Practice Parameter: Immunotherapy for Guillain-Barr 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.

Objective of the guideline:

To provide an evidence-based statement to guide physicians in the management of Guillain-Barr syndrome (GBS).

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 AANs Quality Standards Subcommittee (QSS).

AANs Class of evidence for therapy

Class I. High quality randomized controlled trials (RCTs) Class II. Prospective matched group cohort studies or RCTs lacking adequate randomization concealment or blinding, or potentially liable to attrition or outcome ascertainment bias Class Other studies such as natural history studies III.

Class IV.

Uncontrolled studies, case series, or expert opinion

AANs Recommendation Levels

Level A Level B Established as effective, ineffective or harmful, or as useful/predictive or not useful/predictive Probably effective, ineffective or harmful, or as useful/predictive or not useful/predictive

Level Possibly effective, ineffective or harmful, or as C useful/predictive or not useful/predictive Level Data inadequate or conflicting; Treatment, test, U or predictor unproven

Introduction:
Prevalence: GBS affects between one and four per 100,000 of the worlds 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.

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

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

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.

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

Analysis of the evidence

Author / Year Greenwood, 1984
Compare PE with supportive treatment

Class Results II RCT Improved by one or more disability grades after four weeks
PE group 50%; Control group 40%

Osterman, 1984
Compare PE with supportive treatment

II RCT

Improved by one or more disability grades after four weeks (p<0.025).

PE group 77.8%; Control group 30%

Complete muscle strength recovery after one year.

PE group 94.4%; Control group 80%

Analysis of the evidence

Author/Year Class Results Improvement by one or more grades at one month (p<0.01)
PE group 59%; Control group 39%

The Guillain- II Barr RCT syndrome Study Group, 1985

Compare PE with supportive treatment

Failed to recover walking unaided after 6 months. (p<0.05)

PE group 18%; Control group 29%

Ventilated patients improvement by one or more disability grades at one month (p<0.01)
PE group 50%; Control group 35%

Analysis of the evidence

Author / Year Class Results

Farkkila, II RCT 1987

Compare PE with supportive treatment

Handgrip strength was significantly greater in the PE group (p<0.001) The mean ( SD) time on ventilator was slightly shortened
PE group (n=4) 11.7 12.2 days; Control group (n=3) 15.3 6.1 days

The mean recovery time in days was almost identical between the two groups
PE 76.6 88.4 vs. Supportive Treatment 79.1 55.8

Analysis of the evidence

Author/Year French Co-op Group on plasma exchange in GBS, 1987
Compare PE with supportive treatment

Class Results II RCT PE patients recovered walking with assistance faster than the control patients (p<0.01) Recovered 1 or more disability grades after 4 weeks
PE group 67/109; Control group 41/111

For ventilated patients, time to onset of recover walking assistance was shorter in the PE than the control group (p<0.05)

Analysis of the evidence

Author / Year French Co-op Group on plasma exchange in GBS, 1997
Compare PE with supportive treatment

Class

Results

II RCT In the PE group, time to onset of motor recovery was significantly shortened compared to the control group (p=0.0002).

The number of patients with one or more grades of improvement at one month was significantly more
PE group 56.5%; Control group 28.3%

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).

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).

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.

Analysis of the evidence

Author/Year Class Results

van der Mech, et al., 1992

Compare IVIg with PE

II Nonblinded RCT

Patients improved by one or more grades (p=0.024) after four weeks

IVIg group 53%; PE group 34%

Median time to recovery of unaided walking (p=0.07)

IVIg group 55 days; PE group 69days

Analysis of the evidence

Author/Year Class Results

Grses, 1995
Compare IVIG with supportive treatment

III Alternate allocation Controlled trial (children)

Recovered full strength after four weeks (p=0.06)

IVIg group 77.8%; Control group 22.2%

Median time to recover unaided walking

IVIg group 15 days (r=1120); Control group 24.5 days (r=21-28)

After one year all the IVIg patients had recovered

Analysis of the evidence

Author/Year Class Results

Bril, et al., 1996

Compare IVIG with supportive treatment

II RCT

Median time to recover ability to do manual work

IVIg group 65 days; PE group 90 days

Mean disability grade improvement

IVIg group 1.2; PE group 1.0

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.

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).

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.

Analysis of evidence
Author/Year Class Results

PSGBS II Group, 1997 Single To compare IVIg blind with PE and with PE followed by IVIg RCT

No significant difference in any outcome measure between any of the three regimens The difference between the change in disability grade between PE and IVIg was so small as to fulfill previously declared criteria for equivalence

Analysis of evidence
Author / Class Results Year Nomura et al., 2001
To compare IVIg with PE and with PE followed by IVIg

II RCT

No significant difference in any outcome measure

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).

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).

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

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).

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.

Analysis of evidence
Author/Year Swick and McQuillen, 1976
Effect of ACTH

Class II RCT

Results Average disease duration, excluding one ACTH patient who died ACTH group 4.4 months; Placebo patients 9.0 months.

Hughes et al., II 1978 RCT

Effect of prednisolone

Less improvement in disability grade after one, three and 12 months in the prednisolone than the untreated patients, which was significant (p<0.05) for those randomized within seven days from onset

Analysis of evidence
Author/Year Class Results

Mendell et al., 1985

Effect of plasma exchange and prednisone

II Alternate allocation controlled trial I RCT

No significant difference in any outcome

Shukla et al., 1988

Effect of prednisolone

No significant difference in any outcome

Analysis of evidence
Author/Year GBS Steroid Trial Group, 1993
Effect of iv methylprednisolone

Class I RCT

Results The mean difference in disability grade after four weeks was 0.06 (-0.23 0.36) grade more improvement in the steroid than the placebo group Neither this nor any other outcome variable showed a significant difference No significant difference in any outcome

Singh et al., 1996

Effect of prednisolone

II Alternate allocation CT

Analysis of evidence
Author/Year The Dutch GBS Group, 1994
Effect of iv methylPrednisolone added to IVIg

Class III observational series with historical controls

Results
76% improved one grade; Control group 53% (p=0.04)

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).

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

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.

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).

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 Fishers 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.

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.

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.

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.