Practice Parameter: Immunotherapy for GuillainBarr syndrome

A report of the Quality Standards Subcommittee (QSS) of the American Academy of eurolo!y
"A# $u!hes% &'( )*& +i,dic-s% &'( " Barohn% &'( ) Benson% '" #ornblath% &'( A* $ahn% &'( .& &eythaler% &'( "G &iller% &'( ./ Slad-y( .# Ste0ens% &' Published in Neurology 2003;61:736-740.

1b,ecti0e of the !uideline:

/o pro0ide an e0idence-based statement to !uide physicians in the mana!ement of Guillain-Barr syndrome (GBS)2

&ethods of e0idence re0ie3:

&)'4I ) search from 5677 and the #ochrane library (March 2002)2 8Polyradiculoneuritis9 limited by 8human9 and cross referenced 3ith 8therapy29 Search results 3ere re0ie3ed by at least t3o members of the GBS practice parameter !roup2 "ecommendations 3ere !raded accordin! to the le0els established by the AA :s Quality Standards Subcommittee (QSS)2

AA :s #lass of e0idence for therapy

#lass I2 $i!h ;uality randomi<ed controlled trials ("#/s) #lass II2 Prospecti0e matched !roup cohort studies or "#/s lac-in! ade;uate randomi<ation concealment or blindin!% or potentially liable to attrition or outcome ascertainment bias 1ther studies such as natural history studies >ncontrolled studies% case series% or e?pert opinion

#lass III2 #lass I=2

AA :s "ecommendation 4e0els
4e0el )stablished as effecti0e% ineffecti0e or A harmful% or as useful@predicti0e or not useful@predicti0e 4e0el Probably effecti0e% ineffecti0e or harmful% B or as useful@predicti0e or not useful@predicti0e 4e0el Possibly effecti0e% ineffecti0e or harmful% # or as useful@predicti0e or not useful@predicti0e 4e0el 'ata inade;uate or conflictin!( /reatment% > test% or predictor unpro0en

Introduction:
Pre0alence: GBS affects bet3een one and four per 5AA%AAA of the 3orld:s population annually2 )conomic Impact: /he costs in the >S ha0e been estimated as B55A%AAA for direct health care and BC7A%AAA in lost producti0ity per patient2

Introduction:
$ealth 1utcomes: "espiratory failure re;uirin! 0entilation in about DEF of patients 3ith GBS 'eath in GF to 5EF of GBS patients Persistent disability in about DAF patients 3ith GBS Persistent fati!ue in 7HF of patients 3ith GBS

Question #1: Does initial i unothera!y hasten reco"ery #ro $%& sy !to s'

'ia!nostic criteria
In most studies% the primary outcome measure used disability scale% 3here: A I normal 5 I symptoms but able to run D I unable to run C I unable to 3al- unaided G I bed-bound E I needin! 0entilation 7 I dead &ost studies included patients 3ith se0ere disease% at least !rade C on that scale2

Analysis of the e0idence

Plasma )?chan!e #ochrane re0ie3 obtained data from si? #lass II trials comparin! plasma e?chan!e (P)) alone to supporti0e care /he P) re!imens in0ol0ed e?chan!in! about one plasma 0olume on fi0e separate occasions spaced out o0er one to t3o 3ee-s 1ne trial 3hich used t3o plasma 0olume e?chan!es on alternate days for a total of four e?chan!es

Analysis of the e0idence

Author / Year Green3ood% 56JG Clas s II "#/ Results Impro0ed by one or more disability !rades after four 3ee-s
PE group 50%; Control group 40%

(o !are )* +ith su!!orti"e treat ent

1sterman% 56JG
(o !are )* +ith su!!orti"e treat ent

II "#/

Impro0ed by one or more disability !rades after four 3ee-s (pKA2ADE)2

PE group 77 !%; Control group "0%

#omplete muscle stren!th reco0ery after one year2

PE group #4 4%; Control group !0%

Analysis of the e0idence

Author/Ye ar /he GuillainBarr syndrome Study Group% 56JE
(o !are )* +ith su!!orti"e treat ent

Clas s II "#/

Results Impro0ement by one or more !rades at one month (pKA2A5)

PE group 5#%; Control group "#%

*ailed to reco0er 3al-in! unaided after 7 months2 (pKA2AE)

PE group $!%; Control group %#%

=entilated patients impro0ement by one or more disability !rades at one month (pKA2A5)
PE group 50%; Control group "5%

Analysis of the e0idence

Author / Year Class Results

*ar--ila II "#/ % 56JH

(o !are )* +ith su!!orti"e treat ent

$and!rip stren!th 3as si!nificantly !reater in the P) !roup (pKA2AA5) /he mean (L S') time on 0entilator 3as sli!htly shortened

PE group &n'4( $$ 7 ) $% % da*s; Control group &n'"( $5 " ) + $ da*s

/he mean reco0ery time in days 3as almost identical bet3een the t3o !roups
PE 7+ + ) !! 4 ,s -upporti,e .reat/ent 7# $ ) 55 !

Analysis of the e0idence

Author/Ye ar Clas s Results P) patients reco0ered 3al-in! 3ith assistance faster than the control patients (pKA2A5) "eco0ered 5 or more disability !rades after G 3ee-s
PE group +7/$0#; Control group 4$/$$$

*rench II #o-op "#/ Group on plasma e?chan!e in GBS% 56JH

(o !are )* +ith su!!orti"e treat ent

*or 0entilated patients% time to onset of reco0er 3al-in! assistance 3as shorter in the P) than the control !roup (pKA2AE)

Analysis of the e0idence

Author / Year Class Results *rench II "#/ In the P) !roup% time to onset of motor reco0ery 3as si!nificantly #o-op shortened compared to the Group on control !roup (pIA2AAAD)2 plasma e?chan!e in GBS% /he number of patients 3ith one 566H or more !rades of impro0ement (o !are )* +ith at one month 3as si!nificantly su!!orti"e more treat ent
PE group 5+ 5%; Control group %! "%

#onclusions
Plasma e?chan!e hastens reco0ery in nonambulant patients 3ith GBS 3ho present 3ithin four 3ee-s from the onset of neuropathic symptoms (#lass II e0idence)2 Plasma e?chan!e also hastens reco0ery in ambulant patients 3ho present 3ithin t3o 3ee-s but the e0idence is limited to one trial (#lass II e0idence)2 /he effects of plasma e?chan!e and I=I! are e;ui0alent in patients re;uirin! aid to 3al-(#lass I e0idence)2 /reatment 3ith #S* filtration has not been ade;uately tested (4imited #lass II e0idence)2

"ecommendations
P) is recommended in non-ambulant patients 3ithin four 3ee-s from onset (4e0el A% #lass II e0idence)2 P) is recommended for ambulant patients 3ithin t3o 3ee-s from onset (4e0el B% limited #lass II e0idence)2

Analysis of the e0idence

I= Immuno!lobulin /hree trials compared I=I! 3ith P)2 /he mean impro0ement in disability !rade four 3ee-s after randomi<ation 3as a0ailable2 In one #lass III trial comparin! I=I! 3ith supporti0e treatment% se0en of nine children 3ho recei0ed I=I! reco0ered completely by four 3ee-s compared 3ith t3o of nine untreated2 #ochrane systematic re0ie3 found no trials comparin! I= immuno!lobulin (I=I!) 3ith placebo2

Analysis of the e0idence

Author/Ye ar 0an der &ech% et al2% 566D
(o !are ,-,g +ith )*

Class

Results

II on- Patients impro0ed by one or blinded more !rades (pIA2ADG) after "#/ four 3ee-s
I0Ig group 5"%; PE group "4%

&edian time to reco0ery of unaided 3al-in! (pIA2AH)

I0Ig group 55 da*s; PE group +#da*s

Analysis of the e0idence

Author/Ye ar Class Results

GMrses% 566E

(o !are ,-,$ +ith su!!orti"e treat ent

III Alternate allocation #ontrolled trial (children)

"eco0ered full stren!th after four 3ee-s (pIA2A7)

I0Ig group 77 !%; Control group %% %%

&edian time to reco0er unaided 3al-in!

I0Ig group $5 da*s &r'$$1%0(; Control group %4 5 da*s &r'%$1%!(

After one year all the I=I! patients had reco0ered

Analysis of the e0idence

Author/Year Class Results
Bril% et al2% 5667 II "#/ &edian time to reco0er ability to do manual 3orI0Ig group +5 da*s; PE group #0 da*s

(o !are ,-,$ +ith su!!orti"e treat ent

&ean disability !rade impro0ement

I0Ig group $ %; PE group $ 0

Conclusions

Intra0enous immuno!lobulin has not been ade;uately compared 3ith placebo (limited #lass II e0idence)2 Such comparison is not no3 needed because% 3hen started 3ithin t3o 3ee-s from the onset% I=I! has e;ui0alent efficacy to P) in hastenin! reco0ery from patients 3ith GBS 3ho re;uire aid to 3al- (#lass I e0idence)2 &ultiple complications 3ere si!nificantly less fre;uent 3ith I=I! than 3ith P) (#lass I e0idence)2 /here is no e0idence concernin! the relati0e efficacy of P) and I=I! in patients 3ith a?onal forms of GBS2

Reco//endations
I=I! is recommended for patients 3ith GBS 3ho re;uire aid to 3al- 3ithin t3o (4e0el A recommendation) or four 3ee-s from the onset of neuropathic symptoms (4e0el B recommendation deri0ed from #lass II e0idence concernin! P) started 3ithin the first four 3ee-s)2 /he effects of I=I! and plasma e?chan!e are e;ui0alent2 (4e0el B recommendation #lass I e0idence concernin! the comparisons bet3een P) and I=I! started 3ithin the first t3o 3ee-s)2

Analysis of the e0idence

#ombination treatments 1ne #lass I trial sho3ed that P) follo3ed by I=I! sho3ed no si!nificant benefit compared 3ith P) alone in any measured outcome2

Analysis of e0idence
Author/Ye Clas ar s PSGBS Group% 566H
.o co !are ,-,g +ith )* an/ +ith )* #ollo+e/ 0y ,-,g

Results o si!nificant difference in any outcome measure bet3een any of the three re!imens /he difference bet3een the chan!e in disability !rade bet3een P) and I=I! 3as so small as to fulfill pre0iously declared criteria for e;ui0alence

II Sin!l e blind "#/

Analysis of e0idence
Author Clas / Year s omura II et al2% "#/ DAA5
.o co !are ,-,g +ith )* an/ +ith )* #ollo+e/ 0y ,-,g

Results o si!nificant difference in any outcome measure

Conclusions
Se;uential treatment 3ith P) follo3ed by I=I! does not ha0e a superior effect to either treatment !i0en alone (#lass I e0idence)2 Se;uential treatment 3ith immunoabsorption follo3ed by I=I! has not been ade;uately tested (4imited #lass I= e0idence)2

Reco//endations
Se;uential treatment 3ith P) follo3ed by I=I! is not recommended (4e0el A recommendation% #lass I e0idence)2 Immunoabsorption follo3ed by I=I! is not recommended (4e0el > recommendation% #lass I= e0idence)2

Analysis of the e0idence

Immunoabsorption An alternati0e techni;ue to P)% 3hich remo0es immuno!lobulins2 $as the ad0anta!e of not re;uirin! the use of a human blood product as a replacement fluid2 In a prospecti0e trial there 3ere no differences in outcome bet3een 55 patients treated 3ith P) and 5C treated 3ith immunoabsorption

Conclusion
/here is only limited #lass I= e0idence from a sin!le small non-randomi<ed% unblinded study2 2

Reco//endation
/he e0idence is insufficient to recommend the use of immunoabsorption (4e0el > recommendation% #lass I= e0idence)2

Analysis of the e0idence

Steroids #ochrane systematic re0ie3 sou!ht all trials of any form of corticosteroid or adrenocorticotrophic hormone treatment for GBS2 Si? randomi<ed trials 3ere identified2 /he corticosteroid re!imens included intramuscular A#/$% intra0enous methylprednisolone%oral prednisolone% or prednisone2 /he primary outcome measure in the systematic re0ie3 3as the impro0ement in disability !rade four 3ee-s after randomi<ation2

Analysis of e0idence
Author/Ye ar S3ic- and &cQuillen% 56H7
*##ect o# 1(.2

Class II "#/

Results A0era!e disease duration% e?cludin! one A#/$ patient 3ho died AC.3 group 4 4 /onths; Place4o patients # 0 /onths 4ess impro0ement in disability !rade after one% three and 5D months in the prednisolone than the untreated patients% 3hich 3as si!nificant (pKA2AE) for those randomi<ed 3ithin se0en days from onset

$u!hes et al2% 56HJ

*##ect o# !re/nisolone

II "#/

Analysis of e0idence
Author/Ye ar &endell et al2% 56JE
*##ect o# !las a e3change an/ !re/nisone

Class

Results o si!nificant difference in any outcome

II Alternate allocation controlled trial I "#/

Shu-la et al2% 56JJ

*##ect o# !re/nisolone

o si!nificant difference in any outcome

Analysis of e0idence
Author/Ye ar Class Results /he mean difference in disability !rade after four 3ee-s 3as A2A7 (-A2DC N A2C7) !rade more impro0ement in the steroid than the placebo !roup either this nor any other outcome 0ariable sho3ed a si!nificant difference o si!nificant difference in any outcome GBS Steroid I "#/ /rial Group% 566C
*##ect o# i" ethyl!re/nisolone

Sin!h et al2% II 5667 Alternate *##ect o# allocation !re/nisolone #/

Analysis of e0idence
Author/Ye ar /he 'utch GBS Group% 566G
*##ect o# i" ethyl)re/nisolone a//e/ to ,-,g

Class

Results

7+% i/pro,ed one grade; III obser0ationa Control group 5"% l series 3ith &p'0 04( historical controls

Conclusion
/he combined e0idence from all trials sho3s no benefit from corticosteroids (#lass I e0idence)2 /he results of a trial of the combination of intra0enous methylprednisolone and I=I! are a3aited2

Reco//endation
#orticosteroids are not recommended in the treatment of GBS (4e0el A% #lass I e0idence)2

Question #2: 1re there s!ecial issues in the anage ent o# chil/ren +ith $%&'

Analysis of the e0idence

GBS in #hildren /he clinical features of GBS in children are similar to those in adults e?cept that se0ere conditions are less common and a?onal forms of the disease are more fre;uent in some populations2 In youn!er children% in particular% pain is fre;uently the only symptom they are able to articulate and e0idence of subtle 3ea-ness and loss of refle?es may be o0erloo-ed2 /here is a lac- of ade;uate randomi<ed controlled treatment trials in children to define the role of either P) or I=I!2

Conclusion
/here are no ade;uate randomi<ed controlled trials of treatment in children2 2

Reco//endation
Plasma e?chan!e or I=I! are treatment options for treatin! children 3ith se0ere GBS (4e0el B recommendation deri0ed from class II e0idence in adults)2

*uture research

&ore research is needed to e0aluate immunotherapy in GBS% particularly the use of combination treatments and further treatment after the initial course2 /here is a need to identify patients 3ho are at !reater ris- of an ad0erse outcome and to disco0er 3hether sub!roups ha0e differential responses to treatment (includin! children% people 3ith a?onal forms of GBS% and *isher:s syndrome)2 "esearch should also in0esti!ate the best methods of supporti0e care for monitorin! autonomic and pulmonary function% 3eanin! from 0entilation% treatin! pain% mana!in! fati!ue% and rehabilitation2

Summary of AA recommendations for immunotherapy for GBS

52 Plasma e?chan!e is recommended in non-ambulant adult patients 3ith GBS 3ho present 3ithin four 3ee-s from the onset of neuropathic symptoms2 Plasma e?chan!e should also be considered in ambulant patients 3ho present 3ithin t3o 3ee-s from the onset of neuropathic symptoms2

Summary of AA recommendations for immunotherapy for GBS

D2 Intra0enous immuno!lobulin (I=I!) is recommended in non-ambulant adult patients 3ith GBS 3ithin t3o or possibly four 3ee-s from the onset of neuropathic symptoms2 /he effects of plasma e?chan!e and I=I! are e;ui0alent2 C2 #orticosteroids are not recommended in the treatment of GBS2

Summary of AA recommendations for immunotherapy for GBS

G2 Se;uential treatment 3ith P) follo3ed by I=I! or immunoabsorption follo3ed by I=I! is not recommended for GBS2 E2 Plasma e?chan!e or I=I! are treatment options for treatin! children 3ith se0ere GBS2