Summary of findings
Description of the condition
Guillain-Barré syndrome (GBS) is the name given to an acute paralysing disease that causes the rapid development of weakness of the limbs and often the facial, swallowing and breathing muscles. Tingling and numbness usually occur in the limbs at the same time. The disease is usually due to multifocal inflammation of the spinal roots and peripheral nerves, especially their myelin sheaths. The axons are often damaged as a secondary consequence of the inflammatory response. In some cases the axons are the primary focus of the attack. The weakness reaches its nadir within a few days or up to four weeks. In 25% of patients it is sufficiently severe to require the use of artificial ventilation. Between 3.5% and 12% of patients die of complications during the acute stage (Hughes 2005; Yuki 2012). Recovery takes several weeks or months and is often incomplete.
The cause of GBS is still under investigation. The favoured hypothesis is that it is due to an autoimmune response directed against antigens in the peripheral nerves that is triggered by a preceding bacterial or viral infection. The triggering mechanism is incompletely understood but may be the consequence of molecular mimicry whereby antibodies or T cells stimulated by antigenic epitopes on the infecting microbe cross-react with neural epitopes. In the commonest form of GBS in Europe and North America the underlying pathological process is acute inflammatory demyelinating polyradiculoneuropathy. The responsible antigen is likely to be in the Schwann cell membrane or the myelin sheath. Axonal forms of the disease are uncommon in Europe and North America but more common in China, Japan, India and Central America. In the axonal varieties the axon membrane is probably the target of the immune response (Yuki 2012). Distinguishing the different forms of the disease during life is difficult but has been attempted with neurophysiological studies (Hadden 1998).
Description of the intervention
Evidence from randomised controlled trials (RCTs) summarised in Cochrane Reviews has shown that plasma exchange and intravenous immunoglobulin (IVIg), but not corticosteroids, have a beneficial effect by hastening recovery (Hughes 2007; Hughes 2010; Hughes 2012; Hughes 2012a; Raphael 2012). Plasma exchange and IVIg have reduced but not prevented prolonged stays in intensive care unit and hospital and long-term disability. Many patients have persistent fatigue (Merkies 1999); 12% still require aid to walk one year after the onset (Rees 1998) and 62% still notice its effect on their own or their carers' lives three to six years later (Bernsen 1999). Exercise and rehabilitation programmes are used and evidence for their benefit is being sought (Bussman 2007; Demir 2008) but it is likely that the need for improved pharmacological treatments will persist.
At the time of writing the protocol for this review (Hughes 2010c), we knew of small RCTs of interferon beta-1a (IFNb-1a) (Pritchard 2003), an immunomodulating agent beneficial in multiple sclerosis, and brain-derived neurotrophic factor (Bensa 2000), a trophic factor known to be important in the development of motor neurons. We also knew of a RCT comparing cerebrospinal fluid exchange with plasma exchange, undertaken on the ground that removal of harmful factors in the fluid surrounding the spinal roots would be beneficial (Wollinsky 2001). None of these trials showed statistically or clinically significant benefit. It was possible that there were other published or unpublished randomised trials of other agents which would be revealed by a systematic search. One new trial was indeed discovered. Zhang 2000 published a RCT of a Chinese herbal medicine in Chinese. In this trial the authors compared tripterygium polyglycoside, an extract of the Thunder God Vine, with corticosteroids and reported a significant beneficial effect. This medicine has anti-inflammatory properties and has been reported to be efficacious in inflammatory conditions such as rheumatoid arthritis (Goldbach-Mansky 2009).
Why it is important to do this review
The treating doctor has a responsibility to know about the evidence for all treatments which have been used for the condition under consideration, in this case GBS. It is also an ethical requirement to undertake a systematic review before embarking on trials of other agents to make sure that they have not already been tested. Such a review should help to identify appropriate agents, outcomes and trial designs. We therefore undertook this systematic review of RCTs of pharmacological treatments other than corticosteroids, IVIg and plasma exchange for GBS. The review was first published in 2011 and updated in 2013.
We proposed to discover whether pharmacological treatments for GBS other than corticosteroids, IVIg and plasma exchange have been tested with randomised trials. If they had, we would undertake a systematic review of the results. If they had not, we would have established the need for more research into other pharmacological agents for GBS.
Criteria for considering studies for this review
Types of studies
We included all RCTs or quasi-randomised (alternate or other systematic allocation) controlled trials. As anticipated we also identified non-randomised studies of pharmacological treatments which had not been subjected to randomised trials. There is no method for searching systematically which would have identified all such studies. We noted in the Discussion case reports and case series discovered during the search for RCTs, in which the diagnosis, treatment and results were sufficiently described that we were able to be confident of the diagnosis, and deduce the pre-treatment and outcome disability grade. Although not planned in the protocol we also searched our personal databases for non-randomised studies.
Types of participants
We included children and adults with GBS of all degrees of severity. GBS was defined according to internationally accepted diagnostic criteria (Asbury 1990) as acute polyradiculoneuropathy causing progressive weakness of two or more limbs, having an onset phase of not more than four weeks and reduced or absent tendon reflexes, and lacking alternative causes. We included acute inflammatory demyelinating polyradiculoneuropathy and axonal forms of the disease, although in practice the two forms were never distinguished in published reports of treatment trials. We included studies that did not conform exactly to these criteria provided that the authors regarded GBS or one of its synonyms, such as acute idiopathic neuropathy or acute inflammatory demyelinating polyradiculoneuropathy, as the preferred diagnosis. We noted any departure from the internationally accepted diagnostic criteria.
Types of interventions
We included all pharmacological treatments or combinations of treatments for acute GBS other than corticosteroids, IVIg and plasma exchange compared with no treatment, placebo treatment, or another treatment. We confined our attention to treatments delivered in the acute stage to modify the duration and severity of clinical disease as defined by the outcome measures below. We defined acute as within the first four weeks after the onset of symptoms of weakness. We did not include treatments for symptoms of GBS unrelated to weakness or disability (e.g. treatments for neuropathic pain or fatigue).
Types of outcome measures
We assessed the outcomes selected for previous Cochrane Reviews of treatments for GBS.
The primary outcome was change in disability grade (Hughes 1978) four weeks after randomisation. We tested the significance of the difference between each pharmacological treatment and placebo, no treatment or other treatments by calculating the mean difference (MD) and would have pooled the results in a meta-analysis if there had been more than one trial of a single intervention. This method of calculating the outcome is a more sensitive measure than a change in proportions improved.
We accepted the disability scale used by the authors of each trial provided that it was closely similar to that selected for this review (Hughes 1978) or could be adapted to correspond to that scale which is now called the GBS disability scale:
- minor symptoms or signs of neuropathy but capable of manual work;
- able to walk without support of a stick but incapable of manual work;
- able to walk with a stick, appliance or support;
- confined to bed or chair bound;
- requiring assisted ventilation;
- Improvement by one or more GBS disability grades after four weeks
- Time from randomisation until recovery of unaided walking
- Time from randomisation until discontinuation of ventilation (for those ventilated)
- Death or disability (inability to walk without aid) after 12 months
- Serious adverse events (that is adverse events which are life-threatening or fatal, or require or prolong hospital stay)
We inserted a 'Summary of findings' table for each comparison and reported in them the primary and secondary outcomes for this review which were available.
Search methods for identification of studies
On 28 August 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 8 in The Cochrane Library), MEDLINE (January 1966 to August 2012), EMBASE (January 1980 to August 2012) and ClinicalTrials.gov (http://www.clinicaltrials.gov/) (12 October 2012) using 'Guillain-Barré syndrome', 'acute polyradiculoneuritis', acute inflammatory demyelinating polyradiculoneuropathy’ and ‘acute motor axonal neuropathy’ as the search terms. We contacted trial authors and other experts in the field to identify additional published or unpublished data. We did not use a treatment term but discarded trials which only tested corticosteroids, intravenous immunoglobulin or plasma exchange during the selection process. We searched the references retrieved by the above process and our personal databases for non-randomised cohort studies, case series and case reports in which the diagnosis, treatment and results were sufficiently described so that we were able to deduce the pre-treatment and outcome disability grade.
Searching other resources
We contacted 13 trial authors or disease experts for information about other trials, including unpublished trials.
Data collection and analysis
Selection of studies
Two review authors checked titles and abstracts identified by the search and decided independently which should be studied further. We obtained the full text of all studies selected as being potentially relevant. Two authors studied the full texts with the aid of a specially designed form and decided independently which fitted the inclusion criteria. We resolved disagreements about inclusion by discussion, if necessary with the help of the third author. We have reported all the RCTs in the Results section. We have reported relevant non-randomised studies in the Discussion.
Data extraction and management
Two review authors extracted data independently onto specially designed forms. The forms were compared and disagreements resolved by reference to the original reports. We tried to obtain missing data from the trial authors.
Assessment of risk of bias in included studies
Two review authors independently assessed the risk of bias with specially designed forms, using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008). Attributes considered were explicit diagnostic criteria, sequence generation, allocation concealment, blinding, completeness of follow-up, freedom from selective reporting and other sources of bias. We graded these items as free of bias, not free of bias or unclear and described the evidence on which our conclusions are based in a 'Risk of bias' table. If the assessments differed, we obtained agreement by consensus, if necessary in consultation with a third author.
Measures of treatment effect
If meta-analysis of more than one trial of the same or comparable agents had been possible we would have calculated a weighted treatment effect across trials using the Cochrane statistical package, Review Manager (RevMan) (RevMan 2008). For dichotomous outcomes, such as improved one or more grade or not in four weeks, we used RevMan to calculate a risk ratio (RR). For continuous outcomes we tested MDs. Uncertainty was expressed with 95% confidence intervals (CIs). The analyses used a fixed-effect approach.
Dealing with missing data
We sought missing data from the authors and reported its absence when not available.
Assessment of heterogeneity
If there had been multiple trials of one intervention and there had been evidence of significant heterogeneity between studies we would have sought explanations for the heterogeneity and if none had been found would have used a random-effects analysis.
Assessment of reporting biases
If there had been more than two trials of one intervention we would have constructed funnel plots and inspected them for evidence of publication bias.
If meta-analysis of more than one trial of the same or comparable agents had been possible we would have calculated a weighted treatment effect across trials using RevMan.
Subgroup analysis and investigation of heterogeneity
We would have liked to examine the effect of treatments in the following subgroups, chosen because of their prognostic importance in previous prospective studies and trials:
- younger and older (children aged less than 18 years; adults from age 18 to 49 years of age; adults aged 50 years or more);
- more severely or less severely affected (able to walk (GBS disability grades 1 to 3), unable to walk (grade 4), and requiring ventilation (grade 5) at randomisation);
- having or not having documented relevant sensory deficit on routine neurological examination at randomisation (symptoms alone will be ignored);
- having, or not having, a history of diarrhoea (gastroenteritis) within the six weeks before the onset of neuropathic symptoms;
- time from onset of symptoms of neuropathy to start of treatment (seven days or less after onset, more than seven and up to 14 days after onset, and more than 14 days after onset);
- axonal versus demyelinating forms of GBS, defined by neurophysiological criteria (Hadden 1998).
No information was available for any of these subgroups.
If there had been more than one trial of one intervention, we would have performed sensitivity analyses in which trials which have a high risk of bias were omitted from the meta-analysis.
Description of studies
Results of the search
The search identified 277 (42 new in this update) possible references to randomised trials in MEDLINE, 564 (344 new in this update) in EMBASE, 234 in CENTRAL, 196 (21 new in this update) in the Neuromuscular Disease Group Specialized Register and none in ClinicalTrials.gov. We selected 20 references for inspection of the full text and identified six RCTs. We included four RCTs and excluded two, one testing acupuncture as this is not a pharmacological treatment (Wang 2006) and one testing gut decontamination (Hammond 1993). In this last trial 40 ventilated patients with neurological disease were randomised but only 15 had GBS for whom separate results were not reported. Search of the personal database of one author (RACH) containing 2241 references to GBS yielded 15 whose title or abstract suggested that they might contain relevant case studies or series concerning the treatments which are the subject of this review. Personal enquiry to 13 experts in the field yielded no more relevant studies.
There were two very small randomised, placebo-controlled, double-blind trials, one of IFNb-1a (Pritchard 2003) and one of brain-derived neurotrophic factor (BDNF) (Bensa 2000). There was one small, randomised, open, controlled trial comparing CSF filtration with plasma exchange (Wollinsky 2001) and another comparing the Chinese herbal medicine tripterygium polyglycoside with intravenous corticosteroids (Zhang 2000).
One historically controlled study of mycophenolate mofetil (Garssen 2007) and other non-randomised case series or case reports of other agents (Bos Eyssen 2011; Hammond 1993) have been reported in the table Characteristics of excluded studies and the Discussion.
Excluded studies which did not fulfil the criteria for inclusion in either the Results or Discussion have only been reported in the table Characteristics of excluded studies. The commonest reasons for exclusion were that the diagnosis was not clear or was not GBS, or that the intervention was not a pharmacological treatment.
Risk of bias in included studies
The risk of bias for the included trials is summarised in Figure 1 and the table Characteristics of included studies. The very small trials of IFNb-1a and BDNF had a low risk of bias but were not large enough to detect or refute efficacy or harm. The trial of CSF filtration had a high risk of bias and was not large enough to detect superiority or equivalence with plasma exchange. The trial of tripterygium polyglycoside had an unclear risk of bias because the paper gave insufficient details.
|Figure 1. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.|
Effects of interventions
See: Summary of findings for the main comparison IFNb-1a versus placebo for Guillain-Barré syndrome; Summary of findings 2 BDNF versus placebo for Guillain-Barré syndrome; Summary of findings 3 CSF filtration versus plasma exchange for Guillain-Barré syndrome; Summary of findings 4 Tripterygium polyglycoside versus corticosteroids for Guillain-Barré syndrome
Interferon beta-1a (IFNb-1a)
One small RCT with a low risk of bias (see Figure 1, Characteristics of included studies and Summary of findings for the main comparison) randomised 13 participants with severe early GBS (unable to walk without aid and within two weeks from the onset of symptoms) to IFNb-1a (Rebif®) and six to placebo (Pritchard 2003). The drug or placebo was given by subcutaneous injection three times a week starting with 22 μg per injection for the first week and continuing with 44 μg for a subsequent 23 weeks. Participants stopped treatment if they became able to walk without aid (grade 2). The trial stopped after 24 weeks. None of the outcomes selected for this review was significantly different between the groups. The mean improvement in disability grade in the IFNb-1a group after four weeks was 1.2 grades and in the placebo group 1.3 grades. Thus the difference in mean change in disability grade after four weeks was 0.10 (95% CI -1.38 to 1.58) of a grade less improvement in the IFNb-1a group. Correspondingly the RR of improvement by one or more grades after four weeks was 1.08 (95% CI 0.42 to 2.77) in favour of IFNb-1a. The median time (95% CI) to unaided walking was 59 (16 to infinity) days in the IFNb-1a group and 18 (11 to 70) in the placebo group. The RR of death was 1.50 (0.07 to 32.29) greater in the IFNb-1a group. The RR of having serious adverse events was 0.92 (0.23 to 3.72), thus being slightly less in the IFNb-1a group. None of the other differences reported by the authors was significantly different: these were the outcomes just mentioned after 24 weeks and changes in Medical Research Council (MRC) sum score and grip strength at either four or 24 weeks. This study was much too small to exclude clinically important benefit or harm from IFNb-1a.
Brain-derived neurotrophic factor (BDNF)
One very small RCT with a low risk of bias (see Figure 1, Characteristics of included studies and Summary of findings 2) randomised six participants with severe early GBS to BDNF and four to placebo (Bensa 2000). The trial was terminated early because the manufacturer withdrew the drug since it was ineffective in a trial for motor neuron disease. The drug or placebo was given by daily subcutaneous injection of r-metHuBDNF 25 μg/kg for 24 weeks. Participants stopped treatment upon reaching grade 2. None of the outcomes reported was significantly different between the groups. After four weeks there was 0.75 (95% CI -1.14 to 2.64) of a grade more improvement in the BDNF group. The RR of improvement by one grade after four weeks was the same, 1.00 (95% CI 0.28 to 3.54), in both groups. The time to unaided walking had a median (95% CI) value of 84 (4 to infinity) days in the BDNF group and 84 (2 to infinity) in the placebo group. The RR of death was 0.67 (95% CI 0.06 to 7.85), being less in the BDNF group. The RR of death or disability after 12 months and RR of having serious adverse events were both 1.33 (95% CI 0.17 to 10.25) more with BDNF. There were also no significant differences in the other outcomes reported, which were arm disability grade at the above times and arm and overall disability grade at 12, 24 and 48 weeks. This study was much too small to exclude clinically important benefit or harm from BDNF.
One RCT with a high risk of bias (Figure 1, Characteristics of included studies and Summary of findings 3) compared 17 participants treated by CSF filtration with 20 who received a conventional course of five plasma exchanges, removing a total of 200 to 250 ml/kg of plasma altogether (Wollinsky 2001). The CSF filtration consisted of removing, filtering and re-infusing 30 to 50 ml CSF five to six times a day for between five and 15 consecutive days. More details are given in the table of Characteristics of included studies. The outcomes selected for this review showed no significant differences between the groups. The mean improvement in disability grade after four weeks was almost exactly the same in both groups: MD 0.02 (95% CI -0.62 to 0.66) more in the CSF filtration group. Similarly, the number of participants with one or more grades of improvement in both groups was similar: RR 0.94 (95% CI 0.48 to 1.84) in favour of the plasma exchange group. These CIs were consistent with a halving or almost doubling of the number. The time until recovery of unaided walking in the surviving participants was shown by the authors in a Kaplan-Meier figure of an analysis from which nine participants were censored. From the published figure, we estimated the median (range) as 42 (13 to 433) days in the CSF filtration group and 90 (6 to 420) days in the plasma exchange group. The authors commented that the times were similar in both groups. There was one death in each group: RR 1.18 (95% CI 0.08 to 17.42) in favour of the plasma exchange group. Four participants in the plasma exchange group had serious adverse events and none in the CSF filtration group: RR 0.13 (95% CI 0.01 to 2.25) in favour of CSF filtration. One in each group had side effects leading to cessation of treatment: RR 1.18 (95% CI 0.08 to 17.42). The small sample sizes in this trial prevent drawing conclusions about the relative efficacy of CSF filtration and plasma exchange. As explained in the Discussion, this treatment is no longer being used because of the danger of producing an inflammatory reaction in the CSF.
One RCT with an unclear risk of bias (Figure 1, Figure 2, Characteristics of included studies and Summary of findings 4) compared 22 participants treated with the Chinese herbal medicine tripterygium polyglycoside with 21 participants treated with high-dose corticosteroids (Zhang 2000). The primary outcome for this review was not reported but after eight weeks, 20 of 22 treated with tripterygium polyglycoside had improved one or more disability grades compared with 13 of 21 treated with high-dose corticosteroids: RR 1.47 (95% CI 1.02 to 2.11) (Figure 2). Only one adverse event was reported: gastrointestinal toxicity in one person treated with tripterygium polyglycoside. The other outcomes for this review were also not reported.
|Figure 2. Forest plot of comparison: 4 Tripterygium polyglycoside versus corticosteroids, outcome: 4.1 Improvement in disability grade by one or more points after 8 weeks.|
Summary of main results
Many patients have long-term disability after GBS despite treatment with IVIg or plasma exchange. There is therefore a need for better treatments. Unfortunately very few other treatments have been tested and those only in very small studies. This review identified four small RCTs, each providing only very low quality evidence. Patients who received the Chinese herbal medicine tripterygium polyglycoside had a significantly better outcome after eight weeks compared with those receiving high-dose corticosteroids. None of the other three trials (of BDNF, IFNb-1a and CSF filtration) was large enough to identify or exclude clinically significant benefit or harm: the CIs in these trials were so wide that the results were consistent with at least half a grade more or less improvement. A half grade has been considered to be an amount which is clinically important (Plasma 1997).
Consideration of treatments tested in controlled trials
Small trials of three treatments did not show significant benefit but it may be premature to abandon interest in two of the three treatments.
- For BDNF, there is now experimental evidence of a neuroprotective role of BDNF in mouse experimental allergic encephalomyelitis (Linker 2010). There are no other case reports or series of the use of BDNF in GBS. The use of neurotrophic factors to protect nerves from axonal degeneration and encourage regeneration remains a possible strategy for the future. Research is needed into the optimal combination, route and dose of trophic factors.
- For IFNb-1a, there are theoretical reasons to expect a beneficial effect in GBS. In multiple sclerosis, there is strong evidence for efficacy in reducing inflammation in the brain and frequency of relapses (Rice 2001). In chronic inflammatory demyelinating polyradiculoneuropathy, neither of two small trials showed a significant effect but a post hoc analysis in one raised the possibility of an IVIg-sparing effect in patients receiving large doses of IVIg (Hughes 2010b; Mahdi-Rogers 2010). In GBS, in addition to the small trial identified in this review (Pritchard 2003), there are two case reports of improvement following the use of IFNb-1a (combined with other treatments) (Créange 1998; Schaller 2001) but this could merely reflect the natural history of the disease. The trial in this review (Pritchard 2003) did not identify significant safety concerns, and, although the trend of the results was worse in the IFNb-1a group, the confidence limits were very wide. Further trials of interferon beta could be considered.
- The trial of CSF filtration was too small to prove that it is equivalent to plasma exchange. Before this trial was performed a series of 24 patients with acute GBS had been treated with CSF filtration: their median time to improve one GBS disability grade was 19 days and their median time to walk unaided was 42 days (Wollinsky 1995). Insufficient information was published to judge the significance of these findings and in the absence of contemporary controls it is not possible to draw conclusions from this series. There have been no subsequent published case reports or series of the use of CSF filtration in GBS. Although there were no serious adverse events in the trial, CSF lymphocytic pleocytosis was noted in 14 of 14 people in whom this was assessed (Wollinsky 2001). There is a theoretical risk of causing meningitis. Meningitis was observed in one participant in the trial but attributed to an earlier lumbar puncture. However, granulocytic reactions have been observed in up to 20% of patients and the procedure has been discontinued in the host department (Ludolph 2010). The theoretical basis for the treatment was that inflammation of the spinal roots is an important part of the pathogenesis and CSF filtration would remove “blocking factors” (Brinkmeier 1992). However, the inflammation in GBS also affects the nerve trunks and terminals (Feasby 2001) and the existence of “blocking factors” has been questioned (Cummins 2003; Otto 2005).
One small trial did show significant results. This trial compared tripterygium polyglycoside with high-dose intravenous corticosteroids (Zhang 2000). The trial was small, had a high risk of bias and was only barely statistically significant when the outcome was measured after eight weeks. The outcome after four weeks stipulated for this review was not available so this conclusion must be viewed with caution. The outcome favoured tripterygium polyglycoside which, if real, might have been due to a beneficial effect of tripterygium polyglycoside or a deleterious effect of corticosteroids. The Cochrane Review of corticosteroids for GBS (Hughes 2012a) concluded that corticosteroids given alone do not have a significant beneficial or harmful effect so that a beneficial effect of tripterygium polyglycoside is more likely. Zhang 2000 reported that tripterygium polyglycoside lowered inflammatory cytokine interleukin-6 concentrations in the serum significantly more than corticosteroids. There are no other reports of the use of tripterygium polyglycoside in GBS. Tripterygium glycoside is an extract from the herb Tripterygium wilfordii which has been used as an anti-inflammatory agent in traditional Chinese medicine for many years. There are reports of benefit in RCTs in prevention of renal allograft rejection and treatment of Crohn's disease and rheumatoid arthritis (Goldbach-Mansky 2009). Further study of the efficacy and side effects of tripterygium polyglycoside in GBS would be appropriate. However, such further investigation will be difficult because there are 380 metabolites in tripterygium extracts ingredients and no standardised method of extraction. The most active ingredients are terpenoids, of which some have been shown to inhibit key pathways in T cell activation and cyclo-oxygenase and nitric oxide production (Goldbach-Mansky 2009).
Mycophenolate mofetil has been licensed since 1996 for use “in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogeneic renal, cardiac or hepatic transplants” (Roche). It is often used in autoimmune diseases but the evidence for efficacy is limited. In one review, mycophenolate mofetil was as efficacious as, but safer than, cyclophosphamide in the treatment of proliferative lupus nephritis (Mak 2009). In another, there was limited evidence of greater efficacy than azathioprine in pemphigus vulgaris (Martin 2009). In other diseases, such as myasthenia gravis (Sanders 2008), there is no evidence of efficacy from the RCTs performed but the absence of evidence may reflect lack of power and not necessarily lack of efficacy.
Mycophenolate mofetil has been tried in one non-randomised (therefore having a high risk of bias) historically-controlled clinical trial in which 26 participants treated with oral mycophenolate mofetil 1000 mg a day for six weeks were compared with 112 participants who had been treated without the drug in a previous RCT run by the same investigators in the same centres (van Koningsveld 2004; Garssen 2007). Both the participants treated with mycophenolate mofetil and the historical controls were simultaneously treated with IVIg 0.4 g IVIg/kg/day and intravenous methylprednisolone 500 mg/day for five consecutive days. There were no significant differences between the groups in any of the outcomes measured. The mean change in disability grade was not given. The RR of improving one disability grade after four weeks was not significantly different, being 0.91 (0.65 to 1.26) less in the mycophenolate mofetil group, which meant that there was a trend towards a worse outcome in the mycophenolate mofetil group. The median time to improve to unaided walking was 70 days in the mycophenolate mofetil group and 28 days in the historical controls, a difference which was not significant when the survival curves were compared with the Kaplan-Meier method (P = 0.22). The RR of death was also not significantly different, being 1.44 (0.31 to 6.71) greater in the historical control group. One of the mycophenolate mofetil participants had to discontinue the study drug temporarily because of abdominal complaints. The follow-up was limited to six months so that 12-month outcomes were not reported. There was no significant difference in other outcomes measured including ability to walk independently after eight weeks, time to improve one disability grade, need for artificial ventilation, MRC sum score and sensory impairment. There was no trend towards more improvement with mycophenolate mofetil at this dose in this historically-controlled study.
There are no other case reports or series of the use of mycophenolate mofetil in GBS. Since the dose used in the GBS trial was only 1000 mg daily, half the dose usually recommended in other autoimmune conditions, a higher dose should be considered if it were decided to pursue this drug in GBS.
Selective digestive tract decontamination
Selective digestive tract decontamination (SDD) has been tested in a retrospective study of 124 mechanically ventilated GBS patients comparing patients in centres where SDD was standard treatment with those in other centres where it was not (Bos Eyssen 2011, Table 1). The results suggested that this treatment reduced the time on the ventilator, probably by preventing pneumonia. It did not affect neurological recovery after six months. Because of the lack of randomisation and the possibility of unrecognised confounding factors this result requires confirmation. However, this treatment has been extensively tested in 36 trials involving 6914 people admitted to intensive care units. The participants had a wide variety of conditions and were not necessarily on artificial ventilation. According to the relevant Cochrane Review (D'Amico 2009), a combination of topical and systemic antibiotics significantly reduced respiratory tract infections and mortality whilst topical antibiotics alone significantly reduced respiratory tract infections but not mortality. Our search, for this review on GBS, identified one trial of SDD which included 15 participants with GBS out of its whole sample of 40 participants with various neurological diseases (Hammond 1993). This trial on its own did not show a significant reduction in incidence of infections or duration of intensive care unit or hospital stay, or mortality. The detailed results of this trial are given in Characteristics of excluded studies. Separate results for the participants with GBS are not available.
Other treatments studied in case reports and case series
Only three other treatments, azathioprine, cyclophosphamide and the anti-T-cell antibody OKT3, have been reported in observational studies fulfilling the criteria for inclusion in this Discussion ( Table 1). Yuill 1970 reported the use of azathioprine in one patient with severe GBS who was left with only mild deficit after five months. Cyclophosphamide was used in two small series of patients with GBS. Ahuja 1980 treated four people with severe GBS with 100 mg cyclophosphamide daily (route not stated) starting between three and 28 days after onset. All improved and there were no serious adverse events but one person had to stop treatment because of diarrhoea. Rosen 1976 reported a series of 15 patients treated with cyclophosphamide 40 mg/kg intravenously, 12 of whom had severe GBS. Ten of the 12 improved by four weeks. Three eventually died. Reversible alopecia was common. The OKT3 monoclonal antibody against T cells was used in three people with severe GBS (Feasby 1991) but the results were not encouraging ( Table 1). None of these studies was large enough to confirm or refute significant benefit or harm.
Immunosuppression causing GBS
There are many reports of GBS occurring in patients who are immunodeficient because of disease, such as Hodgkin’s disease or human immunodeficiency virus, or iatrogenic immunosuppression for peripheral blood stem cell transplants (26 cases after allografts and seven after autografts) (Ostronoff 2008), solid organ transplant (Zhang 2008) or autoimmune disease (Hughes 1990). Recent examples include GBS or GBS-like illnesses following interfering with different components of the immune pathway. These include the antibody rituximab directed against the B cell antigen CD20 (three patients) (Jaso 2010); the tumour necrosis factor antagonists infliximab (nine patients), etanercept (five) and adalimumab (one) (Shin 2006); bortezomib for myeloma (Ravaglia 2008); pegylated interferon alpha-2a for hepatitis C infection (Khiani 2008); and the antibody efalizumab against the anti-CD11a component of lymphocyte function antigen 1 (four patients: this drug has now been withdrawn from the market in any case because of the occurrence of cases of progressive multifocal leukoencephalopathy) (Victor 2008; Turatti 2010). These reports might merely be a testament to the enthusiasm of doctors to report unusual occurrences and be coincidences. If the association is real, it is a timely reminder of our limited understanding of the pathogenesis of GBS. This review has not attempted an exhaustive review of this literature.
Need for more trials
Further studies of tripterygium polyglycoside are needed, to identify its active ingredients and confirm its efficacy and adverse effects. With the availability of many agents which have been shown to be efficacious in other inflammatory diseases such as rheumatoid arthritis and multiple sclerosis, it is remarkable that so little work has been or is being done to test new immunosuppressive regimens in GBS. This systematic review establishes this lack of evidence and provides the basis on which trials of these regimens can be launched. Future trials will need to use the standard GBS disability grade scale used in previous trials. However new, more responsive scales with validated, preferably linear, biometric properties would be advantageous and should be developed. The trial design should take account of the minimum clinically important difference of the selected outcome measure.
Overall completeness and applicability of evidence
The evidence about published RCTs is likely to be complete because we have made use of the methods of the Cochrane Collaboration to search the literature. The evidence from the case studies and series cannot be complete since there is no known search strategy which will detect all published non-randomised studies. We did not discover any unpublished studies and the search for such studies is even less likely to be complete than that for published studies.
Quality of the evidence
The strength of the evidence from the RCTs is limited by the very small number of patients randomised in all and the lack of clarity about the risk of bias in the trial of tripterygium polyglycoside. The evidence from the study of mycophenolate is limited by the lack of randomisation.
Potential biases in the review process
This review might be biased by the fact that each of the authors participated in two of the four RCTs considered and two of the authors have received funding from companies which manufacture medications which are used or might be used for treating GBS.
Agreements and disagreements with other studies or reviews
We know of no other systematic reviews of pharmacological treatments other than corticosteroids, IVIg or plasma exchange for GBS.
Implications for practice
The quality of the evidence from RCTs was very low. Three RCTs of pharmacological agents other than plasma exchange or corticosteroids did not show a significant effect, one testing IFNb-1a against placebo, another BDNF against placebo, a third CSF filtration against plasma exchange. None were large enough to show or refute significant benefit or harm. A fourth trial suggested that the Chinese herbal medicine tripterygium polyglycoside was superior to corticosteroids in hastening recovery but the result requires confirmation. According to very low quality evidence from one historically-controlled trial, there is no benefit from a low dose of the immunosuppressive drug mycophenolate mofetil. There have been very few observational studies and no randomised trials of other agents.
Implications for research
Since currently used immunotherapy does not prevent prolonged illness and leaves many patients with clinically important residual disability, there is a need to discover and test new treatments. Further investigation of the active ingredients of tripterygium polyglycoside and its mechanism, speed of action and benefits and harms in GBS would be appropriate.
We thank Jingjing Zhang, West China Hospital of Sichuan University, for translating and extracting data from five Chinese papers of which one (Zhang 2000) was an included study in this review. The translator is not related to the author of Zhang 2000.
Data and analyses
- Top of page
- Summary of findings [Explanations]
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
Appendix 1. CENTRAL search strategy
#1 MeSH descriptor Guillain-Barre Syndrome explode all trees
#2 "guillain barre"
#3 MeSH descriptor Polyradiculoneuropathy, this term only
#4 MeSH descriptor Polyneuropathies, this term only
#5 "acute polyneuritis" OR "acute polyradiculoneuritis"
#6 "inflammatory neuropathy"
#7 "inflammatory polyneuropathy"
#8 (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7)
Appendix 2. MEDLINE (OvidSP) search strategy
Database: Ovid MEDLINE(R) <1946 to August Week 3 2012>
1 randomized controlled trial.pt. (334518)
2 controlled clinical trial.pt. (84887)
3 randomized.ab. (237772)
4 placebo.ab. (133874)
5 clinical trials as topic.sh. (161939)
6 randomly.ab. (171070)
7 trial.ti. (102704)
8 or/1-7 (774732)
9 (animals not (animals and humans)).sh. (3678890)
10 8 not 9 (714047)
11 guillain barre syndrome.tw. or Guillain-Barre Syndrome/ (6031)
12 POLYRADICULONEUROPATHY/ or POLYNEUROPATHIES/ (7476)
13 (acute polyradiculoneuritis or acute polyneuritis).mp. (166)
14 (inflammatory adj5 neuropath$3).tw. (1480)
15 (inflammatory adj5 polyneuropath$3).tw. (1289)
16 Acute motor axonal neuropathy.tw. (184)
17 or/11-16 (13088)
18 10 and 17 (435)
19 review.pt. (1728141)
20 18 not 19 (277)
21 20 and 20100615:20120828.(ed). (42)
Appendix 3. EMBASE (OvidSP) search strategy
Database: Embase <1980 to 2012 Week 34>
23 crossover-procedure.sh. (34756)
24 double-blind procedure.sh. (110472)
25 single-blind procedure.sh. (16301)
26 randomized controlled trial.sh. (327721)
27 (random$ or crossover$ or cross over$ or placebo$ or (doubl$ adj blind$) or allocat$).tw,ot. (891567)
28 trial.ti. (134221)
29 clinical trial/ (870370)
30 or/23-29 (1489974)
31 (animal/ or nonhuman/ or animal experiment/) and human/ (1201424)
32 animal/ or nonanimal/ or animal experiment/ (3302815)
33 32 not 31 (2735746)
34 30 not 33 (1402277)
35 limit 34 to embase (1086563)
36 Guillain Barre Syndrome/dt (1833)
37 Guillain Barre syndrome/dt [Drug Therapy] (1833)
38 Polyneuropathy/dt or Polyradiculoneuropathy/dt (1319)
39 (guillain barre syndrome or acute polyradiculoneuritis or acute polyneuritis or Acute motor axonal neuropathy).tw. (7265)
40 (inflammatory adj5 (neuropath$3 or polyneuropath$3)).tw. (3642)
41 or/36-40 (11777)
42 35 and 41 (926)
43 review/ (1875069)
44 42 not 43 (564)
45 remove duplicates from 44 (564)
Last assessed as up-to-date: 28 August 2012.
Contributions of authors
RACH wrote the first draft. All authors checked and edited subsequent drafts and approved the final version.
Declarations of interest
All three authors have conducted trials which were relevant for inclusion in this review. RACH has received consulting fees from companies involved with manufacturing drugs used for GBS: Baxter, CSL Behring, Grifols, LFB, Kedrion, Novartis, Talecris and Octapharma. RDMH has received consulting fees, expenses and the cost of a nurse's salary from Baxter Healthcare Ltd UK.
Sources of support
- None, UK.
- None, UK.
Differences between protocol and review
The words "change in", which had been inadvertently omitted, were inserted for the primary outcome: "The primary outcome will be change in disability grade (Hughes 1978) four weeks after randomisation."
Medical Subject Headings (MeSH)
*Tripterygium; Adrenal Cortex Hormones [therapeutic use]; Brain-Derived Neurotrophic Factor [*therapeutic use]; Cerebrospinal Fluid; Filtration; Guillain-Barre Syndrome [*drug therapy]; Immunoglobulins, Intravenous; Interferon-beta [*therapeutic use]; Plant Preparations [*therapeutic use]; Plasma Exchange; Randomized Controlled Trials as Topic
MeSH check words
* Indicates the major publication for the study