ArticlePDF AvailableLiterature Review

Guillain–Barré Syndrome—A Classical Autoimmune Disease Triggered by Infection or Vaccination

Authors:
  • Institute for Educational Leadership

Abstract and Figures

Guillain-Barré syndrome (GBS) is a rare autoimmune disorder, the incidence of which is estimated to be 0.6-4/100,000 person/year worldwide. Often, GBS occurs a few days or weeks after the patient has had symptoms of a respiratory or gastrointestinal microbial infection. The disorder is sub-acute developing over the course of hours or days up to 3 to 4 weeks. About a third of all cases of Guillain-Barré syndrome are preceded by Campylobacter jejuni infection. C. jejuni strains isolated from GBS patients have a lipooligosaccharide (LOS) with a GM1-like structure. Molecular mimicry between LOS and the peripheral nerves as a cause of GBS was demonstrated in animal models of human GBS. Following the "swine flu" virus vaccine program in the USA in 1976, an increase in incidence of GBS was observed and the calculated relative risk was 6.2. Later studies have found that influenza vaccines contained structures that can induce anti-GM1 (ganglioside) antibodies after inoculation into mice. More recent information has suggested that the occurrence of GBS after currently used influenza and other vaccines is rare. GBS involves genetic and environmental factors, may be triggered by infections or vaccinations, and predisposition can be predicted by analyzing some of these factors.
Content may be subject to copyright.
GuillainBarré SyndromeA Classical Autoimmune
Disease Triggered by Infection or Vaccination
Eitan Israeli &Nancy Agmon-Levin &Miri Blank &
Joab Chapman &Yehuda Shoenfeld
Published online: 5 October 2010
#Springer Science+Business Media, LLC 2010
Abstract GuillainBarré syndrome (GBS) is a rare auto-
immune disorder, the incidence of which is estimated to be
0.64/100,000 person/year worldwide. Often, GBS occurs a
few days or weeks after the patient has had symptoms of a
respiratory or gastrointestinal microbial infection. The
disorder is sub-acute developing over the course of hours
or days up to 3 to 4 weeks. About a third of all cases of
GuillainBarré syndrome are preceded by Campylobacter
jejuni infection. C. jejuni strains isolated from GBS patients
have a lipooligosaccharide (LOS) with a GM1-like struc-
ture. Molecular mimicry between LOS and the peripheral
nerves as a cause of GBS was demonstrated in animal
models of human GBS. Following the swine fluvirus
vaccine program in the USA in 1976, an increase in
incidence of GBS was observed and the calculated relative
risk was 6.2. Later studies have found that influenza
vaccines contained structures that can induce anti-GM1
(ganglioside) antibodies after inoculation into mice. More
recent information has suggested that the occurrence of
GBS after currently used influenza and other vaccines is
rare. GBS involves genetic and environmental factors, may
be triggered by infections or vaccinations, and predisposi-
tion can be predicted by analyzing some of these factors.
Keywords GuillainBarré syndrome .Infections .
Autoimmunity .Vaccines .C. jejuni .Influenza
Definition
GuillainBarré syndrome is a disorder in which the immune
system attacks gangliosides on the peripheral nervous
system. The first symptoms of this disorder include varying
degrees of weakness or tingling sensations in the legs. In
many instances, the weakness and abnormal sensations
spread to the arms and upper body [1]. These symptoms
can increase in intensity until the muscles fail completely
and the patient is almost totally paralyzed or there is severe
dysfunction of the autonomic nervous system. In these
cases, the disease is life-threatening and is considered a
medical emergency. Most patients, however, recover from
even the most severe cases of GuillainBarré syndrome,
although some continue to have some degree of weakness.
GuillainBarré syndrome is rare, incidence worldwide is
estimated to be 0.64/100,000 person/year [1]. Often (in
around one third of cases), GuillainBarré occurs a few
days or weeks after the patient has had symptoms of a
respiratory or gastrointestinal microbial infection. Occa-
sionally, surgery or vaccinations will trigger the syndrome.
The disorder can develop over the course of hours, days, or
it may take up to 3 to 4 weeks, and reflexes are usually lost.
E. Israeli :N. Agmon-Levin :M. Blank :Y. Shoenfeld
The Chaim Zabludowicz Center for Autoimmune Diseases,
Sheba Medical Center, Tel-Hashomer,
Tel-Aviv, Israel
N. Agmon-Levin :Y. Shoenfeld (*)
Department of Medicine B& Center for Autoimmune Diseases,
Chaim Sheba Medical Center, Tel-Hashomer,
Tel-Aviv 52621, Israel
e-mail: shoenfel@post.tau.ac.il
Y. Shoenfeld
Sackler Faculty of Medicine,
Incumbent of the Laura Schwarz-Kip Chair for Research
of Autoimmune Diseases,
Tel-Aviv University,
Tel-Aviv, Israel
J. Chapman
Department of Neurology and Sagol Center for Neurosciences,
Sheba Medical Center, Tel-Hashomer,
Tel-Aviv, Israel
Clinic Rev Allerg Immunol (2012) 42:121130
DOI 10.1007/s12016-010-8213-3
Due to slow down of signals travelling along the nerve,
nerve conduction velocity test can aid the diagnosis. The
cerebrospinal fluid contains more protein than usual, but
normal cell count, so a spinal tap is important for the
diagnosis.
Clinical Variants
Although ascending paralysis is the most common form of
spread in GBS, other variants also exist. Miller Fisher
Syndrome is a rare variant of GBS, proceeding in the
reverse order of the more common form of GBS. It usually
affects the ocular movements first and presents as oph-
thalmoplegia, ataxia, and areflexia. Anti-GQ1b (a ganglio-
side, see Possible Mechanism that can Trigger GBSin the
Discussionsection) antibodies are present in 90% of
cases but not anti-GD3 antibodies [2]. Acute motor axonal
neuropathy (AMAN) [3] also termed Chinese paralytic
syndrome is prevalent in China and Mexico. The disease
may be seasonal and recovery can be rapid. Anti-GD1a
antibodies [4] are present. Anti-GD3 antibodies are found
more frequently in AMAN. Acute motor sensory axonal
neuropathy is similar to AMAN but also affects sensory
nerves with severe axonal damage. Recovery is slow and
often incomplete [5].
GBS as an Autoimmune Disease
To establish that a disease has an autoimmune etiology,
WitebskyRose postulates that an autoimmune response be
recognized in the form of an autoantibody or cell-mediated
immunity, that the corresponding antigen be identified, and
that an analogous autoimmune response be induced in
experimental animals. Finally, the immunized animals must
develop a similar disease [6].
How does GBS match the criteria for an autoimmune
disease? Shoenfeld et al. [7] addressed this question and
concluded that four major WitebskyRose criteria [6] are
fulfilled in GBS. (1) Autoantigens (i.e., myelin constitu-
ents) evoking an autoantibody response could be demon-
strated; (2) the presence of autoantibodies has been
confirmed and several pathogenic mechanisms by which
they may exert their influence have similarly demonstrated
in vitro; (3) active immunization with myelin constituents
has been shown to cause an autoimmune phenomena
resembling human GBS; (4) an adoptive transfer of
autoantibodies and or autoreactive T cells results in nerve
demyelination, clinical signs, and laboratory findings of
GBS [8]. Additionally, GBS is commonly seen in associ-
ation with other autoimmune diseases, changes in T cells
subclasses, and change in cytokine profile [7].
Willison [9] studied the motor nerve terminal as a model
site of injury, and through combined active and passive
immunization paradigms, have developed murine neuropa-
thy phenotypes mediated by anti-ganglioside antibodies.
This has been achieved through use of glycosyltransferase
and complement regulator knock-out mice, both for cloning
anti-ganglioside antibodies and inducing disease. Through
such studies, Willison and his group have proven a
neuropathogenic role for murine anti-ganglioside antibodies
and human GBS-associated antisera and identified several
determinants that influence disease expression including (a)
the level of immunological tolerance to microbial glycans
that mimic self-gangliosides; (b) the ganglioside density in
target tissue; (c) the level of complement activation and the
neuroprotective effects of endogenous complement regu-
lators; and (d) the role of calcium influx in mediating
axonal injury.
Environmental Factors Involved in GBSInfection
and Vaccination
Infections and GBS
An infection can induce or trigger autoimmune disease via
two mechanismsantigen-specific or antigen non-specific
which can operate either independently or together. An
autoimmune disease will only arise, however, if the individual
is genetically predisposed to that particular condition. A
common explanation for how infectious agents stimulate
autoimmunity in an antigen-specific way is via molecular
mimicry. Antigenic determinants of microorganisms can thus
be recognized by the host immune system as being similar to
antigenic determinants of the host itself. Molecular mimicry
among sugar structures is common and leads to numerous
manifestations of infection-associated and antibody-mediated
neuropathies. About a third of all cases of GuillainBarré
syndrome are preceded by Campylobacter jejuni infection
[10]. This bacterium expresses a lipooligosaccharide mole-
cule that mimics various gangliosides present in high
concentrations in peripheral nerves. Numerous viruses also
collect gangliosides as they incorporate plasma membrane
from the host cell. As a result, viral infections (i.e., influenza,
parainfluenza, polio, herpes) are often associated with
GuillainBarré syndrome, and both bacterial and viral
vaccines have been linked with induction of the condition
[11].
Numerous epidemiological studies and anecdotal cases
have established an association between infections and
GuillainBarré syndrome (Table 1).
Kinnunen et al. [12] performed a retrospective analysis
of the incidence of GuillainBarré syndrome (GBS) in
Finland in 19811986. Monthly rates showed an increased
122 Clinic Rev Allerg Immunol (2012) 42:121130
incidence from baseline of GBS (8.2 per million) in March
1985, following by a few weeks of the onset of the
nationwide oral poliovirus vaccine campaign and partly
overlapping it. Analysis of the time series in depth
suggested, however, that a change point in the occurrence
of GBS had already taken place before the oral poliovirus
vaccine campaign. Widespread circulation of wild-type 3
poliovirus in the population immediately preceded the oral
poliovirus vaccine campaign and the peak occurrence of
GBS. These results demonstrate a temporal association
between poliovirus infections, caused by either wild virus
or live attenuated vaccine, and an episode of increased
occurrence of GBS.
Shoenfeld et al. [7], in a comprehensive review about
GBS as an autoimmune disease, cite numerous bacterial
and viral infections associated with the disease. Among the
viruses, echo, coxsackie, varicella, mumps, rubella, influ-
enza, and HIV are documented as infections preceding
episodes of GBS. Bacterial infections preceding GBS
included Borrelia,Mycoplasma pneumoniae, and C.jejuni.
A strong association between C.jejuni infection and
GBS, with an OR of 9.5, was also demonstrated in another
study, confirming a causal association [13].
Microbiological studies carried out on 84 patients resulted
in a probable diagnosis of infectious diseases etiology in 46
(55%). Coxsackieviruses (15%), Chlamydia pneumoniae
(8%), cytomegalovirus (7%), and M. pneumoniae (7%) were
the most frequently involved agents. Serological evidence of
aC.jejuni infection was found in six patients (7%). The
authors conclude that the etiology of antecedent diseases is
distributed over a wide spectrum of pediatric infectious
diseases. Most of the children who had been vaccinated
showed concomitant infectious diseases, thus obscuring the
causative role for GBS [14].
Another strong association between GBS and influenza
infections was documented by Stowe et al. [15]. The
authors used the self-controlled case series method to
investigate the relation of GuillainBarré syndrome with
influenza vaccine and influenza-like illness using cases
recorded in the General Practice Research Database from
1990 to 2005 in the United Kingdom. The relative
incidence of GuillainBarré syndrome within 90 days of
vaccination was 0.76 (95% confidence interval, 0.411.40).
In contrast, the relative incidence of GuillainBarré
syndrome within 90 days of an influenza-like illness was
7.35 (95% confidence interval, 4.3612.38), with the
greatest relative incidence (16.64, 95% confidence interval,
9.3729.54) within 30 days. The relative incidence was
similar (0.89, 95% confidence interval, 0.421.89) when
the analysis was restricted to a subset of validated cases.
The authors found no evidence of an increased risk of
GuillainBarré syndrome after seasonal influenza vaccine.
The finding of a greatly increased risk after influenza-
like illness is consistent with anecdotal reports of a
preceding respiratory illness in GuillainBarré syndrome
and has important implications for the risk/benefit assess-
ment that would be carried out, should pandemic vaccines
be deployed in the future.
Two recent reports (2009) document association of GBS
and relatively rare viral infections: Lebrun et al. [16] report
two cases of GBS after Chikungunya virus infection in
Réunion Island, which correlated with epidemiological data
conferring the association between the two. Chikungunya
virus is an RNA alphavirus (group A arbovirus) in the
family Togaviridae. Aedes aegypti and Aedes albopictus are
the known mosquito vectors. Anti-Chikungunya IgM was
found in serum and CSF, although genomic products in
serum and CSF were negative, which was not surprising,
given the brief period (45 days) of viremia. These findings
strongly supported a disseminated acute Chikungunya
infection and support the conclusion that Chikungunya
virus was probably responsible for the GBS. In 2006,
Table 1 Infectious agents associated with GBS
Infectious agent Year Incidence per 10
6
Time post
infection
Reference
Chikungunya virus 2009 Up 22% from
baseline (3.3)
23 weeks [16]
Influenza 19902005 7.3 90 days [15]
16.6 30 days
RI
Coxsackieviruses; Chlamydia CMV; M.pneumoniae;C.jejuni Prospective ? 6 weeks [14]
Echo/Coxackie; varicela; mumps; rubella; influenza; HIV; Borrelia;M.
pneumoniae;C.jejuni
90? Weeks [7]
C.jejuni 2003 9.5 OR ? [13]
Polio (circulating type 3) 19811986 Increase from
(8.2) baseline
Weeks [12]
Hepatitis E 2009 1 case Weeks [17]
Clinic Rev Allerg Immunol (2012) 42:121130 123
Chikungunya virus was found on Réunion Island; seropre-
valence on the island was estimated to be 38.2% among
785,000 inhabitants (95% confidence interval 35.9%
40.6%).
Epidemiologic data also support a causal relationship
between Chikungunya infection and GBS: The incidence
rate of GBS increased 22% in 2006 (26/787,000, persons)
over the rate in 2005 (21/775,000 or 2.7/10,000 persons)
and then declined to a rate closer to baseline in 2007 (23/
800,000 or 2.87/100,000 persons).
Loly et al. [17] report a case of GuillainBarré syndrome
in a patient sporadically contaminated in a Western
country. This is the third report of GBS in a patient with
hepatitis E, and the first occurring in a patient sporadically
contaminated in a Western country. The authors believe it
is the first description of the presence of anti-ganglioside
GM2 antibodies in GBS associated with a hepatotropic
virus, suggesting possible molecular mimicry involving
gangliosides.
In all the above reports, the time between the infection
disease and the onset of GBS was a few weeks, ranging
from 2 to 3 weeks to 3 months. This time period is in
agreement with a temporal association between an environ-
mental trigger and the onset of an autoimmune disease.
Adding the high odds ratio of association calculated for
some of these infections, (OR = 9.5 for C.jejuni) and
augmentation of the relative incidence following infection,
(RI=7.316.6 for influenza), the conclusion is quite
obvious, that these bacterial and viral infections, as well
as others are strong environmental agents involved with the
onset of GBS.
Most infectious agents, such as viruses, bacteria and
parasites, can induce autoimmunity via a number of
mechanisms. In many cases, it is not a single infection
but rather the burden of infectionsfrom childhood that is
responsible for the induction of autoimmunity in adulthood,
many years after the original infection [18].
Vaccinations and GBS
There are anecdotal reports of GBS occurring in a time
frame after immunizations that can indicate a temporal
association between the two events. The period between
vaccination and first symptoms of GBS, range from as short
as 35 days, to 610 weeks, and up to a few months and
even years (Table 2). The temporal association and lack of
infections in those individual cases can indicate a causal
association [1923]. However, in the epidemiological
studies cited, no significant causal association was found.
Incidence observed for GBS following the vaccinations was
either small,in the expected range, same as back-
ground,extremely rare, or lower then baseline. Only
two studies with polio vaccination found an increase
incidence from a background of 8.2:10
6
and an OR of
7.27 (10, 11).
Influenza Vaccination
Following the swine flu) influenza A/New Jersey) virus
vaccine program in the USA in 1976, an increase in
incidence of GBS was observed [24](Table3). The
National Influenza Immunization Program was suspended
on December 16, 1976 and nationwide surveillance for
GBS was begun. This surveillance uncovered a total of
1,098 patients with onset of GBS from October 1, 1976, to
January 31, 1977, from all50 states. A total of 532 patients
had received an A/New Jersey influenza vaccination prior
to their onset of GBS (vaccinated cases), and 15 patients
received a vaccination after their onset of GBS. Epidemi-
ologic evidence indicated that many cases of GBS were
related to vaccination. When compared to the unvaccinated
population, the vaccinated population had a significantly
elevated attack rate in every adult age group. The estimated
attributable risk of vaccine-related GBS in the adult
population was just under one case per 100,000 vaccina-
tions. The period of increased risk was concentrated
primarily within the 5-week period after vaccination,
although it lasted for approximately 9 or 10 weeks. The
mean interval from vaccination to onset was 3.9 weeks. The
incidence rose from 2.6:10
6
for nonrecipients to 13.3:10
6
for vaccine recipients (corrected later by Breman and
Hayner [25] to be 11.7:10
6
), and the calculated relative
risk was 6.2. More recent information suggested that the
occurrence of GBS after currently used influenza and other
vaccines is extremely rare [26]. Case control studies have
shown no evidence of a significant increase in risk of
having received an immunization preceding GBS (i.e.,
measles, mumps, rubella) compared with contemporary
controls [2729].
Retrospective examination of the incidence of GBS for
the seasons of the 19923 and 19934 influenza vaccina-
tion programs in the USA suggested that influenza
vaccination only caused 12 extra cases of GBS per million
vaccines [30]. The calculated relative risk in different
studies from 1978 to 2005 produced RR values ranging
from 0.4 to 1.7. Only one study documenting the years
19911999 came up with higher RR values (4.38.5),
which may establish a significant causal association
between the influenza vaccination program and incidence
of GBS. Despite this evidence, GBS is an autoimmune
condition and the knowledge that immunizations are
designed to activate the immune system give rise to
continued unease about immunization following the disease
[31,32]. This unease is enhanced by a report of two cases
of GBS recurring following swine influenza vaccine [33].
In addition, recurrent attacks of chronic inflammatory
124 Clinic Rev Allerg Immunol (2012) 42:121130
demyelinating polyradiculoneuropathy have followed teta-
nus toxoid immunization [31,34]. However, many patients
have received immunizations after the acute phase of their
disease, sometimes repeatedly [35], without suffering a
relapse. The number of such patients has, however, not
been monitored and the actual risk is not known. In the
absence of adequate evidence and the difficulty of
conducting an adequately powered randomized trial, it
would be appropriate to audit a recovered GBS patient
population to discover the proportion receiving immuniza-
tions and the corresponding outcome. Although the
experiment has never been done in GBS, patients with
multiple sclerosis have been randomized to receive or not
receive influenza vaccine, and no evidence emerged to
suggest that immunization stimulated relapse [36,37].
There are structural differences between nodes in the
central nervous system (CNS) and peripheral one (PNS)
that might explain the susceptibility of the PNS in GBS
[38]. In the PNS, specialized microvilli project from the
outer collar of Schwann cells and come very close to nodal
axolemma of large fibers. The projections of the Schwann
cells are perpendicular to the node and are radiating from
the central axons. However, in the CNS, one or more of the
astrocytic processes come in close vicinity of the nodes.
These processes may stem from multi-functional astrocytes,
as opposed to from a population of astrocytes dedicated to
contacting the node. On the other hand, in the PNS, the
basal lamina that surrounds the Schwann cells is continuous
across the node.
Discussion
An etiology for the 1976 increase in incidence of GBS
following the influenza vaccination program was suggested
by Nachamkin et al. [39]. The authors hypothesized that the
Table 2 Correlation between vaccinations and GBS
Vaccine Year Incidence Time post vaccination Reference
Hepatitis B 2004 1 case 10 weeks [73]
HBV 19832002 19 cases 3 days9 months [73]
Measles; rubella 2003 Under baseline 610 weeks [74]
Live measles and rubella 1976 2 cases 1 week [75]
Meningococcal MCV4 20052006 Small 6 weeks [76]
Smallpox 20022004 Expected range 12 days [77]
Hepatitis A 2004 1 case 5 days [78]
Polio 2003 7.27 OR ? [13]
19811986 Increase from baseline 10 weeks [12]
Sabine strain 1996 38 cases Sabine strain isolated daysweeks of onset [79]
MMR 19821986 Background 80 daysyears [80]
Tetanus 90Extremely rare 6 weeks [81]
Tetanus-diphtheria 1997 1 case 4 days [19]
H influenza type B 1993 1 case (+4) 10 days [20]
Rabies (Semple vaccine) 905 cases ? [82]
(Diploid human cells) 1980 1 case 14 days [83]
Vaccination years/country Relative risk Significance Reference
1976/USA 6.2 Yes [84]
19781979 USA 1.4 No [85]
19801981 USA 1.4 No [86]
19761977 USA Attrib. risk 1:100,000 Yes [24]
19921994 England/Wales 1.7 No [29,31]
19911999 USA 4.38.5 Yes [87]
19931994 1.7 No [88]
20022003 USA 0.4
19922004 Canada 1.45 Small [89]
19902005/UK 0.76 No [15]
Table 3 Causal correlation
between influenza vaccination
and GBS
Clinic Rev Allerg Immunol (2012) 42:121130 125
swine flu vaccine contained contaminating moieties (such
as C.jejuni antigens that mimic human gangliosides or
other vaccine components) that elicited an anti-GM1
antibody response in susceptible recipients. Surviving
samples of monovalent and bivalent 1976 vaccine, com-
prising those from 3 manufacturers and 11 lot numbers,
along with several contemporary vaccines were tested for
hemagglutinin (HA) activity, the presence of Campylobac-
ter DNA, and the ability to induce anti-Campylobacter and
anti-GM1 antibodies after inoculation into C3H/HeN mice.
The researchers found that, although C.jejuni was not
detected in 1976 swine flu vaccines, these vaccines induced
anti-GM1 antibodies in mice, as did vaccines from 1991 to
1992 and from 2004 to 2005. Preliminary studies suggest
that the influenza HA induces anti-GM1 antibodies. The
authors concluded that influenza vaccines contain structures
that can induce anti-GM1 antibodies after inoculation into
mice.
Possible Mechanism that can Trigger GBS
Molecular mimicry is one mechanism by which infectious
agents may trigger an immune response against autoan-
tigens. Although several examples of molecular mimicry
between microbial and self-components are known [40], in
most cases, the epidemiological relationship between
autoimmune disease and microbial infection has not been
established. In other cases, moreover, no replicas of human
autoimmune disease have been obtained by immunizing
with the mimic of an infectious agent. Replicas associated
with definite, epidemiological evidence of microbial infec-
tion are required to test the molecular mimicry theory of the
development of autoimmune diseases. GuillainBarre´
syndrome, the prototype of postinfectious autoimmune
diseases, ranks as the most frequent cause of acute flaccid
paralysis, and C. jejuni is the most frequent antecedent
pathogen. Epidemiological studies, which established the
relationship between GBS and antecedent C. jejuni infec-
tion, showed that one fourth to one third of GBS patients
develop the syndrome after being infected. GBS was
considered a demyelinating disease of the peripheral
nerves, but the existence of primary axonal GBShas
been confirmed and is now widely recognized. Ganglioside
GM1 is an autoantigen for IgG Abs in patients with axonal
GBS subsequent to C. jejuni enteritis. C. jejuni strains
isolated from such patients have a lipooligosaccharide
(LOS) with a GM1-like structure. To verify that molecular
mimicry between an environmental agent and the peripheral
nerves causes GBS, Yuki et al. [41] sensitized animals with
C. jejuni LOS and produced a model of human GBS,
generated anti-GM1 mAb by immunization with the LOS,
and determined the distribution of GM1 in human spinal
nerve roots. As further proof that an autoimmune reaction
causes neuromuscular disease, the authors also showed that
anti-GM1 monoclonal antibody (mAb) blocked muscle
action potentials in a musclespinal cord co-culture. On
sensitization with C. jejuni lipooligosaccharide, rabbits
developed anti-GM1 IgG antibody and flaccid limb
weakness. Paralyzed rabbits had pathological changes in
their peripheral nerves identical with those present in
GuillainBarre´ syndrome. Immunization of mice with the
lipooligosaccharide produced mouse antibodies, from
which mAb were produced, that reacted with GM1 and
bound to human peripheral nerves. The mouse mAb and
anti-GM1 IgG from patients with GuillainBarre´ syn-
drome did not induce paralysis but blocked muscle action
potentials in a musclespinal cord co-culture, indicating
that anti-GM1 antibody can cause muscle weakness[41].
New tests were developed recently, for better detection
of antiganglioside-specific antibodies and antiganglioside
complexes [42]. The antibody specifically recognizes a
new conformational epitope formed by two gangliosides
(ganglioside complex) in the acute-phase sera of some
GBS patients. In particular, the antibodies against GD1a/
GD1b and/or GD1b/GT1b complexes are associated with
severe GBS requiring artificial ventilation. Some patients
with Miller Fisher syndrome also have antibodies against
ganglioside complexes including GQ1b; such as GQ1b/
GM1 and GQ1b/GD1a. The antibodies against ganglioside
complexes may therefore directly cause nerve conduction
failure and severe disability in GBS.
C.jejuni infection also often precedes acute motor
axonal neuropathy (AMAN), a variant of GBS. Anti-
GM1, anti-GM1b, anti-GD1a, and anti-GalNAc-GD1a
IgG antibodies are associated with AMAN. Carbohydrate
mimicry (Galbeta13GalNAcbeta14(NeuAcalpha23)Gal-
beta1) was seen between the lipooligosaccharide of C.
jejuni isolated from an AMAN patient and human GM1
ganglioside. Sensitization with the lipooligosaccharide of
C.jejuni induces AMAN in rabbits as does sensitization
with GM1 ganglioside. Paralyzed rabbits have pathological
changes in their peripheral nerves identical to changes seen
in human GBS. C.jejuni infection may induce anti-
ganglioside antibodies by molecular mimicry, eliciting
AMAN. This is a verification of the causative mechanism
of molecular mimicry in an autoimmune disease. To
express ganglioside mimics, C.jejuni requires specific gene
combinations that function in sialic acid biosynthesis or
transfer. The knock-out mutants of these landmark genes of
GBS show reduced reactivity with GBS patients' sera, and
fail to induce an anti-ganglioside antibody response in
mice. These genes are crucial for the induction of neuro-
pathogenic cross-reactive antibodies [43].
Koga et al. [44] performed a comprehensive analysis of
bacterial risk factors for the development of GBS after C.
jejuni enteritis. C.jejuni strains carry a sialyltransferase
126 Clinic Rev Allerg Immunol (2012) 42:121130
gene (cst-II), which is essential for the biosynthesis of
ganglioside-like lipooligosaccharides (LOSs). Strains of C.
jejuni from patients with GBS had LOS biosynthesis locus
class A more frequently (72/106; 68%) than did strains
from patients with enteritis (17/103; 17%). Class A strains
predominantly were serotype HS:19 and had the cstII
(Thr51) genotype; the latter is responsible for biosynthesis
of GM1-like and GD1a-like LOSs. Both anti-GM1 and
anti-GD1a monoclonal antibodies regularly bound to class
A LOSs, whereas no or either antibody bound to other LOS
locus classes. Mass-spectrometric analysis showed that a
class A strain carried GD1a-like LOS as well as GM1-like
LOS. Logistic regression analysis showed that serotype
HS:19 and the class A locus were predictive of the
development of GBS. The high frequency of the class A
locus in GBS-associated strains, which was recently
reported in Europe, provided the first GBS-related C. jejuni
characteristic that is common to strains from Asia and
Europe. The class A locus and serotype HS:19 seem to be
linked to cstII polymorphism, resulting in promotion of
both GM1-like and GD1a-like structure synthesis on LOS
and, consequently, an increase in the risk of producing
antiganglioside autoantibodies and developing GBS. The
sialyltransferase gene polymorphism may also direct the
clinical features of GBS.
The C.jejuni sialyltransferase (cst-II) consists of 291
amino acids, and the 51st determines its enzymatic activity.
Strains with cst-II (Thr51) expressed GM1-like and GD1a-
like LOS, whereas strains with cst-II (Asn51) expressed
GT1a-like and GD1c-like LOS. Patients infected with the
cst-II (Thr51) strains had anti-GM1 or anti-GD1a IgG
antibodies, and showed limb weakness. Patients infected
with the cst-II (Asn51) strains had anti-GQ1b IgG anti-
bodies and showed ophthalmoplegia and ataxia. The cst-II
gene is responsible for the development of GuillainBarré
and Fisher syndromes, and the polymorphism (Thr/Asn51)
determines which syndrome develops after C.jejuni
enteritis [45].
The Role of the Nodes of Ranvier
Vucic et al. [1] reviewed the role of sodium channels in the
pathology of GBS. Specifically, the rapid improvement in
clinical deficits following immunomodulatory treatment
(such as IVIG) [46], often within hours, cannot be
explained by axonal remyelination, but possibly by removal
of antibodies or other circulating factors that may interfere
with Na
+
channel function. Inactivation of Na
+
channels
results in a conduction block and slowing of conduction
velocity. In GBS patients, Na
+
channel blocking factors
have been demonstrated in the CSF. GM1 gangliosides,
immunological targets in GBS, are localized to the nodes of
Ranvier where sodium and other targets are clustered. By
using binding assay of cholera and tetanus toxins, respec-
tively, it was established [47] that GM1 and G1b-series
gangliosides are predominantly localized to axonal and glial
structures of the nodes of Ranvier and to paranodal/
internodal axolemma, while polysialogangliosides not of
the G1b-series are present on the internodal Schwann cell
surface. Shavit and colleagues [48] have demonstrated also
a conduction block using protease-activated receptor 1
(PAR-1) on the nodes of Ranvier, implicating this structure
and PAR-1 activation in the pathogenesis of conduction
block in inflammatory and thrombotic nerve diseases. An
immune response to this structure may induce conduction
block which is one of the electrophysiological hallmarks of
GBS.
As mentioned above, antecedent infections, particularly
infections with C.jejuni, are associated with production of
IgG antibodies against gangliosides, especially GQ1b.
GQ1b gangliosides are abundantly expressed in the para-
nodal myelin sheets of extraoculomotor nerves, the neuro-
muscular junction, and dorsal root ganglia. Anti-GQ1b IgG
antibodies are strongly associated with Fisher syndrome
and correlate with clinical features of ophthalmoplegia and
ataxia. The neurological effects of anti-GQ1b antibodies are
induced by complement-mediated destruction of both
perisynaptic Schwann cells and axonal terminals, resulting
in neuromuscular junction blockade. Patch clamp techni-
ques have shown that anti-GQ1b antibodies inhibit presyn-
aptic Ca2
+
inflow and interact with proteins of the
exocytotic apparatus, thereby interfering with neurotrans-
mitter release, which prevents activation of postsynaptic
neurons and ultimately results in muscle weakness.
Conclusion
Judging by the evidence presented here, the etiology of
GBS can be multifactorial, as in other autoimmune
diseases. It involves genetic and environmental factors,
may be triggered by infections or vaccinations, and
predisposition can be predicted by analyzing some of these
factors. Shoenfeld et al., in a series of three enlightening
reviews, depict the Mosaic of Autoimmunity. The authors
present the multifactorial character of autoimmune diseases,
including GBS, and concentrate on genetic factors, hor-
monal and environmental ones, and focus also on predic-
tion and therapy of these disorders [4951]. GBS is unique
in the aspect that it can be triggered both by infection (C.
jejuni) or vaccination (influenza, polio), and in this respect,
it can serve as a model for the linkage between exposure to
environmental agents and autoimmune diseases. Many
other autoimmune diseases may be triggered by infections
and/or vaccinations, the pathologic mechanism may involve
molecular mimicry, and they can be treated by IVIG [52
Clinic Rev Allerg Immunol (2012) 42:121130 127
71]. However, GBS is still a classical example of an
autoimmune disease triggered by either infection or
vaccination.
The Global Advisory Committee on Vaccine safety
considers that investigation of a possible causal relationship
could best be achieved by large-scale studies of the
incidence of GBS before and after an immunization
program. All incident cases would need to be carefully
ascertained and documented to ensure as accurate a
diagnosis as possible and to identify the form of GBS
(principally AIDP or AMAN). Improved understanding of
the pathogenesis of all forms of GBS will assist the
investigation of possible associations between GBS and
immunization. In this context, the collection of serum
samples from incident cases of GBS would contribute to
the identification of the different forms of the disease and of
understanding their possible relationship with vaccines.
Such studies would be particularly helpful in investigating
neurological adverse events following immunization that
occur in association with pandemic or prepandemic
influenza vaccines [72]. On August 31, 2009, the Centers
for Disease Control and Prevention (CDC) and the
American Academy of Neurology (AAN) started a cam-
paign, requesting neurologists to report any possible new
cases of GuillainBarré syndrome (GBS) following 2009
H1N1 flu vaccination using the CDC and U. S. Food and
Drug Administration Vaccine Adverse Event Reporting
System. Although they do not anticipate that the 2009
H1N1 vaccine will have an increased risk of GBS, out of an
abundance of caution, and given that GBS may be of
greater concern with any pandemic vaccine because of the
association of GBS with the 1976 swine flu vaccine, the
CDC and AAN asked neurologists to report any potential
new cases of GBS after-vaccination as part of the CDC's
national vaccine safety monitoring campaign (http://www.
aan.com/press/?fuseaction=release.view&release=757).
This campaign is now in progress.
Competing interests Y. Shoenfeld declares an association with the
following organizations: the US National Vaccine Injury Compensa-
tion Program. The other authors declare no competing interests.
References
1. Vucic S, Kiernan MC, Cornblath DR (2009) GuillainBarre
syndrome: an update. J Clin Neurosci 16:733741
2. Hughes RA, Cornblath DR (2005) GuillainBarre syndrome.
Lancet 366:16531666
3. McKhann GM, Cornblath DR, Ho T, Li CY, Bai AY, Wu HS et al
(1991) Clinical and electrophysiological aspects of acute paralytic
disease of children and young adults in northern China. Lancet
338:593597
4. Ho TW, Mishu B, Li CY, Gao CY, Cornblath DR, Griffin JW et al
(1995) GuillainBarre syndrome in northern China. Relationship
to Campylobacter jejuni infection and anti-glycolipid antibodies.
Brain 118(Pt 3):597605
5. Griffin JW, Li CY, Ho TW, Xue P, Macko C, Gao CY et al (1995)
GuillainBarre syndrome in northern China. The spectrum of
neuropathological changes in clinically defined cases. Brain 118
(Pt 3):577595
6. Rose NR, Bona C (1993) Defining criteria for autoimmune
diseases (Witebsky's postulates revisited). Immunol Today
14:426430
7. Shoenfeld Y, George J, Peter JB (1996) GuillainBarre as an
autoimmune disease. Int Arch Allergy Immunol 109:318326
8. Shoenfeld Y, Cervera R, Gershwin ME (2008) Diagnostic criteria
in autoimmune diseases. Humana, Totowa
9. Willison HJ (2005) The immunobiology of GuillainBarre
syndromes. J Peripher Nerv Syst 10:94112
10. Gruenewald R, Ropper AH, Lior H, Chan J, Lee R, Molinaro VS
(1991) Serologic evidence of Campylobacter jejuni/coli enteritis
in patients with GuillainBarre syndrome. Arch Neurol 48:1080
1082
11. Melnick SC, Flewett TH (1964) Role of infection in the Guillain
Barre syndrome. J Neurol Neurosurg Psychiatry 27:395407
12. Kinnunen E, Junttila O, Haukka J, Hovi T (1998) Nationwide oral
poliovirus vaccination campaign and the incidence of Guillain
Barre syndrome. Am J Epidemiol 147:6973
13. Liu GF, Wu ZL, Wu HS, Wang QY, Zhao-Ri GT, Wang CY et al
(2003) A casecontrol study on children with GuillainBarre
syndrome in North China. Biomed Environ Sci 16:105111
14. Schessl J, Luther B, Kirschner J, Mauff G, Korinthenberg R
(2006) Infections and vaccinations preceding childhood Guillain
Barre syndrome: a prospective study. Eur J Pediatr 165:605612
15. Stowe J, Andrews N, Wise L, Miller E (2009) Investigation of the
temporal association of GuillainBarre syndrome with influenza
vaccine and influenzalike illness using the United Kingdom
general practice research database. Am J Epidemiol 169:382388
16. Lebrun G, Chadda K, Reboux AH, Martinet O, Gauzere BA
(2009) GuillainBarre syndrome after chikungunya infection.
Emerg Infect Dis 15:495496
17. Loly JP, Rikir E, Seivert M, Legros E, Defrance P, Belaiche J et al
(2009) GuillainBarre syndrome following hepatitis E. World J
Gastroenterol 15:16451647
18. Kivity S, Agmon-Levin N, Blank M, Shoenfeld Y (2009)
Infections and autoimmunityfriends or foes? Trends Immunol
30:409414
19. Bakshi R, Graves MC (1997) GuillainBarre syndrome after
combined tetanus-diphtheria toxoid vaccination. J Neurol Sci
147:201202
20. Gervaix A, Caflisch M, Suter S, Haenggeli CA (1993) Guillain
Barre syndrome following immunisation with Haemophilus
influenzae type b conjugate vaccine. Eur J Pediatr 152:613614
21. Gross TP, Hayes SW (1991) Haemophilus conjugate vaccine and
GuillainBarre syndrome. J Pediatr 118:161
22. Holliday PL, Bauer RB (1983) Polyradiculoneuritis secondary to
immunization with tetanus and diphtheria toxoids. Arch Neurol
40:5657
23. Morris K, Rylance G (1994) GuillainBarre syndrome after
measles, mumps, and rubella vaccine. Lancet 343:60
24. Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, Keenlyside
RA, Ziegler DW, Retailliau HF et al (1979) GuillainBarre
syndrome following vaccination in the National Influenza Immu-
nization Program, United States, 19761977. Am J Epidemiol
110:105123
25. Breman JG, Hayner NS (1984) GuillainBarre syndrome and its
relationship to swine influenza vaccination in Michigan, 1976
1977. Am J Epidemiol 119:880889
128 Clinic Rev Allerg Immunol (2012) 42:121130
26. Fenichel GM (1999) Assessment: neurologic risk of immuniza-
tion: report of the therapeutics and technology assessment
subcommittee of the American Academy of Neurology. Neurol-
ogy 52:15461552
27. Winer JB, Hughes RA, Anderson MJ, Jones DM, Kangro H,
Watkins RP (1988) A prospective study of acute idiopathic
neuropathy. II. Antecedent events. J Neurol Neurosurg Psychiatry
51:613618
28. Rees J, Hughes R (1994) GuillainBarre syndrome after measles,
mumps, and rubella vaccine. Lancet 343:733
29. Hughes R, Rees J, Smeeton N, Winer J (1996) Vaccines and
GuillainBarre syndrome. Bmj 312:14751476
30. Lasky T, Terracciano GJ, Magder L, Koski CL, Ballesteros M,
Nash D et al (1998) The GuillainBarre syndrome and the 1992
1993 and 19931994 influenza vaccines. N Engl J Med
339:17971802
31. Hughes RA, Choudhary PP, Osborn M, Rees JH, Sanders EA
(1996) Immunization and risk of relapse of GuillainBarre
syndrome or chronic inflammatory demyelinating polyradiculo-
neuropathy. Muscle Nerve 19:12301231
32. Ropper AH, Victor M (1998) Influenza vaccination and the
GuillainBarre syndrome. N Engl J Med 339:18451846
33. Seyal M, Ziegler DK, Couch JR (1978) Recurrent GuillainBarre
syndrome following influenza vaccine. Neurology 28:725726
34. Pollard JD, Selby G (1978) Relapsing neuropathy due to tetanus
toxoid. Report of a case. J Neurol Sci 37:113125
35. Wijdicks EF, Fletcher DD, Lawn ND (2000) Influenza vaccine
and the risk of relapse of GuillainBarre syndrome. Neurology
55:452453
36. Myers LW, Ellison GW, Lucia M, Novom S (1976) Swine-
influenza vaccination in multiple sclerosis. N Engl J Med
295:1204
37. Miller AE, Morgante LA, Buchwald LY, Nutile SM, Coyle PK,
Krupp LB et al (1997) A multicenter, randomized, double-blind,
placebo-controlled trial of influenza immunization in multiple
sclerosis. Neurology 48:312314
38. Salzer JL (1997) Clustering sodium channels at the node of
Ranvier: close encounters of the axon-glia kind. Neuron 18:843
846
39. Nachamkin I, Shadomy SV, Moran AP, Cox N, Fitzgerald C, Ung
H et al (2008) Anti-ganglioside antibody induction by swine (A/
NJ/1976/H1N1) and other influenza vaccines: insights into
vaccine-associated GuillainBarre syndrome. J Infect Dis
198:226233
40. Agmon-Levin N, Blank M, Paz Z, Shoenfeld Y (2009) Molecular
mimicry in systemic lupus erythematosus. Lupus 18:11811185
41. Yuki N, Susuki K, Koga M, Nishimoto Y, Odaka M, Hirata K et al
(2004) Carbohydrate mimicry between human ganglioside GM1
and Campylobacter jejuni lipooligosaccharide causes Guillain
Barre syndrome. Proc Natl Acad Sci USA 101:1140411409
42. Kusunoki S, Kaida K, Ueda M (2008) Antibodies against
gangliosides and ganglioside complexes in GuillainBarre syn-
drome: new aspects of research. Biochim Biophys Acta
1780:441444
43. Komagamine T, Yuki N (2006) Ganglioside mimicry as a cause of
GuillainBarre syndrome. CNS Neurol Disord Drug Targets
5:391400
44. Koga M, Gilbert M, Takahashi M, Li J, Koike S, Hirata K et al
(2006) Comprehensive analysis of bacterial risk factors for the
development of GuillainBarre syndrome after Campylobacter
jejuni enteritis. J Infect Dis 193:547555
45. Yuki N (2007) Campylobacter sialyltransferase gene polymor-
phism directs clinical features of GuillainBarre syndrome. J
Neurochem 103(Suppl 1):150158
46. Kivity SKU, Daniel N, Nussinovitch U, Papageorgiou N, Shoe-
nfeld Y (2009) Evidence for the use of intravenous immunoglo-
bulinsa review of the literature. Clin Rev Allergy Immunol
38:201269
47. Ganser AL, Kirschner DA (1984) Differential expression of
gangliosides on the surfaces of myelinated nerve fibers. J
Neurosci Res 12:245255
48. Shavit E, Beilin O, Korczyn AD, Sylantiev C, Aronovich R,
Drory VE et al (2008) Thrombin receptor PAR-1 on myelin at the
node of Ranvier: a new anatomy and physiology of conduction
block. Brain 131:11131122
49. Shoenfeld Y, Blank M, Abu-Shakra M, Amital H, Barzilai O,
Berkun Y et al (2008) The mosaic of autoimmunity: prediction,
autoantibodies, and therapy in autoimmune diseases2008. Isr
Med Assoc J 10:1319
50. Shoenfeld Y, Gilburd B, Abu-Shakra M, Amital H, Barzilai O,
Berkun Y et al (2008) The mosaic of autoimmunity: genetic
factors involved in autoimmune diseases2008. Isr Med Assoc J
10:37
51. Shoenfeld Y, Zandman-Goddard G, Stojanovich L, Cutolo M,
Amital H, Levy Y et al (2008) The mosaic of autoimmunity:
hormonal and environmental factors involved in autoimmune
diseases2008. Isr Med Assoc J 10:812
52. Blank M, Gershwin ME (2008) Autoimmunity: from the mosaic
to the kaleidoscope. J Autoimmun 30:14
53. Frazer IH (2008) Autoimmunity and persistent viral infection: two
sides of the same coin? J Autoimmun 31:216218
54. Katzav A, Ben-Ziv T, Chapman J, Blank M, Reichlin M,
Shoenfeld Y (2008) Anti-P ribosomal antibodies induce defect
in smell capability in a model of CNS-SLE (depression). J
Autoimmun 31:393398
55. Ortega-Hernandez OD, Agmon-Levin N, Blank M, Asherson RA,
Shoenfeld Y (2009) The physiopathology of the catastrophic
antiphospholipid (Asherson's) syndrome: compelling evidence. J
Autoimmun 32:16
56. Ryan KR, Patel SD, Stephens LA, Anderton SM (2007) Death,
adaptation and regulation: the three pillars of immune tolerance
restrict the risk of autoimmune disease caused by molecular
mimicry. J Autoimmun 29:262271
57. Shoenfeld Y, Selmi C, Zimlichman E, Gershwin ME (2008) The
autoimmunologist: geoepidemiology, a new center of gravity, and
prime time for autoimmunity. J Autoimmun 31:325330
58. Song F, Wardrop RM, Gienapp IE, Stuckman SS, Meyer AL,
Shawler T et al (2008) The Peyer's patch is a critical immunoreg-
ulatory site for mucosal tolerance in experimental autoimmune
encephalomylelitis (EAE). J Autoimmun 30:230237
59. Ceribelli A, Cavazzana I, Cattaneo R, Franceschini F (2008)
Hepatitis Cvirus infection and primary Sjogren's syndrome: a
clinical and serologic description of 9 patients. Autoimmun Rev
8:9294
60. Conti F, Rezai S, Valesini G (2008) Vaccination and autoimmune
rheumatic diseases. Autoimmun Rev 8:124128
61. Doria A, Canova M, Tonon M, Zen M, Rampudda E, Bassi N et al
(2008) Infections as triggers and complications of systemic lupus
erythematosus. Autoimmun Rev 8:2428
62. Doria A, Sarzi-Puttini P, Shoenfeld Y (2008) Infections, rheuma-
tism and autoimmunity: the conflicting relationship between
humans and their environment. Autoimmun Rev 8:14
63. Doria A, Zampieri S, Sarzi-Puttini P (2008) Exploring the
complex relationships between infections and autoimmunity.
Autoimmun Rev 8:8991
64. Lunardi C, Tinazzi E, Bason C, Dolcino M, Corrocher R, Puccetti
A (2008) Human parvovirus B19 infection and autoimmunity.
Autoimmun Rev 8:116120
65. Nancy AL, Shoenfeld Y (2008) Chronic fatigue syndrome with
autoantibodiesthe result of an augmented adjuvant effect of
hepatitis-B vaccine and silicone implant. Autoimmun Rev 8:52
55
Clinic Rev Allerg Immunol (2012) 42:121130 129
66. Orbach H, Shoenfeld Y (2007) Vaccination infection and
autoimmunity: myth and reality VIAMR 2005-10-26-28, Beau-
Rivage Palace Hotel, Lausanne, Switzerland. Autoimmun Rev
6:261266
67. Plot L, Amital H (2009) Infectious associations of Celiac disease.
Autoimmun Rev 8:316319
68. Poole BD, Templeton AK, Guthridge JM, Brown EJ, Harley JB,
James JA (2009) Aberrant EpsteinBarr viral infection in systemic
lupus erythematosus. Autoimmun Rev 8:337342
69. Seite JF, Shoenfeld Y, Youinou P, Hillion S (2008) What is the
contents of the magic draft IVIg? Autoimmun Rev 7:435439
70. Toplak N, Kveder T, Trampus-Bakija A, Subelj V, Cucnik S,
Avcin T (2008) Autoimmune response following annual influenza
vaccination in 92 apparently healthy adults. Autoimmun Rev
8:134138
71. Tozzoli R, Barzilai O, Ram M, Villalta D, Bizzaro N, Sherer Y et
al (2008) Infections and autoimmune thyroid diseases: parallel
detection of antibodies against pathogens with proteomic technol-
ogy. Autoimmun Rev 8:112115
72. Global Advisory Committee on Vaccine Safety, 1213 December
2007 (2008) Wkly Epidemiol Rec. 83, 3744
73. Khamaisi M, Shoenfeld Y, Orbach H (2004) GuillainBarre
syndrome following hepatitis B vaccination. Clin Exp Rheumatol
22:767770
74. Esteghamati A, Gouya MM, Keshtkar AA, Mahoney F (2008)
Relationship between occurrence of GuillainBarre syndrome and
mass campaign of measles and rubella immunization in Iranian 5
14 years old children. Vaccine 26:50585061
75. Grose C, Spigland I (1976) GuillainBarre syndrome following
administration of live measles vaccine. Am J Med 60:441443
76. Centers for Disease Control and Prevention (CDC) (2006)
Update: GuillainBarre syndrome among recipients of Menactra
meningococcal conjugate vaccineUnited States, June 2005
September 2006. MMWR Morb Mortal Wkly Rep 55:1120
1124
77. Sejvar JJ, Labutta RJ, Chapman LE, Grabenstein JD, Iskander J,
Lane JM (2005) Neurologic adverse events associated with
smallpox vaccination in the United States, 20022004. Jama
294:27442750
78. Blumenthal D, Prais D, Bron-Harlev E, Amir J (2004) Possible
association of GuillainBarre syndrome and hepatitis A vaccina-
tion. Pediatr Infect Dis J 23:586588
79. Friedrich F, Filippis AM, Schatzmayr HG (1996) Temporal
association between the isolation of Sabin-related poliovirus
vaccine strains and the GuillainBarre syndrome. Rev Inst Med
Trop São Paulo 38:5558
80. Patja A, Paunio M, Kinnunen E, Junttila O, Hovi T, Peltola H
(2001) Risk of GuillainBarre syndrome after measlesmumps
rubella vaccination. J Pediatr 138:250254
81. Tuttle J, Chen RT, Rantala H, Cherry JD, Rhodes PH, Hadler S
(1997) The risk of GuillainBarre syndrome after tetanus-toxoid-
containing vaccines in adults and children in the United States.
Am J Public Health 87:20452048
82. Chaleomchan W, Hemachudha T, Sakulramrung R, Deesomchok
U (1990) Anticardiolipin antibodies in patients with rabies
vaccination induced neurological complications and other neuro-
logical diseases. J Neurol Sci 96:143151
83. Boe E, Nyland H (1980) GuillainBarre syndrome after vaccina-
tion with human diploid cell rabies vaccine. Scand J Infect Dis
12:231232
84. Marks JS, Halpin TJ (1980) GuillainBarre syndrome in recipi-
ents of A/New Jersey influenza vaccine. Jama 243:24902494
85. Hurwitz ES, Schonberger LB, Nelson DB, Holman RC (1981)
GuillainBarre syndrome and the 19781979 influenza vaccine. N
Engl J Med 304:15571561
86. Kaplan JE, Katona P, Hurwitz ES, Schonberger LB (1982)
GuillainBarre syndrome in the United States, 19791980 and
19801981. Lack of an association with influenza vaccination.
Jama 248:698700
87. Geier MR, Geier DA, Zahalsky AC (2003) Influenza vaccination
and GuillainBarre syndrome small star, filled. Clin Immunol
107:116121
88. Haber P, DeStefano F, Angulo FJ, Iskander J, Shadomy SV,
Weintraub E et al (2004) GuillainBarre syndrome following
influenza vaccination. Jama 292:24782481
89. Juurlink DN, Stukel TA, Kwong J, Kopp A, McGeer A, Upshur RE
et al (2006) GuillainBarre syndrome after influenza vaccination in
adults: a population-based study. Arch Intern Med 166:22172221
130 Clinic Rev Allerg Immunol (2012) 42:121130
... The underlying causes of the GBS pathology are not yet fully understood [9,10], However, the following factors have been described as a trigger for GBS: many infections have been linked with GBS, the most common are gastrointestinal or respiratory illnesses. Up to 70% of patients have reported an antecedent illness between one and six weeks before the presentation of GBS [11], about a third of all GBS cases are preceded by Campylobacter jejuni infection [12]. ...
... In our study we include symptomatic cases of CHIKV; asymptomatic cases can be at least 47%, more than those included in this study [52]. In the studies that have used PCR to detect CHIKV infection, they have had a low number of samples to associate CHIKV and GBS [53] Our model indicates that, before 2016 there were 2.5 cases of GBS per week and, from 2016, 5.5 cases of GBS per week that do not correlate to arboviruses; this indicates that there are different etiologies of GBS, probably the most studied infection by Campylobacter jejuni infection [12] and there is evidence that GBS cases in the pediatric population in Mexico have a relationship with this bacterium [54]. ...
Article
Full-text available
The Dengue (DENV), Zika (ZIKV), and Chikungunya (CHIKV) virus infections have been linked to Guillain-Barré syndrome (GBS). GBS has an estimated lethality of 4% to 8%, even with effective treatment. Mexico is considered a hyperendemic country for DENV due to the circulation of four serotypes, and the ZIKV and CHIKV viruses have also been circulating in the country. The objective of this study was to predict the number of GBS cases in relation to the cumulative incidence of ZIKV / DENV / CHIKV in Mexico from 2014 to 2019. A six-year time series ecological study was carried out from GBS cases registered in the Acute Flaccid Paralysis (AFP) Epidemiological Surveillance System (ESS), and DENV, ZIKV and CHIKV estimated cases from cases registered in the epidemiological vector-borne diseases surveillance system. The results shows that the incidence of GBS in Mexico is positively correlated with DENV and ZIKV. For every 1,000 estimated DENV cases, 1.45 GBS cases occurred on average, and for every 1,000 estimated ZIKV cases, 1.93 GBS cases occurred on average. A negative correlation between GBS and CHIKV estimated cases was found. The increase in the incidence of GBS cases in Mexico can be predicted by observing DENV and ZIKV cases through the epidemiological surveillance systems. These results can be useful in public health by providing the opportunity to improve capacities for the prevention of arbovirus diseases and for the timely procurement of supplies for the treatment of GBS.
... To identify common GO biological processes that might be affected by COVID-19 in the thirteen diseases/disorders we classified them into three groups based on their main pathological characteristics: (i) neurological diseases of autoimmune origin (ii) NDs of non-autoimmune origin and (iii) neuropsychiatric disorders. The neurological diseases of autoimmune origin group includes MS, MG and GBS, which are diseases in which autoreactivity represents a main pathological characteristic [37][38][39], whereas the NDs of nonautoimmune origin group includes ALS, HD, PD, AD, Prion Disease and CA, in which, although autoreactivity can be found in some cases, it does not represent a main pathological characteristic. In addition, the neuropsychiatric disorders group includes BD, Neurotic Disorder and Schizophrenia. ...
Article
Full-text available
Coronavirus Disease 2019 (COVID-19) is associated with increased incidence of neurological diseases and neuropsychiatric disorders after infection, but how it contributes to their development remains under investigation. Here, we investigate the possible relationship between COVID-19 and the development of ten neurological disorders and three neuropsychiatric disorders by exploring two pathological mechanisms: (i) dysregulation of host biological processes via virus–host protein–protein interactions (PPIs), and (ii) autoreactivity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epitopes with host “self” proteins via molecular mimicry. We also identify potential genetic risk factors which in combination with SARS-CoV-2 infection might lead to disease development. Our analysis indicated that neurodegenerative diseases (NDs) have a higher number of disease-associated biological processes that can be modulated by SARS-CoV-2 via virus–host PPIs than neuropsychiatric disorders. The sequence similarity analysis indicated the presence of several matching 5-mer and/or 6-mer linear motifs between SARS-CoV-2 epitopes with autoreactive epitopes found in Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Myasthenia Gravis (MG) and Multiple Sclerosis (MS). The results include autoreactive epitopes that recognize amyloid-beta precursor protein (APP), microtubule-associated protein tau (MAPT), acetylcholine receptors, glial fibrillary acidic protein (GFAP), neurofilament light polypeptide (NfL) and major myelin proteins. Altogether, our results suggest that there might be an increased risk for the development of NDs after COVID-19 both via autoreactivity and virus–host PPIs.
... MFS is triggered as the humoral and cellular immune response cross-reacts with a shared antigenic determinant on peripheral nerves (molecular mimicry) [1]. The spectrum of these autoimmune syndromes is commonly provoked by an initial infection such as viral, bacterial, or post-vaccination [4]. Several postinfectious MFS and GBS cases are associated with COVID-19 [5]. ...
Article
Reports of COVID-19 infection detailing its symptoms and outcomes point to its effects systemically, including that of the nervous system, such as the rare Miller Fisher syndrome (MFS). In this report, we identified a 43-year-old Caribbean man who arrived in the USA with ataxia and ascending bilateral lower extremity weakness after COVID-19 infection. Before arrival, the patient was diagnosed with Guillain-Barré syndrome (GBS). He was treated with IV methylprednisolone and a round of IV immunoglobulin (IVIG); however, he showed a minimal response. Upon admission to our ED, he had severe tachypnea and flaccid symmetrical quadriparesis combined with areflexia. Moreover, he had begun to exhibit signs of multiple cranial nerve palsies, including ophthalmoplegia and facial diplegia. Additionally, his laboratory cerebrospinal fluid (CSF) analysis was grossly normal. Therefore, he was diagnosed with MFS. Furthermore, he developed acute depression and exhibited signs of mania. The patient was treated with IV methylprednisolone and the second round of a five-day course of IVIG, resulting in marked clinical improvement. This case highlights the need for a multidisciplinary care approach in patients with MFS. It also points to the possible benefit of multiple IVIG rounds in MFS patients who do not improve after the first course.
... The term GBS includes several variants: the acute inflammatory demyelinating polyradiculoneuropathy (AIDP), which is the most common and primarily expresses demyelinating features; the acute axonal motor neuropathy, less common and characterized by a worse prognosis; the acute motor-sensory axonal polyneuropathy, with both motor and sensory involvement; the Miller Fisher syndrome (MFS), consisting of ophthalmoplegia, ataxia, and areflexia; the Bickerstaff's brain stem encephalitis, which is considered a variant of the MFS and characterized by altered consciousness, paradoxical hyperreflexia, ataxia, and ophthalmoparesis; other less common presentations, include the pharyngeal-cervical-brachial motor variant, the pure facial diplegia and the pandysautonomic variant [158,159]. The pathogenesis of GBS is primarily immuno-mediated by an immune response triggered by preceding infections or vaccinations throughout a cross-reactivity involving the axonal or myelin constituents of the peripheral nerves [160]. ...
Article
Full-text available
The COVID-19 pandemic has led to unprecedented demand on the global healthcare system. Remarkably, at the end of 2021, COVID-19 vaccines received approvals for human use in several countries worldwide. Since then, a solid base for response in the fight against the virus has been placed. COVID-19 vaccines have been shown to be safe and effective drugs. Nevertheless, all kinds of vaccines may be associated with the possible appearance of neurological complications, and COVID-19 vaccines are not free from neurological side effects. Neurological complications of COVID-19 vaccination are usually mild, short-duration, and self-limiting. However, severe and unexpected post-vaccination complications are rare but possible events. They include the Guillain-Barré syndrome, facial palsy, other neuropathies, encephalitis, meningitis, myelitis, autoimmune disorders, and cerebrovascular events. The fear of severe or fatal neurological complications fed the “vaccine hesitancy” phenomenon, posing a vital communication challenge between the scientific community and public opinion. This review aims to collect and discuss the frequency, management, and outcome of reported neurological complications of COVID-19 vaccines after eighteen months of the World Health Organization’s approval of COVID-19 vaccination, providing an overview of safety and concerns related to the most potent weapon against the SARS-CoV-2.
... Because two-thirds of patients with GBS manifest flu-like syndrome caused by gastrointestinal and respiratory tract infections before 4 weeks of the onset of weakness, infection is considered a major and important trigger for GBS, particularly Campylobacter jejuni infection (1). In addition, vaccinations have been considered another trigger, although there exist controversial opinions (2). However, in the 1970s, data from Mayo Clinic and Massachusetts General Hospital first recorded 97 cases of postoperative GBS, some of these patients did not involve a history of infection or vaccination, thus, the researchers proposed surgery as a trigger for GBS (3,4). ...
Article
Full-text available
Aim To analyze clinical associations between Guillain-Barré syndrome (GBS) and trauma. Material and Methods We retrospectively reviewed the data of eight patients with post-traumatic GBS between July 2011 and December 2018 at the Second Xiangya Hospital, China, and analyzed the triggers, clinical manifestation, examination results, treatment, prognosis, and potential mechanism related to post-traumatic GBS. Results The included patients had GBS preceded by no risk factors other than trauma. Their age ranged from 15 to 60 years (the median age was 52 years), and six patients were males. The potential traumatic triggers included spinal surgery ( n = 2), high-intensity exercise ( n = 2), traumatic brain injury ( n = 1), excessive fatigue ( n = 1), ischemic stroke ( n = 1), and cardiopulmonary resuscitation ( n = 1). The major manifestation was symmetrical limb weakness and/or numbness in all patients. The diagnosis of GBS was based on the results of electromyography, albumino-cytological dissociation, or antiganglioside antibody in cerebrospinal fluid, and other diseases were excluded. Immunotherapy improved symptoms, except in one patient who died. Conclusions Trauma is a probable risk factor for GBS that is very easily overlooked, thereby leading to misdiagnosis in clinical practice. We emphasize a new concept of post-traumatic GBS to promote doctors' awareness when they meet people with weakness and sensory deficits after trauma, which benefit early diagnosis, timely treatment, and reduced mortality rate of GBS.
... Guillain Barre Syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy that occurs after viral infections and vaccinations by temporal association at a frequency of 0.6-4/100,000 person/year worldwide [1]. The most common immunization that can cause an adverse event of GBS is Influenza vaccine. ...
Article
Full-text available
Since the beginning of the COVID-19 pandemic, great hesitancies regarding the COVID-19 immunization have existed. The most striking adverse events reported include thrombosis with thrombocytopenia syndrome (TTS), myocarditis, and Guillain Barre Syndrome (GBS). Post-vaccination GBS is known since the time of Influenza vaccination, but several cases of GBS have also been reported in the current COVID-19 vaccination era. As a result, our patient with a history of GBS post-Influenza vaccination, went unvaccinated for SARS-CoV-2, due to fear of GBS re-activation. Consequently, he contracted COVID-19 pneumonitis complicated with deep venous thrombosis, requiring a prolonged hospitalization. Weighing the risks and benefits of vaccination to COVID-19 is difficult, especially for people with a previous history of GBS related to Influenza vaccination. We reviewed and analyzed the reported cases of GBS temporary related to COVID-19 vaccination to determine the safety of their administration in those with a history of GBS.
... Although the calculated relative risk was 6.2, an increase in the number of cases of multiple sclerosis was not observed (10). Later studies suggested that influenza vaccines can induce the production of antiganglioside GM1 antibodies in animal models by a molecular mimicry theory (11). It has been reported that the cumulative incidence of confirmed COVID-19 cases in MS patients is two-fold higher when the cases without PCR test in the Barcelona are included (12). ...
Article
Full-text available
Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (MOGAD) is a newly identified autoimmune demyelinating disorder that is often associated with acute disseminated encephalomyelitis and usually occurs postinfection or postvaccination. Here we report a case of MOGAD after mRNA severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. A previously healthy 68-year-old woman presented to our department with gradually worsening numbness on the right side of her face, which began 14 days after her second dose of an mRNA-1273 vaccination. The patient's brain MRI revealed a right cerebellar peduncle lesion with gadolinium enhancement, a typical finding of MOGAD. A neurological examination revealed paresthesia on her right V2 and V3 areas. Other neurological examinations were unremarkable. Laboratory workups were positive for serum MOG-IgG as assessed by live cell-based assays and the presence of oligoclonal bands in the cerebrospinal fluid (CSF). The patient's serum test results for cytoplasmic-antineutrophil cytoplasmic antibodies, perinuclear-cytoplasmic-antineutrophil cytoplasmic antibodies, GQ1b-antibodies, and aquaporin-4 antibodies (AQP4-IgG) were all negative. Tests for soluble interleukin (IL)-2 receptors in the serum, IL-6 in the CSF and skin pricks, and angiotensin converting enzyme tests were all unremarkable. The patient was diagnosed with MOGAD after receiving an mRNA SARS-CoV-2 vaccination. After two courses of intravenous methylprednisolone treatment, the patient's symptoms improved and her cerebellar peduncle lesion shrunk slightly without gadolinium enhancement. To date, there have only been two cases of monophasic MOGAD following SARS-CoV-2 vaccination, including both the ChAdOx1 nCOV-19 and mRNA-1273 vaccines, and the prognosis is generally similar to other typical MOGAD cases. Although the appearance of MOG antibodies is relatively rare in post-COVID-19–vaccine demyelinating diseases, MOGAD should be considered in patients with central nervous system (CNS) demyelinating diseases after receiving a SARS-CoV-2 vaccine.
... Laxmivandana et al., [25] reported that NPEV positivity was high in AFP cases with residual paralysis as compared to recovered cases, which matched with this study result. Meanwhile, negative results for EVs when cultured on RD cell line among AFP that explained the another causes may not be viral cases it either be Guillain-Barré Syndrome (GBS) [26], traumatic neuritis (intra muscular injection in the motor neuron lead to neuron trauma then paralysis in the injected leg) [27], hypokalemia (deficiency of the calcium in bones lead to paralysis) [28] bacterial infection (Campylobacter jejuni, Clostridium botulinum, Corynebacterium diphtheriae, Treponema pallidum,and Clostridium tetani) [29,30], or Reptiles-snake venom (Cobra, krait, mamba, Australian elapid and sea snake) [7]. ...
Article
Pathophysiologisch werden beim Guillain-Barré-Syndrom neuronale Membranlipide autoimmun zerstört. Das GBS tritt in der Regel 1–4 Wochen nach einer Infektion der Atemwege oder des Magen-Darm-Trakts auf und beginnt mit einer plötzlich einsetzenden muskulären Schwäche. Diese betrifft vor allem die unteren Extremitäten und den Beckengürtel, kann sich im weiteren Verlauf aber auch auf die oberen Extremitäten ausbreiten. Auch andere Beschwerden und Sonderformen sind möglich.
Book
According to the Autoimmune Diseases Coordinating Committee (ADCC), between 14.7 and 23.5 million people in the USA–up to eight percent of the population–are affected by autoimmune disease. Autoimmune diseases are a family of more than 100 chronic, and often disabling, illnesses that develop when underlying defects in the immune system lead the body to attack its own organs, tissues, and cells. In Diagnostic Criteria in Autoimmune Disease, the editors have gathered in a comprehensive handbook a critical review, by renowned experts, of more than 100 autoimmune diseases, divided into two main groups, namely systemic and organ-specific autoimmune diseases. A contemporary overview of these conditions with special emphasis on diagnosis is presented. Each chapter contains the essential information required by attending physicians as well as bench scientists to understand the definition of a specific autoimmune disease, the diagnostic criteria, and the treatment.
Article
Guillain-Barre syndrome (GBS) has emerged as the most frequent cause of acute flaccid paralysis worldwide. Its most frequent form, acute inflammatory demyelinating polyneuropathy (AIDP), is the prototypic acquired demyelinating disease of the peripheral nervous system. The importance of GBS in this text lies both in its own prominence as a major cause of neurologic morbidity and in the similarities and contrasts with acquired demyelinating disorders of the central nervous system. This chapter outlines the history of GBS, followed by its clinical manifestations, pathology of AIDP, pathophysiology, and molecular genetics. It is noted that GBS and multiple sclerosis (MS) represent the major immune-mediated disorders of the PNS and the CNS, respectively. The data for GBS suggests that the immunologic mechanism can involve molecular mimicry, at least in some GBS variants. Finally, in both GBS and MS, it is likely that multiple mechanisms render the axon vulnerable. These mechanisms include damage as a bystander to inflammatory disease, as a consequence of the intimate cell-cell interactions between the myelin-forming cell and axon, and possibly as the target of the immune attack.
Chapter
Dilated cardiomyopathy (DCM) is characterized by dilatation and contractile dysfunction of the myocardium. It may be secondary to various clinical conditions or idiopathic. Inhere we propose a new criteria system for diagnosis of an autoimmune DCM. The proposed criteria are based on the accumulating evidence stating that autoimmunity has a key role in some patients and, presumably, a different clinical entity. Diagnosis requires establishing the autoimmune basis of the disease following an echocardiographic diagnosis. This new proposed entity has a possible therapeutic significance, because we assume that patients with established autoimmune DCM will gain the greatest beneficial effect of immunosuppressive and immunomodulating treatment.
Article
An ongoing surveillance program was intensified during the 1979-1980 and the 1980-1981 influenza seasons to determine whether an increased risk of acquiring Guillain-Barré syndrome (GBS) within eight weeks after influenza vaccination existed for adults in the United States who received influenza vaccine, when compared with adults who had not been vaccinated recently. Five hundred twenty-eight cases of GBS with onset between Sept 1 and March 31, including seven following recent vaccination, were reported by participating neurologists in 1979-1980; 459 cases, including 12 following recent vaccination, were reported in 1980-1981. The relative risk of acquiring GBS following influenza vaccination—0.6 in 1979-1980 and 1.4 in 1980-1981—was not significantly different from 1.0 in either season. These results suggest that there was no increased risk of acquiring GBS associated with the influenza vaccines administered during these seasons and that the causative "trigger agent" in the A/New Jersey (swine) influenza vaccine administered in 1976 has not been present in subsequent influenza vaccine preparations. (JAMA 1982;248:698-700)
Article
In late 1976, when 32% of the eligible population of Ohio received the A/New Jersey influenza (swine flu) vaccine, systematic contact of neurologists was used to evaluate the possible association of Guillain-Barré syndrome (GBS) with receipt of the vaccine. The overall rate of GBS was significantly higher among vaccine recipients (13.3/10⁶) than in nonrecipients (2.6/10⁶). Peak time of onset was two to three weeks after receiving the vaccine, and cases among vaccinees were less likely to have a history of antecedent infection than were cases in unvaccinated persons. Even when the effect of one highly associated vaccine lot was removed, an elevated risk of GBS remained in vaccinees regardless of manufacturer or vaccine type (bivalent or monovalent). Systematic surveillance is needed for rare serious reactions from all vaccines. (JAMA 243:2490-2494, 1980)