This document summarizes guidelines from the American Academy of Neurology (AAN) on immunotherapy for Guillain-Barré syndrome (GBS). It reviews the evidence from clinical trials on plasma exchange, intravenous immunoglobulin (IVIg), corticosteroids, and combination treatments. The AAN recommends plasma exchange for non-ambulant GBS patients within 4 weeks of onset and considers it for ambulant patients within 2 weeks. IVIg is also recommended for GBS patients requiring walking assistance within 2-4 weeks of onset as it has equivalent efficacy to plasma exchange. Corticosteroids and combination treatments are not recommended based on lack of proven benefit.

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).

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4. 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).

5. 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

6. 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

7. 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.

8. 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

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

10. 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.

11. 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

12. Analysis of the evidence
Author / 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%

13. Analysis of the evidence
Author/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%

14. Analysis of the evidence
Author /
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

15. Analysis of the evidence
Author/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)

16. Analysis of the evidence
Author /
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%

17. 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).

18. 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).

19. 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.

20. Analysis of the evidence
Author/Year Class Results
van der
Meché,
et al., 1992
Compare IVIg with
PE
II Non-
blinded
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

21. Analysis of the evidence
Author/Year Class Results
Gürses,
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=11-
20);
Control group 24.5 days
(r=21-28)
 After one year all the IVIg
patients had recovered

22. 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

23. 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.

24. 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).

25. 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.

26. Analysis of evidence
Author/Year Class Results
PSGBS
Group, 1997
To compare IVIg
with PE and with
PE followed by IVIg
II
Single
blind
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

27. Analysis of evidence
Author /
Year
Class Results
Nomura
et al.,
2001
To compare
IVIg with PE
and with PE
followed by
IVIg
II RCT  No significant difference in any
outcome measure

28. 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).

29. 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).

30. 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

31.  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

32. 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.

33. Analysis of evidence
Author/Year Class Results
Swick and
McQuillen,
1976
Effect of ACTH
II
RCT
 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
II
RCT
 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

34. Analysis of evidence
Author/Year Class Results
Mendell et
al., 1985
Effect of plasma
exchange and
prednisone
II Alternate
allocation
controlled
trial
 No significant difference in any
outcome
Shukla et al.,
1988
Effect of
prednisolone
I RCT  No significant difference in any
outcome

35. Analysis of evidence
Author/Year Class Results
GBS Steroid
Trial Group,
1993
Effect 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.,
1996
Effect of
prednisolone
II Alternate
allocation
CT
 No significant difference in any
outcome

36. Analysis of evidence
Author/Year Class Results
The Dutch
GBS Group,
1994
Effect of iv
methyl-
Prednisolone
added to IVIg
III
observational
series with
historical
controls
76% improved one grade;
Control group 53% (p=0.04)

37.  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

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

39. 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.

40.  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

41. 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.

42. 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.

43. 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.

44. 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.

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