Practice Parameter: Immunotherapy for Guillain-Barré syndrome

1. Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology RAC Hughes, MD; EFM Wijdicks, MD; R Barohn, MD; E Benson, DR Cornblath, MD; AF Hahn, MD; JM Meythaler, MD; RG Miller, MD; JT Sladky; JC Stevens, MD Published in Neurology 2003;61:736-740.

2. Objective of the guideline: To provide an evidence-based statement to guide physicians in the management of Guillain-Barré syndrome (GBS).

3. Methods of evidence review: • MEDLINE search from 1966 and the Cochrane library (March 2002). • “Polyradiculoneuritis” limited by “human” and cross referenced with “therapy.” • Search results were reviewed by at least two members of the GBS practice parameter group. • Recommendations were graded according to the levels established by the AAN’s Quality Standards Subcommittee (QSS).

4. AAN’s Class of evidence for therapy

5. AAN’s Recommendation Levels

6. Introduction: Prevalence: GBS affects between one and four per 100,000 of the world’s population annually. Economic Impact: The costs in the US have been estimated as $110,000 for direct health care and $360,000 in lost productivity per patient.

7. Introduction: Health Outcomes: • Respiratory failure requiring ventilation in about 25% of patients with GBS • Death in 4% to 15% of GBS patients • Persistent disability in about 20% patients with GBS • Persistent fatigue in 67% of patients with GBS

8. Question #1: Does initial immunotherapy hasten recovery from GBS symptoms?

9. Diagnostic criteria In most studies, the primary outcome measure used disability scale, where: • 0 = normal • 1 = symptoms but able to run • 2 = unable to run • 3 = unable to walk unaided • 4 = bed-bound • 5 = needing ventilation • 6 = dead Most studies included patients with severe disease, at least grade 3 on that scale.

10. Analysis of the evidence Plasma Exchange • Cochrane review obtained data from six Class II trials comparing plasma exchange (PE) alone to supportive care • The PE regimens involved exchanging about one plasma volume on five separate occasions spaced out over one to two weeks • One trial which used two plasma volume exchanges on alternate days for a total of four exchanges

11. Analysis of the evidence

12. Analysis of the evidence

13. Analysis of the evidence

14. Analysis of the evidence

15. Analysis of the evidence

16. Conclusions • Plasma exchange hastens recovery in non-ambulant patients with GBS who present within four weeks from the onset of neuropathic symptoms (Class II evidence). • Plasma exchange also hastens recovery in ambulant patients who present within two weeks but the evidence is limited to one trial (Class II evidence). • The effects of plasma exchange and IVIg are equivalent in patients requiring aid to walk(Class I evidence). • Treatment with CSF filtration has not been adequately tested (Limited Class II evidence).

17. Recommendations • PE is recommended in non-ambulant patients within four weeks from onset (Level A, Class II evidence). • PE is recommended for ambulant patients within two weeks from onset (Level B, limited Class II evidence).

18. Analysis of the evidence IV Immunoglobulin • Three trials compared IVIg with PE. The mean improvement in disability grade four weeks after randomization was available. • In one Class III trial comparing IVIg with supportive treatment, seven of nine children who received IVIg recovered completely by four weeks compared with two of nine untreated. • Cochrane systematic review found no trials comparing IV immunoglobulin (IVIg) with placebo.

19. Analysis of the evidence

20. Analysis of the evidence

21. Analysis of the evidence

22. Conclusions • Intravenous immunoglobulin has not been adequately compared with placebo (limited Class II evidence). • Such comparison is not now needed because, when started within two weeks from the onset, IVIg has equivalent efficacy to PE in hastening recovery from patients with GBS who require aid to walk (Class I evidence). • Multiple complications were significantly less frequent with IVIg than with PE (Class I evidence). • There is no evidence concerning the relative efficacy of PE and IVIg in patients with axonal forms of GBS.

23. Recommendations • IVIg is recommended for patients with GBS who require aid to walk within two (Level A recommendation) or four weeks from the onset of neuropathic symptoms (Level B recommendation derived from Class II evidence concerning PE started within the first four weeks). • The effects of IVIg and plasma exchange are equivalent. (Level B recommendation Class I evidence concerning the comparisons between PE and IVIg started within the first two weeks).

24. Analysis of the evidence Combination treatments • One Class I trial showed that PE followed by IVIg showed no significant benefit compared with PE alone in any measured outcome.

25. Analysis of evidence

26. Analysis of evidence

27. Conclusions • Sequential treatment with PE followed by IVIg does not have a superior effect to either treatment given alone (Class I evidence). • Sequential treatment with immunoabsorption followed by IVIg has not been adequately tested (Limited Class IV evidence).

28. Recommendations • Sequential treatment with PE followed by IVIg is not recommended (Level A recommendation, Class I evidence). • Immunoabsorption followed by IVIg is not recommended (Level U recommendation, Class IV evidence).

29. Analysis of the evidence Immunoabsorption • An alternative technique to PE, which removes immunoglobulins. • Has the advantage of not requiring the use of a human blood product as a replacement fluid. • In a prospective trial there were no differences in outcome between 11 patients treated with PE and 13 treated with immunoabsorption

30. Conclusion • There is only limited Class IV evidence from a single small non-randomized, unblinded study. Recommendation • The evidence is insufficient to recommend the use of immunoabsorption (Level U recommendation, Class IV evidence).

31. Analysis of the evidence Steroids • Cochrane systematic review sought all trials of any form of corticosteroid or adrenocorticotrophic hormone treatment for GBS. Six randomized trials were identified. • The corticosteroid regimens included intramuscular ACTH, intravenous methylprednisolone,oral prednisolone, or prednisone. • The primary outcome measure in the systematic review was the improvement in disability grade four weeks after randomization.

32. Analysis of evidence

33. Analysis of evidence

34. Analysis of evidence

35. Analysis of evidence

36. Conclusion • The combined evidence from all trials shows no benefit from corticosteroids (Class I evidence). • The results of a trial of the combination of intravenous methylprednisolone and IVIg are awaited. Recommendation • Corticosteroids are not recommended in the treatment of GBS (Level A, Class I evidence).

37. Question #2: Are there special issues in the management of children with GBS?

38. Analysis of the evidence GBS in Children • The clinical features of GBS in children are similar to those in adults except that severe conditions are less common and axonal forms of the disease are more frequent in some populations. • In younger children, in particular, pain is frequently the only symptom they are able to articulate and evidence of subtle weakness and loss of reflexes may be overlooked. • There is a lack of adequate randomized controlled treatment trials in children to define the role of either PE or IVIg.

39. Conclusion • There are no adequate randomized controlled trials of treatment in children. Recommendation • Plasma exchange or IVIg are treatment options for treating children with severe GBS (Level B recommendation derived from class II evidence in adults).

40. Future research • More research is needed to evaluate immunotherapy in GBS, particularly the use of combination treatments and further treatment after the initial course. • There is a need to identify patients who are at greater risk of an adverse outcome and to discover whether subgroups have differential responses to treatment (including children, people with axonal forms of GBS, and Fisher’s syndrome). • Research should also investigate the best methods of supportive care for monitoring autonomic and pulmonary function, weaning from ventilation, treating pain, managing fatigue, and rehabilitation.

41. Summary of AAN recommendations for immunotherapy for GBS 1. Plasma exchange is recommended in non-ambulant adult patients with GBS who present within four weeks from the onset of neuropathic symptoms. Plasma exchange should also be considered in ambulant patients who present within two weeks from the onset of neuropathic symptoms.

42. Summary of AAN recommendations for immunotherapy for GBS 2. Intravenous immunoglobulin (IVIg) is recommended in non-ambulant adult patients with GBS within two or possibly four weeks from the onset of neuropathic symptoms. The effects of plasma exchange and IVIg are equivalent. 3. Corticosteroids are not recommended in the treatment of GBS.

43. Summary of AAN recommendations for immunotherapy for GBS 4. Sequential treatment with PE followed by IVIg or immunoabsorption followed by IVIg is not recommended for GBS. 5. Plasma exchange or IVIg are treatment options for treating children with severe GBS.