS and MFS
Around 70% of patients have anti-­GQ1b antibodies
Bickerstaff brainstem Ataxia, ophthalmoplegia, hyperreflexia, altered level of
encephalitis consciousness
66% of patients have anti-­GQ1b antibodies
Acute ophthalmoplegia Acute paralysis of the external (extraocular) and/or
(without ataxia) internal (intrinsic) eye muscles without ataxia. Unilateral
involvement may occur [93]

Abbreviations: GBS, Guillain-­Barré syndrome; MFS, Miller Fisher syndrome.

TA B L E 3 Ganglioside antibodies in
Ganglioside antibody Associated clinical findings and utility
Guillain-­Barré syndrome and associated
clinical utility. Anti-­GM1 Elevated IgG and IgM at baseline and persistently high
IgG early in the disease course correlate with poor clinical
recovery [94]
Also present in up to 80% of patients with MMN which
presents with weakness (usually in the upper limbs) and
conduction block on electrophysiology. This is important as
MMN does not respond to plasma exchange
Anti-­GM2 May suggest CMV infection
Anti-­GD1a Younger patients with facial weakness and prominent axonal
damage [95]
Associated with poor outcome [96]
Anti-­GT1a Often indicate bulbar involvement in the pharyngeal-­cervical-­
brachial variant of GBS [97]
Anti-­GQ1b Highly specific for MFS, BBE, and GBS/MFS overlap syndrome

Abbreviations: BBE, Bickerstaff brainstem encephalitis; CMV, cytomegalovirus; GBS, Guillain-­Barré

syndrome; Ig, immunoglobulin; MFS, Miller Fisher syndrome; MMN, multifocal motor neuropathy.

corticosteroids) and may benefit from B cell depleting immunomod- lower back, interscapular or radicular, and may then persist for several
ulation with the monoclonal antibody rituximab if given early in the months, unresponsive to immunosuppression [58]. Infective peripheral
disease course [55–57]. neuropathies that can resemble GBS and present with acute flaccid
Other peripheral nerve disorders may mimic GBS. Vasculitic neu- paralysis include those caused by Borrelia burgdorferi (Lyme disease),
ropathies can be acute (although more frequently subacute, with HIV, pure paralytic forms of rabies, and diphtheric polyneuropathy.
onset over several weeks and progression over months) but are usually Poliovirus tends to affect the anterior horn cells of the spinal cord,
asymmetrical and multifocal (mononeuritis multiplex) whereas GBS, and poliomyelitis-­related neuronopathy occurs in unvaccinated indi-
even in its variant forms (except rare monomelic cases), is symmetri- viduals, often after a prodromal flu-­like phase with fever and myalgia
cal. In the early phase of disease, GBS pain is most commonly in the [59, 60]. Non-­polio enteroviruses, instead, typically cause diarrhoea,
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8 of 15 BELLANTI and RINALDI

F I G U R E 4 Differential diagnosis of Guillain-­Barré syndrome. CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; CNS,
central nervous system; LEMS, Lambert–Eaton myasthenic syndrome; MOGAD, myelin oligodendrocyte glycoprotein antibody-­associated
disease.

fever and general malaise followed, 1 or 2 weeks later, in around 20% Neuromuscular junction disorders
of cases, by peripheral neuropathy [61]. HIV-­related neuropathy is
usually due to seroconversion and may mimic GBS, but CSF WCC is Myasthenia gravis (MG), the most common neuromuscular junction
typically high. HIV patients with low CD4 count and severe immuno- (NMJ) disorder, causes fatigable weakness with diurnal fluctua-
depression can develop neuropathy also from opportunistic infections, tions, preserved reflexes, and decremental response to repetitive
and responsible pathogens include CMV, EBV, herpes simplex virus, nerve stimulation on electrophysiology. Bulbar-­onset MG and MG
and varicella-­zoster virus. Rarely, HIV patients develop weakness due with positive anti-­
muscle-­
specific kinase (anti-­
MuSK) antibodies
to antiretroviral therapy or vitamin B12 deficiency [60, 62]. Poisoning may mimic the pharyngeal-­
cervical-­
brachial variant of GBS (and
with heavy metals (thallium, lead, arsenic, mercury) may cause a sub- vice versa). Lambert–Eaton myasthenic syndrome (LEMS) is often
acute or acute peripheral neuropathy mimicking GBS. In some cases, paraneoplastic, causing weakness that improves with exercise, loss
characteristic features such as upper limb weakness and wrist drop of reflexes, and incremental response to repetitive nerve stimula-
(lead) or pronounced sensory symptoms with ataxia (mercury) help the tion. Although MG, LEMS, and GBS all cause muscle weakness, di-
distinction from GBS. Similarly to GBS, peripheral neuropathy due to urnal fluctuations and exercise-­induced effects are not typical of
vitamin B1 (thiamine) deficiency may present with areflexia and pro- GBS, where reflexes are characteristically absent. Botulism, another
gressive ascending weakness, but does not cause albuminocytological NMJ disorder, presents with acute paralysis and can mimic GBS,
dissociation and does not have demyelinating features on nerve con- with distinct features including descending paralysis and mydriasis.
duction studies. Finally, acute intermittent porphyria (AIP) can cause a Organophosphate intoxication causes flaccid paralysis with a constel-
GBS-­like neuropathy which usually starts with symmetrical, proximal lation of cholinergic symptoms such as diarrhoea, increased urinary
weakness in the upper limbs, followed by involvement of the lower frequency, lacrimation, excessive sweating and salivation, with myo-
limbs. Less commonly, weakness begins distally with wrist or foot drop, sis and bradycardia.
and sensory disturbance is unusual [63]. Porphyric neuropathy can
progress rapidly to tetraparesis, respiratory failure, and death if un-
treated, and tends to follow a prodromal phase with neuropsychiatric Myelopathies
symptoms, abdominal pain, nausea, vomiting, and dysautonomia. Both
AIP-­related neuropathy and GBS have acute onset, rapid progression, Acute spinal cord disorders can mimic GBS in the first few days
and frequent autonomic disturbance; however, porphyric neuropathy following onset. Both acute transverse myelitis (inflammatory or
tends to be axonal on electrophysiology, lacks albuminocytological dis- infective) and GBS can present with acute flaccid paraparesis,
sociation on CSF, and is unresponsive to immunotherapy. sphincter disturbance with or without back pain, and reflexes
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GUILLAIN-­BARRÉ SYNDROME: A REVIEW 9 of 15

can be absent in early myelopathies. Myelin oligodendrocyte using the Medical Research Council sum score (MRC-­SS), the GBS
glycoprotein-­
associated disease (MOGAD) may present with Disability Scale (GDS), formerly known as Hughes Disability Score,
conus medullaris syndrome mimicking GBS [64], usually with the Inflammatory Rasch-­built Overall Disability Scale (I-­RODS), the
prominent sphincter disturbance at onset which is uncommon in Inflammatory Neuropathy Cause and Treatment (INCAT) disability
GBS. However, a cord disorder will have a sensory level whereas scale, and the Overall Neuropathy Limitation Scale (ONLS). Details
GBS will usually not, and MRI (and serology where appropriate) of the GBS outcome measures can be found in Appendix S1.
will aid differential diagnosis.

FLU I D B I O M A R K E R S I N G B S
Myopathies
The introduction of single molecule array technology has had a pro-
Acute muscle disorders include hypokalaemic periodic paralysis, some found impact on biomarker discovery, and there is mounting interest
forms of acute myositis secondary to viral infections, and acute col- in serum and CSF biomarkers of peripheral nerve disease. Three bio-
chicine myopathy. Hypokalaemic periodic paralysis causes recurrent markers have been shown to be potentially useful in GBS: neurofila-
episodes of flaccid paralysis, while viral myositides, like those from ment light chain (NfL), peripherin, and total tau (T-­t au).
influenza A, lead to rapid paralysis with myalgia, rhabdomyolysis, In patients with GBS, median serum levels of NfL on admission
and fever, and may be preceded by prodromal flu-­like symptoms. are significantly higher compared to age-­matched healthy controls
Unlike GBS, hypokalaemic paralysis lacks sensory deficits, sphinc- and return to physiological levels 1 year after disease onset [66].
ter disturbance and bulbar or respiratory muscle involvement. High serum NfL correlates with “axonal” neurophysiology and dis-
Rhabdomyolysis and fever are common in viral myositides but rare ease severity, and high baseline levels are associated with inability
in GBS. Acute colchicine myopathy often manifests with rapidly to run and lower I-­RODS at 1 year. NfL might be used to improve
progressive weakness preceded by diarrhoea; however, the lack of current outcome measures and prognostic models in GBS; however,
cranial nerve involvement, raised creatine kinase, and the finding of it is highly non-­specific and elevated in at least 80 peripheral and
myotonic discharges on electromyography help in differentiating it central nervous system (CNS) diseases [67].
from GBS [65]. Serum levels of peripherin, a type III intermediate filament
protein, have been shown to be significantly elevated in GBS pa-
tients with electrophysiological evidence of axonal damage [68].
Higher central nervous system disorders Peripherin can differentiate acute nodo-­p aranodal axonal injury
from slowly progressive demyelination, and discriminates cen-
Brainstem stroke may mimic GBS, especially if pontine or mesence- tral versus peripheral NfL elevations by selectively rising in GBS
phalic. Pontine strokes due to basilar artery occlusion (or dissection-­ and not in CNS disorders such as multiple sclerosis and dementia.
related subarachnoid haemorrhage or pontine compression) cause Further work is needed to determine its contribution to clinical as-
complete motor and sensory deficits affecting head, trunk, and limbs sessment of patients with GBS and its correlation with long-­term
(locked-­in syndrome), and manifest with quadriplegia, anarthria, dys- functional outcomes.
phagia, horizontal gaze palsy with or without preservation of vertical T-­tau is a microtubule-­
associated protein expressed in both
gaze, vertigo, and altered level of consciousness, typically with hy- central and peripheral axons. Plasma but not CSF levels of T-­tau
peracute onset. Patients with brainstem strokes have hypertonia and are higher in GBS compared to disease-­free and healthy controls,
hyperreflexia, unusual in peripheral neuropathy. Rhombencephalitis and plasma and CSF levels of T-­t au do not correlate [69], possibly
can resemble GBS, but patients will have neighbourhood verte- suggesting that T-­t au found in the blood of GBS patients originates
brobasilar signs, absent in GBS. Finally, Wernicke's encephalopathy from damaged distal peripheral nerve axons. No data are currently
(WE), manifesting with the triad ataxia, eye movement abnormalities available on the correlation of T-­t au with I-­RODS or other outcome
(ophthalmoplegia and/or nystagmus), and encephalopathy, can re- measures, and its potential role as a diagnostic, monitoring, or prog-
semble MFS or BBE. However, patients with MFS do not have altered nostic biomarker remains to be determined.
mental status or higher cortical dysfunction, and are areflexic. BBE
patients may develop a similar encephalopathy but, typically, have
pathologically brisk deep tendon reflexes. TR E ATM E NT

Current disease-­
m odifying therapies in GBS include IVIg and
O U TCO M E M E A S U R E S I N G B S PLEX. Corticosteroids are not recommended in GBS: intra-
venous methylprednisolone (IVMP) does not improve neuro-
Outcome measures in the inflammatory neuropathies are usu- logical outcome [70, 71] and IVMP in combination with IVIg is
ally ordinal composite measures, and sum scores are generally not beneficial [72]. Oral corticosteroids may delay recovery or
used. In GBS, disease activity and clinical disability are measured cause side effects [70, 73]. Finally, a less common treatment is
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10 of 15 BELLANTI and RINALDI

immunoabsorption (IA), which involves selectively removing IgG infusion of plasma or human albumin solution. A further group of
from the blood by passing separated plasma through an absorp- complications pertains to the vascular access, including line infec-
tion column. Although case reports and small case series suggest tion, sepsis, haematomas, venous thrombosis, and vascular damage
that IA may be safe and effective, it is expensive and not avail- [76].
able in all countries, and currently not recommended as first-­or
second-­line therapy for GBS [2].
IVIg and PLEX regimens

Whom and when to treat The usual IVIg regimen for GBS is 2 g/kg given over 5 days. This is
associated with a lower relapse (or treatment-­related fluctuation)
If patients with GBS are to be treated with disease-­modifying ther- risk compared to 2 g/kg over 2 days only [2]. Patients with severe
apy, then this should be started as early as possible within their dis- GBS and poor prognosis should receive one course of IVIg and do
ease course. IVIg and PLEX are thought to work by disrupting the not benefit from a second immunoglobulin dose, which increases
disimmune processes driving nerve damage, preventing further the risk of side effects (thromboembolic and vascular) without im-
nerve injury, and facilitating functional recovery. At nadir or dur- proving neurological outcome [77, 78]. In GBS patients who can
ing the recovery phase, when neuropathic processes have resolved, still walk unaided but are unable to run, two plasma exchanges
such treatments will no longer be of benefit. Moreover, if further within the first 2 weeks of disease onset are recommended. Four
nerve injury can be prevented before it occurs, and/or conduction to five plasma exchanges over 1 or 2 weeks, with a total exchanged
block reversed before axonal degeneration ensues, then the extent volume of 12–15 L, are recommended in patients who are still am-
of disability at nadir is likely to be reduced and the speed of recovery bulatory but have evidence of rapid deterioration (dyspnoea, bul-
increased. Trial evidence has only shown benefit with IVIg started bar, or autonomic dysfunction). There is currently no evidence for
within 2 weeks, and PLEX started within 4 weeks, of the onset of any form of combination therapy, such as PLEX after IVIg or vice
weakness. However, it is generally felt that IVIg is also likely to be ef- versa.
fective up to 4 weeks. Conversely, patients with mild disease (or pure
MFS without GBS overlap) who are destined for a benign disease
course without treatment are unlikely to benefit from such therapies PRO G N OS TI C CO N S I D E R ATI O N S
even within these timeframes and may be harmed by them. Figure 5
illustrates a decision-­making algorithm for whether and when to GBS is a treatable disease and most patients ultimately recover.
treat based on timing and clinical features. About 80% of patients will walk independently and over 50% re-
turn to their previous baseline within a year [79]. However, up to
10% of patients require several months of mechanical ventilation,
IVIg versus PLEX and more than 10% are left with severe disability. Approximately
20% of patients who become ventilator-­dependent and 3–7% of all
Head-­to-­head randomised trials directly comparing IVIg with PLEX GBS patients die [79–81], usually due to sepsis, acute respiratory
have shown no significant difference in treatment efficacy, but IVIg distress syndrome, pulmonary embolism, or cardiac arrest [82].
is less likely to be discontinued than PLEX [74]. The choice of which Negative prognostic factors include age >60 years, rapid onset of
therapy to offer is mostly based on pragmatic considerations and weakness (less than 7 days from symptom onset to hospital admis-
patient/clinician preference, and the latest guidelines do not support sion), severe weakness on admission, the need for mechanical ven-
one treatment over the other [2]. Plasma exchange is not available in tilation, preceding diarrhoea, and features of severe neuropathy on
all centres, and IVIg might be logistically easier. IVIg is generally well electrophysiology.
tolerated but may cause thromboembolism, especially in patients It should be noted that death and disability rates in GBS vary
with a previous thrombotic event [75]. PLEX is also well tolerated significantly between developed and developing countries, largely
but can cause hypotension from rapid fluid shifts, fluid overload, and because treatments like IVIg and PLEX are often unavailable.
vasovagal episodes. Such complications may be more frequent in Additionally, inadequate rehabilitation services further contribute to
GBS patients who often have labile blood pressure due to autonomic disparities in functional outcomes. Small volume plasma exchange
nervous system involvement. Clinicians should consider suspending (SVPE), the repeated removal of small volumes of plasma over several
anti-­hypertensive therapy on treatment days. Allergic or anaphylac- days via sedimentation of patient whole blood, has been evaluated
tic reactions are rare and, when occurring, usually result from the as a potential low-­cost alternative treatment [83]. Although SVPE

F I G U R E 5 Guillain-­Barré syndrome (GBS) treatment flowchart. *Modified Erasmus GBS Respiratory Insufficiency Score (mEGRIS) ≥3/
modified Erasmus GBS Outcome Score (mEGOS) ≥4. A-­CIDP, acute-­onset chronic inflammatory demyelinating polyradiculoneuropathy; AIN,
autoimmune nodopathy; IVIg, intravenous immunoglobulin; PLEX, plasma exchange.
14681331, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ene.16365 by Cochrane Mexico, Wiley Online Library on [07/06/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
|11 of 15
GUILLAIN-­BARRÉ SYNDROME: A REVIEW
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12 of 15 BELLANTI and RINALDI

appears feasible and safe, randomised control trials are needed to IgG degradation
determine its clinical efficacy.
Imlifidase is an IgG-­degrading enzyme derived from Streptococcus
pyogenes which can cleave and inactivate all four subclasses of
Prediction of respiratory insufficiency human IgG. IgG metabolising enzymes are able to block complement
activation in vitro [91] and facilitate recovery in rabbit models of
Early recognition of severe GBS is pivotal to enable prompt interven- GBS with axonal injury, where they also reduce axonal degeneration
tion. The Erasmus GBS Respiratory Insufficiency Score (EGRIS) is a [92]. In light of these findings, imlifidase is currently being evaluated
clinical model used to predict the probability of developing respira- in an open-­label, multicentre, phase II study as potential treatment
tory failure within the first week of admission in patients with GBS. for GBS.
The estimated risk is based on the presence or absence of specific
clinical features upon hospital admission [84]. The modified EGRIS
(mEGRIS), the latest version of the model, can be used to predict CO N C LU S I O N S
respiratory failure at any point during the first 2 months from dis-
ease onset, not just in the first week. On a practical level, such Guillain-­Barré syndrome is a postinfectious, immune-­mediated pe-
risk is greater in patients with rapid disease progression in the first ripheral neuropathy. As our knowledge continues to expand, its
4 weeks, bulbar palsy, and weakness of neck flexion and hip flexion. pathophysiological mechanisms remain partially understood and
These patients should be monitored closely, with a low threshold for many questions are yet to be answered. The focus of care should
admission to the intensive care unit (ICU) if required [85, 86]. remain early diagnosis and treatment, to prevent severe axonal dam-
age and minimise long-­term disability. Meanwhile, novel therapies
and neuropathy fluid biomarkers are under ongoing evaluation and
Prediction of functional outcome may improve clinical management in the foreseeable future.

The modified Erasmus GBS Outcome Score (mEGOS) predicts the AU T H O R C O N T R I B U T I O N S

probability of being unable to walk independently at 6 months [87]. Roberto Bellanti: Conceptualization; writing – original draft; writing
Three variables are included: age at onset, preceding diarrhoea – review and editing. Simon Rinaldi: Supervision; conceptualization;
(which may indicate C. jejuni infection, severe axonal damage, and writing – review and editing.
poor outcome) and severity of muscle weakness (on admission
and at day 7) measured using the MRC-­SS. The International GBS C O N F L I C T O F I N T E R E S T S TAT E M E N T
Outcome Study (IGOS) provides online tools based on mEGRIS and On behalf of all the authors, the corresponding author states that
mEGOS, to estimate respiratory and motor prognosis, respectively there are no conflicts of interest.
(https://​gbsto​ols.​erasm​usmc.​nl).
DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were cre-
P OTE NTI A L TH E R A PI E S A N D FU T U R E ated or analyzed in this study.
D I R EC TI O N S
ORCID
Complement inhibition Roberto Bellanti https://orcid.org/0000-0003-4543-0162

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