The spectrum of antecedent infections in

Guillain-Barr6 syndrome
A case-control study
B.C. Jacobs, MD, PhD; P.H. Rothbarth, MD, PhD; F.G.A. van der Meche, MD, PhD; P. Herbrink, PhD;
P.I.M. Schmitz, PhD; M.A. de Klerk; and P.A. van Doorn, MD, PhD

Article a b s t r a c t 4 b j e c t i u e : To determine which antecedent infections are specifically associated with the Guillain-Barre
syndrome (GBS). Background: Infections with many agents have been reported preceding GBS. Some infections are
related to specific clinical and immunologic subgroups in GBS. Most agents were reported in case reports and uncontrolled
small series of GBS patients only, and their relation to GBS and its subgroups remains unclear. Method: A serologic study
for 16 infectious agents in 154 GBS patients and 154 sex- and age-matched controls with other neurologic diseases. Acute
phase, pretreatment samples were used from clinically well-defined GBS patients. The seasonal distribution of serum
sampling in the GBS and control group was the same. Results: Multivariate analysis showed that in GBS patients,
infections with Campylobacter jejuni (32%),cytomegalovirus ( 13%), and Epstein-Barr virus (10%)were significantly more
frequent than in controls. Mycoplasma pneumoniae infections occurred more often in GBS patients (5%) than in controls
in univariate analysis. Infections with Huemophilus influenzae ( l % ) , parainfluenza 1 virus (l%), influenza A virus (l%),
influenza B virus (1961, adenovirus (1%),herpes simplex virus (l%),and varicella zoster virus (1%)were also demonstrated
in GBS patients, but not more frequently than in controls. C. jejuni infections were associated with antibodies to the
gangliosides GM1 and GDlb and with a severe pure motor form of GBS. Cytomegalovirus infections were associated with
antibodies to the ganglioside GM2 and with severe motor sensory deficits. Other infections were not related to specific
antiganglioside antibodies and neurologic patterns. Conclusions: Recent infections with C. jejuni, cytomegalovirus,
Epstein-Barr virus, and M. pneumoniae are specifically related to GBS. The variety of infections may contribute to the
clinical and immunologic heterogeneity of GBS.
NEUROLOGY 1998;51~1110-1115

The Guillain-Barre syndrome (GBS) is an acute poly- distinct clinical variants of GBS. The variety of re-
neuropathy that may lead to a variety of motor and ported infectious agents in GBS may therefore underlie
sensory deficits. It is considered a postinfectious dis- the immunologic and clinical heterogeneity in GBS.
ease as approximately two-thirds of patients report Controversy exists over whether infections with
some form of preceding infectious illness. These in- other frequently reported agents, such as Epstein-
fections may effect an immune response against pe- Ban- virus (EBV) and Mycoplasma pneumoniae, are
ripheral nerve antigens, as suggested by the interval more often present in GBS patients compared with
of 1 to 4 weeks between antecedent infection and controlslOJ1or not.2 The majority of these “GBS-
onset of weakness. A remarkable diversity of infec- related infections” were reported only in small and
tious agents has been reported in patients with selected groups of GBS patients, without age-, sex-,
GBS.I The association between GBS and infections and season-matched controls, and may therefore rep-
with Campylobacter jejuni and cytomegalovirus resent coincidental findings. In addition, many of
(CMV) has been demonstrated in case-control these infections were clinically defined without sero-
s t ~ d i e s .Furthermore,
~-~ C. jejuni infections are asso- logic confirmation, or with serology performed on se-
ciated with antibodies against the ganglioside GM1, rum samples obtained long after neurologic onset or
and a severe, pure motor variant of GBS with a poor after treatment. Moreover, in most studies, the
prognosis after plasma e x ~ h a n g e . ~ GBS
. ~ patients possible association among these infections, antigan-
with a CMV infection more frequently have antibod- glioside antibodies, and clinical presentation was
ies against the ganglioside GM2,7.Rand have severe not investigated. Therefore, the role of infectious
sensory deficits a n d cranial nerve involvement.9 agents in GBS, other than C. jejuni and CMV, is not
These findings strongly indicate that C. jejuni and established.
CMV infections determine the specificity of the im- The aim of the current study was to determine the
mune response against peripheral nerves leading to spectrum of antecedent infections in a large, un-
From the Departments of‘ Neurology (Drs. Jacobs, van der Meche, and van Doorn, and M.A. de Klerk), Immunology (Dr. Jacobs), and Virology (Dr.
Rothbarth), Erasmus University, Rotterdam; the Department of Trial and Statistics (Dr. Schmitz), Dr. Daniel den Hoed Cancer Center, Rotterdam; and the
Department of Immunology and Infectious Diseases (Dr. Herbrink), Diagnostic Centre SSDZ, Delft, The Netherlands.
Supported by grants from the Prinses Beatrix Fonds (no. 90-3161 and 95-0519) and the Willem H. Kroger Stichting (no. 92-011).
Address correspondence and reprint requests to Dr. B.C. Jacobs, Department of Neurology, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR
Rotterdam, The Netherlands.
1110 Copyright 0 1998 by the American Academy of‘ Neurology
selected group of GBS patients and to investigate
whether these infections are m o r e common in GBS
than in a matched control group. In addition, w e
investigated whether these infections in GBS pa-
t i e n t s are associated with specific antiganglioside
antibodies and distinct clinical presentations.
Patients and methods. Patients. The GBS patients in
this study participated in the Dutch Guillain-Barre trial
comparing the therapeutic effect of plasma exchange (PE)
and intravenous immunoglobulins (Mg),12 or in the pilot
study evaluating the therapeutic effect of methyl-
prednisolone in addition to IVIg (MP-Mg).13The 147 pa-
tients in the PE/IVIg trial entered the study from June
1986 to December 1989, and the 25 patients in the MP-
IVIg pilot study from September 1990 to September 1992.
The GBS patients were referred to academic or other large
hospitals in The Netherlands. All patients fulfilled the di-
agnostic criteria for GBS,14 were unable to walk 10 meters
independently, and were admitted within 2 weeks of onset
of weakness. All patients were evaluated with respect to
the presence of paresthesias, sensory deficits (two-point
discrimination, position sense, and tactile function in
hands and feet), cranial nerve involvement, functional
score, and Medical Research Council (MRC) sumscore, at
study entry and subsequently at 16 time points according
to a previously established protocol during a follow-up pe-
riod of 6 months. At entry, all patients were asked if they
had infectious illness in the preceding 4 weeks. Pretreat-
ment serum samples obtained within 2 weeks of neurologic
onset were available from 154 (90%) of the 172 patients
included in these therapeutic studies. The 18 excluded
cases did not differ from the other patients regarding their
antecedent illnesses, neurologic manifestations, and course
of disease.
Controls. As a control group for the serology studies,
we used serum samples from 154 sex- and age ( 2 4 year)-
matched control patients with other neurologic diseases
(OND) than GBS. The controls resided in the southwest
area of The Netherlands and were referred to the Univer-
sity Hospital Rotterdam in the period from 1990 to 1996.
The population in this area reflects that of other parts in
The Netherlands with respect to relevant demographic
characteristics, such as urbanization ratio. The time of
serum sampling in the control group and the group of GBS
patients had the same seasonal distribution. The OND
controls had chronic inflammatory demyelinating polyneu-
ropathy (CIDP) (n = 21), other forms of neuropathy (n =
60), MS (n = 41), cerebrovascular accidents (n = 141, mo-
tor neuron disease (n = 6)) MG (n = 6), or ot,her neurologic
disorders (n = 6). All samples were obtained at admission
to the hospital and before treatment. In addition, serum
samples from 50 healthy subjects were tested.
Znfection serology. Serum samples from GBS patients
were tested to determine recent infections with 16 viruses
or bacteria frequently reported in GBS. The assays were
performed according to routine techniques with previously
established criteria for positivity. C. jejuni infections were
defined as the presence of IgM, IgA, or high titer IgG in
ELISA.6 CMV,S M. pneumoniae, and hepatitis A virus in-
fections were defined as the presence of IgM, and Hae-
mophilus influenzae infections as the presence of IgM, IgA,
and IgG antibodies in ELISA. Hepatitis B virus infection
was defined as the presence of hepatitis B virus surface
antigen in ELISA. Infections with herpes simplex virus,
varicella zoster virus, measles virus, influenza A and B
virus, parainfluenza 1 and 2 virus, adenovirus, and respi-
ratory syncytial virus were determined by complement fix-
ation and were defined as the presence of a n antibody titer
264. EBV infections were determined as the presence of
IgM against viral capsid antigen in immunofluoresence. To
determine IgM antibodies to EBV and CMV, sera were
preabsorbed with Gull-sorb (Gull Laboratories, Salt Lake
City, UT) to remove the IgG antibodies to these agents. To
determine IgM antibodies to C. jejuni, H. influenzae, M.
pneumoniae, and hepatitis A virus, p-specific class-capture
ELISAs were used. These precautions to determine the
IgM serology increased the sensitivity of the assays and
prevented false positivity by binding of IgM rheumatoid
factors with IgG antibodies. Because this study focused on
the infections that were more frequent in GBS patients
than controls, we only determined the serology for specific
infections in the controls if more than five GBS patients
were positive for this infection, the minimal number to be
significant in the McNemar’s test. The frequency of CMV
and C. jejuni infections in the patients included in the
PE/IVIg trial were reported p r e v i o ~ s l y , but
~ , ~ ~without
~
comparison with the matched control group.
Antiganglioside antibodies. Pretreatment serum sam-
ples from all GBS patients were tested for IgM, IgG, and
IgA antibodies against the peripheral nerve gangliosides
LM1 (sialosyl paragloboside), GM1, GM2, GM3, GDla,
GDlb, GTlb, and GQlb by ELISA and confirmed in thin-
layer chromatography overlay, according to methods de-
scribed previously.6
Statistical analysis. Differences in frequency of infec-
tions between GBS patients and OND controls were tested
with the McNemar’s test,15 and between GBS patients and
healthy controls with the chi-square test without continu-
ity correction or Fisher’s exact test. The odds ratio for each
infectious agent was also estimated using a multivariate
conditional logit model for matched case-control data, with
disease status (GBS or control) as dependent variable and
the infectious agents as independent variables.16 With re-
spect to the clinical features of GBS patients, differences in
proportions were tested with the chi-square test without
continuity correction or Fisher’s exact test, and differences
in medians with the Wilcoxon-Mann-Whitney U test. The
time for patients to reach independent locomotion was an-
alyzed by the Kaplan-Meier method and the log-rank test.
All calculations were performed using STATA 5.0 for
Windows 95 (Stata Statistical Software, Release 5.0, Col-
lege Station, TX).A p value < 0.05 was considered to be
significant.
Results. Infections and antecedent illness in GBS pa-
tients. In the 4 weeks preceding GBS, 105 (68%) of the
154 patients reported some form of infectious illness, as
indicated by their clinical symptoms. The most common
identified cause of recent infections in patients with GBS
was C. jejuni (32%)(table 1).Other recent infections in
GBS patients were CMV (13%), EBV (lo%), M. pneu-
moniae (5%), and, less often, H. influenzae (l%), parainflu-
enza 1 virus (l%), influenza A virus (1%), influenza B virus
(l%), adenovirus (l%),herpes simplex virus (l%), and vari-
cella zoster virus (1%) (see table 1).The majority of GBS
patients with positive serology had clinical symptoms of
October 1998 NEUROLOGY 51 1111
Table 1 Zncidence of positive infection serology and symptoms of antecedent infectious illness an GBS patients
_ _ ~
All,
n = 154,
Infection serology n (R)
Campylobacter jejuni
C ytomegalovirus
Epstein-Barr virus
Mycoplasma pneumoniae
Haemophilus influenme
Parainfluenza 1 virus
Influenza A virus
Influenza B virus
Adenovirus
Herpes simplex virus
Varicella zoster virus
> 1 infectious agent
2 1 infectious agent
“ p < 0.05 compared with patients without these symptoms of infection.
GBS = Guillain-Barre syndrome; URTI = upper respiratory tract infection; other
preceding infectious illness (see table 1).Patients with C.
jejuni infections had diarrhea more often compared with
patients without this infection ( p < 0.001); symptoms of
upper respiratory tract infection (URTI) were less fre-
quently found ( p = 0.001). C. jejuni infections were also
associated with other manifestations of infectious illness
than diarrhea and URTI, such a s nausea, vomiting, and
abdominal pain. Patients with antecedent CMV infection
frequently had URTI and other manifestations of infection
such as nausea, fever, and exanthema, but none had diar-
rhea. Other manifestations of infection were fever and sore
throat in EBV-infected patients and pneumonia and pan-
creatitis in M. pneumoniue-infected patients. In the 49 pa-
tients who did not report symptoms of antecedent
infectious illness, a substantial proportion had positive se-
rology for infections with C. jejuni (29%), CMV (18%),EBV
(16%), and M. pneumoniae (4%) (see table 1). The high
proportion of C. jejuni infections in these patients is in
accordance with the frequent subclinical course of this in-
fection. Positive serology for recent infection with parain-
fluenza 2 virus, hepatitis A and B virus, respiratory
syncytial virus, or measles virus could not be demon-
strated. None of the infections in GBS patients showed a
clear seasonal predominance.
Positive serology for more than one infection was found
in 13 (8%)of the GBS patients. Most of these GBS patients
had positive EBV serology, and were additionally positive
for C. jejuni and CMV (n = 21, C. jejuni (n = 2), M. pneu-
moniae (n = 31, CMV (n = 21, and H . influenme (n = 1).
The other patients were positive for C M V and additionally
for C. jejuni (n = I),M . pneumoniae (n = l ) , and influenza
A virus (n = 1).
Antecedent infections in GBS patients compared with
controls. Serology for infections with C. jejuni, CMV,
EBV, and M . pneunzoniae was also performed in the two
control groups. Univariate analysis showed that these in-
fections were all significantly more frequent in GBS pa-
tients compared with matched OND controls (table 2). The
1112 NEUROLOGY 51 October 1998
Diarrhea, URTI, Other, None,
n = 25, n = 68, n = 12, n = 49,
n (5%) n (%) n (%) n (%)
19 (76)”
O*
l(4)
0
0
0
0
0
0
0
0
0
20 (80)”
= symptoms other than diarrhea or URTI.
attributable proportion of these infections, i.e., the propor-
tion of patients that can be attributed to these infections
provided they play a causal role in GBS, was calculated as
0.44 (see table 2). Using a multivariate conditional logit
model for matched case-control data, only infections with
C . jejuni, CMV, and EBV appeared to be independently
associated with GBS. Acute infections in the OND controls
were not significantly associated with any of the diagnostic
categories. The OND patients with positive serology had
MS (n = 8), CIDP (n = 4), other polyneuropathies (n = 7),
cerebrovascular accident (n = 11, MG (n = l), Friedreich’s
ataxia (n = l),or concussion (n = 1). Differences in the
frequency of C . jejuni, CMV, EBV, and M . pneumoniae
infections between GBS patients and controls could not be
adjusted to differences in their inclusion period because
retrospective analysis revealed that the annual incidence
of these infections did not change significantly in the time
period from 1986 to 1996. In addition, we found no signifi-
cant association between the hospital or year of admission
and the frequency of specific infections in the groups of
GBS patients or controls.
Antecedent infections, antiganglioside antibodies, and
clinical subgroups. C . jejuni infection was significantly
associated with antibodies against GM1 and GDlb, and
CMV infections with antibodies against GM2 (table 3). In-
terestingly, the only GBS patient with herpes simplex vi-
rus had high titers of IgG antibodies against LM1, GM3,
GDla, GDlb, GTlb, and GQlb. This patient, who had a
pure motor variant of GBS with ophthalmoplegia and hy-
poglossal palsy, needed artificial ventilation and recovered
to independent locomotion 69 days after IVIg. Infections
with EBV or M . pneumoniae, or any of the other agents,
were not associated with the tested antiganglioside anti-
bodies. Antibody titers to GM1 and GM2 were also deter-
mined in a subgroup of the OND and healthy controls, but
were not found to be associated with the presence of C.
jejuni or CMV infections.6.*
Infections with C. jejuni and CMV were each associated
Table 2 Incidence of recent infections i n GBS patients compared with matched OND controls and healthy subjects

GBS OND Healthy

patients, controls, subjects,
n = 154, n = 154, Attributable n = 50,
Infection serology n (%) n (%) OR (95% CI)* p Value*? proportion*$ n (%) OR (95% CI)$ p Value§¶
__
Campylobacter jejuni 49 (32) 18 (12) 3.1 (1.7 to 5.9) 0.0001 0.22 4 (8) 5.4 (1.9 to 15.1) 0.001
Cytomegalovirus 20 (13) 3 (2) 9.5 (2.3 to 84) 0.0002 0.12 0 - 0.005
Epstein-Barr virus 16 (10) 1(1) 16.0 (2.5 to 671) 0.0003 0.09 0 - 0.01
Mycoplasma pneumoniae 7 (5) 1(1) 7.0 (0.9 to 316) 0.03 0.04 0 - 0.20
21 infectious agent11 79 (51) 23 (15) 7.2 (3.6 to 16.5) <0.0001 0.44 4 (8) 12.1 (4.3 to 33.8) <0.001

* GBS patients compared with OND controls.

i- Determined by McNemar’s test.
$ Attributable proportion is calculated as (odds ratio - l)/odds ratio X frequency in GBS patients.
5 GBS patients compared with healthy subjects.
11 Determined by chi-square or Fisher’s exact test.
‘jRecent infection with at least one of the agents reported in this table.

GBS = Guillain-Barre syndrome; OND = other neurologic diseases; OR = odds ratio; CI = confidence interval; - = cannot be
calculated.

with a distinct clinical presentation in GBS, as we previ-
ously d e ~ c r i b e d .In
~ , ~addition, the case-control study en-
abled us to investigate the association tietween these
infections and sex and age. The interaction between sex
and C. jejuni infection was almost significant; the odds
ratio (95% confidence interval) in male GBS patients was
14.4 (3.1 to 68.1) and in female GBS patients 2.9 (3.1 to
7.1) ( p = 0.08). The median age of the GBS patients with
EBV infection was 29 years, and with M. pneumoniae in-
fection 28 years, indicating that they were significantly
younger than the other GBS patients (median 50 years)
( p = 0.002 a n d p = 0.001, respectively). Eleven (69%) of
the 16 EBV infected patients had respiratory insufficiency,
which was a significantly higher proportion compared with
patients with other or no infections (37%) ( p = 0.01). In-
fections with these or other micro-organisms were not sig-
nificantly associated with time to reach nadir, MRC
sumscore a t entry and nadir, distribution of weakness,
cranial nerve involvement, sensory loss, paresthesias, or
time to recovery. Also, the GBS patients with multiple
positive serology did not significantly differ from the other
patients with respect to their neurologic presentation.
Discussion. In the current study, C. jejuni, C M Y ,
EBV, and M. pneumoniae were identified as the most
common causes of antecedent infections in GBS.
These infections were found more frequently in GBS
patients than in age- and sex-matched controls with
OND. Infections with herpes simplex virus, varicella
zoster virus, influenza A and B virus, parainfluenza
1 virus, adenovirus, and H. influenzae were also
identified, but their frequency was not significantly
higher than in controls. These findings confirm the
concept that certain infections are specifically re-
lated to GBS, although a spectrum of infections may
precede the disorder.
Previous case-control studies demonstrated C. je-

Table 3 Association between antecedent infections and antiganglioside antibodies i n GBS patients

Campylobacter jejuni, EBV, Mycoplasma pneumoniae, No infection,t

Antiganglioside n = 4!3, n = 16, n = 7, n = 75,
antibodies* n (%) n (%I n (%I n (%I

GM1 20 (41)$ 0
GM2 3 (6) 0
GM3 0 0
GDla 2 (4) 0
GDlb 14 (29)s 0
GTlb 0 0
GQlb 2 (4) 0
LM1 3 (6) 1(14)

* IgM, IgG, or IgA antibodies against ganglioside.

i- No serologic defined infection with the agents reported in this table.
$ This patient also had a positive C. jejuni serology.
p < 0.05 compared with patients without this infection.
GBS = Guillain-Ban6 syndrome; Ig = immunoglobulin; CMV = cytomegalovirus; EBV = Epstein-Barr virus.
October 1998 NEUROLOGY 51 1113
juni infections in 14%to 36%of GBS patients, and in
1%to 10% of ~ o n t r o l s ,which
~ - ~ is in accordance with
our findings. The current study justifies the conclu-
sion that C. jejuni is the predominant cause of ante-
cedent infection in GBS. However, C. jejuni is also
the predominant cause of acute bacterial enteritis in
The Netherlands, and our study shows that in pa-
tients with OND and healthy controls, C. jejuni oc-
curs more frequently than infections with CMV,
EBV, and M. pneumoniae. Therefore, one may argue
that GBS is a postinfectious disease not related t o
specific infections, in which the predominance of C.
jejuni infections simply reflects the high frequency of
this infection in the community. However, there is a
strong association between C. jejuni infections and a
distinct severe and pure motor variant of GBS.*,6
This argues for a specific role of these bacteria in
inducing immune responses to motor nerve antigens
in a subgroup of GBS patients. GM1 may be one of
the targets because anti-GM1 antibodies are associ-
ated with C. jejuni infections in GBS,5,6and higher
concentrations of GM1 are present in myelin of mo-
tor fibers compared with sensory fibers.”
CMV was the most common viral cause of ante-
cedent infection, present in 13% of GBS patients.
This finding is in accordance with the 15%reported
by Dowling and Cook,l’ and the 11%and 22% re-
ported by others.2JRThe presence of IgM antibodies
to CMV suggests a recent CMV infection, although
reactivation of a latent infection cannot be excluded.
According to the report of Dowling and Cook, CMV
infections in GBS patients are clustered in time peri-
ods of 10 to 16 weeks,” but this could not be con-
firmed in our study. The high frequency of sensory
and cranial nerve involvement in CMV-associated
GBS patients may indicate that CMV infections in-
duce specific antibodies against antigens present in
these nerves. Anti-GM2 antibodies are associated
with CMV infections in GBS,7,8but the distribution
of GM2 in the human peripheral nerve system is
unknown. Others reported that CMV infections in-
duce antibodies against sulfatide and other sulfated
glycosphingolipids from human peripheral nerves.I9
Interestingly, antisulfatide antibodies were reported
to be related to sensory nerve involvement in GBS
and other neuropathies.20 The association between
CMV infections and antisulfatide antibodies in GBS
patients, however, has not been established.
The current study is the first to demonstrate a
significantly higher frequency of EBV and M. pneu-
moniae infections in GBS patients compared with
case-matched controls. These frequencies in GBS pa-
tients are similar to those found by the group of
Dowling and Cook, i.e., EBV 10% versus 8% and M .
pneumoniae 5% versus 5%.11J0Provided these infec-
tions play a role in the pathogenesis of GBS, 9% of
GBS cases can be attributed to EBV infections, and
4% t o infections with M. pneumoniae. These signifi-
cant but low attributable proportions may explain
why Winer et a1.,2 in a smaller case-control study,
were not able to demonstrate an association with one
1114 NEUROLOGY 51 October 1998
of these infections. Accordingly, M. pneumoniae in-
fections in our study were significantly associated
with GBS in univariate analysis only. We found no
relation between EBV and M. pneumoniae infections
and antibodies against the major peripheral nerve
gangliosides. However, M. pneumoniae infections in
GBS were reported t o be associated with antibodies
against galactocerebroside, the predominant glyco-
lipid in human peripheral nerves.21 The ubiquitous
distribution of this antigen in the peripheral nervous
system may explain why we did not find an associa-
tion with involvement of specific nerve fibers.
Thirteen (8%) of the GBS patients in our study
had a positive serology for more than one infectious
agent, as was also found in other serologic studies.ls
This may indicate that dual-antigen induced im-
mune responses play a role in a subgroup of GBS
patients, as was also suggested for other immune-
mediated neuropathies.22Because we did not culture
the organisms, the possibility that some of these pa-
tients had a single infection inducing polyclonal B
cell activation or antibodies against common or cross-
reactive structures on different micro-organisms re-
sulting in a false double positive serology cannot be
excluded. However, studies based on culture alone will
underestimate the frequency of recent infections, as
most infections precede GBS for several weeks, and the
infectious agents may be cleared at the time of neuro-
logic onset. Our findings should be confirmed in pro-
spective large case-control studies using culture,
serologic, and molecular biology techniques to deter-
mine recent infections.
C. jejuni, CMV, EBV, and M. pneumoniae may
have a general feature that explains their specific
association with GBS. These agents may share the
capacity to induce immune responses to peripheral
nerve glycoconjugates, as indicated by their coexis-
tence with antibodies to gangliosides and other gly-
colipids in GBS patients. Moreover, infections with
M. pneumoniae, C M V , and EBV are associated with
cold agglutinins, which preferentially bind to carbo-
hydrate antigens at 4 “ C , a characteristic shared
with antiganglioside a n t i b o d i e ~ .Monoclonal
~~ cold
agglutinins t o disialylated gangliosides from patients
with chronic ataxic neuropathy were found to reduce
nerve excitability and neurotransmitter release in
the mouse hemidiaphragm ~ r e p a r a t i o n Antigan-
.~~
glioside antibodies in GBS patients with C. jejuni
infection may be induced by molecular mimicry, as
ganglioside-like structures were identified in C. je-
juni lipopolysaccharides.25In addition, it was demon-
strated that anti-GM2 antibodies cross-react with
CMV-infected cells? The four GBS-related micro-
organisms also express receptors or toxins that bind
to carbohydrate antigens and may act as carrier pro-
teins in the production of of antiglycoconjugate anti-
bodies. C. jejuni produces a toxin that specifically
binds to gangliosides.26 M. pneumoniae binds with
sialylated carbohydrates from the blood group I anti-
gen and induces antibodies against this s t r u c t ~ r e . ~ 7
Further research is needed to investigate if molecu-
lar mimicry with gangliosides or production of
glycolipid-reactive carrier proteins explains the pre-
dominance of these infections in GBS.
References
1. Leneman F. The Guillain-Barre syndrome. Arch Intern Med
1966;118:139-144.
2. Winer JB, Hughes RAC, Anderson MJ, Jones DM, Kangro H,
Watkins RPF. A prospective study of acute idiopathic neurop-
athy. 11. Antecedent events. J Neurol Neurosurg Psychiatry
1988;51:613-618.
3. Mishu B, Ilyas AA, Koski CL, e t al. Serologic evidence of
previous Campylobacter jejuni infection in patients with the
Guillain-Barre syndrome. Ann Intern Med K993;118:947-953.
4. Rees J H , Soudain SE, Gregson NA, Hughes RAC. Campy-
lobacter jejuni infection in Guillain-Barre syndrome. N Engl
J Med 1995;333:1374-1379.
5. Rees JH, Gregson NA, Hughes RAC. Anti-ganglioside GM1
antibodies in Guillain-Barre syndrome and their relationship
to Campylobacter jejuni infection. Ann Neurol 1995;38:809-
816.
6. Jacobs BC, van Doorn PA, Schmitz PIM, et al. Campylobacter
jejuni infections and anti-GM1 antibodies in Guillain-Barre
syndrome. Ann Neurol 1996;40:181-187.
7. Irie S,Saito T, Nakamura K, et al. Association of anti-GM2
antibodies in Guillain-Barre syndrome with acute cytomegalo-
virus infection. J Neuroimmunol 1996;68:19-26.
8. Jacobs BC, van Doorn PA, Groeneveld JHM, Tio-Gillen AP,
van der Meche FGA. Cytomegalovirus infections and anti-
GM2 antibodies in Guillain-Barre syndrome. J Neurol Neuro-
surg Psychiatry 1997;62:641- 643.
9. Visser LH, van der Meche FGA, Meulstee J , et al. Cytomega-
lovirus infection and Guillain-Barre syndrome: the clinical,
electrophysiological, and prognostic features. Neurology 1996;
47:668-673.
10. Goldschmidt B, Menonna J , Fortunato J , Dowling P, Cook SD.
Mycoplasma antibody in Guillain-Barre syndrome and other
neurological disorders. Ann Neurol 1980;7:108-112.
11. Dowling PC, Cook SD. Role of infection in Guillain-Barre syn-
drome: laboratory confirmation of herpesviruses in 41 cases.
Ann Neurol 1981;9(suppl):44-55.
12. Van der Meche FGA, Schmitz PIM, the Dutch Guillain-Barre
Study Group. A randomized trial comparing intravenous im-
mune globulin and plasma exchange in Guillain-Barre syn-
drome. N Engl J Med 1992;326:1123-1129.
13. The Dutch Guillain-Barre Study Group. Treatment of
Guillain-Barr6 syndrome with high-dose immune globulins
combined with methylprednisolone: a pilot study. Ann Neurol
1994;35:749-752.
14. Asbury AK, Cornblath DR. Assessment of current diagnostic
criteria for Guillain-Barre syndrome. Ann Neurol 1990;
27(suppl):21-24.
15. Fleiss JL. Statistical methods for rates and proportions, ch. 8.
New York: John Wiley, 1981.
16. Breslow NE, Day NE. Statistical methods in cancer research,
vol. 1. The analysis of case-control studies. Lyon, France:
IARC, 1980.
17. Ogawa-Goto K, Funamoto N, Ohta Y, Abe T, Nagashima K.
Myelin gangliosides of human peripheral nervous system: an
enrichment of GM1 in the motor nerve myelin isolated from
cauda equina. J Neurochem 1992;59:1844-1849.
18. Boucquey D, Sindic CJM, Lamy M, Delmee M, Tomasi J P ,
Laterre EC. Clinical and serological studies in a series of 45
patients with Guillain-Barre syndrome. J Neurol Sci 1991;
104~56-63.
19. Ogawa-Goto K, Kubota K, Kurotani A, Abe T. Antibodies
against sulfated glycosphingolipids of peripheral nerve my-
elins detected in patients with human cytomegalovirus infec-
tion. J Neuroimmunol 1994;55:55-60.
20. Van den Berg LH, Lankamp CLAM, de Jager AEJ, et al.
Anti-sulfatide antibodies in peripheral neuropathy. J Neurol
Neurosurg Psychiatry 1993;56:1164-1168.
21. Kusunoki S, Chiba A, Hitoshi S, Takizawa H, Kanazawa I.
Anti-Gal-C antibody in autoimmune neuropathies subsequent
to mycoplasma infection. Muscle Nerve 1995;18:409-413.
22. Westall FC, Root-Bernstein R. Cause and prevention of
postinfectious and postvaccinal neuropathies in light of a new
theory of autoimmunity. Lancet 1986;i:251-252.
23. Willison HJ, Veitch J . Immunoglobulin subclass distribution
and binding characteristics of anti-GQlb antibodies in Miller
Fisher syndrome. J Neuroimmunol 1994;50:159-165.
24. Willison HJ, O’Hanlon GM, Paterson GJ, et al. A somatically
mutated human anti-ganglioside antibody that induces exper-
imental neuropathy in mice is encoded by the variable region
heavy chain gene, V1-18. J Clin Invest 1996;97:1155-1164.
25. Yuki N, Taki T, Inagaki F, et al. A bacterium lipopolysac-
charide that elicits Guillain-Barr6 syndrome has a GM1
ganglioside-like structure. J Exp Med 1993;178:1771-1775.
26. Suzuki S, Kawaguchi M, Mizuno K, Takama K, Yuki N. Im-
munological properties and ganglioside recognition by Campy-
Zobacter jejuni-enterotoxin and cholera toxin. FEMS Immunol
Med Microbiol 1994;8:207-212.
27. Loomes LM, Uemura K, Childs RA, et al. Erythrocyte recep-
tors for Mycoplasma pneumoniae are sialylated oligosaccha-
rides of Ii antigen type. Nature 1984;307:560-563.
October 1998 NEUROLOGY 51 1116
The spectrum of antecedent infections in Guillain-Barré syndrome: A case-control study
B. C. Jacobs, P. H. Rothbarth, F.G.A. van der Meché, et al.
Neurology 1998;51;1110-1115
DOI 10.1212/WNL.51.4.1110

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