See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/263935465

Guillain-Barr?? syndrome: Pathogenesis, diagnosis, treatment and prognosis

Article in Nature Reviews Neurology · July 2014

DOI: 10.1038/nrneurol.2014.121 · Source: PubMed

CITATIONS READS

985 8,076

6 authors, including:

Christa Walgaard Md Bart C Jacobs

Erasmus University Rotterdam Erasmus MC
30 PUBLICATIONS 3,006 CITATIONS 241 PUBLICATIONS 12,539 CITATIONS

SEE PROFILE SEE PROFILE

Pieter A van Doorn

Erasmus MC
611 PUBLICATIONS 37,555 CITATIONS

SEE PROFILE

All content following this page was uploaded by Pieter A van Doorn on 05 December 2014.

The user has requested enhancement of the downloaded file.

Presse Med. 2013; 42: e193–e201 on line on
ß 2013 Elsevier Masson SAS www.em-consulte.com/revue/lpm
All rights reserved. www.sciencedirect.com IMMUNE-MEDIATED NEUROPATHIES

Quarterly Medical Review

Diagnosis, treatment and prognosis of

Guillain-Barré syndrome (GBS)

Pieter A. van Doorn

Erasmus MC, Department of Neurology, Rotterdam, The Netherlands

Correspondence:
Available online: 28 April 2013 Pieter A. van Doorn, Erasmus MC, Department of Neurology’s-Gravendijkwal 230, 3015CE Rotterdam, The Netherlands.
p.a.vandoorn@erasmusmc.nl

Summary

Guillain-Barré syndrome (GBS) is an acute polyneuropathy with a variable degree of weakness

that reaches its maximal severity within 4 weeks. The disease is mostly preceded by an
infection and generally runs a monophasic course. Both intravenous immunoglobulin (IVIg) and
plasma exchange (PE) are effective in GBS. Rather surprisingly, steroids alone are ineffective.
Mainly for practical reasons, IVIg usually is the preferred treatment. GBS can be subdivided in
the acute inflammatory demyelinating polyneuropathy (AIDP), the most frequent form in the
western world; acute motor axonal neuropathy (AMAN), most frequent in Asia and Japan; and
in Miller-Fisher syndrome (MFS). Additionally, overlap syndromes exist (GBS-MFS overlap).
About 10% of GBS patients have a secondary deterioration within the first 8 weeks after start
of IVIg. Such a treatment-related fluctuation (TRF) requires repeated IVIg treatment. About 5%
of patients initially diagnosed with GBS turn out to have chronic inflammatory demyelinating
polyradiculoneuropathy (CIDP) with acute onset (A-CIDP). It is yet unknown whether GBS
patients who remain able to walk (‘mildly affected GBS patients’), or patients with MFS, also
benefit from IVIg. Despite current treatment, GBS remains a severe disease, as about 25% of
patients require artificial ventilation during a period of days to months, about 20% of patients
are still unable to walk after 6 months and 3–10% of patients die. Additionally, many patients
have pain, fatigue or other residual complaints that may persist for months or years. Pain can
also be very confusing in making the diagnosis, especially when it precedes the onset of
weakness. Advances in prognostic modelling resulted in the development of a simple
prognostic scale that predicts the chance for artificial ventilation, already at admission; and in
an outcome scale that can be used to determine the chance to be able to walk unaided after 1,
3 or 6 months. GBS patients with a poor prognosis potentially might benefit from a more
intensified treatment. A larger increase in serum IgG levels after standard IVIg treatment
(0.4 g/kg/day for 5 consecutive days) seems to be related with an improved outcome after
GBS. This was one of the reasons to start the second course IVIg trial (SID-GBS trial) in GBS
patients with a poor prognosis. This study is currently going on. The international GBS outcome
study (IGOS) is a new worldwide prognostic study that aims to get further insight in the
(immune)pathophysiology and outcome of GBS, both in children and adults. Hopefully these
and other studies will further help to improve the understanding and especially the outcome in
patients with GBS.
e193

tome 42 > n86 > juin 2013

http://dx.doi.org/10.1016/j.lpm.2013.02.328
 PA van Doorn
A lmost a century ago, the French neurologists Guillain,
Barré and Strohl described two soldiers who developed acute
paralysis with areflexia that spontaneously recovered [1].
They reported the combination of increased protein concen-
tration with a normal cell count in the CSF, or albuminocyto-
logical dissociation, which differentiated the condition form
poliomyelitis. Despite the fact that Landry had already repor-
ted similar cases in 1859, the combination of these clinical and
laboratory features became known as Guillain-Barré syndrome
(GBS) [2]. GBS most frequently is a post-infectious disorder,
mostly with Campylobacter jejuni, cytomegalovirus, Epstein-
Barr virus or M. pneumoniae [3–6]. In typical cases, among the
first symptoms are pain, numbness, paraesthesia, or weakness
in the limbs. The main features of GBS however are rapidly
progressive bilateral and relatively symmetric weakness of the
limbs with or without involvement of respiratory or cranial
nerve-innervated muscles. By definition, maximal weakness is
reached within 4 weeks, but most patients have reached their
maximal weakness already within 2 weeks [7]. Patients then
have a plateau phase of variable duration ranging from days to
several weeks or months. This phase is followed by a recovery
phase of variable duration (figure 1). Despite the positive
effect of intravenous immunoglobulin (IVIg) or plasma
exchange (PE), about 20% of the patients unable to walk
unaided (‘severely affected patients’) remain unable to do
so after half a year. Moreover, many patients remain other-
wise disabled or severely fatigued. Even 3–6 years after onset,
GBS had great impact on social life and the ability to perform
activities [8,9]. It is clear that GBS often remains a severe
disease for which better treatment is required, at least in a
proportion of patients [10].
Figure 1
Course of Guillain-Barré syndrome (GBS), antecedent infections and anti-ganglioside antibodies
e194
Diagnosis of Guillain-Barré syndrome (GBS)
[7]
Clinical features
The diagnosis of GBS is often straightforward, especially when
weakness is preceded with an infection within 1–3 weeks from
onset (box 1). In some patients however, the diagnosis can be
more difficult especially when pain is present already before
the onset of weakness, or when weakness initially is only
present in the legs [11]. Also in children, the presence of
pain may initially suggest other disorders like discitis, which
may seriously delay the diagnosis and may even be very
troublesome because progressive respiratory weakness may
be missed [12]. Therefore, several features especially should
raise doubt about the diagnosis (box 2). Several disorders or
conditions that may mimic GBS need to be excluded or made
unlikely before the diagnosis of GBS can be made (box 3).
Cerebrospinal fluid (CSF) examination
CSF examination is especially helpful to rule out other causes of
weakness, for example Lyme disease or HIV-related radiculitis,
both associated with increased number of mononuclear cells. If
there is an increased cerebrospinal fluid total protein (without
cellular reaction), this may help making the diagnosis, espe-
cially when there are some none-typical features. It is impor-
tant to realise however that about 50% of GBS patients still
have a normal CSF protein in the first week after onset of
weakness, and that the absence of an increased CSF protein
does not rule out the diagnosis.
EMG examination
EMG is especially helpful when it shows signs of a polyneuro-
pathy in clinically not yet involved areas, for example when it
tome 42 > n86 > juin 2013
Diagnosis, treatment and prognosis of Guillain-Barré syndrome (GBS)
Box 1
Criteria for the diagnosis of typical Guillain-Barré syndrome
(GBS) (adapted from Asbury [7])
Features required for diagnosis:
 progressive weakness in both arms and both legs;
 areflexia.
Features strongly supporting diagnosis:
 progression of symptoms over days to 4 weeks;
 relative symmetry of symptoms;
 mild sensory symptoms or signs;
 cranial nerve involvement, especially bilateral weakness of
facial muscles;
 recovery beginning 2–4 weeks after progression ceases;
 autonomic dysfunction;
 absence of fever at onset;
 high concentration of protein in cerebrospinal fluid, with fewer
cells than 10  10/L;
 typical electrodiagnostic features;
 pain (is often present).
Features excluding diagnosis:
 diagnosis of botulism, myasthenia, poliomyelitis, or toxic
neuropathy;
 abnormal porphyrin metabolism;
 recent diphtheria;
 purely sensory syndrome, without weakness.
Box 2
Features that should raise doubt about the diagnosis
 Marked persistent asymmetry of weakness.
 Bladder or bowel dysfunction at onset.
 Persistent bladder or bowel dysfunction.
 Sharp sensory level.
 Severe pulmonary dysfunction with limited limb weakness at
onset.
 Severe sensory signs with limited weakness at onset.
 Fever at onset of neurological symptoms.
 Increased number of mononuclear cells in CSF (> 50  106/L).
 Polymorphonuclear cells in CSF.
shows signs of a polyneuropathy in the arms in patients with
weakness only in the legs. It also enables to differentiate GBS in
AMAN (axonal features) and AIDP (demyelinating features)
[13].
Anti-ganglioside antibodies
Anti-ganglioside antibodies, as monomer or as complexes, can
be found in a proportion of GBS patients, however especially in
tome 42 > n86 > juin 2013
IMMUNE-MEDIATED NEUROPATHIES
Box 3
Differential diagnosis of Guillain-Barré syndrome (GBS)
Intracranial/spinal cord:
 brain stem encephalitis, meningitis carcinomatosis/
lymphomatosis, transverse myelitis, cord compression.
Anterior horn cells:
 poliomyelitis, West Nile virus.
Spinal nerve roots:
 compression, inflammation (e.g. Cytomegalovirus), CIDP,
meningitis carcinomatosis/lymphomatosis.
Peripheral nerves:
 drug-induced neuropathy, acute intermittent porphyria, critical
illness polyneuropathy, vasculitic neuropathy, diphtheria,
vitamin B1 deficiency (Beri-beri), heavy metal or drug
intoxication, tick paralysis, metabolic disturbances
(hypokalaemia, hypophosphatemia, hypermagnesia,
hypoglycemia).
Neuromuscular junction:
 myasthenia gravis, botulism, organophosphate poisoning.
Muscle:
 critical illness polyneuromyopathy, polymyositis,
dermatomyositis, acute rhabdomyolysis.
patients with AMAN (especially IgG anti-GM1 antibodies), and
in patients with MFS (anti-GQ1b antibodies) that cross-react
with Campylobacter [4,10,14–20]. Especially the presence of
anti-GQ1b antibodies can be helpful in making the diagnosis in
patients with MFS (table I). The results of these anti-ganglioside
antibody essays however may last several days or weeks
making these tests not always very suitable for use in clinical
practise.
A recent paper based on yet published and well-discussed data
proposed new criteria for GBS and Miller-Fisher syndrome.
These criteria are mainly suggested to be helpful in immuniza-
tion safety or epidemiological studies [21]. Three levels of
diagnostic certainty about the diagnosis of GBS are categorized
based on the presence of absence of clinical, EMG and CSF
studies (table II). Whether these Brighton criteria also work in
clinical practise now needs further evaluation. It is assumed
that rare variants of GBS consisting about 1% of the total
population are not captured within these criteria.
To further move on with the criteria for GBS, it especially would
be helpful to have access to new carefully prospectively gathe-
red data on a large group of well-described and followed GBS
patients. This preferentially includes both mildly and severely
affected GBS patients, both children and adults, and patients
e195
 PA van Doorn

Table I respiratory function and the prevention of infections [22]. Since

Spectrum of Guillain-Barré syndrome (GBS) and serum anti-
ganglioside antibodies
GBS subgroup
Acute inflammatory demyelinating
polyneuropathy (AIDP)
Acute motor (and sensory) axonal
neuropathy (AMAN or AMSAN)
Miller-Fisher syndrome/GBS
overlap syndrome
from various regions around the globe (so to include reasonable
large numbers of both AIDP and AMAN cases). These new data
potentially give relevant information, also on less frequently
encountered clinical subgroups, including on patients who do
not fulfil all standard diagnostic criteria usually required to be
randomized in controlled trials, e.g. on patients with a pro-
gressive phase of 4–6 weeks, having (near) normal reflexes, or
on those having over 50 CSF WBC/ul or on patients having only
weakness of their legs. This would help to have better insight in
the complete spectrum of GBS.
Treatment
Importance of general care in Guillain-Barré
syndrome (GBS)
Patients with GBS especially need excellent multidisciplinary
care to prevent and manage the potential fatal complications.
This indicates the need for careful monitoring of cardiac and
about 25% of severely involved patients require ventilation,
the need for this needs carefully and regularly be evaluated.
This means at least the regular measurement of vital capacity
Antibodies and respiratory frequency, and timely transfer to an intensive
Unknown care unit when indicated (box 4). A new simple scale that can
be used already at hospital admission helps to predict the
GM1, GM1b, GD1a, chance that a particular patient needs artificial ventilation [23].
GalNac–GD1a
Among other issues that need attention already early in the
GQ1b, GD3, GT1a
course of disease are prophylaxis for deep vein thrombosis,
cardiac and hemodynamic monitoring (among other symptoms
of autonomic dysfunction), pain management, management of
possible bladder and bowel dysfunction, psychosocial support
and rehabilitation. Many patients and their relatives benefit
from joining a patient organisation such as The GBS/CIDP
Foundation International (www.GBS-CIDP.org).
The beneficial effect of immunotherapy
It has been shown that plasma exchange (PE) is beneficial
when applied within the first 4 weeks from onset, but the
largest effect was seen when started early (within the first
2 weeks) [24–28]. The usual regimen is a five times PE during
2 weeks, with a total exchange of about five plasma volumes. A
French PE trial showed that two PE sessions is more effective
than no PE in patients being mildly affected form GBS [29]. The
first RCT on the use of IVIg (0.4 g IVIg/kg bodyweight/day for
five consecutive days) was published in 1992, demonstrating
that IVIg is as effective as PE [30]. After these results were
published, IVIg has replaced PE as the preferred treatment in
many centres, mainly because of its greater convenience and
availability [23]. The Cochrane review on the use of IVIg in GBS

Table II
Criteria for Guillain-Barré syndrome (GBS) for vaccinations or epidemiological research [21]

Items that are fulfilled/requested Levels of diagnostic certainty

1 2 3

1. Bilateral and flaccid weakness of the limbs + + +

2. Decreased or absent tendon reflexes in weak limbs + + +
3. Monophasic illness pattern + + +
4. Onset to nadir of weakness: 12 h–28 days + subsequent plateau + + +
5. Cytoalbuminologic dissociation # (i.e elevation CSF protein level and CSF white cells < 50  106/L) + +/#
6. Electrophysiological (EMG) findings consistent with GBS + #
7. Absence of identified alternative diagnosis for weakness + # +

Levels of diagnostic certainty range from 1 (most likely) to 3 (least likely).

Level 1: is the highest level (diagnosis of GBS is most likely). All items positive.
Level 2: items 1–4 positive; # 5 (CSF) positive, or when CSF is not collected/available: 6 (EMG) and 7 (absence of identified alternative diagnosis for weakness) positive.
Level 3: items 1–4 and 7 positive.
e196

tome 42 > n86 > juin 2013

Diagnosis, treatment and prognosis of Guillain-Barré syndrome (GBS)
Box 4
Management of Guillain-Barré syndrome (GBS) during course of
disease
Diagnosis:
 diagnosis of GBS is mainly based on clinical features and CSF;
 laboratory investigations include blood studies and EMG.
Give good general care:
 monitor progression, and prevent and manage potential fatal
complications, especially:
– regular monitor pulmonary function (vital capacity,
respiration frequency) initially every 2–4 hours, in stable
phase every 6–12 hours,
– check for autonomic dysfunction (blood pressure, heart rate,
pupils, ileus),
– check for swallowing dysfunction,
– recognize and treat pain (WHO guideline). Try to avoid
opioids,
– prevent (and treat) infections and pulmonary embolism,
– prevent decubitus and contractures.
Consider specific treatment with IVIg or PE:
 indication to start IVIg or PE;
 severely affected patients (inability to walk unaided = GBS
disability scale  3);
 start preferable within first 2 weeks from onset;
 IVIg: 0.4 g/kg for 5 days (unknown whether 1.0 g/kg for 2 days
is superior);
 PE: standard 5x PE with total exchange of five plasma volumes;
 unknown whether IVIg is effective in mildly affected patients
(GBS disability scale  2) or MFS patients;
 indication for re-treatment with IVIg: secondary deterioration
after initial improvement or stabilization (treatment-related
fluctuation): treat with 0.4 g/kg for 5 days;
 no proven effect of re-treatment with IVIg in patients who
continue to worsen.
Is there an indication for ICU admission?
 Rapidly progressive severe weakness often with impaired
respiration (vital capacity < 20 ml/kg) [23].
 Need for artificial ventilation.
 Insufficient swallowing with high chance for pulmonary
infection.
 Severe autonomic dysfunction.
 Use prognostic model to determine change for artificial
ventilation [23].
Fluctuations during course of disease or continued slow
progression?
 Consider treatment-related fluctuation (TRF): repeat treatment.
 Consider acute onset CIDP (A-CIDP) and treat accordingly.
Rehabilitation and fatigue:
 start physiotherapy early during course of disease;
 start rehabilitation as soon as improvement starts;
tome 42 > n86 > juin 2013
IMMUNE-MEDIATED NEUROPATHIES
Box 4 (Continued)
 consider a physical training program for severe fatigue;
 consider to contact patient organization for additional
information and help.
showed that there was no difference between IVIg and PE with
respect to the improvement in disability grade after 4 weeks,
the duration of mechanical ventilation, mortality, or residual
disability [31]. The combination of PE followed by IVIg was not
significantly better than PE or IVIg alone [26]. It appeared that
oral steroids (or intravenous methylprednisolone 500 mg/day
for five consecutive days) alone are not beneficial in GBS [32].
The combination of IVIg and intravenous metylprednisolone
was not more effective than IVIg alone, but there might be
some additional short-term effects of this combined treatment
when a correction was made for known prognostic factors [33].
The overall conclusion is that according to moderate quality
evidence, corticosteroids given alone do not significantly has-
ten recovery from GBS or affect the long-term outcome.
According to low quality evidence, oral corticosteroids may
even delay recovery [34]. In a pilot-study, we studied the
additional effect of a 6-week treatment of mycophenolate in
GBS, which did not show a positive effect [35]. There definitely
is an effect of immunotherapy on the course of GBS, but new
studies improving also the final outcome of GBS remain
urgently needed [27]. An ongoing RCT (SID-GBS) studies the
effect of a second course of IVIg given shortly after the first IVIg
course only in GBS patients with a poor prognosis. This study is
currently running in The Netherlands. An international obser-
vational study on the effect of a second-dose IVIg in GBS
patients with a poor prognosis (I-SID-GBS) has just started.
This study is linked to the International GBS Outcome Study
(IGOS), a study performed by the Inflammatory Neuropathy
Consortium (INC).
When should treatment be started?
The North-American PE trial showed an effect of PE when
applied within the first 4 weeks after onset/weakness. Most
effect however was observed when PE was started within the
first 2 weeks form onset. After the publication of this trial, most
RCT’s have enrolled patients being within the time window of
2 weeks from onset of weakness and unable to walk without
assistance [27].
Should mildly affected patients be treated?
Mildly affected is arbitrarily often defined as being able to walk,
with or without assistance. A retrospective study demonstrated
that these patients frequently have residual disabilities. The
RCT’s evaluating the effect of IVIg did not study the effect in
e197
 PA van Doorn

mildly affected patients. One large French trial studied the

effect of PE also in patients who could walk with or without
aid, but not run. Onset of motor recovery was faster in patients
who received two PE sessions compared to no PE [29]. Based on
this study there seems to be an indication also to treat mildly
affected GBS patients with PE, but one must keep in mind that
yet no randomized placebo controlled studies have evaluated
the effect of PE or IVIg in these mildly affected GBS patients
[10,27].

Should patients with Miller-Fisher syndrome (MFS)

be treated?
No RCT’s have been performed on the effect of PE or IVIg in
patients with MFS. Observational studies suggested that the
final outcome in patients with MFS generally is good [36]. From
a large Japanese uncontrolled observational study, it was found
that IVIg slightly hastened the amelioration of ophthalmoplegia
and ataxia, but the times of disappearances of these symptoms
were similar among the IVIg, PE and no-treatment group. It was
concluded that IVIg and PE seem not to have influenced MFS
patients’ outcome, presumably because of good natural reco-
very [37–39].
What to do if a patient continues to deteriorate after
treatment?
A proportion of GBS patients continue to deteriorate after PE or
a standard course of IVIg. In these cases, it is unknown what
would be the best option: wait and see, or to start additional
treatment. The reason why some patients continue to dete-
riorate and may be paralytic for months is not known. These
patients might have a severe or prolonged immune attack
causing severe axonal degeneration. Treatment might act
insufficiently in these individuals. It is presently not known
how to treat patients who continue to deteriorate. Do these
patients need PE after they have been treated with IVIg? This
has not been investigated, but it has been shown that the
combination of PE followed with IVIg is not superior compared
to PE or IVIg alone [26]. A small open study suggested that a
repeated course of IVIg may be effective in severe unrespon-
sive GBS patients [40]. Additionally it has been shown that a
larger increase in serum IgG levels, 2 weeks after starting a first
IVIg course, was associated with a better outcome [41]. The
international trial studying the effect of a second IVIg dose in
patients with a poor prognosis (I-SID-GBS), based upon the
modified Erasmus Guillain-Barré Outcome score (mEGOS), is
currently running [42].
What to do if a patient deteriorates after initial
improvement?
About 5 to 10% of GBS patients deteriorate after initial
improvement or stabilization following IVIg treatment, a condi-
tion named ‘‘treatment-related clinical fluctuation’’ [43,44].
e198
Figure 2
Guillain-Barré syndrome (GBS), treatment-related fluctuations
(GBS-TRF) and acute onset CIDP (A-CIDP)
Although no RCT has evaluated the effect of a repeated IVIg
dosage in this condition, it is common practise to give a second
IVIg course (2 g/kg in 2–5 days), since these patients are likely
to improve after re-initiating this treatment [27]. It is conside-
red that these patients may have a prolonged immune-res-
ponse that causes ongoing nerve damage needing treatment
for a longer period of time. Some of these GBS patients may
even have several episodes of deterioration. This often raises
the question whether these patients may have chronic inflam-
matory demyelinating polyneuropathy with acute onset (A-
CIDP) (figure 2) [45].
How many deteriorations would alter the diagnosis
from GBS to A-CIDP?
This is an important question, but the answer is not fully known
yet. We have evaluated our series of patients and concluded
that the diagnosis of A-CIDP should be suspected when patients
initially diagnosed with GBS, do have three or more of these
deteriorations or when they have a subsequent deterioration
after 9 weeks from onset of GBS [45] (box 5). It is important to
look for these secondary deteriorations because GBS patients
may improve after a new course of IVIg and some of these
patients turn out to have a variant of CIDP with acute onset
(A-CIDP) needing chronic maintenance treatment [45].
Importance of pain in the acute and chronic
phase of GBS
Pain is a common and severe symptom in patients with GBS.
Recognition of pain is important, especially in patients unable
to communicate due to intubation. Pain as a presenting symp-
tom of GBS, before the onset of weakness, may be misleading
in making the diagnosis of GBS. Pain has been described in up to
89% of patients with GBS. Recognition of the presence and type

tome 42 > n86 > juin 2013

Diagnosis, treatment and prognosis of Guillain-Barré syndrome (GBS)
Box 5
Differences between GBS-TRF and acute onset CIDP (A-CIDP) [45]
GBS-TRF patients:
 more frequent cranial nerve dysfunction;
 more rapid onset of weakness;
 more severe weakness;
 only one or two TRF’s;
 first TRF sooner compared to deterioration in A-CIDP;
 TRF(’s) occur(s) < 2 months from onset.
A-CIDP patients:
 no ventilatory support;
 more demyelinating features on EMG;
 when three or more exacerbations;
 when deterioration occurs > 2 months from onset.
of pain is important because specific treatments can be offered
[11,46].
Autonomic failure
Autonomic dysfunction, like labile blood pressure, tachycardia
or heart rate disturbances, often occurs in GBS patients. Reco-
gnition of autonomic dysfunction is important, because it may
be an important cause of death in GBS. Three to 10% of patients
die, presumable partly due to (sudden) autonomic failure. It is
yet not well possible to predict which patients will develop
serious autonomic failure and therefore need continue moni-
toring [47]. From observational studies, it seems that patients
not only die while being admitted on an ICU due to serious
autonomic failure or pulmonary problems, but also the first
period after discharge from an ICU can be a high-risk period
especially when a patient has a tracheostoma and stasis of
sputum.
The presence and treatment of severe fatigue after
Guillain-Barré syndrome (GBS)
Fatigue after GBS is an important problem. It was found that
severe fatigue was even present in 60–80% of patients. Eighty
percent of patients reported fatigue as being among their three
most disabling symptoms [48]. A 12-week bicycle exercise
training however was likely to be effective in 16 severely
fatigued but neurologically well-recovered GBS and four stable
CIDP patients [49]. The rather intensive, three times weekly
training program we used was well tolerated in patients who
were neurologically rather well recovered from GBS, and self-
reported fatigue scores decreased significantly. Physical fitness,
functional outcome, and quality of life were also improved. A
RCT however still needs to be done. Although the effect of the
tome 42 > n86 > juin 2013
IMMUNE-MEDIATED NEUROPATHIES
physical training program cannot fully be explained yet, it
seems to help, possible also by ensuring and changing life style.
Prognosis of Guillain-Barré syndrome (GBS)
Several studies have been published on the prognosis in GBS.
Some of these found a relationship between electromyographic
(EMG) features and an increased chance to need artificial
ventilation or to have a poorer outcome. One large study
showed that demyelinating features when assessing the per-
onal nerve was related with a high chance needing artificial
ventilation [50]. We recently constructed and validated a pro-
gnostic model, Erasmus GBS Respiratory Insufficiency Scale
(EGRIS) that can be used already at the day of admission to
determine the change for artificial ventilation [23]. Days bet-
ween onset of weakness and admission, Medical Research
Council sum score, and presence of facial and/or bulbar weak-
ness were the main predictors of mechanical ventilation. This
simple model only requiring clinical features potentially can be
of great help to make decisions where to admit patients: at a
general neurology ward or at the intensive care unit. Regarding
the prognosis of outcome after one to 6 months from onset,
age is generally considered to be a poor prognostic factor.
Another prognostic model (Erasmus GBS Outcome Scale) has
been constructed and validated to determine outcome after
6 months [51]. A modification of this model (mEGOS) showed
that it is already possible to determine outcome 1 week after
hospital admission. When using three simple clinical factors:
high age, preceding diarrhea, and low Medical Research Council
sum score both at hospital admission and at 1 week were
independently associated with being unable to walk at
4 weeks, 3 months, and 6 months (all P 0.05–0.001). This
model offers the possibility to select patients with a poor
prognosis already within the first week after admission. This
is important, not only for counseling, but also when considering
more intensified treatment for GBS already early in the course
of disease. In this early phase of disease, it is more likely that
intensified treatment is still effective because irreversible nerve
damage has not yet been occurred. We now use this mEGOS to
select patients to study the effect of a second-dose immuno-
globulin (SID-GBS trial). Prognosis of GBS is an important issue
because treatment really needs to be improved. In light of this,
it is of extreme importance that the Inflammatory Neuropathy
Consortium (INC) has recently started a large international
collaborative study. This International GBS outcome study
(IGOS) is conducted by a worldwide consortium of neurologists,
it investigates outcome especially in relation to clinical, immu-
nological, microbiological, and genetic factors.
Future directions
New treatment options in GBS are absolutely necessary
because the prognosis in a large group of GBS patients is
e199
 PA van Doorn

still far from good. One option in the acute phase could be a
second IVIg treatment in patients with a poor prognosis. The
SID-GBS RCT is going on in The Netherlands, and the interna-
tional second-dose IVIg study (I-SID-GBS) has been started.
Recent experiments indicate that agents that interfere with
complement activation are potentially attractive candidates to
be tested in a very early phase of GBS [52]. Since it is now
possible to predict outcome in individual patients more accura-
tely, new drugs like eculizumab or other regimens could be
tested especially in a restricted GBS population with a poor
prognosis. Focus also on the pathophysiological effect of treat-
ment, such as studying the mechanism of action of IVIg, poten-
tially could also lead to more personalized treatment once it is
shown that some patients require other IVIg dosages or treat-
ment regimens. Treatment trials, especially in rare diseases,
usually require a long period of time to include sufficient patients.
A new trial design in a selected population (like is being done in
the SID-GBS RCT) uses covariate adjustment which reduces the
sample size required to reach sufficient power [53]. Using the
most appropriate outcome measurements to evaluate the effect
of treatment is essential. This is currently under investigation in
the Peripheral Neuropathy Outcome Study (Perinoms) [54]. New
trials investigating less aggressive treatments are also indicated
in mildly affected patients, and possibly also in patients with MFS.
More attention should be paid to pain, autonomic dysfunction,
and severe fatigue, all yet often under-recognised conditions.
The Inflammatory Neuropathy Consortium (INC) is an excellent
platform to conduct these studies.
Disclosure of interest: the author initiated the ongoing randomized
controlled second-dose IVIg trial in GBS patients with a poor prognosis (SID-
GBS), sponsored by Sanquin; and the international second-dose IVIg
prospective follow-up study in GBS (I-SID-GBS) sponsored by Talecris.

References
[1] Guillain G, Barré JA, Strohl A. Sur un
syndrome de radiculo-névrite avec hyper-
albuminose du liquide céphalorachidien
sans réaction cellulaire. Remarques sur les
caractères cliniques et graphiques des
réflexes tendineux. Bull Soc Med Hop Paris
1916;28:1462-70.
[2] Landry O. Note sur la paralyse ascendente
aiguë. Gazette Hebdomadaire Med Chir
1859;6:472-4 ([486–8]).
[3] Hughes RA, Cornblath DR. Guillain-Barré
syndrome. Lancet 2005;366:1653-66.
[4] Yuki N, Hartung HP. Guillain-Barré syn-
drome. N Engl J Med 2012;366:2294-304.
[5] Jacobs BC, Rothbarth PH, Van Der Meché FG,
Herbrink P, Schmitz PI, de Klerk MA et al.
The spectrum of antecedent infections in
Guillain-Barré syndrome: a case-control
study. Neurology 1998;51:1110-5.
[6] Hadden RD, Karch H, Hartung HP, Zielasek J,
Weissbrich B, Schubert J et al. Preceding
infections, immune factors, and outcome in
Guillain-Barré syndrome. Neurology
2001;56:758-65.
[7] Asbury AK, Cornblath DR. Assessment of
current diagnostic criteria for Guillain-Barré
syndrome. Ann Neurol 1990;27(Suppl.):
S21-4.
[8] Bernsen RA, de Jager AE, Schmitz PI, Van
Der Meché FG. Residual physical outcome
and daily living 3 to 6 years after Guillain-
Barré syndrome. Neurology 1999;53:
409-10.
[9] Bernsen RA, Jacobs HM, de Jager AE, Van
Der Meché FG. Residual health status after
Guillain-Barré syndrome. J Neurol Neuro-
surg Psychiatry 1997;62:637-40.
[10] van Doorn PA, Ruts L, Jacobs BC. Clinical
features, pathogenesis, and treatment of
e200
Guillain-Barré syndrome. Lancet Neurol
2008;7:939-50.
[11] Ruts L, Drenthen J, Jongen JL, Hop WC, Visser
GH, Jacobs BC et al. Pain in Guillain-Barré
syndrome: a long-term follow-up study.
Neurology 2010;75:1439-47.
[12] Roodbol J, de Wit MC, Walgaard C, de Hoog
M, Catsman-Berrevoets CE, Jacobs BC.
Recognizing Guillain-Barré syndrome in
preschool children. Neurology
2011;76:807-10.
[13] Hadden RD, Cornblath DR, Hughes RA,
Zielasek J, Hartung HP, Toyka KV et al.
Electrophysiological classification of Guillain-
Barré syndrome: clinical associations and
outcome. Plasma Exchange/Sandoglobulin
Guillain-Barré Syndrome Trial Group. Ann
Neurol 1998;44:780-8.
[14] Willison HJ. The immunobiology of Guillain-
Barré syndromes. J Peripher Nerv Syst
2005;10:94-112.
[15] Willison HJ. Ganglioside complexes: new
autoantibody targets in Guillain-Barré syn-
dromes. Nat Clin Pract Neurol 2005;1:2-3.
[16] Kusunoki S, Kaida K, Ueda M. Antibodies
against gangliosides and ganglioside
complexes in Guillain-Barré syndrome:
new aspects of research. Biochim Biophys
Acta 2008;1780:441-4.
[17] Yuki N. Fisher syndrome and Bickerstaff
brainstem encephalitis (Fisher-Bickerstaff
syndrome). J Neuroimmunol 2009;
215:1-9.
[18] Yuki N. Molecular mimicry between gan-
gliosides and lipopolysaccharides of Cam-
pylobacter jejuni isolated from patients
with Guillain-Barré syndrome and Miller
Fisher syndrome. J Infect Dis 1997;
176(Suppl. 2):S150-3.
[19] Yuki N. Anti-ganglioside antibody and
neuropathy: review of our research. J
Peripher Nerv Syst 1998;3:3-18.
[20] Ang CW, Jacobs BC, Laman JD. The
Guillain-Barré syndrome: a true case of
molecular mimicry. Trends Immunol
2004;25:61-6.
[21] Sejvar JJ, Kohl KS, Gidudu J, Amato A, Bakshi
N, Baxter R et al. Guillain-Barré syndrome
and Fisher syndrome: case definitions and
guidelines for collection, analysis, and pre-
sentation of immunization safety data.
Vaccine 2011;29:599-612.
[22] Hughes RA, Wijdicks EF, Benson E, Cornblath
DR, Hahn AF, Meythaler JM et al. Supportive
care for patients with Guillain-Barré syn-
drome. Arch Neurol 2005;62:1194-8.
[23] Walgaard C, Lingsma HF, Ruts L, Drenthen J,
van Koningsveld R, Garssen MJ et al.
Prediction of respiratory insufficiency in
Guillain-Barré syndrome. Ann Neurol
2010;67:781-7.
[24] The Guillain-Barré syndrome Study Group.
Plasmapheresis and acute Guillain-Barré
syndrome. Neurology 1985;35:1096-104.
[25] French Cooperative Group on Plasma
Exchange in Guillain-Barré Syndrome. Effi-
ciency of plasma exchange in Guillain-Barré
syndrome: role of replacement fluids. Ann
Neurol 1987;22:753-61.
[26] Plasma Exchange/Sandoglobulin Guillain-
Barré Syndrome Trial Group. Randomised trial
of plasma exchange, intravenous immunoglo-
bulin, and combined treatments in Guillain-
Barré syndrome. Lancet 1997;349:225-30.
[27] Hughes RA, Swan AV, Raphael JC, Annane D,
van Koningsveld R, van Doorn PA. Immuno-
therapy for Guillain-Barré syndrome: a sys-
tematic review. Brain 2007;130:2245-57.

tome 42 > n86 > juin 2013

Diagnosis, treatment and prognosis of Guillain-Barré syndrome (GBS)
[28] Raphael JC, Chevret S, Hughes RA, Annane
D. Plasma exchange for Guillain-Barré
syndrome. Cochrane Database Syst Rev
2012;7:CD001798.
[29] The French Cooperative Group on Plasma
Exchange in Guillain-Barré Syndrome.
Appropriate number of plasma exchanges
in Guillain-Barré syndrome. Ann Neurol
1997;41:298-306.
[30] Van Der Meché FG, Schmitz PI. A randomi-
zed trial comparing intravenous immune
globulin and plasma exchange in Guillain-
Barré syndrome. Dutch Guillain-Barré Study
Group. N Engl J Med 1992;326:1123-9.
[31] Hughes RA, Swan AV, van Doorn PA.
Intravenous immunoglobulin for Guillain-
Barré syndrome. Cochrane Database Syst
Rev 2012;7:CD002063.
[32] Guillain-Barré Syndrome Steroid Trial Group.
Double-blind trial of intravenous methyl-
prednisolone in Guillain-Barré syndrome.
Lancet 1993;341:586-90.
[33] van Koningsveld R, Schmitz PI, Meché FG,
Visser LH, Meulstee J, van Doorn PA.
Effect of methylprednisolone when added
to standard treatment with intravenous
immunoglobulin for Guillain-Barré syndrome:
randomised trial. Lancet 2004;363:192-6.
[34] Hughes RA, van Doorn PA. Corticosteroids
for Guillain-Barré syndrome. Cochrane Data-
base Syst Rev 2012;8:CD001446.
[35] Garssen MP, van Koningsveld R, van Doorn
PA, Merkies IS, Scheltens-de BM, van
Leusden JA et al. Treatment of Guillain-Barré
syndrome with mycophenolate mofetil: a
pilot study. J Neurol Neurosurg Psychiatry
2007;78:1012-3.
[36] Overell JR, Hsieh ST, Odaka M, Yuki N,
Willison HJ. Treatment for Fisher syndrome,
Bickerstaff’s brainstem encephalitis and
related disorders. Cochrane Database Syst
Rev 2007;1:CD004761.
tome 42 > n86 > juin 2013
View publication stats
[37] Mori M, Kuwabara S, Yuki N. Fisher
syndrome: clinical features, immunopatho-
genesis and management. Expert Rev
Neurother 2012;12:39-51.
[38] Mori M, Kuwabara S. Fisher syndrome. Curr
Treat Options Neurol 2011;13:71-8.
[39] Mori M, Kuwabara S, Fukutake T, Hattori T.
Intravenous immunoglobulin therapy for
Miller Fisher syndrome. Neurology
2007;68:1144-6.
[40] Farcas P, Avnun L, Frisher S, Herishanu YO,
Wirguin I. Efficacy of repeated intravenous
immunoglobulin in severe unresponsive
Guillain-Barré syndrome. Lancet
1997;350:1747.
[41] Kuitwaard K, de Gelder J, Tio-Gillen AP, Hop
WC, van Gelder T, van Toorenenbergen AW
et al. Pharmacokinetics of intravenous immu-
noglobulin and outcome in Guillain-Barré
syndrome. Ann Neurol 2009;66:597-603.
[42] Walgaard C, Lingsma HF, Ruts L, van Doorn
PA, Steyerberg EW, Jacobs BC. Early reco-
gnition of poor prognosis in Guillain-Barré
syndrome. Neurology 2011;76:968-75.
[43] Ruts L, van Koningsveld R, van Doorn PA.
Distinguishing acute-onset CIDP from Guil-
lain-Barré syndrome with treatment-
related fluctuations. Neurology
2005;65:138-40.
[44] Kleyweg RP, Van Der Meché FG. Treatment
related fluctuations in Guillain-Barré syn-
drome after high-dose immunoglobulins or
plasma-exchange. J Neurol Neurosurg Psy-
chiatry 1991;54:957-60.
[45] Ruts L, Drenthen J, Jacobs BC, van Doorn PA.
Distinguishing acute-onset CIDP from fluc-
tuating Guillain-Barré syndrome: a prospec-
tive study. Neurology 2010;74:1680-6.
[46] Ruts L, Rico R, Koningsveld R, van JD, Botero
J, Meulstee I et al. Pain accompanies pure
motor Guillain-Barré syndrome. J Peripher
Nerv Syst 2008;13:305-6.
IMMUNE-MEDIATED NEUROPATHIES
[47] Ruts L, van Doorn PA, Lombardi R, Haasdijk
ED, Penza P, Tulen JH et al. Unmyelinated
and myelinated skin nerve damage in
Guillain-Barré syndrome: correlation with
pain and recovery. Pain 2012;153:399-409.
[48] Merkies IS, Schmitz PI, Samijn JP, Van Der
Meché FG, van Doorn PA. Fatigue in
immune-mediated polyneuropathies. Euro-
pean Inflammatory Neuropathy Cause and
Treatment (INCAT) Group. Neurology
1999;53:1648-54.
[49] Garssen MP, Bussmann JB, Schmitz PI,
Zandbergen A, Welter TG, Merkies IS et al.
Physical training and fatigue, fitness, and
quality of life in Guillain-Barré syndrome
and CIDP. Neurology 2004;63:2393-5.
[50] Durand MC, Porcher R, Orlikowski D, Aboab
J, Devaux C, Clair B et al. Clinical and
electrophysiological predictors of respira-
tory failure in Guillain-Barré syndrome: a
p r o s p e c t i v e s t u d y. L a n c e t N e u r o l
2006;5:1021-8.
[51] van Koningsveld R, Steyerberg EW, Hughes
RA, Swan AV, van Doorn PA, Jacobs BC. A
clinical prognostic scoring system for Guil-
lain-Barré syndrome. Lancet Neurol
2007;6:589-94.
[52] Halstead SK, Zitman FM, Humphreys PD,
Greenshields K, Verschuuren JJ, Jacobs BC
et al. Eculizumab prevents anti-ganglioside
antibody-mediated neuropathy in a murine
model. Brain 2008;131:1197-208.
[53] Lingsma H, Roozenbeek B, Steyerberg E.
Covariate adjustment increases statistical
power in randomized controlled trials. J Clin
Epidemiol 2010;63:1391 ([author reply:
1392–3]).
[54] van Nes SI, Faber CG, Merkies ISJ. Outcome
measures in immune-mediated neuropa-
thies: the need to standardize their use and
to understand the clinimetric essentials. J
Peripher Nerv Syst 2008;13:136-47.
e201