Pharmacological treatment other than corticosteroids, intravenous immunoglobulin and plasma exchange for Guillain-Barré syndrome

  • Review
  • Intervention

Authors


Abstract

Background

Plasma exchange and intravenous immunoglobulin, but not corticosteroids, are beneficial in Guillain-Barré syndrome (GBS). The efficacy of other pharmacological agents is unknown. This review was first published in 2011 and this update in 2013. 

Objectives

To review systematically the evidence from randomised controlled trials (RCTs) for pharmacological agents other than plasma exchange, intravenous immunoglobulin and corticosteroids.

Search methods

On 28 August 2012, we searched the Cochrane Neuromuscular Disease Group Specialized Register CENTRAL (2012, Issue 8 in The Cochrane Library), MEDLINE (January 1966 to August 2012) and EMBASE (January 1980 to August 2012) for treatments for GBS. We considered evidence from non-randomised studies in the Discussion.

Selection criteria

We included all randomised or quasi-RCTs of acute (within four weeks from onset) GBS of all types, ages and degrees of severity. We discarded trials which only tested corticosteroids, intravenous immunoglobulin or plasma exchange. We included other pharmacological treatments or combinations of treatments compared with no treatment, placebo treatment or another treatment.

Data collection and analysis

Change in disability after four weeks was the primary outcome. Two authors checked references and extracted data independently. One author entered and another checked data in Review Manager (RevMan). We assessed risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. We calculated mean differences and risk ratios with their 95% confidence intervals. We assessed strength of evidence with GradePro software.

Main results

Only very low quality evidence was found for four different interventions. This update of the review found no new trials. One RCT with 13 participants showed no significant difference in any outcome between interferon beta-1a and placebo. Another with 10 participants showed no significant difference in any outcome between brain-derived neurotrophic factor and placebo. A third with 37 participants showed no significant difference in any outcome between cerebrospinal fluid filtration and plasma exchange. In a fourth with 20 participants, the risk ratio of improving by one or more disability grades after eight weeks was significantly greater with the Chinese herbal medicine tripterygium polyglycoside than with corticosteroids (risk ratio 1.47; 95% confidence interval 1.02 to 2.11). Serious adverse events were uncommon with each of these treatments and not significantly commoner in the treated than the control groups.

Authors' conclusions

The quality of the evidence was very low. Three small RCTs, of interferon beta-1a, brain-derived neurotrophic factor and cerebrospinal fluid filtration, showed no significant benefit or harm. A fourth small trial showed that the Chinese herbal medicine tripterygium polyglycoside hastened recovery significantly more than corticosteroids but this result needs confirmation. It was not possible to draw useful conclusions from the few observational studies.

Résumé scientifique

Traitement pharmacologique autre que les corticoïdes, l'immunoglobuline intraveineuse et la plasmaphérèse pour le syndrome de Guillain-Barré

Contexte

La plasmaphérèse et l'immunoglobuline intraveineuse, mais pas les corticostéroïdes, sont bénéfiques dans le syndrome de Guillain-Barré (SGB). On ne sait rien de l'efficacité d'autres agents pharmacologiques. Cette revue a été publiée pour la première fois en 2011 et cette mise à jour en 2013.

Objectifs

Examiner systématiquement les résultats d'essais contrôlés randomisés (ECR) portant sur des agents pharmacologiques autres que la plasmaphérèse, l'immunoglobuline intraveineuse et les corticoïdes.

Stratégie de recherche documentaire

Le 28 août 2012, nous avons effectué une recherche portant sur les traitements du SGB, dans le registre spécialisé du groupe Cochrane sur les affections neuro-musculaires, CENTRAL (2012, numéro 8 dans The Cochrane Library), MEDLINE (de janvier 1966 à août 2012) et EMBASE (de janvier 1980 à août 2012). Nous avons pris en compte dans la discussion les résultats d'études non-randomisées.

Critères de sélection

Nous avons inclus tous les essais contrôlés randomisés ou quasi-randomisés portant sur des SGB aigus (moins de quatre semaines après le déclenchement) de tous types, quels que soient l'âge et le degré de gravité. Nous avons écarté les essais qui n'avaient testé que des corticoïdes, l'immunoglobuline intraveineuse ou la plasmaphérèse. Nous avons inclus d'autres traitements ou combinaisons de traitements pharmacologiques comparés à l'absence de traitement, à un placebo ou à un autre traitement.

Recueil et analyse des données

Le principal critère de résultat était l'évolution de l'invalidité après 4 semaines. Deux auteurs ont vérifié les références et extrait les données de façon indépendante. Un auteur a saisi les données dans Review Manager (RevMan) et un autre les a vérifiées. Nous avons évalué les risques de biais en nous conformant au Manuel Cochrane pour les revues systématiques d'interventions (Cochrane Handbook for Systematic Reviews of Interventions). Nous avons calculé les différences moyennes et les risques relatifs avec intervalles de confiance à 95 %. Nous avons évalué la solidité des preuves à l'aide du logiciel GradePro.

Résultats principaux

Nous n'avons trouvé que des données de très faible qualité pour quatre interventions différentes. Cette mise à jour de la revue n'a pas trouvé de nouveaux essais. Un ECR avec 13 participants n'avait constaté de différence significative pour aucun critère de résultat, entre l'interféron bêta-1a et le placebo. Un autre avec 10 participants n'avait constaté de différence significative pour aucun critère de résultat, entre le facteur neurotrophique dérivé du cerveau et le placebo. Un troisième avec 37 participants n'avait constaté de différence significative pour aucun critère de résultat, entre la filtration du liquide céphalo-rachidien et la plasmaphérèse. Dans un quatrième avec 20 participants, le risque relatif d'une amélioration de l'invalidité d'un ou plusieurs degrés après huit semaines était significativement plus élevé avec le médicament chinois à base de plantes tripterygium polyglycoside qu'avec les corticostéroïdes (risque relatif 1,47 ; intervalle de confiance à 95% 1,02 à 2,11). Les événements indésirables graves avaient été rares avec chacun de ces traitements et pas significativement plus fréquents dans les groupes traités que dans les groupes témoins.

Conclusions des auteurs

La qualité des données récoltées était très faible. Trois petits ECR, portant sur l'interféron bêta-1a, le facteur neurotrophique dérivé du cerveau et la filtration du liquide céphalo-rachidien, n'avaient mis en évidence aucun bénéfice ou préjudice significatif. Un quatrième petit essai avait montré que le médicament chinois à base de plantes tripterygium polyglycoside avait hâté le rétablissement significativement plus que les corticostéroïdes, mais ce résultat doit être confirmé. Il n'a pas été possible de tirer de conclusions utiles des quelques études observationnelles.

アブストラクト

ギラン・バレー症候群に対する、副腎皮質ステロイド薬、免疫グロブリン静脈内投与および血漿交換以外の薬物療法

背景

ステロイド薬を除き、血漿交換や免疫グロブリン静脈内投与は、ギラン・バレー症候群(GBS)に有効である。その他の薬剤の有効性については不明である。本レビューは2011年に初版を発表し、2013年に今回の更新を行った。

目的

血漿交換、免疫グロブリン静脈内投与、およびステロイド薬以外の薬剤に関するランダム化比較試験(RCT)のエビデンスを体系的に調査すること。

検索戦略

2012年8月28に、GBSの治療に関して以下を検索した。the Cochrane Neuromuscular Disease Group Specialized Register CENTRAL(2012年8号コクラン・ライブラリ)、MEDLINE(1966年1月~2012年8月)、およびEMBASE(1980年1月~2012年8月)。 非ランダム化研究のエビデンスについては考察で検討した。

選択基準

すべての種類、年齢層、および重症度の急性GBS(発症から4週間以内)に関するあらゆるRCTおよび準RCTを選択した。ステロイド薬、免疫グロブリン静脈内投与、または血漿交換のみについて調べた試験は選択しなかった。その他の薬物療法や併用療法と、無治療、プラセボ治療、または別の治療を比較した試験を選択した。

データ収集と分析

4週間後の障害の変化を主要アウトカムとした。2名のレビューアが独立して参考文献リストを調べ、データを抽出した。Review Manager(RevMan)へのデータ入力を1名のレビューアが行い、もう1名がチェックした。Cochrane Handbook for Systematic Reviews of Interventionsに基づいてバイアスのリスクを評価した。 平均差およびリスク比を、 95%信頼区間と共に算出した。GradeProソフトウェアを用いてエビデンスの強さを評価した。

主な結果

4つの異なる介入を同定したが、エビデンスの質はきわめて低いもののみであった。本レビューの今回の更新では、新規の試験はなかった。13例を対象とした1件のRCTでは、インターフェロンβ-1aとプラセボを比較し、すべてのアウトカムで有意差がみられなかった。10例を対象とした2つめの試験では、脳由来神経栄養因子とプラセボを比較し、すべてのアウトカムで有意差がみられなかった。37例を対象とした3つめの試験では、脳脊髄液濾過と血漿交換を比較し、すべてのアウトカムで有意差がみられなかった。20例を対象とした4つめの試験では、8週間後の障害等級の1つ以上の改善に関するリスク比が、漢方薬のtripterygium polyglycosideでステロイド薬よりも有意に増加した(リスク比1.47;95%信頼区間1.02~2.11)。重篤な有害事象はこれらの治療法のいずれにおいてもまれで、コントロール群の治療法よりも発生頻度が有意に低かった。

著者の結論

エビデンスの質はきわめて低かった。インターフェロンβ-1a、脳由来神経栄養因子、および脳脊髄液濾過に関する3件の小規模RCTでは、有意な有益性や有害性は示さなかった。4つめの小規模試験では、漢方薬のtripterygium polyglycosideがステロイド薬よりも有意に回復を促進したが、本結果については確認を要する。観察研究が少なく、有用な結論を出すことが出来なかった。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.1.6]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Resumo

Outros tratamentos farmacológicos além dos corticoides, imunoglobulina intravenosa e plasmaférese para síndrome de Guillain-Barré

Introdução

A plasmaférese e a imunoglobulina intravenosa, mas não os corticoides, são benéficos para pacientes com síndrome de Guillain-Barré (SGB). A eficácia de outros agentes farmacológicos é desconhecida. Esta revisão teve sua primeira publicação em 2011 e esta atualização foi feita em 2013. 

Objetivos

Revisar sistematicamente as evidências de ensaios clínicos randomizados (ECRs) sobre outros tratamentos farmacológicos para SGB,que não sejam a plasmaférese, a imunoglobulina intravenosa e os corticosteroides.

Métodos de busca

Em 28 de agosto de 2012, nós fizemos buscas nas seguintes bases de dados eletrônicas por estudos sobre tratamentos para a SGB: Cochrane Neuromuscular Disease Group Specialized Register CENTRAL (2012, Issue 8 na The Cochrane Library), Medline (janeiro de 1966 a agosto de 2012) e a Embase (janeiro de 1980 a agosto de 2012). Na discussão desta revisão, apresentamos as evidências de estudos não randomizados.

Critério de seleção

Nós incluímos todos os ensaios clínicos randomizados ou quasi-randomizados de SGB aguda (início dos sintomas em quatro semanas) de todos os tipos, idades e gravidades. Nós excluímos os estudos que testaram apenas corticosteroides, imunoglobulina intravenosa ou plasmaférese. Nós incluímos outros tratamentos farmacológicos ou combinações de tratamentos comparados com nenhum tratamento, tratamento placebo ou outro tratamento.

Coleta dos dados e análises

O desfecho primário foi mudança na incapacidade após quatro semanas. Dois autores checaram as referências e extraíram os dados de forma independente. Um autor inseriu e outro checou os dados no programa Review Manager (RevMan). Nós avaliamos o risco de viés de acordo com o Cochrane Handbook for Systematic Reviews of Interventions.Nós calculamos as diferenças médias e as razões de risco com intervalos de confiança de 95%. Nós avaliamos a força da evidência com o software GradePro.

Principais resultados

Apenas evidência de qualidade muito baixa foi encontrada para quatro intervenções diferentes. Esta atualização da revisão não encontrou ensaios clínicos novos. Um ensaio clínico randomizado com 13 participantes não mostrou diferença significativa em nenhum desfecho entre interferon beta-1a e placebo. Outro, com 10 participantes, não mostrou diferença significativa em nenhum desfecho entre os pacientes que receberam fator neurotrópico cérebro-derivado versus placebo. O terceiro estudo, com 37 participantes, não mostrou diferença significativa em nenhum desfecho entre os pacientes tratados com filtração de líquor (líquido cerebrorraquidiano ou fluido cérebro-espinhal) versus plasmaférese. No quarto estudo, com 20 participantes, o RR (razão de risco) de melhora de um ou mais graus de incapacidade após 8 semanas foi significativamente maior nos grupo tratado com o fitoterápico tripterygium polyglycoside do que no grupo que recebeu corticosteroides (RR 1,47; 95% intervalo de confiança 1,02 a 2,11). Efeitos adversos graves foram infrequentes nos pacientes tratados com essas intervenções e não diferiram significativamente entre os grupos tratados versus controle.

Conclusão dos autores

A qualidade da evidência foi muito baixa. Três ensaios clínicos randomizados pequenos, que testaram interferon beta-1a, fator neurotrofico cérebro-derivado e filtração do líquido cefalorraqudiano, não mostraram benefício ou dano significativo. Um quarto estudo pequeno mostrou que a erva da medicina chinesa tripterygium polyglycoside acelerou a recuperação de forma mais significativa que os corticoides, mas este resultado precisa de confirmação. Não foi possível chegar a conclusões mais úteis a partir dos poucos estudos observacionais existentes sobre esses tratamentos.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Carolina de Oliveira Cruz)

Plain language summary

Drug treatment other than corticosteroids, intravenous immunoglobulin and plasma exchange for acute Guillain Barré syndrome

Guillain-Barré syndrome (GBS) is an acute paralysing disease caused by inflammation of the nerves. Between 3.5% and 12% of people with GBS die of complications during the acute stage. A quarter of patients need artificial ventilation. Recovery takes several weeks or months and is often incomplete. Plasma exchange (washing harmful substances out of the blood) and intravenous immunoglobulin (infusion into the blood stream of human antibodies harvested from blood donations) are beneficial but corticosteroids are not. Since current treatments are insufficient, new methods need to be discovered. We searched for randomised controlled trials (RCTs) of other drugs for GBS. We only found very low quality evidence in the first version of this review and no fresh evidence in this update. One RCT with only 13 participants tested interferon beta-1a, a drug which is beneficial in multiple sclerosis. Another with only 10 participants tested a nerve growth factor which theoretically should be beneficial. A third trial with 37 participants compared cerebrospinal fluid filtration (washing the nerve roots around the spinal cord) and plasma exchange. None of these trials was large enough to confirm or refute benefit or harm in acute GBS. A fourth trial with 20 participants suggested that the Chinese herbal medicine tripterygium polyglycoside improved disability faster than corticosteroids but this result needs confirmation with more research. Serious adverse events were uncommon with each of these treatments and not significantly commoner in the treated than the control groups. There was very little evidence other than that from RCTs. There is a need to develop and test new treatments.

Résumé simplifié

Traitement médicamenteux autre que les corticoïdes, l'immunoglobuline intraveineuse et la plasmaphérèse pour le syndrome aigu de Guillain-Barré

Le syndrome de Guillain-Barré (SGB) est une maladie paralysante aiguë causée par une inflammation des nerfs. Entre 3,5% et 12% des personnes atteintes du SGB meurent de complications pendant la phase aiguë. Un quart des patients nécessitent une ventilation artificielle. Le rétablissement prend plusieurs semaines ou mois et est souvent incomplet. La plasmaphérèse (élimination des substances nocives du sang) et l'immunoglobuline intraveineuse (perfusion dans la circulation sanguine d'anticorps humains provenant de dons de sang) sont bénéfiques, mais pas les corticoïdes. Les traitements actuels étant insuffisants, de nouvelles méthodes devront être mises au point. Nous avons cherché des essais contrôlés randomisés (ECR) portant sur d'autres médicaments pour le SGB. Nous n'avons trouvé que des données de très faible qualité dans la première version de cette revue, et aucun élément nouveau dans cette mise à jour. Un ECR incluant seulement 13 participants avait testé l'interféron bêta-1a, un médicament qui est bénéfique dans la sclérose en plaques. Un autre avec seulement 10 participants avait testé un facteur de croissance nerveuse qui devrait théoriquement être bénéfique. Un troisième essai avec 37 participants avait comparé la filtration du liquide céphalo-rachidien (lavage des racines nerveuses autour de la moelle épinière) et la plasmaphérèse. Aucun de ces essais n'était d'assez grande taille pour confirmer ou infirmer un bénéfice ou un préjudice dans le SGB aigu. Un quatrième essai avec 20 participants laissait penser que le médicament chinois à base de plantes tripterygium polyglycoside faisait reculer l'invalidité plus vite que les corticostéroïdes, mais ce résultat doit être confirmé par de nouvelles recherches. Les événements indésirables graves avaient été rares avec chacun de ces traitements et pas significativement plus fréquents dans les groupes traités que dans les groupes témoins. Il y avait très peu de données hors de celles issues d'ECR. Il est nécessaire de développer et de tester de nouveaux traitements.

Notes de traduction

Traduit par: French Cochrane Centre 1st March, 2013
Traduction financée par: Pour la France : Ministère de la Santé. Pour le Canada : Instituts de recherche en santé du Canada, ministère de la Santé du Québec, Fonds de recherche de Québec-Santé et Institut national d'excellence en santé et en services sociaux.

平易な要約

ギラン・バレー症候群に対する、副腎皮質ステロイド薬、免疫グロブリン静脈内投与および血漿交換以外の薬物療法

ギラン・バレー症候群(GBS)は、神経の炎症によって急性のまひを引き起こす疾患である。GBSの人のうち3.5%~12%が急性期の合併症により死亡する。患者の1/4が人工換気を必要とする。回復には数週間~数カ月かかり、しばしば後遺症が残る。ステロイド薬を除き、血漿交換(有害物質を血液から除去する)や免疫グロブリン静脈内投与(献血から採取したヒト抗体を血流に注入する)は有効である。現在の治療法では不十分なため、新規の治療法を見出す必要がある。GBSに対して上記以外の薬剤を使用したランダム化比較試験(RCT)を検索した。本レビューの初回版ではきわめて質の低いエビデンスしかなく、今回の更新でも新規のエビデンスはなかった。13例のみを対象とした1件のRCTでは、多発性硬化症に有効な薬剤であるインターフェロンβ-1aについて調べた。10例のみを対象とした2つめの試験では、理論的に有効と考えられる神経成長因子について調べた。37例を対象とした3つめの試験では、脳脊髄液濾過(脊髄周囲の神経根を洗浄する)と血漿交換を比較した。これらの試験は、急性GBSにおける有益性や有害性を確定したり否定したりするには規模が不十分であった。20例を対象とした4つめの試験では、漢方薬のtripterygium polyglycosideがステロイド薬よりも早く障害を改善することを示したが、本結果についてはさらなる研究を要する。重篤な有害事象はこれらの治療法のいずれにおいてもまれで、コントロール群の治療法よりも発生頻度が有意に低かった。RCT以外のエビデンスはきわめて少なかった。新規の治療法の開発と調査が必要である。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2016.1.6]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Resumo para leigos

Tratamentos medicamentosos que não sejam os corticosteroides, imunoglobulina intravenosa e troca de plasma para síndrome de Guillain-Barré aguda

A síndrome de Guillain-Barré (SGB) é uma paralisia aguda causada pela inflamação dos nervos. Entre 3,5% e 12% das pessoas com SGB morrem de complicações durante o estado agudo. Um quarto dos pacientes precisa de ventilação mecânica (ajuda de aparelhos para respirar). A recuperação demora várias semanas ou meses e muitas vezes é incompleta. A troca de plasma (para eliminar substâncias danosas do sangue) e a imunoglobulina intravenosa (injeção de anticorpos humanos retirados de doações de sangue) são benéficas, mas os corticoides, não. Como os tratamentos atualmente disponíveis são insuficientes, novos métodos precisam ser descobertos. Nós procuramos por ensaios clínicos randomizados que avaliaram outras medicações para SGB. Nós apenas encontramos evidência de qualidade muito baixa na primeira versão dessa revisão e nenhuma evidência nova nesta atualização. Um estudo com apenas 13 participantes testou o interferon beta-1a, uma droga que funciona para a esclerose múltipla. Outro estudo, com apenas 10 participantes, testou um fator de crescimento de nervos que teoricamente deveria ser benéfico. Um terceiro estudo, com 37 participantes, comparou a filtração do líquido cérebro espinhal (lavar as raízes dos nervos em volta da medula espinhal) versus a troca de plasma. Nenhum desses estudos foi grande o suficiente para confirmar ou refutar os benefícios ou danos na SGB aguda. Um quarto estudo com 20 participantes indica que a erva medicinal chinesa tripterygium polyglycoside poderia acelerar a melhora da incapacidade em comparação com os corticosteroides. Porém esse resultado precisa de confirmação com mais pesquisas. Efeitos adversos graves não foram comuns nos pacientes tratados com essas intervenções e não houve diferença em termos desses efeitos nos grupos tratados comparados aos controles. Quase não existe nenhuma outra evidência disponível além da proveniente dos ensaios clínicos randomizados. Existe a necessidade de desenvolver e testar novos tratamentos para essa doença.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Carolina de Oliveira Cruz)

Summary of findings(Explanation)

Summary of findings for the main comparison. IFNb-1a versus placebo for Guillain-Barré syndrome
  1. 1 Since there is only one trial, the assumed risk has been taken as the that of the control group.
    2 Potential for unblinding.
    3 Only 19 participants.

IFNb-1a versus placebo for Guillain-Barré syndrome
Patient or population: patients with Guillain-Barré syndrome
Settings: 4 UK hospitals1
Intervention: IFNb-1a versus placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlIFNb-1a versus placebo
Improvement in disability grade after 4 weeksThe mean improvement in disability grade after 4 weeks in the control groups was
1.3
The mean Improvement in disability grade after 4 weeks in the intervention groups was
0.1 lower
(1.58 lower to 1.38 higher)
 19
(1 study)
⊕⊝⊝⊝
very low 2,3
Mean (SD) improvement in placebo group (n = 6) was 1.3 (1.5). No significant difference
Improvement in disability grade by one or more points after 4 weeks500 per 1000540 per 1000
(210 to 1000)
RR 1.08
(0.42 to 2.77)
19
(1 study)
⊕⊝⊝⊝
very low 2,3
No significant difference
Death50 per 100075 per 1000
(0 to 0)
RR 1.5
(0.07 to 32.29)
19
(1 study)
⊕⊝⊝⊝
very low 3
1 death out of 13 in the IFNb-1a group and 0 out of 6 in the control group. No significant difference. A fictitious assumed risk of 50 per 1000 for controls has been inserted for illustrative purposes.
Participants with 1 or more serious adverse events333 per 1000306 per 1000
(77 to 1000)
RR 0.92
(0.23 to 3.72)
19
(1 study)
⊕⊝⊝⊝
very low 2,3
No significant difference
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; IFNb-1a: interferon beta-1a; RR: risk ratio; SD: standard deviation
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 BDNF versus placebo for Guillain-Barré syndrome

Summary of findings 2. BDNF versus placebo for Guillain-Barré syndrome
  1. 1 Control group has been used to provide assumed risk.
    2 Only 10 participants.

BDNF versus placebo for Guillain-Barré syndrome
Patient or population: patients with Guillain-Barré syndrome
Settings: 1 Canadian and 2 UK hospitals1
Intervention: BDNF versus placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlBDNF versus placebo
Improvement in disability grade after 4 weeksThe mean improvement in disability grade after 4 weeks in the control groups was
0.25
The mean Improvement in disability grade after 4 weeks in the intervention groups was
0.75 higher
(1.14 lower to 2.64 higher)
 10
(1 study)
⊕⊝⊝⊝
very low 2
Mean (SD) improvement in placebo group (n = 4) was 0.25 (1.71). No significant difference
Improvement in disability grade by one or more points after 4 weeks500 per 1000500 per 1000
(140 to 1000)
RR 1
(0.28 to 3.54)
10
(1 study)
⊕⊝⊝⊝
very low 2
No significant difference
Death250 per 1000168 per 1000
(15 to 1000)
RR 0.67
(0.06 to 7.85)
10
(1 study)
⊕⊝⊝⊝
very low 2
No significant difference
Death or disability after 12 months250 per 1000332 per 1000
(43 to 1000)
RR 1.33
(0.17 to 10.25)
10
(1 study)
⊕⊝⊝⊝
very low 2
No significant difference
Serious adverse events500 per 1000500 per 1000
(140 to 1000)
RR 1
(0.28 to 3.54)
10
(1 study)
⊕⊝⊝⊝
very low 2
No significant difference
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 CSF filtration versus plasma exchange for Guillain-Barré syndrome

Summary of findings 3. CSF filtration versus plasma exchange for Guillain-Barré syndrome
  1. 1 The assumed risk has been taken as the risk on the plasma exchange group.
    2 Not blinded.
    3 Only 37 participants.

CSF filtration versus plasma exchange for Guillain-Barré syndrome
Patient or population: patients with Guillain-Barré syndrome
Settings: one German hospital1
Intervention: CSF filtration versus plasma exchange
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
ControlCSF filtration versus plasma exchange
Improvement in disability grade after 4 weeksThe mean improvement in disability grade after 4 weeks in the control groups was
0.8
The mean Improvement in disability grade after 4 weeks in the intervention groups was
0.02 higher
(0.62 lower to 0.66 higher)
 31
(1 study)
⊕⊝⊝⊝
very low 2,3
Mean (SD) improvement in plasma exchange group was 0.8 (0.95). No significant difference
Improvement in disability grade by one or more points after 4 weeks500 per 1000470 per 1000
(240 to 920)
RR 0.94
(0.48 to 1.84)
37
(1 study)
⊕⊝⊝⊝
very low 2,3
No significant difference
Death50 per 100059 per 1000
(4 to 871)
RR 1.18
(0.08 to 17.42)
37
(1 study)
⊕⊕⊝⊝
low 3
No significant difference
Serious adverse events200 per 100026 per 1000
(2 to 450)
RR 0.13
(0.01 to 2.25)
37
(1 study)
⊕⊝⊝⊝
very low 2,3
No significant difference
Adverse events leading to cessation of treatment50 per 100059 per 1000
(4 to 871)
RR 1.18
(0.08 to 17.42)
37
(1 study)
⊕⊝⊝⊝
very low 2,3
No significant difference
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 4 Tripterygium polyglycoside versus corticosteroids for Guillain-Barré syndrome

Summary of findings 4. Tripterygium polyglycoside versus corticosteroids for Guillain-Barré syndrome
  1. 1 Assumed risk has been taken as that of the corticosteroid group.
    2 Chinese text. Risk of bias classified as unclear by translator.
    3 Oral tripterygium versus intravenous corticosteroids: unblinded.
    4 Primary outcome for this review was to be measured at 4 weeks but only available data come from 8 weeks.
    5 Sample size small.

Tripterygium polyglycoside versus corticosteroids for Guillain-Barré syndrome
Patient or population: patients with Guillain-Barré syndrome
Settings: China1
Intervention: Tripterygium polyglycoside versus corticosteroids
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
CorticosteroidsTripterygium polyglycoside
Improvement in disability grade after 4 weeksSee commentSee commentNot estimable--Not reported
Improvement in disability grade by one or more points after 8 weeks619 per 1000910 per 1000
(631 to 1000)
RR 1.47
(1.02 to 2.11)
43
(1 study)
⊕⊝⊝⊝
very low 2,3,4,5
Just significant difference in favour of tripterygium. This outcome was not one selected for this review.
DeathSee commentSee commentNot estimable43(1 study)⊕⊝⊝⊝very low2,3,4,5No deaths reported in this study in either the tripterygium or corticosteroid control groups.
Adverse events0 per 10000 per 1000
(0 to 0)
RR 2.87
(0.12 to 66.75)
43
(1 study)
⊕⊝⊝⊝
very low 2,3,4,5
1/21 with tripterygium 0/21 with corticosteroids. No significant difference
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

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.

Objectives

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. 

Methods

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

Primary outcomes

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:

  1. healthy;

  2. minor symptoms or signs of neuropathy but capable of manual work;

  3. able to walk without support of a stick but incapable of manual work;

  4. able to walk with a stick, appliance or support;

  5. confined to bed or chair bound;

  6. requiring assisted ventilation;

  7. dead.

Secondary outcomes
  1. Improvement by one or more GBS disability grades after four weeks

  2. Time from randomisation until recovery of unaided walking

  3. Time from randomisation until discontinuation of ventilation (for those ventilated)

  4. Death

  5. Death or disability (inability to walk without aid) after 12 months

  6. 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.

Electronic searches

The search strategies for CENTRAL, MEDLINE and EMBASE are in Appendix 1, Appendix 2 and Appendix 3, respectively.

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.

Data synthesis

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:

  1. younger and older (children aged less than 18 years; adults from age 18 to 49 years of age; adults aged 50 years or more);

  2. 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);

  3. having or not having documented relevant sensory deficit on routine neurological examination at randomisation (symptoms alone will be ignored);

  4. having, or not having, a history of diarrhoea (gastroenteritis) within the six weeks before the onset of neuropathic symptoms;

  5. 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);

  6. axonal versus demyelinating forms of GBS, defined by neurophysiological criteria (Hadden 1998).

No information was available for any of these subgroups.

Sensitivity analysis

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.

Results

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.

Included 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).

Excluded studies

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.

CSF filtration

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.

Tripterygium polyglycoside

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.

Discussion

Summary of main results

Overall summary

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. 

  1. 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.

  2. 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.

  3. 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

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.

Table 1. Other treatments studied in case reports and case series
  1. IV: intravenous
    EBV infection: Epstein Barr infection
    CIDP: chronic inflammatory demyelinating polyradiculoneuropathy

ReferenceRegimenNumber treatedResults
Azathioprine 
Yuill 1970125 mg/d1

By 4 weeks: 1 improved

By end of follow up: 1 had mild residual deficit

Adverse events: none reported

Cyclophosphamide 
Ahuja 1980100 mg/d route not stated4

4 improved by 4 weeks

1 stopped because of diarrhoea

Rosen 197640 mg/kg IV total over 3 to 4 days

12

(3 other cases had CIDP)

By 4 weeks: 10 improved and 1 died

By end of follow up:  3 died, 6 improved and 3 were not followed

Adverse events (out of all 15 cases including CIDP): 2 had pneumonia, 1 haematuria and 11 alopecia

Murine monoclonal antibody OKT3 against CD3 antigen on T cells 
Feasby 1991

5 mg OKT3 IV for 10 days (1 stopped treatment after 3 days because EBV infection diagnosed)

 

3

1 worse, 1 same and 1 improved by 4 weeks

1 developed aseptic meningitis

 

Selective gut decontamination (SDD)
Bos Eyssen 2011Selective decontamination of the digestive tract54Retrospective comparison with 70 not treated with selective decontamination of the gut. "The median duration of mechanical ventilation without SDD was 42 days (interquartile range, IQR 25-77 days) versus 29 days with SDD (IQR 17-45 days)." There was no difference in in neurological recovery after 6 months from first symptoms. Ventilator-associated pneumonia occurred in 12% (95% CI 2 to 22%) in the treated cohort and in 47% (95% CI 35 to 59%) in the non-treated cohort.
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.

Authors' conclusions

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.

Acknowledgements

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

Download statistical data

Comparison 1. IFNb-1a versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Improvement in disability grade after 4 weeks119Mean Difference (IV, Fixed, 95% CI)-0.10 [-1.58, 1.38]
2 Improvement by 1 or more grades after 4 weeks119Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.42, 2.77]
3 Death119Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.07, 32.29]
4 Participants with 1 or more serious adverse events119Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.23, 3.72]
Analysis 1.1.

Comparison 1 IFNb-1a versus placebo, Outcome 1 Improvement in disability grade after 4 weeks.

Analysis 1.2.

Comparison 1 IFNb-1a versus placebo, Outcome 2 Improvement by 1 or more grades after 4 weeks.

Analysis 1.3.

Comparison 1 IFNb-1a versus placebo, Outcome 3 Death.

Analysis 1.4.

Comparison 1 IFNb-1a versus placebo, Outcome 4 Participants with 1 or more serious adverse events.

Comparison 2. BDNF versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Improvement in disability grade after 4 weeks110Mean Difference (IV, Fixed, 95% CI)0.75 [-1.14, 2.64]
2 Improvement in disability grade by one or more points after 4 weeks110Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.28, 3.54]
3 Death110Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.06, 7.85]
4 Death or disability after 12 months110Risk Ratio (M-H, Fixed, 95% CI)1.33 [0.17, 10.25]
5 Serious adverse events110Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.28, 3.54]
Analysis 2.1.

Comparison 2 BDNF versus placebo, Outcome 1 Improvement in disability grade after 4 weeks.

Analysis 2.2.

Comparison 2 BDNF versus placebo, Outcome 2 Improvement in disability grade by one or more points after 4 weeks.

Analysis 2.3.

Comparison 2 BDNF versus placebo, Outcome 3 Death.

Analysis 2.4.

Comparison 2 BDNF versus placebo, Outcome 4 Death or disability after 12 months.

Analysis 2.5.

Comparison 2 BDNF versus placebo, Outcome 5 Serious adverse events.

Comparison 3. CSF filtration versus plasma exchange
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Improvement in disability grade after 4 weeks137Mean Difference (IV, Fixed, 95% CI)0.02 [-0.62, 0.66]
2 Improvement by 1 or more grades after 4 weeks137Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.48, 1.84]
3 Death137Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.08, 17.42]
4 Serious adverse events137Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.01, 2.25]
5 Adverse events leading to cessation of treatment137Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.08, 17.42]
Analysis 3.1.

Comparison 3 CSF filtration versus plasma exchange, Outcome 1 Improvement in disability grade after 4 weeks.

Analysis 3.2.

Comparison 3 CSF filtration versus plasma exchange, Outcome 2 Improvement by 1 or more grades after 4 weeks.

Analysis 3.3.

Comparison 3 CSF filtration versus plasma exchange, Outcome 3 Death.

Analysis 3.4.

Comparison 3 CSF filtration versus plasma exchange, Outcome 4 Serious adverse events.

Analysis 3.5.

Comparison 3 CSF filtration versus plasma exchange, Outcome 5 Adverse events leading to cessation of treatment.

Comparison 4. Tripterygium polyglycoside versus corticosteroids
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Improvement in disability grade by one or more points after 8 weeks143Risk Ratio (M-H, Fixed, 95% CI)1.47 [1.02, 2.11]
2 Adverse events143Risk Ratio (M-H, Fixed, 95% CI)2.87 [0.12, 66.75]
Analysis 4.1.

Comparison 4 Tripterygium polyglycoside versus corticosteroids, Outcome 1 Improvement in disability grade by one or more points after 8 weeks.

Analysis 4.2.

Comparison 4 Tripterygium polyglycoside versus corticosteroids, Outcome 2 Adverse events.

Appendices

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>
Search Strategy:
--------------------------------------------------------------------------------
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>
Search Strategy:
--------------------------------------------------------------------------------

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)

What's new

DateEventDescription
29 January 2013New search has been performedSearches updated to 28 August 2012
15 October 2012New citation required but conclusions have not changedSearch updated. No new trials. One trial excluded. Selective digestive tract decontamination added to the Discussion as a potential intervention.

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

Internal sources

  • None, UK.

External sources

  • 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."

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Bensa 2000

MethodsDouble-blind, parallel-group, RCT
Participants10 patients aged between 18 and 75 years with GBS fulfilling Asbury 1990 criteria within 14 days from the onset of symptoms and having Hughes 1978 disability grade > 3
InterventionsDaily subcutaneous injections r-metHuBDNF 25 μg/kg or placebo (vehicle for active treatment, i.e.150 mM sodium chloride with 0.004% polysorbate 20 buffered to pH 7 with 10 mM sodium phosphate) in vials identical in appearance for 24 weeks or until unaided walking achieved, if earlier
OutcomesPrimary: to investigate safety of r-metHuBDNF
Secondary: to conduct a pilot investigation of the effects of treatment on overall disability after 24 and 48 weeks
NotesInvestigators intended to randomise 14 participants to r-metHuBDNF and 7 to placebo but the trial was curtailed prematurely because the manufacturer removed the drug from the market after negative results in a trial of its use in motor neuron disease
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"randomised by opening an opaque sealed envelope that contained the code number of treatment to be received"
Allocation concealment (selection bias)Low risk"The pharmacist dispensed the coded medication that consisted of r-metHuBDNF 25 μg/kg or placebo in vials identical in appearance. Only the trial statistician and the pharmaceutical company knew the identity of the contents"
Blinding (performance bias and detection bias)
All outcomes
Low risk"The patients were randomised by opening an opaque sealed envelope that contained the code number of treatment to be received. The pharmacist dispensed the coded medication that consisted of r-metHuBDNF 25 μg/kg or placebo in vials identical in appearance. Only the trial statistician and the pharmaceutical company knew the identity of the contents"
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete case analysis
Selective reporting (reporting bias)Low riskComplete case analysis
Other biasHigh riskBDNF participants had more severe disease and were randomised later. The numbers were small

Pritchard 2003

MethodsDouble-blind, randomised, parallel-group trial with 2:1 verum to placebo ratio
ParticipantsPatients with GBS fulfilling Asbury 1990 criteria within 14 days from the onset of symptoms and having Hughes 1978 disability grade > 2
InterventionsIFNb-1a (Rebif®) by subcutaneous injection 3 times a week starting with 22 μg per injection for the first week and continuing with 44 μg for subsequent weeks until a total of 24 weeks. Participants stopped treatment upon reaching grade 2
OutcomesAfter 4 weeks 7 of 13 in the IFNb-1a group had improved one disability grade and 3 of 6 in the placebo group. Serious adverse events, including one death, occurred in 4 of 13 in the IFNb-1a group and 2 of 6 in the placebo group
NotesParticipants in both groups received IVIg. This was a safety and tolerability study. There was no unexpected interaction with IVIg. A significant effect on efficacy outcomes was not expected because of the small sample size
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskEach centre was given study drug in a computer-generated (information from the authors) random sequence by the trial statistician balanced to achieve a 2:1 ratio of IFNb-1a to placebo
Allocation concealment (selection bias)Low riskEach centre was given study drug in random sequence balanced to achieve a 2:1 ratio of IFNb-1a to placebo and concealed until all outcome measures, including attribution of causality of adverse events, had been collected
Blinding (performance bias and detection bias)
All outcomes
High riskNo attempt was made to mask skin lesions from assessors
Incomplete outcome data (attrition bias)
All outcomes
Low riskComplete case analysis reported
Selective reporting (reporting bias)Low riskComplete case analysis of all outcomes reported
Other biasLow riskNone detected

Wollinsky 2001

MethodsParallel-group, open, randomised trial
ParticipantsGBS fulfilling standard Asbury criteria, unable to walk 5 m unaided, < 30 days from onset, age > 15 years
Interventions

CSF filtration 30 to 50 ml removed, filtered and reinfused usually 5 to 6 times daily for 5 to 15 consecutive days

versus

Plasma exchange total 200 to 250 ml/kg in 5 or 6 treatments daily or on alternate days for 7 to 14 days

OutcomesGBS disability grade after 28 and 56 days, side effects and lack of improvement after 56 days
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk“by means of Documenta Geigy table”
Allocation concealment (selection bias)High risk“Blocks of two. Investigators aware of block size”
Blinding (performance bias and detection bias)
All outcomes
High riskAll outcomes except death. No mention of blinding assessors
Incomplete outcome data (attrition bias)
All outcomes
High riskThe scores of 2 participants, one from each group, who died were carried forward with the last score before death and the score was not given
Selective reporting (reporting bias)Low riskComplete case analysis of all outcomes reported
Other biasHigh risk

Two PE patients had transverse myelitis and were retained in the analysis without presentation of the results without them

One patient in each group was crossed over: it was not possible to place a catheter in the CSFF patient. The PE patient went into hypovolaemic shock. In both cases the last value on the initial treatment was carried forward but the actual value was not given

Zhang 2000

  1. a

    RCT: randomised controlled trial
    BDNF: brain-derived neurotrophic factor
    GBS: Guillain-Barré syndrome
    PE: plasma exchange
    CSFF: cerebrospinal fluid filtration

MethodsParallel-group, RCT
Participants43 people with GBS diagnosed according to Asbury 1990 criteria
InterventionsOral tripterygium polyglycoside (a Chinese herbal medicine) 60 to 80 mg daily for 4 weeks and then 30 to 45 mg daily for 4 further weeks, versus intravenous dexamethasone 15 to 20 mg daily for 15 days, then 5 to 10 mg daily for 7 days, then oral prednisone 30 to 60 mg daily decreased by 5 to 10 mg daily every 2 weeks
OutcomesNumber improved at 8 weeks, adverse events and serum IL6 concentrations
NotesEnglish abstract available. Data extracted from full text by translator
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Divided into two groups on layer randomize principle" but method not described according to the translator
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
High riskOral tripterygium polyglycoside compared with intravenous corticosteroids
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot described
Selective reporting (reporting bias)Unclear riskNot described
Other biasUnclear riskNot described

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    CI: confidence interval
    GBS: Guillain-Barré syndrome
    RCT: randomised controlled trial
    CIDP: chronic inflammatory demyelinating polyradiculoneuropathy
    IFNb-1a: interferon beta-1a
    OKT: Orthoclone Monoclonal Antibodies (Ortho Pharmaceutical, Raritan, NJ) [against T cells]
    IVIg: intravenous immunoglobulin

Ahuja 1980Observational study of cyclophosphamide
Bos Eyssen 2011Non randomised retrospective comparison. The method of SDD was not described. This was a retrospective study of 54 mechanically ventilated GBS patients treated with SDD compared with 70 from other centres treated without.
Colin-Jones 1965Not GBS. One person with CIDP treated with 6-mercaptopurine
Créange 1998Not a RCT. Single case report of improvement following IFNb-1a. See text and Table 1
De Grandis 1995Only 8 of 426 participants had GBS and their results were not described separately
Feasby 1991Not a RCT. Three cases treated with OKT3. See text and Table 1
Francesconi 1972No GBS cases included
Gamstorp 1966Not GBS. Single case of CIDP treated with 6-mercaptopurine
Garssen 2007Non-randomised study of mycophenolate mofetil. See Summary of main results
Gorbunov 1995RCT of pulsed versus continuous short-wave diathermy versus no treatment: not a pharmacological treatment
Hammond 1993Only 15 participants had GBS and their results were not separately available in this randomised, double-blind, placebo-controlled trial of intravenous cefotaxime, and amphotericin B, polymyxin E, and tobramycin applied to the oropharynx and enterally. There were altogether 40 participants with neurologic diseases requiring intensive care. "There was no reduction in the incidence of infections (11 in the active group vs 10 in placebo), and duration of ICU stay (30.1 +/- 22.5 vs 20.6 +/- 17.7 days) and hospital stay (49.3 +/- 31.9 vs 40 +/- 33.4 days) were unaffected as was the mortality (15 percent vs 15 percent)."
Hilz 1992Not a RCT but a single case of a method for treating pressure sores
Huang L 1998Ultraviolet irradiation. It is debatable whether this is a pharmacological treatment but in any case it could not be included because there was no description of randomisation or of time from onset when the ultraviolet irradiation was applied
Huang X 1998Time when treatment given not stated. Treatment was ultraviolet irradiation. Allocation was said to be randomised but method unclear
Husstedt 1993No GBS cases included in a study of gingko biloba extract
Li 1998Not stated whether it is randomised. Ultraviolet irradiation. Time from onset differed between irradiation and control groups
Meythaler 2000Treatment started more than 1 year after disease onset. Cross-over design RCT of 4-aminopyridine
Ostronoff 2008Not RCT. Single case report of improvement following rituximab in 1 patient with GBS following haematopoietic stem cell transplantation
Palmer 1965Not GBS. Single case of CIDP treated with 6 mercaptopurine
Palmer 1966Not GBS. Single case of CIDP treated with 6 mercaptopurine
Rosen 1976Not RCT. Case series treated with cyclophosphamide. See Discussion and Table 1
Schaller 2001Not RCT. Single case of GBS treated with IFNb-1a
Wang 2006Not a pharmacological treatment, but acupuncture. 25 participants were randomised to electroacupuncture for 14 days and 24 to IVIg 0.4 g/kg daily for 5 days. Sequence generation was unclear, allocation concealment was done, blinding was not done, outcome data were complete, selective outcome reporting and other sources of bias were unclear. Mean improvement with acupuncture after 4 weeks was 1.58 (0.33) grades and with IVIg 1.68 (0.21) grades. Median (95% CI) time to unaided walking was 79.5 (58.7 to 100.3) and 81.2 (59.8 to 102.6) grades. There were no deaths. Adverse events were not described
Warembourg 1967No GBS cases and not a RCT. See Discussion and Table 1
Yuill 1970Not RCT. Single case report of use of azathioprine
Zagar 1995Review not a RCT

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