practice parameter: immunotherapy for guillain-barré syndrome a report of the quality standards...

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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.

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Page 1: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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.

Page 2: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Objective of the guideline:

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

Page 3: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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).

Page 4: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

AAN’s 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 III.

Other studies such as natural history studies

Class IV.

Uncontrolled studies, case series, or expert opinion

Page 5: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

AAN’s Recommendation Levels

Level A

Established as effective, ineffective or harmful, or as useful/predictive or not useful/predictive

Level B

Probably effective, ineffective or harmful, or as useful/predictive or not useful/predictive

Level C

Possibly effective, ineffective or harmful, or as useful/predictive or not useful/predictive

Level U

Data inadequate or conflicting; Treatment, test, or predictor unproven

Page 6: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Introduction:

Prevalence: GBS affects between one and four per 100,000 ofthe 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.

Page 7: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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

Page 8: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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

Page 9: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Diagnostic criteriaIn most studies, the primary outcome measureused 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.

Page 10: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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

Page 11: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of the evidenceAuthor / Year

Class

Results

Greenwood, 1984 Compare PE with supportive treatment

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%

Page 12: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of the evidenceAuthor/Year

Class

Results

The Guillain-Barré syndrome Study Group, 1985 Compare PE with supportive treatment

II RCT

Improvement by one or more grades at one month (p<0.01)

PE group 59%; Control group 39%

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%

Page 13: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of the evidenceAuthor / Year

Class Results

Farkkila, 1987 Compare PE with supportive treatment

II RCT 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

Page 14: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of the evidenceAuthor/Year

Class

Results

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

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)

Page 15: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of the evidenceAuthor / Year

Class Results

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

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%

Page 16: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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).

Page 17: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Recommendations PE is recommended in non-ambulant patients

within four weeks from onset (Level A, Class IIevidence).

PE is recommended for ambulant patients within two weeks from onset (Level B, limited Class II evidence).

Page 18: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of the evidenceIV 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.

Page 19: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of the evidenceAuthor/Year

Class Results

van der Meché, et al., 1992 Compare IVIg with PE

II Non-blindedRCT

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

Page 20: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of the evidenceAuthor/Year

Class Results

Gürses, 1995 Compare IVIG with supportive treatment

III Alternate allocationControlled 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=11-20);Control group 24.5 days (r=21-28)

After one year all the IVIg patients had recovered

Page 21: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of the evidenceAuthor/Year Class Results

Bril, et al., 1996Compare 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

Page 22: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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.

Page 23: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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).

Page 24: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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.

Page 25: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of evidenceAuthor/Year

Class

Results

PSGBS Group, 1997 To compare IVIg with PE and with PE followed by IVIg

II Single blindRCT

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

Page 26: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of evidence

Author / Year

Class

Results

Nomura et al., 2001To compare IVIg with PE and with PE followed by IVIg

II RCT

No significant difference in any outcome measure

Page 27: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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).

Page 28: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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).

Page 29: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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

Page 30: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

There is only limited Class IV evidence from a single small non-randomized, unblinded study.

 

Conclusion

The evidence is insufficient to recommend the use of immunoabsorption (Level U recommendation, Class IV evidence).

Recommendation

Page 31: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of the evidenceSteroids 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.

Page 32: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of evidenceAuthor/Year

Class Results

Swick and McQuillen, 1976 Effect of ACTH

IIRCT

Average disease duration, excluding one ACTH patient who died

ACTH group 4.4 months; Placebo patients 9.0 months.

Hughes et al., 1978 Effect of prednisolone

IIRCT

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

Page 33: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of evidence

Author/Year

Class Results

Mendell et al., 1985Effect of plasma exchange and prednisone

II Alternate allocation controlled trial

No significant difference in any outcome

Shukla et al., 1988Effect of prednisolone

I RCT No significant difference in any outcome

Page 34: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of evidenceAuthor/Year

Class Results

GBS Steroid Trial Group, 1993Effect of iv methyl-prednisolone

I RCT 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

Singh et al., 1996Effect of prednisolone

II Alternate allocation CT

No significant difference in any outcome

Page 35: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of evidenceAuthor/Year

Class Results

The Dutch GBS Group, 1994Effect of iv methyl-Prednisolone added to IVIg

III observational series with historical controls

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

Page 36: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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.

Conclusion

Corticosteroids are not recommended in the treatment of GBS (Level A, Class I evidence).

Recommendation

Page 37: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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

Page 38: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Analysis of the evidenceGBS 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.

Page 39: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

There are no adequate randomized controlled trials of treatment in children.

 

Conclusion

Plasma exchange or IVIg are treatment options for treating children with severe GBS (Level B recommendation derived from class II evidence in adults).

Recommendation

Page 40: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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.

Page 41: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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.

Page 42: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

Summary of AAN recommendations for immunotherapy for GBS2. 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.

Page 43: Practice Parameter: Immunotherapy for Guillain-Barré syndrome A report of the Quality Standards Subcommittee (QSS) of the American Academy of Neurology

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.