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Immunotherapy For Guillain-Barré Syndrome A Systematic Review
Immunotherapy For Guillain-Barré Syndrome A Systematic Review
REVIE W ARTICLE
Immunotherapy for Guillain-Barre¤ syndrome:
a systematic review
Richard A. C. Hughes,1 Anthony V. Swan,1 Jean-Claude Raphae«l,2 Djillali Annane,2 Rinske van Koningsveld3
and Pieter A. van Doorn3
1
Department of Clinical Neuroscience, King’s College London, Guy’s Campus, London, UK, 2Service de Re¤animation Me¤dicale,
Guillain-Barre¤ syndrome (GBS) is an acute inflammatory disorder of the peripheral nervous system thought to
be due to autoimmunity for which immunotherapy is usually prescribed. To provide the best evidence on which
to base clinical practice, we systematically reviewed the results of randomized trials of immunotherapy for GBS.
We searched the Cochrane Library, MEDLINE and EMBASE in July 2006 and used the methods of the Cochrane
Neuromuscular Disease Group to extract and synthesize data. Almost all trials used a 7-point disability grade
scale. In four trials with altogether 585 severely affected adult participants, those treated with plasma exchange
(PE) improved significantly more on this scale 4 weeks after randomization than those who did not, weighted
mean difference (WMD) 20.89 (95% confidence interval (CI) 21.14 to 20.63). In five trials with altogether 582
participants, the improvement on the disability grade scale with intravenous immunoglobulin (IVIg) was very
similar to that with PE, WMD 20.02 (95% CI 20.25 to 0.20). There was also no significant difference between
IVIg and PE for any of the other outcome measures. In one trial with 148 participants, following PE with IVIg
did not produce significant extra benefit. Limited evidence from three open trials in children suggested that IVIg
hastens recovery compared with supportive care alone. Corticosteroids were compared with placebo or suppor-
tive treatment in six trials with altogether 587 participants.There was significant heterogeneity in the analysis of
these trials which could be accounted for by analysing separately four small trials of oral corticosteroids with
altogether 120 participants, in which there was significantly less improvement after 4 weeks with corticosteroids
than without, WMD 20.82 (95% CI 20.17 to 21.47), and two large trials of intravenous methylprednisolone with
altogether 467 participants, in which there was no significant difference between corticosteroids and placebo
WMD 20.17 (95% CI 0.06 to 20.39). None of the treatments significantly reduced mortality. Since 20% of
patients die or have persistent disability despite immunotherapy, more research is needed to identify better
treatment regimens and new therapeutic strategies.
Keywords: Guillain-Barre¤ syndrome; treatment; systematic review; plasma exchange; intravenous immunoglobulin;
corticosteroid
Abbreviations: CI ¼ confidence interval; GBS ¼ Guillain-Barre¤ syndrome; IVIg ¼ intravenous immunoglobulin; PE ¼ plasma
exchange; RR ¼ relative rate; WMD ¼ weighted mean difference
Received December 28, 2006. Accepted January 5, 2007. Advance Access publication March 2, 2007
Introduction
Guillain-Barré syndrome (GBS) is the major cause of acute whose pathological substrate may be acute inflammatory
neuromuscular paralysis with an annual incidence of 1.3–2 demyelinating polyradiculoneuropathy (AIDP) or acute
per 100 000 throughout the world (Van Koningsveld et al., axonal motor or motor and sensory axonal neuropathy
2000; Govoni and Granieri, 2001). It is a clinical syndrome (Griffin et al., 1995). AIDP is much more common than
ß The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
2246 Brain (2007), 130, 2245^2257 R. A. C. Hughes et al.
axonal forms in the Western world. Experimental evidence Table 1 Guillain-Barre¤ syndrome disability scale
implicates autoantibodies to gangliosides as the cause of the
0. Healthy
axonal subgroups of GBS and of Fisher syndrome (Willison 1. Minor symptoms or signs of neuropathy but capable of manual
and Yuki, 2002). These autoantibodies may be generated by work/capable of running
the immune response to an infective organism, such as 2. Able to walk without support of a stick (5 m across an open
Campylobacter jejuni, cross-reacting with epitopes on the space) but incapable of manual work/running
3. Able to walk with a stick, appliance or support (5 m across an
axon (Yuki et al., 2004). The resemblance of AIDP to
open space)
experimental autoimmune neuritis suggests pathogenetic 4. Confined to bed or chair bound
mechanisms involving T-cell induced macrophage- 5. Requiring assisted ventilation (for any part of the day or night)
associated demyelination (Hughes and Cornblath, 2005). 6. Death
This proposed autoimmune aetiology led to the introduc-
The original scale is shown in regular print (Hughes et al., 1978) and
tion of immunotherapy. Before its introduction, 10% of
Statistical analysis
Material and methods We calculated a weighted treatment effect across trials using the
Data acquisition Cochrane statistical package RevMan 4.2 with a fixed effect model
We used the search strategy of the Cochrane Neuromuscular when the results were homogeneous and a random effects model
Disease Group (Annane et al., 2004). We searched the Cochrane when they were not. Results were expressed as relative risks (RR)
Library and the trials register of the Group, MEDLINE and with 95% confidence intervals (CIs) for dichotomous outcomes
EMBASE for randomized trials using Guillain-Barré syndrome or and weighted mean difference (WMD) with 95% CIs for
acute polyradiculoneuritis and plasma exchange or plasmapheresis continuous outcomes. In two instances, the standard deviation of
or intravenous immunoglobulin or corticosteroid or adrenocorti- the change in disability grade after 4 weeks was not available and,
cotrophic hormone or treatment or therapy as the search terms. to calculate the WMD of the improvement in disability grade, we
We also searched for quasi-randomized trials, which are those imputed the largest values of the standard deviation for any of the
which use methods such as alternate allocation and are not truly other trials with that intervention (Bril et al., 1996; Diener et al.,
randomized. We checked the bibliographies in reports of the 2001). Coefficients from logistic regression analyses, representing
randomized trials and contacted their authors and other experts to the odds ratio of relative recovery rates from different studies on a
identify additional published or unpublished data. We updated logarithmic scale, were combined using a weighted average with
these searches on July 13, 2006. Two reviewers checked titles and weights inversely proportional to their variances. This was achieved
abstracts identified from these sources and obtained the full text of using the Generic Inverse Variance facility in RevMan.
GBS systematic review Brain (2007), 130, 2245^2257 2247
R. A. C. Hughes et al.
syndrome, 1997
Wollinsky et al., 2001 Two centres n ¼ 37 CSF filtration 150 to 300 ml No significant differences in any outcome. Mean
Open Adults daily for 5 to 15 days versus change in disability grade at 4 weeks was 0.82 with
Parallel group Cannot walk 45 m unassisted PE daily or every other CSF filtration (n ¼17) and 0.80 with PE (n ¼ 20)
day for 7 to 14 days
GBS systematic review
Table 3 Characteristics of included studies of intravenous immunoglobulin
Study Trial design (RCT unless stated) Participants Treatment Results
Bril et al., 1996 Single centre n ¼ 50 IVIg 0.5 g/kg daily for 4 days No significant differences in
Parallel group Adults versus PE 40 ^50 ml/kg daily multiple outcomes
for 5 days
2249
(95% CI 0.54 to 0.14)
(continued)
2250 Brain (2007), 130, 2245^2257 R. A. C. Hughes et al.
(95% CI 2 to 39%)
PE (Table 3) (van der Meché et al., 1992; Bril et al., 1996;
Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome
Trial Group, 1997; Nomura et al., 2000; Diener et al.,
2001). The weighted mean disability grade improvement
Results
was almost identical, being 0.02 more with IVIg than with
PE (95% CI 0.25 more improvement to 0.20 less
improvement) (Fig. 1B). There was also no significant
et al., 2001).
Two trials compared different doses or regimens of IVIg.
One, in adults, randomized 39 patients with GBS of any
severity and contraindications for PE to 3 or 6 days of IVIg
versus 6 days
Adults with
n ¼ 54
n ¼ 39
to PE
with same total dose of 2.0 g/kg given as 1.0 g/kg daily for
2 days (Korinthenberg et al., 2005). There were no
significant differences in the primary or secondary outcome
measures reported by the authors (Table 3) except that
Trial design (RCT unless stated)
Parallel group
Parallel group
with the 2-day than the 5-day regimen but the 95% CIs
Multicentre
Multicentre
Number of
Bansal et al., 2004 Alternate allocation n ¼ 20 Prednisolone 15 mg 4 times daily No significant differences in
Single centre for 4 days, 10 mg 3 times daily for changes in GBS disability grade
Open 3 days, 10 mg 3 times daily for 10 days after 1, 2, 3, and 4 weeks and
Parallel group and then tapered or no treatment 3 months; disease duration;
residual disability; death; relapse
2251
placebo infusions No significant differences in ability
to walk unaided after 8 weeks or
time to walk independently
2252 Brain (2007), 130, 2245^2257 R. A. C. Hughes et al.
−4 −2 0 2 4
Favours treatment Favours control
−4 −2 0 2 4
Favours IVIg Favours PE
Study Corticosteroids Control WMD (random) WMD (random)
C or sub-category N Mean (SD) N Mean (SD) 95% CI 95% CI
01 Oral regimens
Bansal 1986 10 −2.38(0.97) 10 −3.97(0.70) 1.59 [0.85, 2.33]
Hughes 1978 21 −0.24(0.94) 19 −0.74(0.81) 0.50 [−0.04, 1.04]
Shukla 1988 6 −0.67(1.75) 8 −0.88(1.13) 0.21 [−1.39, 1.81]
Singh 1996 24 −0.20(2.00) 22 −0.80(2.10) 0.60 [−0.59, 1.79]
Subtotal (95% CI) 61 59 0.82 [0.17, 1.47]
Test for heterogeneity: Chi² = 6.16, df = 3 (P = 0.10), I² = 51.3%
Test for overall effect: Z = 2.47 (P = 0.01)
02 Intravenous regimens
GBS Steroid 1993 124 −0.80(1.14) 118 −0.73(1.21) −0.07 [−0.37, 0.23]
van Koningsveld 2004 112 −1.13(1.30) 113 −0.83(1.35) −0.30 [−0.65, 0.05]
Subtotal (95% CI) 236 231 −0.17 [−0.39, 0.06]
Test for heterogeneity: Chi² = 0.98, df = 1 (P = 0.32), I² = 0%
Test for overall effect: Z = 1.46 (P = 0.15)
−4 −2 0 2 4
Favours Steroid Favours Control
Fig. 1 Weighted mean difference of the change in disability grade 4 weeks after randomization. Negative change represents improvement.
(A) Plasma exchange versus no treatment (from Raphae«l et al., 2002) (B) Plasma exchange versus intravenous immunoglobulin (from Hughes
et al., 2006a) (C) corticosteroids versus no treatment or placebo (from Hughes et al., 2006b).
after 4 weeks, time to independent walking, duration of primary outcome measure: there was no significant differ-
ventilation, death or death and disability 12 months later ence in the mean improvement in disability after 4 weeks
(Tables 5 and 6). between those who received corticosteroids and those who
One non-randomized trial compared immunoabsorption did not (Fig. 1C). The WMD of change in grade was 0.36
followed by IVIg in 24 patients with immunoabsorption (95% CI 0.88 to 0.16), indicating less improvement in
alone in 13 patients. There was no significant difference in the corticosteroid-treated participants. There was significant
improvement after 4 weeks. The mean difference was 1.10, heterogeneity in this analysis so that a random effects model
95% CI 0.36–1.84, more improvement in the immuno- was used for the computation. Inspection of the forest plot
absorption followed by IVIg group than in the group suggested more benefit from the intravenous regimens so
treated with immunoabsorption alone (Haupt et al., 1996). that we undertook a separate analysis of the trials which
There were also no significant differences in any other used oral and intravenous regimens. In the four small trials
outcome. which used oral corticosteroids (Shukla et al., 1988; Singh
and Gupta, 1996; Bansal et al., 2004), there were in total 120
Corticosteroids participants and there was significantly less improvement
Eight trials randomized altogether 623 participants to with corticosteroids than without, WMD 0.82 of a
corticosteroids or placebo or supportive care (Table 4). grade (95% CI 0.17 to 1.47, P50.0001). In the two
Six trials with 587 participants had information about our large trials which used intravenous methylprednisolone
GBS systematic review Brain (2007), 130, 2245^2257 2253
P50.001. aTreatment 1 is the first and Treatment 2 the second in each row.
(Guillain-Barré Syndrome Steroid Trial Group, 1993; Van When we analysed the number of patients who improved
Koningsveld et al., 2004), there were 467 participants and the one or more disability grades after 4 weeks, information
change in grade was not significantly different in the was only available for five trials with 567 participants. The
corticosteroid from the placebo allocated participants, same trends were observed but there was no significant
WMD 0.17 of a grade (95% CI 0.06 to 0.39) more heterogeneity and the differences were less significant.
improvement in the corticosteroid-treated patients. The relative rate of improving by one or more grades
2254 Brain (2007), 130, 2245^2257 R. A. C. Hughes et al.
was 1.08 (95% CI 0.93–1.24) more in the corticosteroid (Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome
treated than the control participants, a non-significant Trial Group, 1997; Nomura et al., 2000; Diener et al.,
difference. In the three small oral corticosteroid trials there 2001), the number of patients with adverse events was not
were 100 participants and the relative rate of improvement significantly different between the treatments (RR 0.84, 95%
was less in the corticosteroid-treated participants but not CI 0.45–1.59, less in the IVIg-treated patients). In one of
significantly less, 0.8 (95% CI 0.5–1.16). When this analysis the large trials (van der Meché et al., 1992), significantly
was confined to the two large trials which used intravenous less patients treated with IVIg had multiple complications
methylprednisolone, the relative rate of improvement did not than with PE: only 5 of 74 IVIg had multiple
quite achieve significance, being 1.14 (95% CI 0.97–1.34) of complications compared with 16 of 73 PE patients, RR
a grade more in the corticosteroid-treated patients. The 0.31, 95% CI 0.12–0.80.
effects of two known important prognostic variables, age
(less than 50 years and 50 years or more) and initial Subgroups
similar effects and the confidence limits are so narrow that treatment, except for diarrhoea which was associated with
an important clinical difference is unlikely to have been a better response to IVIg in one (van der Meché et al.,
missed. One trial found no significant difference between 1992) and to PE in the other (Plasma Exchange/
the combination of PE followed by IVIg with either Sandoglobulin Guillain-Barré Syndrome Trial Group,
treatment alone but the sample sizes were not large 1997). Unfortunately neither these nor other randomized
enough to rule out a small beneficial effect of the trials included sufficient participants with axonal forms
combination treatment. Oral corticosteroids given for two of GBS to permit conclusions about whether they
or more weeks significantly slowed recovery. When the respond differently to treatment than people with AIDP.
results of two trials were synthesized intravenous methyl- In children, who have a better prognosis than adults,
prednisolone did not produce significant long- or short- the available trial evidence is not of primary quality
term benefit. When a correction for prognostic factors was but consistently points to a beneficial effect of IVIg,
taken into account, a minor synergistic effect on short-term which is supported by a good quality observational study
hospital and population-based studies has not changed, the United Kingdom Department of Health, Guy’s and
ranging from 5% to 15% (Hughes and Cornblath, 2005). St Thomas’ Charity and the European Neuromuscular
The greater mortality in the observational studies than Centre.
in the trials might reflect the exclusion of patients with
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