Treatment For Ataxia in Multiple Sclerosis (Review)

Treatment for ataxia in multiple sclerosis (Review)
Mills RJ, Yap L, Young CA
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2007, Issue 1
http://www.thecochranelibrary.com
Treatment for ataxia in multiple sclerosis (Review)

Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Treatment for ataxia in multiple sclerosis (Review) i

[Intervention Review]
Treatment for ataxia in multiple sclerosis
Roger J Mills1 , Leesien Yap2 , Carolyn A Young3
1 Clinical
Trials Unit, The Walton Centre for Neurology and Neurosurgery, Liverpool, UK. 2 Neurosciences, The Walton Centre for
Neurology and Neurosurgery, Liverpool, UK. 3 The Walton Centre for Neurology and Neurosurgery, Liverpool, UK
Contact address: Roger J Mills, Clinical Trials Unit, The Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley,
Liverpool, L9 7LJ, UK. rjm@crazydiamond.co.uk.
Editorial group: Cochrane Multiple Sclerosis Group.

Publication status and date: Edited (no change to conclusions), published in Issue 1, 2009.
Review content assessed as up-to-date: 26 August 2006.
Citation: Mills RJ, Yap L, Young CA. Treatment for ataxia in multiple sclerosis. Cochrane Database of Systematic Reviews 2007, Issue
1. Art. No.: CD005029. DOI: 10.1002/14651858.CD005029.pub2.
ABSTRACT
Background
Disabling tremor or ataxia is common in multiple sclerosis (MS) and up to 80% of patients experience tremor or ataxia at some point
during their disease. A variety of treatments are available, ranging from pharmacotherapy or stereotactic neurosurgery to neurorehabil-
itation.
Objectives
To assess the efficacy and tolerability of both pharmacological and non-pharmacologic treatments of ataxia in patients with MS.
Search methods
The following electronic resources were searched: Cochrane MS Group trials register (June 2006), the Cochrane Central Register of
Controlled Trials (The Cochrane Library Issue 2, 2006), MEDLINE (January 1966 to June 2006), EMBASE (Jan 1988 to June 2006)
and the National Health Service National Research Register (NRR) including the Medical Research Council Clinical Trials Directory
(Issue 2, 2006). Manual searches of bibliographies of relevant articles, pertinent medical and neurology journals and abstract books of
major neurology and MS conferences (2001-2006) were also performed. Direct communication with experts and drug companies was
sought.
Selection criteria
Blinded, randomised trials which were either placebo-controlled or which compared two or more treatments were included. Trials
testing pharmacological agents must have had both participant and assessor blinding. Trials testing surgical interventions or effects
of physiotherapy, where participants could not have been blinded to the treatment, must have had independent assessors who were
blinded to the treatment. Cross-over trials were included.
Data collection and analysis
Three independent reviewers extracted data and the findings of the trials were summarised. A meta-analysis was not performed due to
the inadequacy of outcome measures and methodological problems with the studies reviewed.
Treatment for ataxia in multiple sclerosis (Review) 1
Main results
Ten randomised controlled trials met the inclusion criteria. Six placebo-controlled studies (pharmacotherapy) and four comparative
studies (one stereotactic neurosurgery and three neurorehabilitation) were reviewed. No standardised outcome measures were used
across the studies. In general, pharmacotherapies were unrewarding and data on neurosurgery or rehabilitation is insufficient to lead to
a change in practice.
Authors’ conclusions
The absolute and comparative efficacy and tolerability of pharmacotherapies to treat ataxia in MS are poorly documented and no
recommendations can be made to guide prescribing. Although studies on neurosurgery and neurorehabilitation showed promising
results, the absolute indications for treating with those methods cannot be developed. Standardised, well validated measures of ataxia
and tremor need to be developed and employed in larger randomised controlled trials with careful blinding.
PLAIN LANGUAGE SUMMARY
The use of different treatment for incoordination of limb movement (ataxia) or tremor in people with multiple sclerosis
MS is a chronic disease of the central nervous system which typically affects both young and middle aged adults. It can result in many
different symptoms including ataxia.
In order to help these symptoms, several different treatments, such as physiotherapy, neurosurgery, and oral medications containing
cannabis extract, isoniazid or baclofen have been used. The authors conducted a search of the medical literature and found that only 10
out of 59 studies met the criteria of minimum methodological quality necessary for inclusion in this review. These studies represented
a total of 172 MS patients with ataxia. This review has found that there is not enough evidence to suggest that any treatment (drugs,
physiotherapy or neurosurgery) provides sustained improvement in ataxia or tremor. More research is required.
BACKGROUND writing and drawing tests and measuring the volume of water spilt
from a cup (Alusi 1999, Alusi 2003, Erasmus 2001); to rating
The word ataxia (from the Greek) literally means disorder or con- scales such as the Kurtzke functional system (Kurtzke 1983) and
fusion (Simpson 1990). Clinically, it is used to describe various the Fahn tremor rating [Fahn 1988]; to more complex kinematic
abnormalities that can occur in the execution of voluntary move- analyses using three dimensional, infrared or video tracking of
ment; including incoordination, dysmetria, dysdiadochokinesis reflective markers placed at joints with or without accompanying
and tremor. It results from lesions in the cerebellum and its con- electromyography (Quintern 1999, Murray 1999).
nections (Ghez 2000).
This review evaluates the effectiveness and tolerability of treat-
The incidence of ataxia in MS is high with about 80% of pa-
ments for ataxia in patients with MS.
tients experiencing symptoms at some point during their disease
(Swingler 1992). The multiplicity of lesions, in MS, make histo-
logical correlation with clinical features difficult (Alusi 1999, Alusi
2001a), however, in MS patients with chronic cerebellar ataxia, dis- OBJECTIVES
ability has been shown to correlate with the number of infratento-
rial T1 hypointense lesions seen on MR imaging (Hickman 2001). To assess the efficacy and tolerability of both pharmacological and
The influence of sensory afferents on cerebellar dysfunction has non-pharmacologic treatments of ataxia and tremor in patients
been demonstrated in MS, in keeping with other cerebellar disor- with MS.
ders (Quintern 1999).
There are several ways of assessing ataxia and tremor ranging from
simple functional tests such as timed walks, target board tests, METHODS
Criteria for considering studies for this review Search methods for identification of studies
Types of studies Electronic searches
Blinded, randomised trials (RCTs) which either were placebo-con- 1) Electronic searches of: i) Cochrane MS Group Trials Register
trolled or which compared two or more treatments were included. (June 2006), ii) The Cochrane Central Register of Controlled
Quasi-randomised or unrandomised trials were excluded. Trials Trials (The Cochrane Library, Issue 2, 2006) (Appendix 1), iii)
testing pharmacological agents must have had both participant MEDLINE (1966-June 2006),(Appendix 2) iv) EMBASE (1988-
and assessor blinding. Trials testing surgical interventions or ef- June 2006) (Appendix 3).
fects of physiotherapy, where participants could not be blinded to
the treatment, must, at least, have had independent assessors who
were blinded to the treatment. Cross-over trials were included. Searching other resources
2) Reference lists from published reviews on symptom control in
multiple sclerosis and identified RCTs.
Types of participants 3) Personal communication with first authors of relevant trials or
reviews, and other multiple sclerosis experts.
Patients, of any age and either sex, with MS (satisfying either 4) Drug manufacturers for drugs identified in relevant RCTs.
the Poser (Poser 1983) or McDonald (McDonald 2001) criteria) 5) National Health Service National Research Register (NRR)
of any course type, were included. The patients must have had including the Medical Research Council Clinical Trials Directory.
symptoms or signs of ataxia, the presence of action tremor without 6) Manual searches of pertinent medical and neurology journals
other features of ataxia also qualified. (Neurology, Journal of Neurology; Multiple Sclerosis, Clinical
Patients within thirty days of a relapse or within thirty days of Rehabilitation; Neurosurgery; Journal of Neurosurgery; Journal
receiving corticosteroids were excluded (studies where this was not of Neurology; Neurosurgery and Psychiatry) and abstract books
explicitly stated were included). Studies including patients with (2001-2006) of ECTRIMS (European Committee for Treatment
other diagnoses were excluded unless individual data for the MS and Research in Multiple Sclerosis); EFNS (European Federa-
patients could be obtained either from the published results or tion of Neurological Societies); ENS (European Neurological So-
through contact with the authors. ciety); ABN (Association of British Neurologists); AAN (Amer-
ican Academy of Neurology) and ANA (American Neurological
Association).
Types of interventions Unpublished trials were identified using strategies 3), 4), 5) and
6).
Use of a pharmacological agent in at least one arm of the study for
at least one week. Surgical interventions, such as deep brain stim-
ulation, or orthoses, such as splints or weights, or physiotherapy
were considered if they were amenable to assessor blinding. Data collection and analysis
Study selection and data extraction
Titles and abstracts of papers identified using the above strategies
Types of outcome measures were assessed by three independent reviewers (RJM, CAY and LY);
full text versions were viewed where possible. Agreement on which
studies meet the inclusion criteria was reached by consensus.
Assessment of methodological quality
Primary outcomes
The methodological quality of the studies was assessed, according
Efficacy: whether the intervention produces a change in severity to the guidelines in the Cochrane Reviewer’s Handbook (Clarke
of ataxia as measured by any validated method. 2003), for: selection bias, performance bias, attrition bias and de-
Safety: the incidence of adverse, or serious adverse, events. tection bias. A summary rating of A (low bias), B (moderate bias)
or C (high bias) was given to each study independently by each
reviewer. Differences in assessment were reached by consensus.
Studies with high risk of bias were discarded. Patient and study
Secondary outcomes
characteristics and outcome data were abstracted by the three re-
Efficacy: change in activity limitation (disability) ratings or in qual- viewers.
ity of life scores. Duration of treatment efficacy. Analysis

Meta analysis was not performed given the diversity of interven- Three different types of comparative studies of variable durations
tions and outcome measures. A description of the results for each have been reviewed. Armutlu 2001 compared the effects of neu-
individual study is given. romuscular rehabilitation with and without the addition of John-
stone pressure splints. Wiles 2001 compared hospital physiother-
apy with home physiotherapy and no treatment. Lord 1998 de-
scribed a parallel study of facilitation physiotherapy (impairment
RESULTS based) versus task orientated physiotherapy (disability based).
Description of studies Risk of bias in included studies

See: Characteristics of included studies; Characteristics of excluded (1) Isoniazid and pyridoxine versus placebo
studies. Bozek 1987 studied 10 MS patients; disease stability in the pre-
Ten, of 56 identified studies, met the inclusion criteria. ceding month was not reported. Patients, treating physicians and
(1) Isoniazid and pyridoxine versus placebo assessors were blinded but there was a risk of unblinding of treating
Two crossover studies (Bozek 1987; Hallett 1985) have been re- physician by liver function test monitoring. There was moderate
viewed. In both studies, the treatment arms were of four weeks attrition bias with 20% dropout rate due to side effects or non
duration with a one week washout period in Hallet 1985, before efficacy.
crossover, and no washout period in Bozek 1987. Different doses Hallett 1985 recruited 7 MS patients with postural cerebellar
of isoniazid were used: Hallett 1985 started with a minimal dose tremor; disease stability in the preceding month was not reported.
of 300mg once per day, increased to twice a day during the second Patients, treating physician and assessor were blinded. There was
week, three times a day in the third week and four times a day moderate attrition bias with 14% dropout rate plus loss of quan-
in the fourth week. In Bosek 1987 the acetylator phenotype of titative data in another 14%.
the patient (based on the ability to acetylate a standard 11mg/kg In both studies the method of allocation concealment was unclear.
dose of sulfamethazine) determined the daily dosage of isoniazid Both studies used videotaped tremor ratings and tremograms as
administered. Slow acetylators received Isoniazid 12mg/kg per day outcome measures.
and rapid acetylators 20mg/kg per day. (2) Cannabis based medicine versus placebo
Wade 2004 involved three centres across the UK with clearly spec-
(2) Cannabis based medicine versus placebo ified patient eligibility criteria. 160 patients with clinically con-
One parallel (Wade 2004) and two crossover studies (Fox 2004, firmed MS, which had been stable for four weeks, were recruited.
Killestein 2002) have been reviewed. Killestein 2002 compared Each had one of five target symptoms: spasticity, spasms, bladder
oral preparations of dronabinol, cannabis sativa plant extract and problems, tremor or pain and were willing to abstain from alterna-
placebo in a two fold cross over trial. Fox 2004 used oral Cannador tive cannabinoid use for 7 days prior to screening and throughout
in a crossover study and Wade 2004 used cannabis based medicinal the study. Only 13 patients had tremor as their primary symp-
extract (Sativex), administered by sublingual spray, in a parallel tom. All 13 tremor patients completed the study. Patients, treat-
group study. ing physicians and assessors were blinded but patient blinding was
(3) Baclofen versus placebo compromised by dose dependent side effects; an unblinding ques-
One crossover study using baclofen has been reviewed (Orsnes tionnaire was not administered.
2000). The starting dose was 5mg three times daily and dose Fox 2004 included 14 patients with clinically definite MS with
escalation by 5mg every 3 days to 15mg 3 times daily or the visible upper limb tremor; disease stability in the preceding month
maximum tolerance dosage with no side effects experienced. After was not reported. Thirteen patients completed the study. Patients,
11 days on this dosage, measurements were performed and the treating physicians and assessors were blinded but both patient
treatment was tapered over about one week. There was a two week and treating physician blinding was compromised since doses were
washout period before crossing to the alternative treatment using titrated to side effects. Nine out of 14 patients were correct in an
identical regime. unblinding questionnaire.
(4) Thalamotomy versus deep brain stimulation (DBS) Killestein 2002 included 16 patients with clinically confirmed MS
One comparative study has been reviewed (Schuurman 2000). with spasticity, tremor being a secondary study aim. Patients with
Up to two years follow up assessments were reported. Patients Ashworth (Ashworth 1964) spasticity score of at least 2 in at least
were randomised to either thalamic stimulation or thalamotomy one limb were included and those who had used cannabinoids in
in a single blinded randomised controlled trial. Of the 68 trial the two months preceding study entry were excluded. All patients
patients 10 had MS and were randomised equally between the two completed the study. Patients, treating physicians and assessors
treatments. were blinded, but patient and treating physician unblinding was
(5) Comparative physiotherapy /neurorehabilitation studies noted (exact percentage not given).

The methods of allocation concealment were unclear in Killestein pists were used for assessment.
2002. Fox 2004 used a computer generated list of numbers held Wiles 2001 included 42 patients with definite or probable multiple
by the dispensing pharmacy. In Wade 2004, randomisation was sclerosis who complained of difficulties with walking. Patients were
conducted using permuted blocks of size 4, stratified by nominated required to be at least 18 years old, able to walk for 5 minutes
primary symptom and centre. The pharmacist at each centre was with or without aid, and be relapse free. There was a 7% dropout
provided with a randomised scheme for each primary symptom rate. Patients and treating physiotherapists were unblinded to the
and assigned the treatments in sequential patient number order treatment; a blinded physiotherapist was used for assessments.
from the appropriate randomisation list. Outcome measures varied Lord 1998 included 23 patients with MS referred to a specialist
across the studies. Wade 2004 used a 100mm visual analogue rehabilitation service and who were able to walk 10 m with or
scale (VAS) for tremor (anchors not given), a tremor activities of without supervision and who had been relapse free in the three
daily living (ADL) questionnaire and a nine hole peg test (9HPT). months prior to entry to study. There was a 13% dropout rate due
Killestein 2002 used the 9HPT and a daily VAS as tremor outcome to relapse. Patients and treating physiotherapists were unblinded to
measures. Fox 2004 used spirography, 9HPT, accelerometry and the treatment; a blinded physiotherapist was used for assessments.
videotaped tremor assessments. However, patients were unlikely to have had strong preference for
(3) Baclofen versus placebo either form of treatment.
Fourteen patients with clinically definite MS and stable disease for Randomisation was performed in both Lord 1998 and Wiles 2001
at least one month were included in the Orsnes 2000 study. All using sealed envelopes. The method of allocation concealment in
patients had moderate functional deficits and were able to walk Armutlu 2001 was unclear. All the studies used various clinical
unaided and without support for at least 3 minutes. Antispasticity scoring systems of balance, gait and ataxia.
agents were withheld for one week prior to entry to the study and
no medication that could affect spasticity was allowed during the
study period; no alcohol during the last 12 hours before the tests Effects of interventions
was permitted. All patients completed the study. Both patients
A meta-analysis was not attempted in view of the different inclu-
and treating physicians were blinded. It was unclear whether an
sion criteria for each study and the variety of the outcome mea-
independent assessor was used.
sures used.
The method of allocation concealment was unclear. The ataxia
(1) Isoniazid and pyridoxine versus placebo
outcome measure was a measurement of postural sway generated
In Bozek 1987, a patient was withdrawn due to a probable hyper-
by computer from data from a force plate.
sensitivity reaction. This resolved when isoniazid was discontin-
(4) Thalamotomy versus deep brain stimulation (DBS)
ued. Hallett 1985 reported no side effects from isoniazid.
Schuurman 2000 included 68 patients with severe unilateral or
Bozek 1987 reported minimal clinical improvement on videotaped
bilateral tremor of the arms refractory to at least 1 year of phar-
assessment (the level of statistical significance was not given), there
macotherapy. There were 10 MS patients. Patients were excluded
was no significant change in tremograms. Hallett 1985 reported
if they were younger than 18 years of age; had cognitive dysfunc-
that 4 out of 7 patients were ’better’ on subjective assessment, there
tion, had concomitant medical disease with poor pre-morbid state,
were no significant changes in accelerometry.
advanced cerebral atrophy on computed tomography or had pre-
Neither study made any assessments beyond the duration of the
viously undergone thalamotomy. Patients and the surgeons were
study drug administration. There were no changes in disability
necessarily unblinded to the treatment but assessment of tremor
scores (disability status scores Kurtzke 1983).
was made by a blinded neurologist. The thalamic stimulation pa-
(2) Cannabis based medicine versus placebo
tients received more frequent medical contact.
Across the studies, cannabis was well tolerated. Common side
Randomisation was performed according to a computer generated
effects were mild dizziness, intoxication and drowsiness.
code, with adjustment for the cause and extent of tremor (unilat-
Wade 2004 reported no change in VAS and 9HPT scores. Fox
eral vs bilateral). Ataxia outcomes were made at time points of up
2004 found that all changes in ataxia outcomes were non signifi-
to six months post procedure and included assessment of video-
cant apart from worsening in finger tapping speed. Killestein 2002
taped tremor, a tremor scale and patient’s opinion of the surgical
found that 9HPT scores were significantly worse with dronabinol
outcome.
but were no different with plant extract.
(5) Comparative physiotherapy/neurorehabilitation studies
Disability outcomes were largely unchanged although Killestein
Armutlu 2001 included 26 MS patients with either secondary pro-
2002 found that plant extract caused significant worsening of the
gressive or primary progressive MS who had prominent ataxia with
Multiple Sclerosis Functional Composite (MSFC) whereas dron-
slight muscle weakness and could walk unaided. Corticosteroids
abinol led to improvement in the mental health and quality of life
were discontinued at least 1 month before the start of the study.
domains of the Short Form-36 (SF-36). None of the studies made
All patients completed the study. Patients and treating physiother-
any assessments beyond the duration of the study drug adminis-
apists were unblinded to the treatment; two blinded physiothera-
tration.

The conclusion derived from all three studies was that cannabis Blinding of both patient and clinician/assessor is the central tenet
based medicine resulted in no significant improvement in tremor. in eliminating performance bias; it is crucial if self rating out-
(3) Baclofen versus placebo come measures are used. However, despite best efforts in trial de-
Orsnes 2000 noted that 9 out of 14 patients reported side effects sign, there are some interventions which are very difficult to blind.
from baclofen, such as fatigue and dizziness. These effects were Pharmacological agents with inevitable side effects, such as intox-
transient and mild. ication, make the use of agents such as alcohol (Koller 1984a,
There was no statistically significant change in postural stability Koller 1984b) or cannabinoids open to unintentional unblinding
or the other outcomes of general disability. No assessments were (Zajicek 2003). Surgical procedures, if compared to no interven-
made beyond the duration of the study drug administration. tion, cannot be double blinded and even sham operations only re-
(4) Thalamotomy versus deep brain stimulation (DBS) sult in single blinding. Similarly, physiotherapy vs. no treatment is
There were adverse effects in both treatment groups of gait dis- impossible to blind; however, comparative studies of physiother-
turbance, dysarthria and, paradoxically, arm ataxia. There was one apy may approximate to patient blinding.
surgery related death due to intracerebral heamorrahage although
this was not in an MS patient. Some of these adverse symptoms Outcomes
were persistent at 6 months. There is no fully validated tremor outcome measure specific for
Tremor was abolished by both thalamotomy and thalamic stim- MS and so it was unsurprising that several different outcome mea-
ulation in all patients immediately post surgery. However, at 6 sures were used between the studies. There were various subjec-
months, tremor had returned in almost all the MS patients, albeit tive clinical assessments of videotaped performance, accelerome-
of less severity than pre operative levels. For the MS patients, there try from wrist worn devices, surface electromyographic (EMG)
was no change in general disability scores. recordings, self rating scales, time to complete a 9HPT, balance
(5) Comparative physiotherapy /neurorehabilitation studies time and analysis of stance on a forceplate.
In all three studies, there were no adverse events reported.
Armutlu 2001 reported improvements in single limb stance time Subjective clinical assessments of tremor, based on videotaped per-
of between 10 and 30 seconds plus step width of about 3cm, formance, are reproducible if an individual rater is used. How-
after physiotherapy. The addition of Johnstone pressure splints ever, they can suffer from problems with interrater reliability be-
gave no extra advantage. Wiles 2001 found that 16 sessions of cause severity is assessed by reference to the clinician’s own experi-
physiotherapy, in either hospital or at home, improved balance ence and opinion rather than to some common standard (Hooper
time by about 5 seconds. Hospital treatment similarly gave very 1998). In addition, for assessment of gait, videotaped evaluation
small improvement in time taken to complete a 9HPT (mean does not correlate well with ’live’ evaluation (Wiles 2003). The
values of 190 seconds vs. 207 seconds) whereas home therapy did sensitivity to change of this type of assessment is not known.
not. Lord 1998 found significant improvements in Berg balance
tests with both forms of physiotherapy. The use of accelermoters, EMG and forceplates have the advantage
Both Wiles 2001 and Lord 1998 found small improvements of of providing objective data, although some interpretation may still
rely on subjective analysis of traces produced (Hallett 1985). There
about 1.5 units in the Rivermead mobility index. Armutlu 2001
is no work on what would represent minimum clinically detectable
found improvement in the EDSS (Expanded disability status scale
Kurtzke 1983) of 0.5 units. Only Wiles 2001 made assessments changes e.g. a 10% reduction in peak tremor velocity may be
beyond the treatment duration; it was found that scores had re- statistically significant but may not be noticeable by the patient
turned to pre treatment levels after two months. or clinician. Even noticeable changes may not, of course, result in
any benefit in the subject being able to perform a particular task.
Although tests such as 9HPT have been well validated in MS as an

outcome of upper limb/prehensile function, particularly as part of
the MSFC (Rudick 2002), as a pure measure of ataxia it could be
DISCUSSION confounded by weakness, spasticity or visual impairment.
Of the 56 studies conducted over the past 25 years, only ten sat- Study size
isfied the criteria of minimum methodological quality necessary
for inclusion in this review. These trials represented the study of a Sample size calculations rely on knowledge of the performance of
total of 172 MS patients with ataxia or tremor. Several studies had the outcome measures used. Therefore, determination of sample
very small sample sizes (n<20). All had a moderate risk of bias, size was problematic for the studies in this review because of the
mainly due to inadequate blinding or subject attrition. Nearly all lack of validated outcome measures. Only three studies attempted
the interventions resulted in little or no lasting change in ataxia. formal power calculations either based on limited previous expe-
rience (Wiles 2001, Wade 2004) or by looking for large (50%)
Blinding changes in scores (Fox 2004). Many of the older pharmacotherapy

studies were probably underpowered and Orsnes 2000 acknowl- There was no improvement in disability scores at six month follow
edged that small sample size may have confounded his results up; there may have been unmasking of other cerebellar symptoms.
As with many surgical procedures, case selection is important in
Comparative studies require greater numbers than placebo (or no
determining outcome and so it may not be suitable, or desirable,
treatment) controlled studies, in to order to demonstrate differ-
for large groups of MS patients. There is a risk of serious adverse
ences between treatments and this may partly account for the stud-
events.
ies by Armutlu 2001 and Lord 1998 failing to detect such between
treatment effects.
Some notable exclusions AUTHORS’ CONCLUSIONS

There were two studies of intravenous treatments of 5HT3 re-
ceptor antagonists (Rice 1997, Monaca-Charley 2003) that were
Implications for practice
excluded because treatment was limited to a single dose. It was not A large number of studies have attempted to assess the efficacy
clear why longer treatment regimes were not used; it is difficult and tolerability of various pharmacological agents and non-phar-
to make any recommendations for treatment of chronic symp- macological therapies and have been identified by this systematic
toms from a single dose study. Rice 1997 promised a study of an review. Only about a fifth were of sufficient methodological qual-
oral 5HT3 receptor antagonist but this does not appear to have ity to warrant being reviewed in greater detail. The variability in
been published. Attempts at contacting the authors, via the con- inclusion criteria for each study and the lack of standardised, sen-
tact details given in publications, were unsuccessful and so it was sitive and reliable assessment tools for tremor and ataxia made di-
not possible to determine whether this trial had been undertaken. rect comparison of studies unfeasible. No firm recommendations
The CAMS study (Zajicek 2003) was a large study of tetrahy- to change practice can be drawn from this review.
drocannabinol given orally. Ataxia was only a self rated secondary
outcome and, by the investigators’ own admission, there was sig- Implications for research
nificant unblinding (66-71% of treating physicians and 71% of
There is a need for well designed RCTs focussing on ataxia in MS.
patients correctly identified active study drug, p<0.001) due to
Some pharmacotherapautic agents need to be reassessed in a more
side effects. It was therefore not included in the review. rigorous way; further agents need to be developed. Safety and effi-
Results cacy of functional neurosurgery in MS needs further clarification
in order to guide referral pathways for this potentially useful treat-
Many studies failed to show significant differences in primary out- ment.
come measures for pharmacotherapy vs placebo and indeed some
showed deleterious effects (Killestein 2002, Fox 2004) It is diffi- All future studies need to be adequately powered but this cannot
cult to interpret this as true absence of effect. The combination be done before a well validated, sensitive and, preferably, interna-
of performance bias and attrition bias plus small sample sizes and tionally agreed, outcome measure or assessment tool has been de-
deficiencies in outcome measures are likely to result in potentially veloped. Such a tool must be easily available and readily performed
sizeable confounds. When measured, there was little benefit seen by both the patient and assessor. More comparative studies with
in secondary outcomes of general disability scores or quality of life. larger study populations are also encouraged.
Physiotherapy was safe and improved outcomes by small amounts,
however, there was a suggestion that treatment effects would not
be sustained (Wiles 2001).
ACKNOWLEDGEMENTS
Surgical treatment showed good effect in the short term for those
with severe symptoms and could even abolish tremor. However The authors would like to thank Dr Tim Friede for his advice and
for MS, the tremor was likely to have returned by six months. statistical guidance on the protocol for this review.

REFERENCES
References to studies included in this review Aisen 1991 {published data only}
Aisen ML, Holzer M, Rosen M, Dietz M, McDowell F.
Armutlu 2001 {published data only} Glutethiamide treatment of disabling action tremor in
Armutlu K, Karabudak R, Nurlu G. Physiotherapy patients with multiple sclesrosis and traumatic brain injury.
approaches to the treatment of ataxic multiple sclerosis: a Archives of Neurology 1991;48(5):513–5.
pilot study. Neurorehabilitation and Neural Repair 2001;15
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Alusi SH, Aziz TZ, Glickman S, Jahanshahi M, Stein JF,
Bozek 1987 {published data only}
Bain P.G. Stereotactic lesional surgery for the treatment of
Bozek CB, Kastrukoff LF, Wright JM, Perry TL, Larsen TA.
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A controlled trial of isoniazid therapy for action tremor in
study. Brain 2001;124(8):1576–89.
multiple sclerosis. Journal of Neurology 1987;234(1):36–9.
Fox 2004 {published data only} Bakhos 2002 {published data only}
Fox P, Bain PG, Glickman S, Carroll C, Zajicek J. The effect Bakhos CT, Jabre MG, Habub KG, Chemaly R. Gabapentin
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Neurology 2004;62(7):1105–9. 2002; Vol. 58:459.
Hallett 1985 {published data only} Benabid 1998 {published data only}
Hallett M, Lindsey JW, Adelstein BD, Riley PO. Controlled Benabid AL, Pollak P, Gao D, Hoffmann D, Limousin
trial of isoniazid therapy for severe postural cerebellar tremor P, Gay E. Chronic electrical stimulation of the ventralis
in multiple sclersosis. Neurology 1985;35(9):1374–7. intermedius nucleus of the thalamus as a treatment of
movement disorders. Journal of Neurology Neurosurgery and
Killestein 2002 {published data only}
Psychiatry 1996;84(2):203–14.
Killestein J, Hoogervorst EL, Reif M, Kalkers NF, Van
Loenan AC, Staats PG, et al.Safety, tolerability, and afficacy Berk 2002 {published data only}
of orally administered cannabinoids in multiple sclerosis. Berk C, Carr J, Sinden M, Martzke J, Honey CR. Thalamic
Neurology 2002;58(9):1404–7. deep brain stimulation for the treatment of tremor due to
Lord 1998 {published data only} multiple sclerosis: a prospective study of tremor and quality
Lord SE, Wade DT, Halligan PW. A comparison of two of life. Journal of Neurosurgery 2002;97(4):815–20.
physiotherapy treatment approaches to improve walking Bittar 2005 {published data only}
in multiple sclerosis: a pilot randomized controlled study. Bittar R.G, Hyam J, Nandi D, Wang S, Liu X, Joint C, et
Clinical Rehabilitation 1998;12:447–86. al.Thalamotomy versus thalamic stimulation for multiple
Orsnes 2000 {published data only} sclerosis tremor. Journal of clinical neuroscience 2005;12(6):
Orsenes GB, Sorenson PS, Larsen TK, Ravnborg M. Effect 638–42.
of baclofen on gait in spastic multiple sclersosis patients. Brice 1980 {published data only}
Acta Neurologica Scandinavica 2000;101(4):244–8. Brice J, Mclellan L. Suppression of intention tremor by
Schuurman 2000 {published data only} contingent deep-brain stimulation. Lancet 1980;315
Schuurman PR, Bosch DA, Bossuyt PM, Bonsel GJ, van (8180):1221–2.
Someren EJ, de Bie RM, et al.A comparison of continuous
Cardini 2000 {published data only}
thalamic stimulation and thalamotomy for supression of
Cardini RG, Crippa AC, Catteneo D. Update on multiple
severe tremor. New England Journal of Medicine 2000;342
sclerosis rehabilitation. Journal of Neurovirology 2000;6
(7):461–8.
(suppl 2):179–85.
Wade 2004 {published data only}
Wade DT, Makela P, Robson P, House H, Bateman C. Do Critchley 1998 {published data only}
cannabis-based medicinal extracts have general or specific Critchley GR, Richardson PL. VIM thalamotomy for the
effects on symptoms in multiple sclerosis? A double-blind, releif of the intention tremor of multiple sclerosis. British
randomized, placebo-controlled study on 160 patients. Journal of Neurosurgery 1998;12(6):559–62.
Multiple Sclerosis 2004;10(4):434–41. Duquette 1985 {published data only}
Wiles 2001 {published data only} Duquette P, Pleines J, du Souich P. Isoniazid for tremor in
Wiles CM, Newcombe RG, Fuller KJ, Shaw S, Furnival- multiple sclerosis: a controlled trial. Neurology 1985;35
Doran J, Pickersgill TP, et al.Controlled randomised (12):1772–5.
crossover trial of the effects of physiotherapy on mobility in Feys 2004 {published data only}
chronic multiple sclerosis. Journal of Neurology Neurosurgery Feys P, Helsen W, Liu X, Mooren D, Albrecht H, Nuttin
and Psychiatry 2001;70(2):174–9. B, et al.Effects of peripheral cooling on intention tremor in
multiple sclerosis. Journal of Neurology Neurosurgery and
References to studies excluded from this review
Psychiatry 2004;76(3):373–9.
Francis 1986 {published data only} sclerosis: an evaluation of outcome measures. Neurology
Francis DA, Grundy D, Heron JR. The response to 2001;57(10):1876–82.
isoniazid of action tremor in multiple sclerosis and its
Monaca-Charley 2003 {published data only}
assessment using polarised light goniometry. Journal of
Monaca-Charley C, Stojkovic T, Duhamel A, De Seze J,
Neurology Neurosurgery and Psychiatry 1986;49(1):87–9.
Ferriby D, Vermersch P. Double-blind crossover study
Fuller 1996 {published data only} with dolasetron mesilate, a 5-HT3 receptor antagonist in
Fuller KJ, Dawson K, Wiles CM. Physiotherapy in chronic cerebellar syndrome secondary to multiple sclerosis. Journal
multiple sclerosis: a controlled trial. Clinical Rehabilitation of Neurology 2003;250(10):1190–4.
1996;10:195–204.
Montgomery 1999 {published data only}
Gbadamosi 2001 {published data only} Montgomery EB Jr, Baker KB, Kinkel RP, Barnett G.
Gbadamosi J, Buhmann C, Moench A, Heesen C. Failure Chronic thalamic stimulation for the tremor of multiple
of ondansetron in treating cerebellar tremor in MS patients- sclerosis. Neurology 1999;53(3):625–8.
an open label pilot study. Acta Neurologica Scandinavica
2001;104(5):308–11. Morgan 1975 {published data only}
Morgan M.H, Hewer R.L, Cooper R. ’Application of an
Geny 1996 {published data only}
objective method of assessing intention tremor-a further
Geny C, Nguyen JP, Pollin B, Feve A, Ricolfi F, Cesaro
study on the use of weights to reduce intention tremor’.
P, et al.Improvement of severe postural cerebellar tremor
Journal of Neurology Neurosurgery and Psychiatry 1975;38
in multiple sclerosis by chronic thalamic stimulation.
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Movement Disorders 1996;11(5):489–94.
Goldman 1992 {published data only} Morrow 1985 {published data only}
Goldman MS, Kelly PJ. Symptomatic and functional Morrow J, McDowell H, Ritchie C, Patterson V. Isoniazid
outcome of stereotactic ventralis lateralis thalamotomy and action tremor in multiple sclerosis. Journal of Neurology
for intention tremor. Journal of Neurosurgery 1992;77(2): Neurosurgery and Psychiatry 1985;48(3):282–3.
223–9. Nandi 2004 {published data only}
Hooper 2002 {published data only} Nandi D, Aziz TZ. Deep brain stimulation in the
Hooper J, Taylor R, Pentland B, Whittle IR. A prospective management of neuropathic pain and multiple sclerosis
study of thalamic deep brain stimulation for the treatment tremor. Journal of Clinical Neurophysiology 2004;21(1):
of movement disorders in multiple sclerosis. British Journal 31–9.
of Neurosurgery 1992;77(2):223–9. Niranjan 2000 {published data only}
Jobst 1989 {published data only} Niranjan A, Kondziolka D, Baser S, Heyman R, Lunsford
Jobst U. Posturographic biofeedback training in equilibrium LD. Functional outcomes after gamma knife thalamotomy
disorders. Fortschritte der Neurologie Psychiatrie 1989;57(2): for essential tremor and MS-related tremor. Neurology
74–80. 2000;55(3):443–6.
Jones 1996 {published data only} Quintern 1999a {published data only}
Jones L, Lewis Y, Harrison J, Wiles CM. The effectiveness Quintern J, Immisch I, Albrecht H, Pollmann W, Glasauer
of occupational therapy and physiotherapy in multiple S, Straube A. Influence of visual and proprioceptive
sclerosis patients with ataxia of the upper limb and trunk. afferences on upper limb ataxia in patients with multiple
Clinical Rehabilitation 1996;10:277–82. sclerosis. Journal of Neurological Sciences 1999;163(1):61–9.
Koller 1984a {published data only}
Rice 1997 {published data only}
Koller WC, Biary N. Effect of alcohol on tremors:
Rice GP, Lesaux J, Vandervoort P, Macewan L, Ebers GC.
comparison with propranolol. Neurology 1984;34(2):
Ondansetron, a 5-HT3 antagonist, improves cerebellar
221–2.
tremor. Journal of Neurology Neurosurgery and Psychiatry
Koller 1984b {published data only} 1997;62(3):282–4.
Koller WC. Pharmacologic trials in the treatment of
cerebellar tremor. Archives of Neurology 1984;41(3):280–1. Sabra 1982 {published data only}
Sabra AF, Hallett M, Sudarsky L, Mullally W. Treatment of
Lemster 1994 {published data only}
action tremor in multiple sclerosis with isoniazid. Neurology
Lemster B, Huang LL, Irish W, Woo J, Carroll PB, Abu-
1982;32(8):912–3.
Elmagd K, et al.Influence of FK 506 (tacrolimus) on
circulating CD4+ T cells expressing CD25 and CD45RA Samra 1970 {published data only}
antigens in 19 patients with chronic progressive multiple Samra K, Waltz JM, Riklan M, Koslow M, Cooper IS.
sclerosis participating in an open label drug safety trial. Relief of intention tremor by thalamic surgery. Journal of
Autoimmunity 1994;19(2):89–98. Neurology Neurosurgery and Psychiatry 1970;33(1):7–15.
Matsumoto 2001 {published data only} Scheinberg 1984 {published data only}
Matsumoto J, Morrow D, Kaufman K, Davis D, Ahlskog Scheinberg L, Gesser BS. INH in multiple sclerosis.
JE, Walker A, et al.Surgical therapy for tremor in multiple Neurology 1984;34:134.
Schimrigh 2001 {published data only} follow up. Journal of Neurology Neurosurgery and Psychiatry
Schimrigh S, Lukas C, Hoffmann V, Hellwig K. Budipine 2005;76(12):1664–9.
is effective in treatment of intentional tremor in multiple
sclerosis. Journal of Neurology. 2001; Vol. 248:176. Additional references
Schulder 1999 {published data only}
Alusi 1999
Schulder M, Sernes TJ, Karimi R. Thalamic stimulation
Alusi SH, Glickman S, Aziz TZ, Bain PG. Tremor in
in patients with multiple sclerosis: long-term follow up.
multiple sclerosis. Journal of Neurolology Neurosurgery and
Stereotactic Functional Neurosurgery 2003;80:48–55.
Psychiatry 1999;66:131–4.
Sechi 1989 {published data only}
Alusi 2001a
Sechi GP, Zuddas M, Pireda M, Agnetti V, Sau G, Piras ML,
Alusi SH, Worthington J, Glickman S, Bain PG. A study of
et al.Treatment of cerebellar tremors with carbemazepine: a
tremor in multiple sclerosis. Brain 2001;124:720–30.
controlled trial with long term follow up. Neurology 1989;
39(8):1113–5. Alusi 2003
Sechi 2003 {published data only} Alusi SH, Glickman S, Patel N, Worthington J, Bain
Sechi G, Agnetti V, Sulas FM, Sau G, Corda D, Pitzolu PG. Target board test for the quantification of ataxia in
MG, et al.Effects of topiramate in patients withh cerebellar tremulous patients. Clinical Rehabilitation 2003;17(2):
tremor. Progress in Neuro-Psychopharmacology and Biological 140–9.
Psychiatry 2003;27(6):1023–7. Ashworth 1964
Shahzadi 1995 {published data only} Ashworth B. Preliminary trial of carisoprodol in multiple
Shahzadi S, Tasker RR, Lozano A. Thalamotomy for sclerosis. Practitioner 1964;192:540–42.
essential and cerebellar tremor. Stereotactic Functional Clarke 2003
Neurosurgery 1995;65:11–7. Clarke M, Oxman AD, editors. Cochrane Handbook for
Solaris 1999 {published data only} Systematic Reviews of Interventions 4.2.0 [updated March
Solaris A, Filippini G, Gasco P, Colla L, Salmaggi A, La 2003]. Cochrane Database of Systematic Reviews. Oxford:
Mantia L, et al.Physical rehabilitation has a positive effect Update Software, 2003, issue 2.
on disability in multiple sclerosis patients. Neurology 1999; Erasmus 2001
52(1):57–62. Erasmus LP, Sarno S, Albrecht H, Schwecht M, Pollmann
Speelman 1984 {published data only} W, Konig N. Measurement of ataxic symptoms with a
Speelman JD, Van Manen J. Sterotactic thalamotomy for graphics tablet: standard values in controls and validity in
the releif of intention tremor of multiple sclerosis. Journal multiple sclerosis patients. Journal of Neuroscience Methods
of Neurology Neurosurgery and Psychiatry 1984;47(6):596–9. 2001;108(1):25–37.
Striano 2006 {published data only} Fahn 1988

Striano P, Coppola A, Vacca G, Zara F, Bresica Morra Fahn S, Tolosa E, Marin C. Clinical rating scale for tremor.
V, Orefice G, et al.Levetiracetam for cerebellar tremor Parkinson’s disease and movement disorders. Urban and
in multiple sclerosis: an open-label pilot tolerabilty and Schwarzenberg, 1988:225–34.
efficacy study. Journal of Neurology 2006;253(6):762–6. Ghez 2000
Taha 1999 {published data only} Ghez C, Thach WT. The cerebellum. Principles of Neural
Taha JM, Janszen MA, Favre J. Thalamic deep brain Science. 4th Edition. McGraw Hill, 2000.
stimulation for the treatment of head, voice, and bilateral Hickman 2001
limb tremor. Journal of Neurosurgery 1999;91(1):68–72. Hickman SJ, Brierley CM, Silver NC, Moseley IF, Scolding
Waubabt 2001 {published data only} NJ, Compston DA, et al.Infratentorial hypointense lesion
Waubant E, Hosseini H, N’guyen JP, Jedynak CP, Welter volume on T1-weighted magnetic resonance imaging
ML, Apartis E, et al.Efficacy of thalamic stimulation in correlates with disability in patients with chronic cerebellar
multiple sclerosis. Multiple Sclerosis. 2001; Vol. 7:S29. ataxia due to multiple sclerosis. Journal of Neurological
Science 2001;187(1-2):35–9.
Zajicek 2003 {published data only}
Zajicek J, Fox P, Sanders H, Wright D, Vickery J, Nunn A, Hooper 1998
et al.Cannabinoids for treatment of spasticity and other Hooper J, Taylor R, Pentland B, Whittle IR. Rater reliability
symptoms related to multiple sclerosis (CAMS study): of Fahn’s tremor rating scale in patients with multiple
multicentre randomised palcebo-controlled trial. Lancet sclerosis. Archives of Physical Medicine and Rehabilitation
2003;362(9395):1517–26. 1998;79(9):1076–9.
Zajicek 2005 {published data only} Kurtzke 1983
Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram Kurtzke JF. Rating neurological impairment in multiple
WM, Reilly SM, et al.Cannabinoids iin multiple sclerosis sclerosis: an expanded disability status scale (EDSS).
(CAMS) study: safety and efficacy data for 12 months Neurology 1983;33:1444–52.

McDonald 2001 afferences on upper limb ataxia in patients with multiple
McDonald WI, Compston A, Edan G, Goodkin D, sclerosis’. Journal of Neurological Science 1999;163(1):61–9.
Hartung H.P, Lublin F.D, et al.’Recommended diagnostic Rudick 2002
criteria for multiple sclerosis: guidelines from the Rudick R.A, Cutter G, Reingold S. ’The multiple sclerosis
International Panel on the diagnosis of multiple sclerosis’. functional composite: a new clinical outcome measure
Annals of Neurolology 2001;50(1):121–7. for multiple sderosis trials’. Multiple Sclerosis 2002;8(5):
Murray 1999 359–65.
Murray I.A, Johnson G.R. ’Upper limb kinematics Simpson 1990
and dynamics: the development and validation of a Simpson J, (editor). Oxford English Dictionary. 3rd Edition.
measurement technique’. Measurement and simulations in OUP, 1990.
musculoskeletal biomechanics meeting, UK. 1999. Swingler 1992
Swingler R.J, Compston D.A. ’The morbidity of multiple
Poser 1983 sclerosis’. Quarterly Journal of Medicine 1992;83:325–37.
Poser C.M, Paty D.W, Scheinberg L, McDonald W.I,
Davis F.A, Ebers G.C. ’New diagnostic criteria for multiple Wiles 2003
sclerosis: guidelines for research protocols’. Annals of Wiles C.M, Newcombe R.G, Fuller K.J, Jones A, Price
Neurology 1983;13(3):227–31. M. ’Use of videotape to assess mobility in a controlled
randomized crossover trial of physiotherapy in chronic
Quintern 1999 multiple sclerosis’. Clinical Rehabilitation 2003;17(3):
Quintern J, Immisch I, Albrecht H, Pollmann W, Glasauer 256–63.
S, Straube A. ’Influence of visual and proprioceptive ∗
Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Armutlu 2001
Methods parallel group
Participants 26 MS patients
Interventions physiotherapy plus Johnstone pressure splint vs. physiotherapy alone (4 weeks)
Outcomes objective measures of gait and equilibrium testing
Notes assessor only blinding
Risk of bias
Item Authors’ judgement Description
Allocation concealment? Unclear B - Unclear
Bozek 1987
Methods crossover
Interventions isoniazid vs placebo ( 4 weeks each)
Outcomes videotaped assessment of tremor, accelerometry
Notes
Risk of bias
Fox 2004
Methods crossover
Interventions oral Cannador vs placebo (2 weeks each)

Fox 2004 (Continued)
Outcomes tremor index, accelerometry, ataxia scale, spiral draw, finger tap, 9HPT
Notes
Risk of bias
Hallett 1985
Methods crossover
Interventions isoniazid vs. placebo (4 weeks each)
Outcomes videotaped assessment of tremor, accelerometry, self rating of improvement
Notes
Risk of bias
Killestein 2002
Methods twofold crossover
Interventions dronabinol vs. cannabis sativa plant extract vs. placebo (4 weeks each)
Outcomes 9HPT
Notes
Risk of bias

Lord 1998
Interventions Facilitation vs. task orientated physiotherapy (5-7 weeks)
Outcomes Berg balance test
Risk of bias
Orsnes 2000
Methods crossover
Interventions baclofen vs. placebo (18 days each)
Outcomes forceplate measurements
Notes
Risk of bias
Schuurman 2000
Participants 10 MS patients (68 patients with tremor in total)
Interventions thalamic stimulation vs. thalamotomy
Outcomes videotaped assessment of tremor, modified tremor scale
Risk of bias

Schuurman 2000 (Continued)
Wade 2004
Participants 13 MS patients with tremor (160 MS patients in total)
Interventions sublingual Sativex vs. placebo (10 weeks)
Outcomes VAS, tremor ADL questionnaire, 9HPT
Notes
Risk of bias
Allocation concealment? Yes A - Adequate
Wiles 2001
Methods twofold crossover
Interventions home physiotherapy vs hospital physiotherapy vs. no treatment (8 weeks each)
Outcomes single leg balance time, 9HPT, videotaped clinical assessment of gait
Risk of bias
Allocation concealment? Yes A - Adequate
outcomes refer to primary measures of ataxia or tremor only

Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Aisen 1991 Not a randomised controlled trial
Alusi 2001b Not a randomised controlled trial
Bakhos 2002 High risk of bias
Benabid 1998 Not a randomised controlled trial
Berk 2002 Not a randomised controlled trial
Bittar 2005 Not a randomised controlled trial
Brice 1980 Not a randomised controlled trial
Cardini 2000 Assessor unblinded
Critchley 1998 Not a randomised controlled trial
Duquette 1985 Not a randomised controlled trial
Feys 2004 Not a randomised controlled trial
Francis 1986 Not a randomised controlled trial
Fuller 1996 Assessor unblinded
Gbadamosi 2001 Not a randomised controlled trial
Geny 1996 Not a randomised controlled trial
Goldman 1992 Not a randomised controlled trial
Hooper 2002 Not a randomised controlled trial
Jobst 1989 Assessor unblinded
Jones 1996 Not a randomised controlled trial
Koller 1984a Unable to extract separate MS data
Koller 1984b study methods not clear
Lemster 1994 Unable to extract separate tremor/ataxia data
Matsumoto 2001 Not a randomised controlled trial

(Continued)
Monaca-Charley 2003 Treatment duration less than one week
Montgomery 1999 Not a randomised controlled trial
Morgan 1975 Assessor unblinded
Morrow 1985 Not a randomised controlled trial
Nandi 2004 Not a randomised controlled trial
Niranjan 2000 Not a randomised controlled trial
Quintern 1999a Not a randomised controlled trial
Rice 1997 Treatment duration less than one week
Sabra 1982 Not a randomised controlled trial
Samra 1970 Not a randomised controlled trial
Scheinberg 1984 Not a randomised controlled trial
Schimrigh 2001 Not a randomised controlled trial
Schulder 1999 Not a randomised controlled trial
Sechi 1989 Assessor unblinded
Sechi 2003 Not a randomised controlled trial
Shahzadi 1995 Not a randomised controlled trial
Solaris 1999 Unable to extract separate tremor/ataxia data
Speelman 1984 Not a randomised controlled trial
Striano 2006 Not a randomised controlled trial
Taha 1999 Not a randomised controlled trial
Waubabt 2001 Not a randomised controlled trial
Zajicek 2003 High risk of bias for ataxia outcome
Zajicek 2005 High risk of bias for ataxia outcome

DATA AND ANALYSES
This review has no analyses.
APPENDICES
Appendix 1. CENTRAL search strategy

1. Multiple sclerosis
2. Multiple-sclerosis*:me
3. 1 or 2
4. Demyelinating Disease
5. Demyelinating Diseases
6. Demyelinating-Diseases*:me
7. 4 or 5 or 6
8. Transverse Myelitis
9. Myelitis-Transverse*:me
10. 8 or 9
11. Neuromyelitis Optica
12. Neuromyelitis-Optica*:me
13. 11 or 12
14. Optic Neuritis
15. Optic-Neuritis*:me
16. 14 or 15
17. Encephalomyelitis Acute Disseminated
18. Encephalomyelitis-Acute-Disseminated*:me
19. 17 or 18
20. Adem
21. Devic
22. 3 or 7 or 10 or 13 or 16 or 19 or 20 or 21
23.“ataxia” [tw]
24. “tremor”[tw]
25. ATAXIA explode all trees [MESH]
26. TREMOR explode all trees [MeSH]
27. 23 OR 22
28. 22 AND 27
Appendix 2. MEDLINE (PubMed) search strategy

1.Multiple Sclerosis[MESH]
2.Myelitis, Transverse[MESH:noexp]
3.Demyelinating Diseases[MESH:noexp]
4.Encephalomyelitis, Acute Disseminated[MESH]
5.“multiple sclerosis” OR “transverse myelitis” OR “optic neuritis” OR device OR adem OR “neuromyelitis optica” Field: Title/
Abstract
6.#1 OR #2 OR #3 OR #4 OR #5
7.“Clinical Trial”[Publication Type]
8.randomized Field: Title/Abstract
9.placebo Field: Title/Abstract
10.“drug therapy”[Subheading]
11.randomly Field: Title/Abstract
12.trial Field: Title/Abstract
13.groups Field: Title/Abstract
14.#7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13
15.#6 AND #14
16.“Animals”[MeSH]
17.“Humans”[MeSH]
18. #16 NOT (#16 AND #17)
19.#15 NOT #18
20 “ataxia”[tw]
21.“tremor”[tw]
22 ATAXIA explode all tress [MESH]
24. 20 OR 24
25. 19 AND 24
Appendix 3. EMBASE (EMBASE.com) search strategy

1’encephalomyelitis’/exp
2 ’demyelinating disease’/exp
3 ’multiple sclerosis’/exp
4 ’myelooptic neuropathy’/exp
5 ’multiple sclerosis’:ti,ab
6: neuromyelitis optica:ti,ab
7. enecephalomyelitis:ti,ab
8. adem:ti,ab
9 .devic:ti,ab
10. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9
11. ’crossover procedure’/exp
12. ’double blind procedure’/exp
13. ’single blind procedure’/exp
14. ’randomized controlled trial’/exp
15.random*:ti,ab
16.factorial*:ti,ab
17. crossover:ti,ab
18.cross AND over:ti,ab
19. placebo*:ti,ab
20. ’double blind’:ti,ab
21.’single blind’:ti,ab
22. assign*:ti,ab
23.alloact*:ti,ab
24. volunteer*:ti,ab
25.11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24
26.10 and 25
27. 26 and human
28. “ataxia”[MESH
29. “tremor” [tw]
30. ATAXIA explode all tress [MESH]
32. 28 OR 31
33. 27 AND 32
WHAT’S NEW
Last assessed as up-to-date: 26 August 2006.
Date Event Description
28 August 2008 Amended Converted to new review format.
HISTORY
Protocol first published: Issue 4, 2004
Review first published: Issue 1, 2007
CONTRIBUTIONS OF AUTHORS
Link with editorial base - RJM
Review the correspondence - RJM
Draft the protocol - RJM, CAY, TF
Search for trials - LY, RJM, CAY,
Obtain copies of trials - RJM, LY
Select which trials to include - RJM, CAY, LY
Extract data from trials - RJM, CAY, LY
Enter data into Revman - RJM
Carry out the analysis - RJM, CAY, LY
Interpret the analysis - RJM, CAY, LY
Draft the final review - RJM, CAY, LY
Update the review - RJM, CAY, LY
DECLARATIONS OF INTEREST
Nil known

INDEX TERMS
Medical Subject Headings (MeSH)
Ataxia [rehabilitation; surgery; ∗ therapy]; Baclofen [therapeutic use]; Cannabis; Multiple Sclerosis [∗ complications]; Muscle Relaxants,
Central [therapeutic use]; Phytotherapy; Randomized Controlled Trials as Topic; Thalamus [surgery]
MeSH check words

Humans


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Treatment for ataxia in multiple sclerosis (Review)

Mills RJ, Yap L, Young CA

Treatment for ataxia in multiple sclerosis (Review)

Treatment for ataxia in multiple sclerosis (Review) i

Treatment for ataxia in multiple sclerosis

Roger J Mills1 , Leesien Yap2 , Carolyn A Young3

Editorial group: Cochrane Multiple Sclerosis Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

Types of studies Electronic searches

Treatment for ataxia in multiple sclerosis (Review) 3

Description of studies Risk of bias in included studies

Treatment for ataxia in multiple sclerosis (Review) 4

Treatment for ataxia in multiple sclerosis (Review) 5

Although tests such as 9HPT have been well validated in MS as an

Treatment for ataxia in multiple sclerosis (Review) 6

Some notable exclusions AUTHORS’ CONCLUSIONS

Treatment for ataxia in multiple sclerosis (Review) 7

Striano 2006 {published data only} Fahn 1988

Treatment for ataxia in multiple sclerosis (Review) 10

Treatment for ataxia in multiple sclerosis (Review) 11

Characteristics of included studies [ordered by study ID]

Methods parallel group

Outcomes objective measures of gait and equilibrium testing

Notes assessor only blinding

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Interventions isoniazid vs placebo ( 4 weeks each)

Outcomes videotaped assessment of tremor, accelerometry

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Interventions oral Cannador vs placebo (2 weeks each)

Treatment for ataxia in multiple sclerosis (Review) 12

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Interventions isoniazid vs. placebo (4 weeks each)

Outcomes videotaped assessment of tremor, accelerometry, self rating of improvement

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Methods twofold crossover

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Treatment for ataxia in multiple sclerosis (Review) 13

Methods parallel group

Interventions Facilitation vs. task orientated physiotherapy (5-7 weeks)

Outcomes Berg balance test

Notes assessor only blinding

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Interventions baclofen vs. placebo (18 days each)

Outcomes forceplate measurements

Item Authors’ judgement Description

Allocation concealment? Unclear B - Unclear

Methods parallel group

Participants 10 MS patients (68 patients with tremor in total)

Interventions thalamic stimulation vs. thalamotomy

Outcomes videotaped assessment of tremor, modified tremor scale

Notes assessor only blinding