Guideline:
EFNS guideline on treatment of multiple sclerosis relapses
Bibliographic Source(s)
- Sellebjerg F Barnes D Filippini G Midgard R Montalban X Rieckmann P Selmaj K Visser LH Sorensen PS EFNS Task Force on Treatment of Multiple Sclerosis Relapses. EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses. Eur J Neurol 2005 Dec;12(12):939-46. [55 references] PubMed
Guideline Status
This is the current release of the guideline.
Guideline Category
Treatment
Intended Users
Physicians
Guideline Objective(s)
To review the literature on treatment of multiple sclerosis (MS) relapses to provide evidence-based treatment recommendations
Target Population
Patients presenting with relapses of multiple sclerosis (MS)
Interventions and Practices Considered
- Intravenous or oral methylprednisolone
- Plasma exchange
- Interdisciplinary rehabilitation programme
Note: Intravenous immunoglobulin (IVIG) and natalizumab (withdrawn from market) were considered but not recommended
Major Outcomes Considered
- Effectiveness of treatment in improving recovery rate reducing relapse rate short-term suppression of magnetic resonance imaging (MRI) disease activity and recovery from optic neuritis
- Adverse effects of glucocorticoid treatment
Methods Used to Collect/Select Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods used to Collect/Select the Evidence
The task force searched literature databases (Embase and PubMed) in English for papers using the search terms "multiple sclerosis" "attack" "relapse" "exacerbation" and "treatment" in November 2004. The Cochrane Library and the reference lists of individual papers were searched for studies not identified in the Embase and PubMed searches. Studies of various treatments for patients suffering from relapses of multiple sclerosis (MS) were considered for the guidelines and were rated as class I to class IV studies according to the recommendations for EFNS scientific task forces (see the "Rating Scheme for the Strength of the Evidence" field).
Number of Source Documents
Not stated
Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective randomized controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies case series case reports or expert opinion
Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence
Not stated
Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations
The results of the literature searches were circulated by e-mail to the task force members for comments. The task force chairman prepared a first draft of the manuscript based on the results of the literature review and comments from the task force members. The draft and the recommendations were discussed during telephone conferences until consensus was reached within the task force. Recommendations were rated from A to C according to the EFNS guidelines for scientific task forces (see the "Rating Scheme for the Strength of the Recommendations" field). Where there was insufficient evidence to support firm recommendations the term "Good practice point" was used.
Rating Scheme for the Strength of the Recommendations
Rating of Recommendations
Level A rating (established as effective ineffective or harmful) requires at least one convincing class I study or at least two consistent convincing class II studies.
Level B rating (probably effective ineffective or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective ineffective or harmful) requires at least two convincing class III studies.
Good practice point: For insufficient evidence to support firm recommendations the term 'Good practice point' was used.
Cost Analysis
A formal cost analysis was not performed and published cost analyses were not reviewed.
Method of Guideline Validation
Peer Review
Description of Method of Guideline Validation
The guidelines were validated according to the European Federation of Neurological Societies (EFNS) criteria (Hughes RAC Barnes MP Baron J Brainin M [2001]. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces. Eur J Neurol 8:549-550).
Major Recommendations
The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C Good Practice Point [GPP]) are defined at the end of the "Major Recommendations" field.
There is consistent evidence from several class I studies and meta-analyses for a beneficial effect of glucocorticoid treatment in relapses of multiple sclerosis (MS). Hence treatment with intravenous (IV) or oral methylprednisolone in a dose of at least 500 mg daily for 5 days should be considered for treatment of relapses (level A recommendation). Treatment with IV methylprednisolone (1 g once daily for 3 days) should be considered as an alternative treatment (good practice point; Rieckmann et al. 2004). Treatment with IV methylprednisolone (1 g once daily for 3 days with an oral tapering dose) may be considered for treatment of acute optic neuritis (level B recommendation).
There is no evidence of major differences in the efficacy of methylprednisolone treatment given IV or orally in terms of clinical efficacy or side-effects but prolonged oral treatment may possibly be associated with a higher prevalence of side-effects. Furthermore because of the low number of patients included in the available clinical trials some efficacy differences between the IV and oral route of administration cannot be excluded. The optimal dosage the specific glucocorticoid to be used and whether to use a taper after initial pulse therapy have not been adequately addressed in randomized controlled trials. This implies a need for new randomized studies assessing risk/benefit ratios and adverse effects of specific glucocorticoids dose and route of administration for treatment of MS relapses.
There is insufficient data to clearly define patient subgroups who are more likely to respond to methylprednisolone treatment but treatment may be more efficacious in patients with clinical magnetic resonance imaging (MRI) or cerebrospinal fluid (CSF) evidence (increased myelin basic protein [MBP] concentration in CSF) indicating higher disease activity (level C recommendation). Administration of treatment in an inpatient or outpatient setting has not been addressed in clinical trials but consideration could be given to administering the first course of methylprednisolone as an inpatient (good practice point).
In patients who fail to respond to therapy with methylprednisolone in the dose range used in the randomized placebo-controlled trials treatment with higher doses (up to 2 g daily for 5 days) should be considered (level C recommendation; Rieckmann et al. 2004).
Patients with inflammatory demyelination including patients with MS who have not responded to treatment with methylprednisolone may benefit from plasma exchange treatment but only about one-third of treated patients are likely to respond. This treatment regimen should probably be restricted to a subgroup of patients with severe relapses (level B recommendation). A randomized controlled study specifically addressing the effect of plasma exchange in patients with severe relapses of MS not responding to methylprednisolone treatment would be desirable.
A more intense interdisciplinary rehabilitation programme should be considered after treatment with IV methylprednisolone as evidence from a single trial suggests that this probably further improves recovery (level B recommendation).
There is insufficient data to support the use of intravenous immunoglobulin (IVIG) therapy as monotherapy for relapses of MS. Treatment with intravenous immunoglobulin as an add-on to treatment of MS relapses with methylprednisolone or as monotherapy for acute optic neuritis is not efficacious (level A recommendation). Neither is natalizumab as monotherapy efficacious in MS relapses.
Definitions:
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective randomized controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies case series case reports or expert opinion
Rating of Recommendations
Level A rating (established as effective ineffective or harmful) requires at least one convincing class I study or at least two consistent convincing class II studies.
Level B rating (probably effective ineffective or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective ineffective or harmful) requires at least two convincing class III studies.
Good practice point: For insufficient evidence to support firm recommendations the term 'Good practice point' was used.
Clinical Algorithm(s)
None provided
References Supporting the Recommendations
- Rieckmann P Toyka KV Bassetti C Beer K Beer S Buettner U Chofflon M Gotschi-Fuchs M Hess K Kappos L Kesselring J Goebels N Ludin HP Mattle H Schluep M Vaney C Baumhackl U Berger T Deisenhammer F Fazekas F Freimuller M Kollegger H Kristoferitsch W Lassmann H Markut H Strasser-Fuchs S Vass K Altenkirch H Bamborschke S Baum K Benecke R Bruck W Dommasch D Elias WG Gass A Gehlen W Haas J Haferkamp G Hanefeld F Hartung HP Heesen C Heidenreich F Heitmann R Hemmer B Hense T Hohlfeld R Janzen RW Japp G Jung S Jugelt E Koehler J Kolmel W Konig N Lowitzsch K Manegold U Melms A Mertin J Oschmann P Petereit HF Pette M Pohlau D Pohl D Poser S Sailer M Schmidt S Schock G Schulz M Schwarz S Seidel D Sommer N Stangel M Stark E Steinbrecher A Tumani H Voltz R Weber F Weinrich W Weissert R Wiendl H Wietholter H Wildemann U Zettl UK Zipp F Zschenderlein R Izquierdo G Kirjazovas A Packauskas L Miller D Koncan Vracko B Millers A Orologas A Panellus M Sindic CJ Bratic M Svraka A Vella NR Stelmasiak Z Selmaj K Bartosik-Psujik H Mitosek-Szewczyk K Belniak E Mochecka A Bayas A Chan A Flachenecker P Gold R Kallmann B Leussink V Maurer M Ruprecht K Stoll G Weilbach FX Multiple Sclerosis Therapy Consensus Group. Escalating immunotherapy of multiple sclerosis--new aspects and practical application. J Neurol 2004 Nov;251(11):1329-39. [57 references] PubMed
Type of Evidence supporting the Recommendations
The type of supporting evidence is identified and graded for selected recommendations (see "Major Recommendations").
Potential Benefits
Appropriate treatment of multiple sclerosis relapses
Potential Harms
- Side effects of glucocorticoid treatment include: reddening of the face transient ankle swelling metallic taste in the mouth during infusion gastrointestinal side effects minor infections glucosuria exacerbation of acne insomnia episodes of euphoria distal paraesthesia and mild weight gain.
- Pulsed methylprednisolone treatment has marked short-term effects on bone metabolism and the available studies do not entirely rule out adverse effects on bone structures
- Severe-side-effects of methylprednisolone treatment are rare but psychosis acute pancreatitis and anaphylactoid reactions to intravenous treatment have been reported.
- There is no evidence of major differences in the methylprednisolone treatment given intravenously or orally in terms of clinical efficacy or side-effects but prolonged oral treatment may possibly be associated with a higher prevalence of side-effects.
See the original guideline document for more information on adverse effects of glucocorticoid treatment.
Qualifying Statements
This guideline provides the view of an expert task force appointed by the Scientific Committee of the European Federation of Neurological Societies (EFNS). It represents a peer-reviewed statement of minimum desirable standards for the guidance of practice based on the best available evidence. It is not intended to have legally binding implications in individual cases.
Description of Implementation Strategy
The European Federation of Neurological Societies has a mailing list and all guideline papers go to national societies national ministries of health World Health Organisation European Union and a number of other destinations. Corporate support is recruited to buy large numbers of reprints of the guideline papers and permission is given to sponsoring companies to distribute the guideline papers from their commercial channels provided there is no advertising attached.
Implementation Tools
Staff Training/Competency Material
For information about availability see the "Availability of Companion Documents" and "Patient Resources" fields below.
IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness
Bibliographic Source(s)
- Sellebjerg F Barnes D Filippini G Midgard R Montalban X Rieckmann P Selmaj K Visser LH Sorensen PS EFNS Task Force on Treatment of Multiple Sclerosis Relapses. EFNS guideline on treatment of multiple sclerosis relapses: report of an EFNS task force on treatment of multiple sclerosis relapses. Eur J Neurol 2005 Dec;12(12):939-46. [55 references] PubMed
Adaptation
Not applicable: The guideline was not adapted from another source.
Source(s) of Funding
European Federation of Neurological Societies
Guideline Committee
European Federation of Neurological Societies Task Force on Treatment of Multiple Sclerosis Relapses
Composition of Group that Authored the Guideline
Task Force Members: F. Sellebjerg Danish MS Centre Copenhagen University Hospital Copenhagen Denmark; D. Barnes Department of Neurology Atkinson Morley's Hospital Wimbledon UK; G. Filippini Unit of Epidemiology and Clinical Trial Centre Istituto Nazionale Neurologico C. Besta Milan Italy; R. Midgard Department of Neurology Molde Hospital Molde Norway; X. Montalban Clinical Neuroimmunology Unit University Hospital Vall d'Hebron Barcelona Spain; P. Rieckmann Department of Neurology Julius-Maximilians University of Würzburg Würzburg Germany; K. Selmaj Department of Neurology Medical University of Lodz Lodz Poland; L. H. Visser Department of Neurology St Elisabeth Hospital Tilburg The Netherlands; P. S. Sørensen Danish MS Centre Copenhagen University Hospital Copenhagen Denmark
Financial Disclosures/Conflicts of Interest
Finn Sellebjerg has received a travel grant and an unrestricted research grant from Pharmacia.
Guideline Status
This is the current release of the guideline.
Guideline Availability
Electronic copies: Available to registered users from the European Federation of Neurological Societies Web site.
Print copies: Available from Dr Finn Sellebjerg Danish MS Centre Department of Neurology Copenhagen University Hospital Blegdamsvej 9 DK- 2100 Copenhagen Denmark; Phone: + 45 3545 2080; Fax: + 45 3545 2684; E-mail: sellebjerg@dadlnet.dk
Availability of Companion Documents
The following are available:
- Brainin M Barnes M Baron JC Gilhus NE Hughes R Selmaj K Waldemar G; Guideline Standards Subcommittee of the EFNS Scientific Committee. Guidance for the preparation of neurological management guidelines by EFNS scientific task forces – revised recommendations 2004. Eur J Neurol. 2004 Sep;11(9):577-81. Electronic copies: Available in Portable Document Format (PDF) from the European Federation of Neurological Societies Web site.
- Guideline papers. European Federation of Neurological Societies. Electronic copies: Available from the European Federation of Neurological Societies Web site.
- Continuing Medical Education questions available from the European Journal of Neurology Web site.
Patient Resources
None available
NGC STATUS
This NGC summary was completed by ECRI on December 7 2006. The information was verified by the guideline developer on January 15 2007.
COPYRIGHT STATEMENT
This NGC summary is based on the original guideline which is subject to the Blackwell-Synergy copyright restrictions.
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