Journal of the Peripheral Nervous System 14:72–74 (2009)

REVIEW
What’s new in Guillain-Barr ´e syndrome in 2007–2008?*

Pieter A. van Doorn

Department of Neurology, Erasmus MC, Rotterdam, The Netherlands

Abstract The years 2007 and early 2008 have been an exciting time for Guillain- Barr ´e syndrome (GBS) research. Epidemiological studies have shown
that the incidence of GBS remains stable at about 2/100,000 per year but that there have been changes in hospitalization use, likely due to the widespread
availability of IVIg. Research into mechanisms has shown the importance of single amino acids in Campylobacter jejuni and the importance of ganglioside
conformation. In a murine model of anti-ganglioside antibody-mediated neuropathy, Eculizumab was effective in reversing clinical disease and preventing
pathology. This suggests trials of Eculizumab in GBS should be considered. Unfortunately, there are no new randomized controlled trials in GBS to report
although the unmet need is great.

What’s new in Guillain-Barr ´ e syndrome (GBS) in 2007–2008?
The years 2007 and early 2008 have been an exciting time for GBS
research. Epidemiological research and bench laboratory research
have moved forward. Animal models showed further insight into the
pathogenesis of GBS and also showed the potential for testing an
effective drug for GBS. This overview highlights only some of the most
important papers published in 2007 and early 2008.
Epidemiology
The incidence of GBS in the USA remained stable over the period
2000–2004 (1.6–1.8/100,000) with a mortality rate of 2.6%. Among the
predictors of poor outcome and death were severity of the disease
(intubation), older age, comorbidity, cardiac complications, and sepsis
(Alshekhlee et al., 2008). Hospital admissions for GBS including those
for rehabilitation were reduced by 20% over a 10-year period. This was
only partially due to less interhospital transfers because of the shift
from plasma exchange to intravenous immunoglobulin (IVIg) (Frenzen,
2007).
Pathogenesis
Campylobacter research revealed that GBS and non-GBS associated
Campylobacter strains share many similarities and that Campylobacter
CST-II is essential for biosynthesis of ganglioside lipooligosaccharide
(LOS). A change in one amino acid in the gene can significantly alter
the enzymatic activity (Hye and Nachamkin, 2007; Koga and Yuki,
2007; Taboada et al., 2007). It is not known why some people get GBS
after an infection and why some GBS patients have a severe course of
disease. It was shown that polymorphisms in macrophage-mediators
(MMP-9 and TNF-á), although not associated with the susceptibility of
GBS, are associated with severe weakness and poor outcome
(Geleijns et al., 2007). Since GD1a is expressed in motor and sensory
nerves, why do some patients get acute motor axonal neuropathy
(AMAN)? It was shown that both the fine specificity and the ganglioside
orientation and exposure contribute to recognition by anti-ganglioside
antibodies (Lopez et al., 2008). This may explain at least partially the
differences in clinical manifestations. Some patients only have
antibodies against ganglioside complexes. These complexes may form
new confirmational epitopes to which antibodies may bind (Kanzaki et
al., 2008; Kusunoki et al., 2008). Antibodies against GD1a/GD1b or
GD1b/GT1b turned out to be related to severe GBS, and antibodies
against complexes containing GQ1b or GT1a were related to
opthalmoplegia in both GBS and Fisher syndrome (FS) patients (Kuijf
et al., 2007). It was investigated whether GBS patients with antibodies
against motor gangliosides may have a variable outcome. It was found
that two distinct patterns of cross-reactive antibodies against motor
gangliosides are related to different outcomes. The presence of IgG1
antibodies against motor gangliosides was associated with diarrhea,
anti- Campylobacter LOS antibodies, and a poor prognosis, whereas
the presence of IgG1 and IgG3 antibodies was related to upper
respiratory tract infections, anti- Haemophilus influenzae LOS
antibodies, and a better outcome (Jacobs et al., 2008).
Animal studies
Sodium channels are concentrated at the nodes of Ranvier. A nice
study in rabbits immunized with ganglioside mixture (GM1) showed
that anti-GM1 antibodies caused complement-mediated disruption of
sodium channel clusters (Susuki et al., 2007). One of themost
attractive papers concerning GBSwas a study in a mouse model of
GBS. It is known that Eculizumab functionally blocks the formation of
C5a and C5b-9 (MAC). In this model, it was shown that intravenous
Eculizumab prevented respiratory paralysis and the functional and
morphological hallmarks of terminal motor neuropathy (Halstead et al.,
2008). In an editorial on these findings, it was concluded that
Eculizumab protects against complement-mediated damage in murine
FS, and that Eculizumab should be considered in treatment of FS or
other autoantibody-mediated neuropathies (Lehmann and Hartung,
2008).
Prognosis
New information on the subtype, course, and prognosis of childhood
GBS became available. A study in 95 children, age 12 months to 16
years, showed that children often have severe neuropathic pain, but
that the neurological long-term prognosis is relatively good
(Korinthenberg et al., 2007). Another paper on GBS in Mexican
children described a peak in incidence in the July–September period
and additionally showed that 46/121 children had the AMAN subtype
(Nachamkin et al., 2007). A study on 76 adult GBS patients admitted to
the intensive care unit (ICU) showed that the median ICU stay was 3
weeks, 80% of patients required artificial ventilation (median 4 weeks),
and 75% of patients had independent ambulation after 3 years.
Therefore, also in severely affected patients, long-term prognosis can
be good (Dhar et al., 2008). A large prognostic study introduced the
Erasmus GBS outcome scale (EGOS). It was shown that three simple
clinical factors obtained within 2 weeks from the onset of GBS: age,
preceding diarrhea, and the GBS disability score, can easily be used to
predict the chance to walk unaided at 6 months (van Koningsveld et
al., 2007).
Treatment

No newly randomized controlled trials (RCT) on GBS treatment were

published. However, in an overview on immunotherapy for GBS, it was
concluded that PE and IVIg are effective, the combination of PE and
IVIg is not significantly more effective, oral steroids slow recovery,
intravenous steroids alone are not significantly beneficial, and 9–17%
of patients die or remain severely disabled (Hughes et al., 2007).
Therefore, improved therapeutic strategies are urgently required. A
pilot study indicated that the additional treatment of GBS patients with
mycophenolate mofetil (CellCept) to IVIg seems to be ineffective.
(Garssen et al., 2007). A Cochrane review concluded that there
presently is no adequate RCT indicating an effective treatment for FS
(Overell et al., 2007).

Conclusion

Research on Campylobacter genes, single nucleotide polymorphisms

in GBS patients, anti-ganglioside antibodies, animal models, the role of
complement, and prognostic modeling for patients with GBS made
clear steps forward. Progression on improved treatment in GBS
patients lags behind. In the next year, it is hoped that a study of a
second IVIg dose in severely ill GBS patients with poor prognosis
based upon the EGOS and a pilot study on the effect of complement
inhibitors in GBS will both begin.