REVIEW ARTICLE

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
Downloaded from http://journals.lww.com/continuum by IJFFeEaHn1cP+LajoIhrqzsRh3b4lzcoecoAEw7nG6RjtwYc1g1UXZ7zMgwDcyv1JNOyjyk7SgZ+rXmsu54SotLc1W9JvuEchDPWUBYm9sjU3E0m5e+0/NnpLcP94dZiRRUhOC+c9CVXck3eJlJwEdXUy/AhTHZZgiRjb/Zo1bAko0cdZWM/1Q== on 03/29/2021
ONLINE
CITE AS:
CONTINUUM (MINNEAP MINN)
2020;26(5, PERIPHERAL NERVE AND
MOTOR NEURON DISORDERS):
1184–1204.
Address correspondence to
Dr Kazim Sheikh, Department of
Neurology, University of
Texas-Medical School at
Houston, 6431 Fannin St,
Houston, TX 77030,
Kazim.Sheikh@uth.tmc.edu.
RELATIONSHIP DISCLOSURE:
Dr Sheikh serves on the medical
advisory board of the GBS/CIDP
Foundation International and on
T
the editorial board of Scientific
Reports. Dr Sheikh has received
personal compensation for
speaking engagements from CSL
Behring and research/grant
support from the Department of
Defense (W81XWH-18-1-0422)
and the National Institute of
Neurological Disorders and
Stroke (R21NS107961).
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Sheikh reports no disclosure.
© 2020 American Academy
of Neurology.
1184
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Guillain-Barré Syndrome
By Kazim A. Sheikh, MBBS
ABSTRACT
PURPOSE OF REVIEW: This article reviews the clinical features, diagnosis and
differential diagnosis, prognosis, pathogenesis, and current and upcoming
treatments of Guillain-Barré syndrome (GBS).
RECENT FINDINGS: GBS is an acute inflammatory neuropathic illness with
striking clinical manifestations and significant morbidity. A substantial
proportion of patients with GBS do not respond to current
immunomodulatory therapies (ie, plasma exchange and IV immunoglobulin
[IVIg]), highlighting the need for new therapies. Prognostic models that can
accurately predict functional recovery and the need for artificial
ventilation have emerged. These models are practical, and online
calculators are available for clinical use, facilitating early recognition of
patients with poor outcome and the opportunity to personalize
management decisions. Clinical and experimental studies have identified
innate immune effectors (complement, macrophage lineage cells, and
activating Fcγ receptors) as important mediators of inflammatory nerve
injury. Two complement inhibitors are undergoing clinical testing for
efficacy in GBS.
SUMMARY: GBS is the most common cause of acute flaccid paralysis in the
United States and worldwide. New treatments for GBS have not emerged
since the 1990s. Our understanding of the pathogenesis of this disorder has
progressed, particularly over the past decade; as a result, new therapeutic
agents targeting different components of the complement cascade are at
advanced stages of clinical development.
INTRODUCTION
he term Guillain-Barré syndrome (GBS) encompasses a group of
heterogeneous but related disorders of peripheral nerves that have
acute onset and almost always a monophasic course. GBS is often
postinfectious and usually paralytic, and a large body of inferred
evidence supports the autoimmune nature of the syndrome. The
two most common forms of GBS are acute inflammatory demyelinating
polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy
(AMAN). The incidence rate of GBS in the United States and Europe is
estimated to be 0.81 to 1.89 (median 1.1) cases per 100,000 person-years. The
incidence increases steadily with advancing age, and the disorder is
marginally more frequent in males than females.1 The lifetime risk of
developing GBS is 1 in 1000.
AIDP is the most common form of the disease in North America and Europe,
accounting for up to 90% of patients, whereas AMAN accounts for less than 10%.
OCTOBER 2020
The relative incidence of AMAN is much higher in Asia, South America, and
Central America.2 These variations in incidence of AIDP and AMAN may reflect
differences in the immunogenetic repertoire and infectious pressures in different
geographic regions.
Most commonly used diagnostic criteria for GBS were developed at the
behest of the National Institute of Neurological Disorders and Stroke (NINDS)
in the context of the swine flu vaccine and GBS in 1976–1977.3 These criteria
are only relevant to major/paralytic forms of GBS; they have been reaffirmed4
and remain convenient for research and clinical use. Two clinical features
are requisite for the diagnosis of paralytic GBS: progressive muscle weakness
that must occur in more than one limb with relative symmetry on both
sides of the body and areflexia, implying loss of reflexes and/or hypoactive
reflexes. Features that strongly support, cast doubt upon, or rule out the
diagnosis of GBS are summarized in TABLE 3-1. The Brighton Collaboration
set forth diagnostic criteria that provide different levels of certainty for the
standardization of case definitions to improve vaccine safety.5 A limitation
of these criteria is the inclusion of a monophasic course that becomes
evident after follow-up, which limits their use in clinical diagnosis at the time
of presentation.

CLINICAL FEATURES
The diagnosis of GBS and related syndromes remains primarily clinical. Early
recognition is crucial because diagnostic tests such as nerve conduction studies

National Institute of Neurological Disorders and Stroke Diagnostic TABLE 3-1

Criteria for Guillain-Barré Syndromea

Features Required
for Guillain-Barré Features Supportive of Features That Rule
Syndrome Diagnosis Diagnosis Features Casting Doubt on Diagnosis Out Diagnosis

Progressive muscle Progression of Marked persistent asymmetry of History of hexacarbon

weakness of more weakness for weakness abuse
than one limb 2–4 weeks

Areflexia or Symmetric involvement Persistent bladder or bowel dysfunction Acute intermittent

hyporeflexia
Mild sensory symptoms or signs
Cranial nerve involvement
Recovery begins
2–4 weeks after nadir
Autonomic dysfunction
Absence of fever
Elevated CSF protein
porphyria
Severe bladder or bowel dysfunction at
onset Recent diphtheritic
3 infection
>50 Leukocytes/mm in CSF
Poliomyelitis,
Presence of polymorphonuclear
botulism, toxic
leukocytes in CSF
neuropathy, functional
Sharp sensory level paralysis
Central nervous system signs except in
Miller Fisher syndrome-Bickerstaff
brainstem encephalitis spectrum
disorders

CSF = cerebrospinal fluid.

a
Data from Asbury AK, Cornblath DR, Ann Neurol.4

CONTINUUMJOURNAL.COM 1185

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GUILLAIN-BARRÉ SYNDROME

and CSF analysis may not be positive in the first week, and immune therapies
should be initiated as soon as possible. This section focuses on the clinical
features and diagnosis of GBS; subsequent sections discuss diagnostic testing
and therapies.
The clinical manifestations of GBS are diverse, reflecting various degrees
of injury to motor, sensory, and autonomic nerve fibers along the spinal roots
and cranial and peripheral nerves. The majority of patients with AIDP present
with sensory symptoms or pain (eg, backache, radicular painful paresthesia);
however, findings on sensory examination are less frequent. Although the
first symptoms are often sensory, AIDP is a predominantly motor
polyradiculoneuropathy characterized by acute progressive symmetric weakness
of proximal and distal muscles. The classic pattern of limb muscle weakness is
ascending, but weakness can start in proximal muscles. Rarely, the weakness can
be confined to the legs in the so-called paraparetic variant. These motor and
sensory symptoms are associated with reduced or absent deep tendon reflexes.
Approximately 25% to 30% of patients develop respiratory muscle weakness and
require mechanical ventilation.6 More than half of patients have cranial nerve
involvement, most commonly facial weakness, ophthalmoplegia, difficulty
swallowing, and altered taste. Dysautonomia of highly variable severity is seen in
the majority of patients and can manifest as reduced sinus arrhythmia, sinus
tachycardia, and other arrhythmias; labile blood pressure; orthostatic
hypotension; abnormal sweating; and pupillary abnormalities. Bladder and
bowel involvement can be seen, but if patients have severe sphincter dysfunction
at presentation, spinal cord or cauda equina disorders should be considered.
Among the axonal variants, the AMAN form of GBS is most common and is
characterized by motor findings with weakness typically beginning in the legs
but, in some patients, affecting arms or cranial muscles initially. Loss of deep
tendon reflexes corresponds to the severity of muscle weakness, likely reflecting
relative sparing of muscle afferent fibers (type Ia sensory fibers), which are
prominently affected in AIDP. A small proportion of Japanese patients with
AMAN are reported to have normal or exaggerated reflexes.7 Sensory
impairment is minimal, and autonomic involvement is less common than in
AIDP. The acute motor-sensory axonal neuropathy (AMSAN) subtype is a less
common8 and, in general, considered more severe form of axonal GBS.9 Patients
with AMSAN typically have severe involvement of sensory and motor nerve
fibers, a greater likelihood of autonomic involvement, and a poor prognosis.
Miller Fisher syndrome, the most common minor subtype of GBS, is
characterized by a triad of ophthalmoplegia, ataxia, and areflexia. Double
vision is the typical presenting symptom. In practice, facial and bulbar
weakness have been included as part of the syndrome. A significant
proportion of patients do not have the classic triad or have overlapping
features that are beyond the triad. Those who have features beyond the classic
triad have Miller Fisher syndrome–related disorder. An altered level of
consciousness or hyperreflexia with external ophthalmoplegia and ataxia
reflects central nervous system involvement indicative of Bickerstaff
brainstem encephalitis. It has been proposed that Miller Fisher syndrome–related
disorders are a clinical continuum of conditions with Bickerstaff brainstem
encephalitis on one end and Miller Fisher syndrome on the other. The inclusion
of Bickerstaff brainstem encephalitis under the rubric GBS is debated as clinically
discernible peripheral nerve involvement may not be obvious by bedside

1186 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

examination. Overlapping forms of Miller Fisher syndrome and AIDP can also KEY POINTS
be seen and are termed Miller Fisher syndrome–GBS overlap syndromes. Other
● Guillain-Barré syndrome
formes frustes of GBS include the pharyngeal-cervical-brachial variant and (GBS) encompasses a
acute autonomic neuropathy. Pure sensory neuropathies with an acute onset, spectrum of acute
a monophasic course (in the absence of systemic disorders) with either axonal neuropathic disorders, with
or demyelinating electrophysiology, or small fiber involvement may be muscle weakness being the
cardinal manifestation in the
viewed as part of the GBS spectrum.10
majority of patients. It is
GBS has a monophasic course in more than 95% of patients, and recurrence the most common cause of
has been reported in less than 5% of cases.11 About two-thirds of patients with acute flaccid paralysis in
GBS have an antecedent respiratory or diarrheal illness in the 4 to 6 weeks before the United States and
worldwide.
the onset of neurologic symptoms. By definition, the disease nadir is reached
within 4 weeks, although two-thirds of patients reach nadir within 14 days. The ● The National Institute of
progressive phase of the disease is followed by a highly variable static period Neurological Disorders and
before the onset of recovery (FIGURE 3-1). Recovery typically begins within 2 to Stroke diagnostic criteria for
4 weeks of nadir but can be delayed up to 6 months. The majority of patients paralytic GBS are simple and
practical for routine clinical
make a complete recovery over 6 to 12 months. use; the key features of the
Residual deficits affecting activities of daily living and quality of life are not criteria include symmetric
uncommon. The most common residual features include fatigue, pain, flaccid weakness,
paresthesia, and reduced muscle strength. Serious disability includes inability decreased deep tendon
reflexes, and exclusion of
to walk independently in approximately 20% of patients. Modern intensive alternative causes.
care has significantly reduced the mortality rate of GBS, but it remains 3% to
7% in recent series.8,12 Advanced age, severity of disease, mechanical ● Although the first
ventilation, pulmonary and cardiac complications, and systemic infections symptoms of acute
inflammatory demyelinating
increase the risk of mortality. Death can occur during the acute progressive
polyradiculoneuropathy
phase or during the recovery phase. Most deaths are attributed to cardiac (AIDP) are often sensory, it is
arrest secondary to autonomic disturbance, respiratory failure or infection, or primarily a motor
pulmonary embolism. polyradiculoneuropathy
causing symmetric
weakness of proximal and
INVESTIGATIONS distal muscles. The classic
Laboratory testing for the diagnosis of GBS includes nerve conduction studies pattern is of ascending
and EMG, CSF analysis, and serologic studies, if warranted. Nerve conduction weakness, but symptoms
studies and EMG, particularly relevant for paralytic forms, provide supportive may also begin proximally.
data by confirming the involvement of peripheral spinal roots and/or nerves to ● Of patients with GBS, 25%
differentiate between axonal and demyelinating subtypes and may provide to 30% will require
intubation because of
respiratory muscle
weakness or pharyngeal
muscle weakness (airway
protection); patients should
be closely monitored for the
need of mechanical
ventilation.

● Miller Fisher syndrome,

the most common minor
subtype of GBS, is
characterized by a triad of
ophthalmoplegia, ataxia,
and areflexia.

FIGURE 3-1
Three conceptualized stages in the monophasic course of a typical patient with Guillain-
Barré syndrome.

CONTINUUMJOURNAL.COM 1187

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GUILLAIN-BARRÉ SYNDROME

prognostic information by estimating the extent and location of axonal injury. A

single study around the time of admission may not be sufficient to accurately
discriminate between axonal and demyelinating variants, and serial studies may
be necessary, which are also required for prognostic information. Although serial
nerve conduction studies and EMG are useful diagnostically, they are not always
practical; at present, the treatment of axonal and demyelinating variants is
similar, and, as discussed below, useful clinical prognostic tools are available. The
main purpose of CSF analysis is to exclude other diagnoses. The utility of
antiglycan (ganglioside) serology for the diagnosis and management of GBS is
not established and, thus, is not necessary for routine clinical care of patients
with AIDP. The presence of specific antiganglioside antibodies can support the
diagnosis of minor variants or formes frustes of GBS, but, because of the
turnaround time of the results in the United States, these studies often do not
influence treatment decisions.
Nerve conduction studies are often normal early in the disease course,
although prolonged minimal F-wave latencies (or absent responses) reflecting
involvement of proximal nerve trunks or roots is a common finding during the
first week. A sural sparing pattern, in which the sural sensory response is
preserved but the upper limb sensory responses are absent or of reduced
amplitude, is another nerve conduction study finding that can be present early in
the course of AIDP. Other nerve conduction changes peak around 2 weeks after
symptom onset in the majority of patients.13 The typical demyelinating changes
on motor nerve conductions in AIDP include prolonged distal motor latencies,
reduced motor nerve conduction velocities, prolonged F-wave latencies (or
absent responses), increased temporal dispersion, and conduction blocks at
noncompressible sites. In contrast, axonal variants of GBS show decreased
compound muscle action potential (CMAP) amplitudes in AMAN and decreased
CMAP and sensory nerve action potential (SNAP) amplitudes in AMSAN in the
absence of typical demyelinating features except conduction block. Motor nerve
conduction changes mimicking reversible conduction block without temporal
dispersion can be seen in AMAN and can be a cause of confusion in classifying

TABLE 3-2 Guillain-Barré Syndrome Disability Scale Scoresa

Score Disability

0 Healthy

1 Minor symptoms or signs of neuropathy but capable of manual work/running

2 Able to walk 10 meters or more without support of a stick (cane) but incapable
of manual work/running

3 Able to walk 10 meters with a stick (cane), appliance, or support

4 Confined to bed or chair bound

5 Requiring assisted ventilation for at least part of the day

6 Death

a
Data from Hughes RA, et al, Lancet.22

1188 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

AMAN and AIDP early in the disease course. This feature is attributed to KEY POINTS
pathologic alterations at the nodes of Ranvier and is termed reversible
● An altered level of
conduction failure. Serial nerve conduction studies may be required to accurately consciousness or
distinguish between AMAN and AIDP as improvement in the conduction block hyperreflexia with external
in AMAN is not associated with the development of abnormal temporal ophthalmoplegia and ataxia
dispersion.14 reflects central nervous
system involvement
CSF analysis characteristically shows normal cell counts and elevated protein
indicative of Bickerstaff
levels, termed albuminocytologic dissociation. This feature is seen in more than brainstem encephalitis.
80% of patients after the first week.15 Lumbar puncture after initiation of IV Miller Fisher syndrome–
immunoglobulin (IVIg) therapy can be diagnostically challenging as IVIg can related disorders are
considered a clinical
increase CSF protein and white blood cell counts. In 10% to 15% of patients, a
continuum with Bickerstaff
mild (<50 cells/mm3) increase in white blood cell count can be present.16,17 CSF brainstem encephalitis on
cell counts greater than 50 cells/mm3 should raise suspicion for Lyme disease, one end and Miller Fisher
human immunodeficiency virus (HIV), cytomegalovirus, or an infiltrative syndrome on the other.
leptomeningeal process; an increased cell count may also raise suspicion for
● Residual symptoms after
paralytic rabies (in certain clinical settings) or poliomyelitis (in certain GBS are common and
geographic locations). include fatigue, pain,
Antiglycan antibodies (mostly antigangliosides) are the most commonly paresthesia, and reduced
recognized autoimmune markers in all forms of GBS. Gangliosides are sialic muscle strength.
acid–containing glycosphingolipids enriched in peripheral nerves.
● Nerve conduction studies
Antiganglioside antibodies are complement-fixing IgG isotypes (IgG1 and IgG3). and EMG provide
GM1, GD1a, GalNAc-GD1a, and GM1b gangliosides are implicated as target confirmation of an acute
antigens in AMAN. IgG anti-GM1 and anti-GD1a antibodies can be detected in up neuropathic process and
may differentiate between
to 50% to 60% of patients with AMAN in Japanese and northern Chinese
demyelinating and axonal
populations, respectively.18,19 The frequency of anti–GalNAc-GD1a and variants of GBS. They are
anti-GM1b antibodies in motor-predominant syndromes is 10% to 15%.20 often relatively normal early
Anti-GQ1b antibodies (often cross-reactive with GT1a) occur in more than 80% in the course; serial studies
of patients with Miller Fisher syndrome, providing the strongest association are often necessary and
may be useful for
between antibodies to a specific ganglioside and a GBS subtype.20 Antiglycan prognostication.
antibodies with various specificities (mostly LM1 and GM1) also occur in up to
25% to 30% of patients with AIDP.20 Recent studies have suggested that ● Partial motor nerve
antibodies to mixtures of gangliosides and other glycolipids can be correlated conduction block without
temporal dispersion may be
with different variants of GBS, but this does not substantially increase sensitivity seen in acute motor axonal
or positive reactivity.21 Antiganglioside antigen testing for GM1, asialo-GM1, neuropathy because of
GD1b, GD1a, GalNAc-GD1a, GT1a, and GQ1b is commercially available in the reversible conduction
United States. failure at the nodes of
Ranvier. Other
demyelinating features,
PROGNOSIS such as reduced conduction
A number of factors, including age (older than 40 years), preceding diarrhea, velocity and prolonged
short interval from onset to nadir of the disease, need for mechanical ventilation, minimal F-wave or distal
motor latencies, are absent.
high-grade deficits on the GBS disability scale (TABLE 3-222), and persistently low
CMAP amplitudes, are considered poor prognostic factors. Predictability of two ● CSF analysis typically
issues is of importance: the need for mechanical ventilation acutely (during the shows albuminocytologic
admission for GBS) and the long-term functional outcome (arbitrarily defined as dissociation. A mild
at 6 or more months after GBS onset). A Dutch group has developed validated pleocytosis (<50 cells/mm3)
can be seen in up to 10% to
clinical models with relatively high accuracy to predict the need for ventilation 15% of patients with GBS. A
and long-term functional outcome, and an online calculator is available.23 The pleocytosis of greater than
Erasmus GBS Respiratory Insufficiency Score (EGRIS) is based on the severity of 50 cells/mm3 suggests an
weakness (quantified as the Medical Research Council [MRC] sum score), the alternative diagnosis.
number of days between the onset of weakness and admission, and facial or

CONTINUUMJOURNAL.COM 1189

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GUILLAIN-BARRÉ SYNDROME

bulbar weakness; it allows prediction of the need for mechanical ventilation

during the first week after admission.6 This model can be used at the time of
admission to triage patients with a high EGRIS score to an intensive care unit
setting. The Modified Erasmus GBS Outcome Score (mEGOS) is a long-term
functional outcome model that is based on three parameters: age, severity of
weakness quantified as the MRC sum score, and the presence or absence of
preceding diarrhea.24 This model can be applied at the time of admission or
1 week after admission and predicts the probability of walking independently at
1, 3, and 6 months. The severity of weakness quantified by the MRC sum score is
a common denominator in these models and is emerging as an important variable
for predicting acute and long-term prognosis. Efforts are under way to correlate
the MRC sum score and serum neurofilament light chain levels (reflecting
cumulative axonal injury) with prognosis.

PATHOLOGY
The pathology of AIDP and axonal variants of GBS is well defined. AIDP is
characterized by demyelination and multifocal perivascular and endoneurial
T-cell infiltrations with patchy involvement of spinal roots and nerve trunks
and distal nerve segments.25 In some series, a proportion of cases showed
immunopathologic changes suggestive of antibody- and complement-mediated
demyelinating nerve injury.26 Macrophages are particularly prominent at sites
of extensive myelin breakdown and contain fragments of degenerating myelin,
and macrophage-mediated myelin stripping (contact-dependent injury) is
considered a hallmark of AIDP pathology (FIGURE 3-2).27 The spectrum of
pathologic changes in AIDP supports the role of T-cell– and antibody-mediated
immune injury, but the contribution of humoral and cellular mechanisms may
substantially vary in individual cases.
The pathology of AMSAN was initially described in Canadian patients who
had severe axonal degeneration in nerve roots and distal nerves without
inflammation or demyelination.9 The pathology of AMAN was characterized in a
series of ultrastructural and immunopathologic studies in patients from northern
China (FIGURE 3-3).27,28 These studies indicated a paucity of T-cell inflammation
and evidence of antibody and complement deposition. The earliest pathologic
changes were centered on motor nodes of Ranvier and included nodal
lengthening with distortion of paranodal myelin. This change was associated
with macrophages overlying nodes of Ranvier, which extended their processes
through the Schwann cell basal lamina covering the node and apposed the
axolemma. Macrophages then extended beneath the myelin terminal loops and
entered the periaxonal space, dissecting the axon from the adaxonal Schwann cell
plasmalemma and advancing into the internodal periaxonal space, where they
typically surrounded a condensed-appearing axon. This arrangement appeared
to be stable for some time, but the axon subsequently underwent wallerianlike
degeneration (contact-dependent injury). Immunohistology showed IgG and
C3d (membrane-bound cleaved product of C3) at the nodes of Ranvier initially
and later at paranodal and internodal axolemma.28 In some cases of AMAN, nodal
changes were not associated with significant axon degeneration; this restricted
nodal injury is believed to correlate with quick recovery in patients with AMAN,
in particular, those with reversible conduction failure.
In sum, the pathology of AIDP, AMAN, and AMSAN shares endoneurial
inflammatory effectors, including components of the innate immune system

1190 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 KEY POINTS

● Prognostic models for

GBS based on clinical
parameters, including
Medical Research Council
(MRC) sum score, which are
collected as part of
standard care, can reliably
predict the need for
mechanical ventilation in the
first week and functional
outcomes at 4 weeks to
6 months after admission.

● AIDP, acute motor axonal

neuropathy, and acute
motor-sensory axonal
neuropathy share common
pathologic features,
including activation of
components of the innate
immune system such as
complement activation and
upregulation of Fc receptors
for IgG (FcγRs). These are
promising therapeutic
FIGURE 3-2
targets.
Contact-dependent macrophage-mediated demyelination in acute inflammatory
demyelinating polyradiculoneuropathy (AIDP). A, Many large foamy (phagocytic)
macrophages (m) are associated with a myelinated nerve fiber undergoing demyelination ● It is believed that GBS is
along its length. Electron micrographs showing macrophage-mediated (M) myelin stripping at triggered by environmental
early (B) and advanced (C) stages. Axons labeled as A in panels B and C. exposures in genetically
Panel A modified with permission from Hafer-Macko C, et al, Ann Neurol.26 © 1996 American Neurological susceptible hosts.
Association.
Panels B and C modified with permission from Griffin JW, et al, Brain.27 © 1995 Oxford University Press.

(complement and macrophage lineage cells) that have upregulation of activating

FcγRs,29 and macrophages that induce contact-dependent Schwann cell/myelin
(AIDP) and axon (AMAN/AMSAN) injury. Detailed pathologic characterization
of AIDP and AMAN has prompted the development of new therapeutics
targeting innate immune effectors, particularly the complement cascade.

PATHOGENESIS
GBS is considered to be an autoimmune disorder. Autoimmune conditions are
characterized by an aberrant activation of the adaptive immune response, with
T cells and B cells reacting (independently or in concert) to tissue-specific
self-antigens in the absence of any direct microbial or tumor invasion of the
affected tissue(s), in this case, peripheral nerves. The precise mechanisms for the
development of GBS remain incompletely understood. There is general consensus
that GBS is triggered by environmental agents in genetically susceptible hosts. It
is likely that a single gene does not impart susceptibility to develop GBS but
that multiple genes are needed to induce aberrant immunity, and environmental
exposures may need to occur in a particular sequence, or in tandem, to provoke
autoimmunity. The genes that impart host susceptibility to develop GBS are not
firmly established. Additionally, random correct alignment of multiple genetic

CONTINUUMJOURNAL.COM 1191

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GUILLAIN-BARRÉ SYNDROME

FIGURE 3-3
Contact-dependent macrophage-mediated nodal and axonal injury in acute motor axonal
neuropathy (AMAN). A, Teased fiber preparations showing opsonization of the nodes of
Ranvier (arrows) of motor nerve fibers with C3d (membrane bound fragment of C3
component of complement). B, Teased fiber preparations showing that many motor fibers
had macrophages (stained for HAM-56 or HLA-DR) overlying and extending processes into
the nodes of Ranvier (arrows point to nodes of Ranvier). C, Electron micrograph showing
longitudinal myelinated motor nerve fiber with condensed axon (A) and adjacent
macrophage and its processes (M) that are separating it from overlying normal appearing
myelin. D, Electron micrograph showing cross sections of two adjacent fibers with different
levels of contact-dependent macrophage-mediated axon injury. The fiber on the left shows
a condensed axon (A) surrounded by periaxonal macrophage (M), whereas the fiber on the
right shows that the axon has degenerated and the macrophage (M) remains inside a
normal-appearing myelin sheath.
Panels A and B modified with permission from Hafer-Macko C, et al, Ann Neurol.28 © 1996 American
Neurological Association.
Panels C and D modified with permission from Griffin JW, et al, Brain.27 © 1995 Oxford University Press.

and environmental risk factors must occur in a correct sequence, with relatively
short latencies, before the development of an acute autoimmune disorder such
as GBS. Alternatively, multiple exposures, including possible infectious or
noninfectious events, occurring during a critical window when individuals are
more susceptible to them, are necessary to overcome tolerance. Breakdown of
self-tolerance (the unresponsiveness of the adaptive immune system to
self-antigens) is an important variable for the development of autoimmune
disorders such as GBS. Regulatory T cells function to maintain tolerance and
suppress other immune cells, such as B cells, T cells, and dendritic cells, to prevent
autoimmune disease. In human studies, the number of regulatory cells present
during the acute phase of GBS is decreased, and these cells are increased following
treatment.30,31 Stimulation or modulation of the immune system from a triggering
event can disrupt the balance needed to maintain immunologic homeostasis,
making the host susceptible to autoimmune disease. This complex construct
provides a potential explanation for the extreme rarity with which GBS develops
in an individual after exposure to common environmental triggers.

1192 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Environmental and Other Triggers KEY POINTS
Infections of the gastrointestinal and upper respiratory tract are common triggers
● Campylobacter jejuni is
of GBS, and Campylobacter jejuni, a gram-negative rod, is the most common the most common trigger for
trigger of GBS (particularly for axonal forms), reported in 13% to 72% of patients GBS, particularly the axonal
in different series, with an overall prevalence estimated around 30%.32 C. jejuni forms, with an estimated
is one of the most common causes of bacterial gastroenteritis worldwide, but GBS prevalence of 30%.
However, the risk of GBS
is an extremely rare complication of this infection. It is estimated that less than
with C. jejuni infection is low
2 in 10,000 cases of C. jejuni infection develop GBS within a 2-month period.33 (less than 2 in 10,000).
The exact susceptibility factors of human host or attributes of C. jejuni that
determine whether GBS follows the infection are not known. Case control studies ● Noninfectious events,
have shown that upper respiratory tract infection caused by cytomegalovirus, including trauma,
vaccinations,
Epstein Barr virus, Mycoplasma pneumoniae, and Haemophilus influenzae are also immunosuppression, and
triggering events, as is nonrespiratory infection with hepatitis E. C. jejuni, M. pregnancy, may rarely
pneumoniae, and H. influenzae have been shown to express glycolipid antigens trigger GBS.
either by structural methods or by cross-reactive binding of antiglycolipid
antibodies in GBS sera. Cytomegalovirus can induce the expression of GM2
gangliosidelike antigens in cell cultures.
Recently, Zika virus, a mosquito-borne RNA flavivirus, was also identified as a
potential trigger for GBS; a French Polynesian study reported an increase in GBS
cases during a Zika virus outbreak in 2013-2014.34 Most post–Zika virus cases in
this series were AMAN, and a substantial proportion had antiglycan antibodies.
Similarly, post-Zika GBS was observed in South America during a major outbreak
in 2015-2016.35 Many patients with post-Zika GBS show a parainfectious rapid
disease onset.
In late 2019, an outbreak of illness caused by the novel coronavirus
SARS-CoV-2 was identified, and the disease was labeled COVID-19. In March
2020, the World Health Organization declared the illness a pandemic. A number
of neurologic complications have been reported in association with COVID-19
infections, and hypogeusia and hyposmia are perhaps the most common. A
number of case reports and series from China and Europe have also reported GBS
in association with COVID-19 infection, including demyelinating, axonal, and
Miller Fisher variants.36–38 CSF studies have generally shown albuminocytologic
dissociation and negative polymerase chain reaction (PCR) for COVID-19.36–38
Patients with GBS who present with fever, cough, hypogeusia, or hyposmia
should be tested for COVID-19. Moreover, there should be disease vigilance for
GBS in patients with COVID-19 infection, which could allow early initiation of
immune therapy.
Less common noninfectious triggering events for GBS include trauma,
vaccinations, immunosuppression, and pregnancy. In 1968, Arnason and Asbury39
reported a series of cases from Massachusetts General Hospital that developed
postsurgical polyneuritis after surgical trauma, and release of sequestered
peripheral nerve antigens was implicated as a trigger. A large 2018 French study
that examined the association of GBS and recent surgery using nationwide French
data concluded that GBS was moderately associated with any type of recent
surgery and more strongly associated with bone and digestive organ surgery.40
Rare sporadic cases of GBS have been described following a number of vaccines. In
1976, influenza vaccination was causatively implicated with exposure to the swine
flu vaccine, although subsequent surveillance found only one additional case of
GBS for every 1 million vaccines. The risk of developing GBS is much higher
following influenza infection than it is from vaccination.41 Patients who develop

CONTINUUMJOURNAL.COM 1193

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GUILLAIN-BARRÉ SYNDROME

their first attack of GBS within 6 to 8 weeks after any vaccination (postvaccination
cases) may be at particularly high risk and should not receive the same vaccine
again. The risk of relapse with influenza vaccination in patients who have
recovered from GBS not temporally associated with vaccination is extremely low.11
Individuals aged 65 or older and those with chronic serious disorders, including
chronic bronchitis and emphysema, are at increased risk of significant
complications from influenza and other infections, and age-appropriate
vaccinations should not be withheld unless a clear contraindication exists.

Molecular Mimicry
Antiganglioside antibodies are considered to be pathogenetically relevant to
AMAN and Miller Fisher syndrome, but the pathologic relevance of antiglycan
(except antigalactocerebroside) antibodies in AIDP is questioned because
relevant experimental data are lacking. Several lines of evidence support the
molecular mimicry hypothesis and pathogenicity of antiganglioside antibodies in
the axonal and Miller Fisher syndrome subtypes of GBS. Work over the past 3
decades has led to the hypothesis that postinfectious molecular mimicry is the
predominant pathophysiologic mechanism in GBS, particularly in Miller Fisher
syndrome and axonal variants, supported by the following key observations:

u C. jejuni enteritis is the most commonly recognized antecedent infection in GBS

u Different variants of GBS, particularly Miller Fisher syndrome and motor axonal variants,
are strongly associated with specific antiganglioside antibodies
u The lipooligosaccharides of C. jejuni isolates from patients with GBS carry relevant
gangliosidelike moieties
u Gangliosides, the purported target antigens, are enriched in nerve fibers
u Pathologic and immunopathologic studies in the axonal forms indicate antibody-mediated
axonal injury or dysfunction
u Active immunization animal studies have directly linked C. jejuni lipooligosaccharides to
the development of antiganglioside antibodies and neuropathy
u Passive transfer of antiganglioside antibodies can produce nodal and axonal injury in
experimental models that mimics the pathology seen in axonal GBS

Although the pathogenesis of AIDP is largely undetermined, evidence of

molecular mimicry exists in a small minority of patients with AIDP. A number of
patients develop GBS after M. pneumoniae infection. M. pneumoniae expresses
antigens that cross-react with galactocerebroside (GalC), a glycolipid that is
enriched in the myelin sheath of Schwann cells in peripheral nerves. These
patients have anti-GalC antibodies and commonly have the demyelinating/AIDP
form of GBS. Experimental animal studies demonstrate that immunization with
GalC and passive intraneural administration of anti-GalC antibodies produce
inflammatory demyelinating nerve pathology resembling the demyelination seen
in patients with AIDP.
Experimental and animal studies have attempted to define the immune
effectors that constitute the final common pathway of endoneurial inflammation
that mediates nerve injury in demyelinating and axonal variants in an effort to
identify therapeutic targets for drug development. That antigen specificity and
the nature of adaptive T-cell and B-cell autoimmune responses are not well
defined, particularly for AIDP. In contrast, strong evidence exists for the role

1194 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

of specific antiglycan antibodies in the pathogenesis of axonal and the Miller KEY POINTS
Fisher variants of GBS. Adaptive autoimmunity uses the powerful effector
● The risk of developing
functions of cells of the innate immune system, including monocytes/macrophages, GBS following influenza
to induce target tissue inflammation and injury in autoimmune disorders. infection is much higher than
Pathologic studies in demyelinating and axonal GBS indicate a central role for the risk of GBS following
macrophage populations (including contact-dependent injury), which are the vaccination. Patients who
develop GBS following
key components of the innate immune system and endoneurial inflammation.
influenza or any other
Recognizing all antigen-specific adaptive immune responses that initiate/orchestrate vaccine should not receive
nerve injury in autoimmune disorders such as GBS may not be necessary if the same vaccine again.
downstream innate immune effectors mediating nerve injury are identified.
Cumulatively, clinical and experimental studies have identified innate immune ● Postinfectious molecular
mimicry is the predominant
effectors that include classic complement pathway,42 macrophage-microglia pathophysiologic
lineage cells, and activating FcγRs43,44 as final common pathway(s) of mechanism in Miller Fisher
inflammatory nerve injury in GBS. syndrome and axonal
variants and in patients who
develop AIDP following
DIFFERENTIAL DIAGNOSIS AND OTHER ACUTE NEUROPATHIES Mycoplasma pneumoniae
The paralytic forms of GBS are relatively easy to recognize with a low probability infection.
of diagnostic confusion. The differential diagnosis for GBS is quite wide and
depends on the clinical subtype, patient’s age, and geographic locale. It includes ● Supportive and intensive
care remains the
central conditions such as encephalomyelitis and rhombencephalitis for Miller
cornerstone of management
Fisher syndrome–Bickerstaff brainstem encephalitis spectrum disorders. of patients with GBS during
Paralytic GBS can be confused with transverse myelitis or myelopathy early on, the acute phase of this
and clinicians should have a low threshold for spinal cord imaging. The monophasic illness, and
immune therapy with
differential diagnosis for paralytic GBS includes the following:
plasma exchange or IV
immunoglobulin (IVIg)
u Infections affecting anterior horn cells, including West Nile virus, enteroviruses (children hastens recovery.
more than adults), rabies (paralytic form), and polio (in appropriate geographic regions)
u Neuromuscular junction disorders, including myasthenic crisis and botulism (particularly
in young children)
u Acute severe myopathies, including immune-mediated necrotizing myopathies (eg, those
associated with antibodies against signal recognition particle and 3-hydroxy-3-
methylglutaryl-coenzyme A [HMG-CoA]) reductase, acute myositis, and rhabdomyolysis
u Periodic paralysis
u A number of other neuropathic and polyradiculopathic conditions that present acutely or
subacutely and can be confused with GBS (TABLE 3-3)

TREATMENT
Two immunomodulatory treatments, IVIg and plasma exchange, are used for the
treatment of GBS, but provision of multidisciplinary medical supportive care
remains the cornerstone of therapy during the acute phase to prevent
complications and facilitate recovery. All patients with GBS should be admitted
to a hospital with an intensive care unit, except for patients with very mild
disease who have reached a plateau phase or are already recovering. The
principles of GBS care include monitoring for major risks to avoid complications
arising from acute respiratory failure, dysautonomia, bulbar weakness,
progressive muscle weakness, and immobility. Close monitoring of forced vital
capacity, blood pressure, heart rate and rhythm, and bulbar function is necessary
to identify patients with deteriorating respiratory function or autonomic
instability or those at risk of aspiration who require intensive care. Close

CONTINUUMJOURNAL.COM 1195

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GUILLAIN-BARRÉ SYNDROME

monitoring of respiratory parameters and use of EGRIS should allow elective

(preemptive) intubation, which is less traumatic for patients and families and
less prone to complications. About one-third of patients require admission to an
intensive care unit. Important aspects of medical management include prevention
of nosocomial infections, prophylaxis for deep venous thrombosis, management

TABLE 3-3 Acute and Subacute Neuropathic Conditions With Features That Overlap
With Guillain-Barré Syndrome

Acute Radiculo/neuropathy Diagnostic Clues

Inflammatory/immune

Acute-onset chronic inflammatory demyelinating Progression >4 weeks or three treatment-related fluctuations in first
polyradiculoneuropathy (CIDP) 8 weeks

Vasculitic neuropathy Frequently asymmetric (can be confluent), predominantly axonal

Sensory ganglionitis Diffuse sensory loss, areflexia, pseudoathetosis, pseudoweakness (may

improve with visual compensation), posterior column degeneration on
MRI with latency of approximately 10 weeks

Intensive care unit setting

Critical illness neuropathy In the setting of sepsis or multiorgan failure, often ventilator
dependence, concomitant myopathy

Metabolic

Diabetes Frequently asymmetric (lumbosacral plexus), weight loss, history of

diabetes mellitus

Porphyria Axonal physiology, predominantly motor, psychiatric features,

abdominal pain, positive metabolic screen

Nutritional

Thiamine deficiency Often history of gastric bypass surgery, alcohol use disorder, vomiting,
acute weight loss, other B vitamins can be low, axonal

Infections

Human immunodeficiency virus (HIV) Early in infection, positive testing, CSF pleocytosis

Herpesviruses, including cytomegalovirus Often in setting of HIV, mixed myelopathic and radicular features, CSF
pleocytosis (polymorphonuclear leukocytes with cytomegalovirus),
polymerase chain reaction (PCR)

Lyme disease Radiculoneuritis, asymmetric, endemic area, tick bite, erythema

migrans, CSF pleocytosis, predominantly axonal

Toxic

Organophosphates Exposure to insecticides, occupation in plastic and petroleum

industries, axonal

Hexacarbons Occupational exposure or inhalant abuse of glues, lacquers, cleaning

solvents, axonal; secondary demyelinating changes including multifocal
motor conduction block can be seen

CSF = cerebrospinal fluid; MRI = magnetic resonance imaging.

1196 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

of bowel and bladder dysfunction, pain management, early physical therapy and KEY POINTS
rehabilitation to avoid complications of immobility (including pressure ulcers), eye
● Randomized clinical trials
care in those with severe facial weakness, and psychosocial support. indicate that IVIg and plasma
Randomized clinical trials have shown the efficacy of plasma exchange up to exchange hasten recovery in
4 weeks after the onset of symptoms and IVIg within 2 weeks after onset in patients with GBS, and both
hastening recovery.45 All trials have used the GBS disability scale (TABLE 3-2) treatments were found to be
equally efficacious.
for enrollment and as the primary outcome measure. Patients with a GBS disability
score of 3 or higher were enrolled in these clinical trials, and an improvement of 1 ● Of patients with GBS
point on this scale at 4 weeks was considered treatment responsiveness. A standard treated with IVIg or plasma
dose of plasma exchange is to exchange 200 mL/kg to 250 mL/kg in four to five exchange in clinical trials,
sessions over 7 to 14 days. The clinical trials of IVIg administered a total of 2 g/kg 40% to 50% did not have a
clinical response (ie, did not
given over 4 to 5 days, although, in practice, this dose is sometimes administered meet primary end point),
over a shorter period in selected patients. Although head-to-head comparisons emphasizing the need for
of IVIg and plasma exchange in clinical trials have shown equivalent efficacy,45 new therapies.
IVIg is considered first-line treatment because of the ease of administration and
● Randomized controlled
widespread availability. In patients whose treatment is being initiated more than data indicate that
2 weeks after onset, it may be reasonable to consider plasma exchange, as clinical combination treatment with
trials have shown efficacy of this treatment in patients enrolled up to 4 weeks plasma exchange followed
after onset. Conceptually, early treatment is preferable as it could limit by IVIg is not superior to
treatment with IVIg or
endoneurial inflammation and nerve injury; data from North American46 and
plasma exchange alone, and
French Cooperative Group47 studies support this notion as the beneficial effects of anecdotal observations
plasma exchange were most marked in patients enrolled within 1 week after onset. indicate that combination
A large proportion of patients do not show significant response to initial treatment with IVIg followed
by plasma exchange is no
immunomodulatory treatment(s) and pose a special challenge as no
better than IVIg alone.
evidence-based recommendations are currently available for this group of Combination therapy is
patients. Randomized controlled trials indicate that 40% to 50% of patients did generally discouraged.
not improve significantly after plasma exchange or IVIg treatment, defined as
improvement by 1 or more points on the GBS disability scale at 4 weeks after ● No evidence- or
consensus-based
treatment (primary outcome measure).45 Two approaches are sometimes used for recommendations are
this group of patients. One is the use of combination therapy (ie, plasma exchange available for additional
followed by IVIg or, less commonly, IVIg followed by plasma exchange). The immunomodulatory
Plasma Exchange/Sandoglobulin GBS Trial compared plasma exchange followed treatments for patients with
GBS for whom initial IVIg or
by IVIg to either modality alone and found no significant differences in treatment plasma exchange treatment
groups, indicating that combination therapy is not superior to monotherapy has failed, and further
with either modality.48 Although IVIg followed by plasma exchange is supportive medical
counterintuitive (ie, the plasma exchange removes the previously infused management should be
tailored according to
circulating immunoglobulin), this approach is sometimes attempted in patients
individual needs in such
with severe disease who do not respond to IVIg alone. A small retrospective study cases.
examined this combination therapy and found that combination therapy was
not superior to IVIg alone.49 In general, the combination of IVIg and plasma
exchange, however sequenced, is discouraged. The second approach is the use
of high-dose or a second dose of IVIg in patients for whom the first IVIg
treatment has failed. This approach carries a risk of complications, and the ISID
(International Second IVIg Dose) study, a recently published observational study,
did not show better outcomes after a second IVIg course in GBS with poor
prognosis.50 A prospective randomized single-center trial examining whether a
second course of IVIg improves outcome is ongoing, and its results are awaited.
The author’s approach in such patients is to use a single treatment modality, early
tracheostomy and percutaneous endoscopic gastrostomy (if warranted), and early
discharge to a rehabilitation or long-term acute care facility (CASE 3-1).

CONTINUUMJOURNAL.COM 1197

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GUILLAIN-BARRÉ SYNDROME

CASE 3-1 A 36-year-old woman was admitted to the hospital with Guillain-Barré
syndrome (GBS) 3 days after the onset of neurologic symptoms. At
admission, she had proximal greater than distal weakness in her legs
more than her arms, areflexia, and distal sensory loss, and her forced
vital capacity was 2.83 L. She reported preceding diarrhea.
Her motor nerve conduction studies (see grid) were notable for
prolonged right median nerve distal latency, partial motor conduction
block in the right fibular (peroneal) nerve, and prolonged F-wave
latencies. Sensory nerve conduction studies (see grid) showed
inexcitable median and ulnar nerves, reduced radial evoked sensory
nerve action potential (SNAP) amplitude, and relatively preserved sural
SNAP, a pattern recognized as sural sparing, as shown in the test results.
CSF analysis showed no white blood cells, and protein was elevated at
51 mg/dL.
She was diagnosed with the acute inflammatory demyelinating
polyradiculoneuropathy (AIDP) variant of GBS, and IV immunoglobulin
(IVIg) was administered for 5 consecutive days without any
complications. Her symptoms worsened after initiation of IVIg; she
became quadriplegic within 48 hours after admission while on IVIg
treatment, and her forced vital capacity dropped to less than 1 L,
requiring ventilatory support. No clinical improvement was seen 1 week
after completion of IVIg. Her family was extremely concerned about the
lack of responsiveness to IVIg. A number of options were considered,
including repeat electrical studies and lumbar puncture, nerve biopsy, a
second dose of IVIg, and plasma exchange. The multidisciplinary team
concluded that none of these approaches were evidence based and
decided to consider predictive modeling for GBS prognosis; they shared
this information with the patient and her family and instituted supportive
medical management. The patient’s Modified Erasmus GBS Outcome
Score (mEGOS) score was 10 at 7 days after admission, predicting a 40%
probability of walking independently at 3 months and 60% probability by
6 months.
The patient underwent tracheostomy and percutaneous endoscopic
gastrostomy and was transferred to a long-term acute care facility. Four
weeks later, the patient was on a tracheostomy collar without ventilator
support with mild recovery of proximal muscle function in the arms but
still confined to bed. Six months later, she was ambulating using a cane.

1198 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Motor Nerve Conduction

Amplitude Conduction
Latency (Normal (Normal Velocity (Normal
Nerve and Site Range) Range) Segment Distance Range)
Median (right)

Wrist 4.6 ms (<3.9 ms) 7.1 mV (>6 mV) Abductor pollicis brevis-wrist NA NA

Elbow 9.5 ms 7.0 mV Wrist-elbow 240 mm 49 m/s (>49 m/s)

Ulnar (right)

Wrist 2.9 ms (<3.1 ms) 8.4 mV (>7 mV) Abductor digiti minimi-wrist NA NA

Below elbow 7.2 ms 7.4 mV Wrist-below elbow 235 mm 55 m/s (>49 m/s)

Above elbow 9.5 ms 6.3 mV Below elbow-above elbow 120 mm 52 m/s (>49 m/s)

Fibular (peroneal) (right)

Ankle 4.4 ms (<5.5 ms) 6.8 mV (>3 mV) Extensor digitorum brevis-ankle NA NA

Fibular head 10.7 ms 5.2 mV Ankle-fibular head 320 mm 51 m/s (>39 m/s)

Popliteal fossa 13.7 ms 5.1 mV Fibular head-popliteal fossa 100 mm 33 m/s

Tibial (right)

Ankle 4.9 ms (<5.8 ms) 4.6 mV (>4 mV) Abductor hallucis-ankle NA NA

NA = not applicable.

Sensory Nerve Conduction

Nerve and Onset Peak Latency Amplitude Conduction Velocity

Site Latency (Normal Range) (Normal Range) Segment Distance (Normal Range)
Median (right)

Wrist No No response No response Digit II-wrist 130 mm NA (>49 m/s)

response (<3.4 ms) (>20 μV)

Ulnar (right)

Wrist No No response No response Digit II-wrist 110 mm NA (>49 m/s)

response (<3.1 ms) (>12 μV)

Radial (right)

Forearm 2.1 ms 2.9 ms (<2.7 ms) 8 μV (>18 μV) Snuffbox-forearm 100 mm 48 m/s (>49 m/s)

Sural (right)

Lower leg 4.1 ms 4.8 ms (<4.5 ms) 8 μV (>6 μV) Ankle-lower leg 185 mm 46 m/s (>49 m/s)

NA = not applicable.

CONTINUED ON
PAGE 1200

CONTINUUMJOURNAL.COM 1199

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GUILLAIN-BARRÉ SYNDROME

CONTINUED FROM
PAGE 1199
COMMENT A substantial proportion of patients with GBS deteriorate during or shortly
after treatment with IVIg or plasma exchange, and no evidence has shown
that combination therapy or repeat IVIg is helpful. Prognostic modeling is
practical for clinical use to make supportive management decisions in
such patients. In the past, some experts would prescribe additional IVIg
for patients who did not respond to a first dose because a study reported
that patients with large increments of serum IgG levels after standard IVIg
treatment (2 g/kg) recovered more quickly than those with smaller
increments.51 However, a second course of IVIg can be complicated by
anaphylaxis, acute kidney injury, thromboembolic events, or hemolytic
anemia. Further, the ISID (International Second IVIg Dose) study, an
observational study, did not show better outcomes after a second course
of IVIg in GBS with poor prognosis.50 It is prudent not to use a second dose
of IVIg in patients with GBS who do not respond to the first dose of IVIg
because of potential risks until evidence-based data are available to
support this treatment paradigm.

Treatment-related fluctuations, defined as worsening of at least 1 point on the

GBS disability scale after initial improvement or stabilization within 8 weeks
after disease onset,52 are another related aspect. Treatment-related fluctuations
can be seen in up to 10% of patients treated with IVIg or plasma exchange. No
evidence-based recommendations are available for patients with
treatment-related fluctuations, and general consensus is retreatment with the
original treatment modality as the preferred approach.
Although the incidence of GBS is slightly lower in children compared to
adults, the immunomodulatory treatment recommendations are similar.
Clinical trial data show that IVIg hastens total recovery.53 A total IVIg dose
of 2 g/kg can be administered over 2 days instead of a 5-day regimen with
the caveat that treatment-related fluctuations can be more common with a
shorter infusion paradigm.53 One trial compared IVIg with plasma exchange
in children requiring mechanical ventilation and found that overall
recovery was comparable, but plasma exchange was slightly superior in
shortening ventilatory support.54 Both plasma exchange and IVIg can be
used in pregnant women; however, IVIg is less likely to cause hemodynamic
instability.
Randomized controlled data do not exist for the use of immunotherapy
in minor variants of GBS, including Miller Fisher syndrome and related
disorders. Some anecdotal observations report beneficial effects of IVIg in the
treatment of minor variants. It is not unreasonable to err on the side of using
immunomodulatory treatments in patients with minor variants of GBS if the
treatment is unlikely to increase the risk of treatment-related adverse events,
because these cases reflect immune/inflammatory nerve injury, albeit restricted,
and some variants such as Miller Fisher syndrome have a propensity to spread
and involve limb muscles.

1200 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Trends KEY POINT
An urgent need exists for new immunomodulatory treatments as a substantial
● Biologics targeting the
proportion of patients with GBS do not respond to current therapies. Emerging complement cascade are at
therapies with potential for GBS include complement and neonatal Fc receptor various stages of clinical
(FcRn) inhibitors and hypersialylated IVIg. The development of these therapies trials in GBS, and neonatal
is driven by current opinion favoring the role of IgG autoantibodies and innate Fc receptor (FcRn) inhibitors
(which can reduce IgG
immune effectors such as complement and activating FcγRs. Complement autoantibody burden) and
inhibitors are already in GBS clinical trials. Eculizumab, a humanized antibody modulators of FcγR are at
against complement component C5, has been studied in a small phase 2 trial in advanced stages of clinical
Japan as an add-on therapy with IVIg.55 This treatment was found to be relatively development with potential
applicability to GBS.
safe, and significantly more patients were able to run at 6 months in the
eculizumab-treated group compared to the placebo group, which was a
secondary outcome measure.56 A phase 3 trial is anticipated with this agent.
Another complement inhibitor, a humanized antibody against the C1q
component of complement is being studied in a phase 1b trial in the United States
as an add-on therapy with IVIg.57 This trial is currently recruiting.58 FcRn
functions to protect IgG from catabolism, and antagonism of this receptor
shortens the half-life of circulating pathogenic antineural autoantibodies, which
can reduce antibody-mediated nerve injury in experimental models relevant to
GBS.59 In this context, a number of FcRn inhibitors are at advanced stages of
clinical development for various indications, including chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP),60 and a rationale exists to
extend the use of these agents to GBS. Another novel agent currently in
human safety studies61 with potential to treat GBS is hypersialylated IgG, an
investigational glyco-modified product derived from commercially available
IVIg with an approximately tenfold enhanced anti-inflammatory activity
compared to IVIg.62 Preclinical studies indicate that sialylated IgG fractions have
tenfold more efficacy than IVIg in animal models of autoantibody-mediated
neuropathy relevant to GBS.63 Hypersialyated IgG likely works via modulation of
FcγR functions.

PATIENT SUPPORT AND EDUCATION

Patients with GBS and their families may benefit from community resources
and education. The GBS/CIDP Foundation International is a nonprofit
organization with the mission to support patients with GBS, CIDP, and related
conditions and their families. They are committed to education, research,
and advocacy.

CONCLUSION
GBS is the most common acute neuropathic illness requiring hospitalization,
which presents as acute flaccid paralysis in the majority of patients. Early diagnosis
and treatment are imperative. Medical supportive care, immunomodulatory
treatments, and prognostic modeling are vital components of acute management.
The need for more potent immunomodulatory therapies still exists, and ongoing
research promises to identify new disease-modifying treatments targeting relevant
immunopathomechanisms. The need of proregenerative therapies to enhance
nerve repair, particularly for patients with severe disease, axonal injury, and
residual deficits, is unmet.

CONTINUUMJOURNAL.COM 1201

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GUILLAIN-BARRÉ SYNDROME

USEFUL WEBSITES

GBS/CIDP FOUNDATION INTERNATIONAL IGOS GBS PROGNOSIS TOOL

The GBS/CIDP Foundation International website The IGOS GBS prognosis tool can be used to
provides information about Guillain-Barré syndrome estimate the prognosis of a patient with
and chronic inflammatory demyelinating Guillain-Barré syndrome.
polyradiculoneuropathy (CIDP), support for patients gbstools.erasmusmc.nl
and their families, news about advocacy, and
volunteer opportunities.
gbs-cidp.org

ACKNOWLEDGMENTS
Dr Sheikh is supported by the US Department of Defense (W81XWH-18-1-0422)
and the National Institute of Neurological Disorders and Stroke (R21NS107961).

REFERENCES

1 Sejvar JJ, Baughman AL, Wise M, Morgan OW. 11 Kuitwaard K, Bos-Eyssen ME, Blomkwist-Markens
Population incidence of Guillain-Barré syndrome: PH, van Doorn PA. Recurrences, vaccinations and
a systematic review and meta-analysis. long-term symptoms in GBS and CIDP. J Peripher
Neuroepidemiology 2011;36(2):123–133. Nerv Syst 2009;14(4):310–315. doi:10.1111/
doi:10.1159/000324710. j.1529-8027.2009.00243.x.
2 Hughes RA, Cornblath DR. Guillain-Barré 12 van den Berg B, Bunschoten C, van Doorn PA,
syndrome. Lancet 2005;366(9497):1653–1666. Jacobs BC. Mortality in Guillain-Barré syndrome.
Neurology 2013;80(18):1650–1654. doi:10.1212/
3 Asbury AK, Arnason BG, Karp HR, McFarlin DE.
WNL.0b013e3182904fcc.
Criteria for diagnosis of Guillain-Barré syndrome.
Ann Neurol 1978;3:565–566. doi:10.1016/S0140- 13 Hadden RD, Cornblath DR, Hughes RA, et al.
6736(05)67665-9. Electrophysiological classification of
Guillain-Barré syndrome: clinical associations
4 Asbury AK, Cornblath DR. Assessment of current
and outcome. Plasma Exchange/Sandoglobulin
diagnostic criteria for Guillain-Barré syndrome.
Guillain-Barré Syndrome Trial Group. Ann Neurol
Ann Neurol 1990;27(suppl):S21–S24.
1998;44(5):780–788. doi:10.1002/ana.410440512.
doi:10.1002/ana.410270707.
14 Uncini A, Susuki K, Yuki N. Nodo-paranodopathy:
5 Sejvar JJ, Kohl KS, Gidudu J, et al. Guillain-Barré
beyond the demyelinating and axonal classification
syndrome and Fisher syndrome: case definitions
in anti-ganglioside antibody-mediated
and guidelines for collection, analysis, and
neuropathies. Clin Neurophysiol 2013;124(10):
presentation of immunization safety data.
1928–1934. doi:10.1016/j.clinph.2013.03.025.
Vaccine 2011;29(3):599–612. doi:10.1016/
j.vaccine.2010.06.003. 15 Fokke C, van den Berg B, Drenthen J, et al.
Diagnosis of Guillain-Barré syndrome and
6 Walgaard C, Lingsma HF, Ruts L, et al. Prediction
validation of Brighton criteria. Brain 2014;137(pt 1):
of respiratory insufficiency in Guillain-Barré
33–43. doi:10.1093/brain/awt285.
syndrome. Ann Neurol 2010;67(6):781–787.
doi:10.1002/ana.21976. 16 Haymaker WE, Kernohan JW. The Landry-Guillain-
Barré syndrome: a clinicopathologic report of 50
7 Yuki N, Kokobun N, Kuwabara S, et al. Guillain-
fatal cases and a critique of the literature.
Barré syndrome associated with normal or
Medicine (Baltimore);28(1):59–141.
exaggerated tendon reflexes. J Neurol 2012;
259(6):1181–1190. doi:10.1007/s00415-011-6330-4. 17 Loffel NB, Rossi LN, Mumenthaler M, et al. The
Landry-Guillain-Barré syndrome. Complications,
8 Doets AY, Verboon C, van den Berg B, et al.
prognosis and natural history in 123 cases.
Regional variation of Guillain-Barré syndrome.
J Neurol Sci 1977;33(1-2):71–79. doi:10.1016/
Brain 2018;141(10):2866–2877. doi:10.1093/brain/
0022-510x(77)90183-6.
awy232.
18 Ogawara K, Kuwabara S, Mori M, et al. Axonal
9 Feasby TE, Gilbert JJ, Brown WF, et al. An acute
Guillain-Barré syndrome: relation to anti-
axonal form of Guillain-Barré polyneuropathy.
ganglioside antibodies and Campylobacter jejuni
Brain 1986;109(pt 6):1115–1126. doi:10.1093/
infection in Japan. Ann Neurol 2000;48(4):
brain/109.6.1115.
624–631. doi:10.1002/1531-8249(200010)48:43.3.
10 Uncini A, Yuki N. Sensory Guillain-Barré syndrome CO;2-F.
and related disorders: an attempt at
systematization. Muscle Nerve 2012;45(4):
464–470. doi:10.1002/mus.22298.

1202 OCTOBER 2020

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

19 Ho TW, Willison HJ, Nachamkin I, et al. Anti-GD1a
antibody is associated with axonal but not
demyelinating forms of Guillain-Barré syndrome.
Ann Neurol 1999;45(2):168–173. doi:10.1002/
1531-8249(199902)45:2<168::aid-ana6>3.0.co;2-6.
20 Willison HJ, Yuki N. Peripheral neuropathies and
anti-glycolipid antibodies. Brain 2002;125(pt 12):
2591–1625. doi:10.1093/brain/awf272.
21 Goodfellow JA, Willison HJ. Antiganglioside,
antiganglioside-complex, and antiglycolipid-
complex antibodies in immune-mediated
neuropathies. Curr Opin Neurol 2016;29(5):
572–580. doi:10.1097/WCO.0000000000000361.
22 Hughes RA, Newsom-Davis JM, Perkin GD, Pierce
JM. Controlled trial prednisolone in acute
polyneuropathy. Lancet 1978;2(8093):750–753.
doi:10.1016/s0140-6736(78)92644-2.
23 IGOS GBS Prognosis Tool. gbstools.erasmusmc.nl.
Accessed August 3, 2020.
24 Walgaard C, Lingsma HF, Ruts L, et al. Early
recognition of poor prognosis in Guillain-Barré
syndrome. Neurology 2011;76(11):968–975.
doi:10.1212/WNL.0b013e3182104407.
25 Asbury AK, Arnason BG, Adams RD. The
inflammatory lesion in idiopathic polyneuritis. Its
role in pathogenesis. Medicine (Baltimore) 1969;
48(3):173–215. doi:10.1097/00005792-196905000-
00001.
26 Hafer-Macko C, Sheikh KA, Li CY, et al. Immune
attack on the Schwann cell surface in acute
inflammatory demyelinating polyneuropathy.
Ann Neurol 1996;39(5):625–635. doi:10.1002/
ana.410390512.
27 Griffin JW, Li CY, Ho TW, et al. Guillain-Barré
syndrome in northern China; the spectrum of
neuropathological changes in clinically defined
cases. Brain 1995;118(pt 3):577–595. doi:10.1093/
brain/118.3.577.
28 Hafer-Macko C, Hsieh ST, Li CY, et al. Acute
motor axonal neuropathy: an antibody-mediated
attack on axolemma. Ann Neurol 1996;40(4):
635–644. doi:10.1002/ana.410400414.
29 Zhang G, Bogdanova N, Gao T, et al. Fcγ
receptor-mediated inflammation inhibits axon
regeneration. PLoS One 2014;9(2):e88703.
doi:10.1371/journal.pone.0088703.
30 Chi LJ, Wang HB, Zhang Y, Wang WZ. Abnormality
of circulating CD4(+)CD25(+) regulatory T cell
in patients with Guillain-Barré syndrome.
J Neuroimmunol 2007;192(1–2):206–214.
doi:10.1016/j.jneuroim.2007.09.034.
31 Maddur MS, Rabin M, Hegde P, et al. Intravenous
immunoglobulin exerts reciprocal regulation of
Th1/Th17 cells and regulatory T cells in Guillain-
Barré syndrome patients. Immunol Res 2014;
60(2–3):320–329. doi:10.1007/s12026-014-8580-6.
32 Moran AP, Prendergast MM, Hogan EL. Sialosyl-
galactose: a common denominator of Guillain-
Barré and related disorders? J Neurol Sci 2002;
196(1–2):1–7. doi:10.1016/s0022-510x(02)00036-9.
CONTINUUMJOURNAL.COM
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
33 Tam CC, Rodrigues LC, Petersen I, et al.
Incidence of Guillain-Barré syndrome among
patients with Campylobacter infection: a general
practice research database study. J Infect Dis
2006;194(1):95–97. doi:10.1086/504294.
34 Cao-Lormeau VM, Blake A, Mons S, et al. Guillain-
Barré syndrome outbreak associated with Zika
virus infection in French Polynesia: a case-control
study. Lancet 2016;387(10027):1531–1539.
doi:10.1016/S0140-6736(16)00562-6.
35 Parra B, Lizarazo J, Jiménez-Arango JA, et al.
Guillain-Barré syndrome associated with Zika
virus infection in Colombia. N Engl J Med 2016;
375(16):1513–1523. doi:10.1056/NEJMoa1605564.
36 Zhao H, Shen D, Zhou H, et al. Guillain-Barré
syndrome associated with SARS-CoV-2
infection: causality or coincidence? Lancet
Neurol 2020;19(5):383–384. doi:10.1016/
S1474-4422(20)30109-5.
37 Goscano G, Palmerini F, Ravaglia S, et al. Guillain-
Barré syndrome associated with SARS-CoV-2.
N Engl J Med 2020;382:2574–2576. doi:10.1056/
NEJMc2009191.
38 Gutiérrez-Ortiz C, Méndez A, Rodrigo-Rey S,
et al. Miller Fisher syndrome and polyneuritis
cranialis in COVID-19. Neurology 2020.
Published online April 17, 2020. doi:10.1212/
WNL.0000000000009619.
39 Arnason BG, Asbury AK. Idiopathic polyneuritis
after surgery. Arch Neurol 1968;18(5):500–507.
doi:10.1001/archneur.1968.00470350058005.
40 Rudant J, Dupont A, Mikaeloff Y, et al. Surgery
and risk of Guillain-Barré syndrome: a French
nationwide epidemiologic study. Neurology
2018;91(13):e1220–e1227. doi:10.1212/
WNL.0000000000006246.
41 Lehmann HC, Hartung HP, Kieseier BC, Hughes
RA. Guillain-Barré syndrome after exposure to
influenza virus. Lancet Infect Dis 2010;10(9):
643–651. doi:10.1016/S1473-3099(10)70140-7.
42 Halstead SK, Zitman FM, Humphreys PD, et al.
Eculizumab prevents anti-ganglioside antibody-
mediated neuropathy in a murine model. Brain
2008;131(pt 5):1197–1208. doi:10.1093/brain/
awm316.
43 He L, Zhang G, Liu W, et al. Anti-ganglioside
antibodies induce nodal and axonal injury via Fcγ
receptor-mediated inflammation. J Neurosci
2015;35(17):6770–6785. doi:10.1523/JNEUROSCI.
4926-14.2015.
44 Zhang G, Bogdanova N, Gao T, Sheikh KA.
Elimination of activating Fcγ receptors in
spontaneous autoimmune peripheral
polyneuropathy model protects from
neuropathic disease. PLoS One 2019;14(8):
e0220250. doi:10.1371/journal.pone.0220250.
45 Hughes RA, Swan AV, van Doorn PA. Intravenous
immunoglobulin for Guillain-Barré syndrome.
Cochrane Database Syst Rev 2014;19(9):CD002063.
doi:10.1002/14651858.CD002063.pub6.
1203
GUILLAIN-BARRÉ SYNDROME
46 The Guillain-Barré Syndrome Study Group.
Plasmapheresis and acute Guillain-Barré
syndrome. Neurology 1985;35(8):1096–1104.
doi:10.1212/WNL.35.8.1096.
47 Efficiency of plasma exchange in Guillain-Barré
syndrome: role of replacement fluids. French
Cooperative Group on Plasma Exchange in
Guillain-Barré syndrome. Ann Neurol 1987;
22(6):753–761. doi:10.1002/ana.410220612.
48 Randomised trial of plasma exchange,
intravenous immunoglobulin, and combined
treatments in Guillain-Barré syndrome. Plasma
Exchange/Sandoglobulin Guillain-Barré
Syndrome Trial Group. Lancet 1997;349(9047):
225–230. doi:10.1016/S0140-6736(96)09095-2.
49 Oczko-Walker M, Manousakis G, Wang S, et al.
Plasma exchange after initial intravenous
immunoglobulin treatment in Guillain-Barré
syndrome: critical reassessment of effectiveness
and cost-efficiency. J Clin Neuromuscul Dis 2010;
12(2):55–61. doi:10.1097/CND.0b013e3181f3dbbf.
50 Verboon C, van den Berg B, Cornblath DR, et al.
Original research: second IVIg course in
Guillain-Barré syndrome with poor prognosis: the
non-randomised ISID study. J Neurol Neurosurg
Psychiatry 2020;91(2):113–121. doi:10.1136/
jnnp-2019-321496.
51 Kuitwaard K, de Gelder J, Tio-Gillen AP, et al.
Pharmacokinetics of intravenous immunoglobulin
and outcome in Guillain-Barré syndrome.
Ann Neurol 2009;66(5):597–603. doi:10.1002/
ana.21737.
52 Visser LH, van der Meché FG, Meulstee J, van
Doorn PA. Risk factors for treatment related
clinical fluctuations in Guillain-Barré syndrome.
Dutch Guillain-Barré study group. J Neurol
Neurosurg Psychiatry 1998;64(2):242–244.
doi:10.1136/jnnp.64.2.242.
53 Korinthenberg R, Schessl J, Kirschner J, Mönting
JS. Intravenously administered immunoglobulin
in the treatment of childhood Guillain-Barré
syndrome: a randomized trial. Pediatrics 2005;
116(1):8–14. doi:10.1542/peds.2004-1324.
54 El-Bayoumi MA, El-Refaey AM, Abdelkader AM,
et al. Comparison of intravenous immunoglobulin
and plasma exchange in treatment of mechanically
ventilated children with Guillain Barré syndrome:
a randomized study. Crit Care 2011;15(4):R164.
doi:10.1186/cc10305.
1204
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
55 ClinicalTrials.gov. JET-GBS—Japanese Eculizumab
Trial for GBS. clinicaltrials.gov/ct2/show/
NCT02493725?cond=02493725&draw=1&rank=1.
Accessed August 3, 2020.
56 Misawa S, Kuwabara S, Sato Y, et al. Safety and
efficacy of eculizumab in Guillain-Barré
syndrome: a multicentre, double-blind,
randomised phase 2 trial. Lancet Neurol 2018;
17(6):519–529. doi:10.1016/S1474-4422(18)30114-5.
57 Lansita JA, Mease KM, Qiu H, et al. Nonclinical
development of ANX005: a humanized anti-C1q
antibody for treatment of autoimmune and
neurodegenerative diseases. Int J Toxicol 2017;
36(6):449–462. doi:10.1177/1091581817740873.
58 ClinicalTrials.gov. A Clinical Study of ANX005
and IVIG in Subjects With Guillain Barré Syndrome
(GBS). clinicaltrials.gov/ct2/show/
NCT04035135?cond=04035135&draw=2&rank=1.
Accessed August 3, 2020.
59 Zhang G, Lin J, Ghauri S, Sheikh KA. Modulation of
IgG-FcRn interactions to overcome antibody-
mediated inhibition of nerve regeneration. Acta
Neuropathol 2017;134(2):321–324. doi:10.1007/
s00401-017-1730-x.
60 ClinicalTrials.gov. A Study to Assess Long-term
Safety, Tolerability and Efficacy of Rozanolixizumab
in Subjects With Chronic Inflammatory
Demyelinating Polyradiculoneuropathy.
clinicaltrials.gov/ct2/show/NCT04051944?
cond=NCT04051944&draw=2&rank=1. Accessed
August 3, 2020.
61 ClinicalTrials.gov. Safety and Tolerability of M254
in Healthy Volunteers and Immune
Thrombocytopenia Purpura (ITP) Patients.
clinicaltrials.gov/ct2/show/NCT03866577?
cond=NCT03866577&draw=2&rank=1. Accessed
August 3, 2020.
62 Washburn N, Schwab I, Ortiz D, et al. Controlled
tetra-Fc sialylation of IVIg results in a drug
candidate with consistent enhanced
anti-inflammatory activity. Proc Natl Acad Sci
U S A 2015;112(11):E1297–E1306. doi:10.1073/
pnas.1422481112.
63 Zhang G, Massaad CA, Gao T, et al. Sialylated
intravenous immunoglobulin suppress
anti-ganglioside antibody mediated nerve injury.
Exp Neurol 2016;282:49–55. doi:10.1016/
j.expneurol.2016.05.020.
OCTOBER 2020