NIAID Guillain Barre Fact Sheet: NIAID
Article title: NIAID Guillain Barre Fact Sheet: NIAID
Conditions: Guillain Barre Syndrome, Campylobacter jejuni
Development of Guillain Barre
Following Campylobacter Infection
Natcher Conference Center, NIH
Bethesda, MD, USA
August 26-27, 1996
Guillain Barre Syndrome (GBS) is a rare disorder, afflicting about 1
person in 100,000. Yet, since the decline in the number of polio cases, it
represents the most common cause of acute neuromuscular paralysis. It is
more common in Japan and China than in North America or Europe and it
affects both sexes of any age. Symptoms range from weakness and tingling
sensations in the legs to spread to the arms and upper body. While most
patients recover with no, or minor, long term effects, total paralysis and
the need for ventilatory assist and death can result.
In about two-thirds of cases, GBS is preceded a few days or weeks by a
mild respiratory or intestinal infection. The organism most commonly
proven to be associated with the development of GBS is Campylobacter
jejuni. C. jejuni has become the leading cause of
gastroenteritis in the developed world and is often acquired by ingestion
of infected poultry products. GBS is thought to arise as a result of the
production of antibody to bacterial sugar-containing surface antigen(s)
that, due to molecular mimicry, cross-react with the myelin sheath and the
axons of nerve cells. The ganglioside GM1 on nerve fibers seems to be a
target for these antibodies, although other gangliosides may also be
involved. Antibody and/or cell mediated immune reactions are believed to
produce degeneration of the nerve or interruption of
The purpose of this workshop was to explore the relationship between
C. jejuni infection and the development of GBS. Scientists studying
this problem from around the world were invited to present their latest
data. Represented were the disciplines of microbiology, neurology, cell
biology, immunology, and genetics. Topics for discussion included: the
identification of the surface antigens of C.jejuni linked to GBS,
the pathology of GBS, the identification of the target molecules on nerves
attacked by anti-bacterial antibodies, animal models for GBS, possible
interventions to prevent the develoment of GBS or its serious sequelae,
and the implications of these findings on the development of a vaccine
against C. jejuni.
Additional support for this meeting was provided by the National
Vaccine Program Office (NVPO), theNational Institute for Neurological
Diseases and Stroke (NINDS), the Food and Drug Administration (FDA), and
the Department of Defense (DOD).
Workshop Conclusions and Recommendations
- With the decrease in polio, GBS has become the leading cause of
acute flaccid paralysis in the world.
- GBS can probably result following a number of bacterial and viral
infections. Campylobacter jejuni induced diarrheal disease is
most often recognized as the precedent infection.
- The epidemiology of Campylobacter associated with GBS is
complex and not well understood. The specific reservoirs for GBS-related
strains are not known. There appears to be seasonality of infection
(summer) in some countries but no seasonality of GBS. The patterns of
association seem to be different in different parts of the world, as
does the age of individuals developing GBS.
- There is an association of GBS with C. jejuni O serotypes 19
and 41. The strongest association has been with O19. For example, in the
U.S., the risk of developing GBS following C. jejuni infection
has been estimated as 1 in 1058, but as 1 in 158 following infection
with C. jejuni O19.
- The structure of LPS is complex and unique in Campylobacter.
These unique structures are evident in O side chains and core
oligosaccharides. Often, portions of these structures resemble mammalian
tissue gangliosides (molecular mimicry) and suggest a mechanism of
immune damage to nerve fibers.
- The Department of Defense has developed, and is testing, a
formalin-inactivated, whole cell, Campylobacter jejuni vaccine
candidate. It is designated strain 81-176 and is a Lior type 5 (heat
labile antigen based typing system) and O type 23/36.
- A significant amount of antibiotic resistance has been developing
among the Campylobacter. This could lead to an increasing problem
in treatment of human disease.
- The development of GBS is rare in children less than 2 years of age
despite their susceptibility to Campylobacter. This may indicate
that some maturation of the immune system is needed for GBS to manifest
- The medical costs associated with Campylobacter induced GBS
has been estimated by the USDA to be between $57 and $425 million per
year in the U.S. Total costs, which include days of lost productivity,
are estimated to be between $247 million and $1.8 billion per year.
- There is need for better standardized case definitions of acute
motor axonal neuropathy (AMAN), acute motor-sensory neuropathy (AMSAN),
acute inflammatory demyelinating polyneuropathy (AIDP), and Miller
Fisher Syndrome (MFS) which are based on clinical, electrophysiologic,
immunologic, and molecular data.
- The CDC surveillance for emerging diarrheal diseases should include
C. jejuni, and C. upsaliensis in their plans. This would
provide a better estimate of Campylobacter infection rates in
- GBS (or more broadly defined acute flaccid paralysis cases) should
be reportable by state health departments to the CDC. Current estimates
are on the order of 1-4 cases of GBS per 100,000 population per year in
the U.S. When combined with increased surveillance for
Campylobacter, a much better picture of the epidemiology of the
organism and its association with GBS should become apparent.
- Surveillance for GBS in targeted populations seems warranted,
particularly in China (efforts are underway) where an increase in GBS is
seen in the summer months and is associated with rural residence, and in
Latin America (not underway) where cases of acute flaccid paralysis has
not declined despite the tremendous decrease in polio cases.
- Studies should proceed on HLA typing of clinically well defined
cases and controls in order to determine if there is a genetic component
to host susceptibility to GBS.
- Standardized microbiological laboratory procedures are needed to
insure isolation of Campylobacter strains associated with GBS. In
particular C. jejuni, and C. upsaliensis should be looked
for. The concept of viable but non-culturable Campylobacter
should be examined.
- Serologic assays for diagnosis of C. jejuni infections need
to be standardized and validated.
- A diagnostic test specific for various Campylobacter species
is needed. It is likely that a large number of Campylobacter
infections go unrecognized.
- An animal model for Campylobacter enteritis with ensuing GBS
is urgently needed. A recently described ferret model for
Campylobacter-induced enteritis may be useful. Mouse, rat,
primate, chicken, and rabbit models for immune neuropathies are being
examined and show promise but need to be developed further, perhaps by
examining pathogen-free animals. The development of transgenic mice
should also be considered.
- There should be a Campylobacter strain bank established in
which bacterial strains isolated from patients who develop Guillain
Barre Syndrome (or variants) can be deposited. These strains should be
available to researchers in the field. There is a role that NIAID could
play in the storage and distribution of strains from the NIAID
- There is a need for standardized reagents, particularly monoclonal
antibodies, that can be used to identify bacterial epitopes and which
can be tested for their ability to react with different neural
"targets". Well characterized reagents could also be distributed to
researchers from an NIAID repository.
- A more complete LPS typing system that will include more of the
strains now classified as "un-typeable" is needed. LPS typing should be
complemented with a molecular typing system based on DNA restriction
length polymorphisms (RFLP), rRNA gene polymorphisms (ribotyping), or by
polymorphism of other genes.
- Continuing effort is warranted to determine the LPS structures
associated with the development of GBS. Identification of specific
epitopes would be helpful. Since sialylated polysaccharides are suspect,
a probe to detect the presence of sialyl transferase may be helpful in
identifying GBS-associated strains.
- The mechanism of immune mediated nerve damage is poorly understood.
The nature of the initial antigen-antibody reaction(s) which leads to
damaging immune reactions which may involve cell mediated immunity,
complement fixation, cytokine production, lymphocyte and macrophage
infiltration, and breech of the blood-nerve barrier need to be better
defined. Why gangliosides on nerves are particularly targeted or
sensitive when compared to the same molecules found on other tissues is
- Studies should be done to try to understand the variations noted in
seasonality, or lack thereof, of GBS, and of the basis for the
differences noted in the serotypes of C. jejuni that have been
associated with the onset of GBS in different studies and in different
regions of the world.
- The mechanism of intravenous immunoglobulin (IVIG) amelioration of
GBS symptoms is not known. More research is needed with the aim of
developing improved therapies.
- A mechanism to share preliminary information among scientists
studying Campylobacter and/or associated GBS would be helpful in
keeping this world-wide research community in contact. The ability to
send such information to an Internet address, for example, that would be
widely accessible was discussed. Posting of interesting new
observations, information, or questions would facilitate research
efforts by all involved. Information on DNA sequences, availability of
new strains or reagents, new techniques, reservoirs of infection,
structures of LPS or proteins, new typing methods, antibiotic resistance
patterns, frequency of isolation of particular serotypes associated with
GBS, epidemiology, etc. could be included in such an exchange.
NIAID, a component of the National Institutes of Health,
supports research on AIDS, tuberculosis and other infectious diseases as
well as allergies and immunology. Prepared by:
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