Treatment for ataxia in multiple sclerosis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy and tolerability of both pharmacological and non‐pharmacologic treatment of ataxia and tremor in patients with multiple sclerosis (MS).
Background
The word ataxia literally means disorder or confusion (Simpson 1990). Clinically, it is used to describe various abnormalities that can occur in the execution of voluntary movement including delayed initiation of movement, dysmetria, dysdiadochokinesis and tremor. Ataxia results from lesions in the cerebellum and its connections (Ghez 2000).
The incidence of ataxia in multiple sclerosis (MS) is high with about 80% of patients experiencing symptoms at some point during their disease (Matthews 1998). The multiplicity of lesions in MS, make histological correlation with clinical features difficult (Alusi 1999, Alusi 2001); however, in MS patients with chronic cerebellar ataxia, disability has been shown to correlate with the number of infratentorial T1 hypointense lesions seen on magnetic resonance (MR) imaging (Hickman 2001). The influence of sensory afferents on cerebellar dysfunction has been demonstrated in MS, in keeping with other cerebellar disorders (Quintern 1999).
There are several ways of assessing ataxia and tremor ranging from simple functional tests such as timed walks, target board tests, writing and drawing tests and measuring the volume of water spilt from a cup (Alusi 1999, Alusi 2003, Erasmus 2001); to rating scales such as the Kurtzke functional system (Kurtzke 1983) and the Fahn tremor rating (Fahn 1988); to more complex kinematic analyses using three dimensional, infrared or video tracking of reflective markers placed at joints with or without accompanying electromyography (Quintern 1999, Murray 1999).
This review evaluates the effectiveness and tolerability of treatments for ataxia in patients with multiple sclerosis.
Objectives
To assess the efficacy and tolerability of both pharmacological and non‐pharmacologic treatment of ataxia and tremor in patients with multiple sclerosis (MS).
Methods
Criteria for considering studies for this review
Types of studies
Blinded, randomised controlled trials (RCTs) which either are placebo‐controlled or compare two or more treatments will be included. Quasi‐randomised or non‐randomised trials will be excluded. Trials testing pharmacological agents must have both participant and assessor blinding. Trials testing surgical interventions or effects of physiotherapy, where participants cannot be blinded to the treatment, must, at least, have independent assessors who are blinded to the treatment. Cross‐over trials will be included.
Types of participants
Patients of any age and either sex, with MS satisfying either the Poser (Poser 1983) or McDonald (McDonald 2001) criteria, of any course type, will be included. The patients must have symptoms or signs of ataxia; the presence of action tremor without other features of ataxia will qualify.
Patients who are within thirty days of a relapse or within thirty days of receiving corticosteroids will be excluded. Studies including patients with other diagnoses will be excluded unless individual data for the MS patients can be obtained either from the published results or through contact with the authors.
Types of interventions
Use of a pharmacological agent in at least one arm of the study for at least one week. Surgical interventions such as deep brain stimulation, or surgical appliances such as splints or weights, or physiotherapy, will be considered if amenable to assessor blinding.
Types of outcome measures
Primary
Efficacy: whether the intervention produces a change in severity of ataxia as measured by any validated method. Methods include: simple functional tests such as timed walks, target board tests, writing and drawing tests and measuring the volume of water spilt from a cup (Alusi 1999, Alusi 2003, Erasmus 2001); rating scales such as the Kurtzke functional system (Kurtzke 1983) and the Fahn tremor rating (Fahn 1988); and more complex kinematic analyses using three dimensional, infrared or video tracking of reflective markers placed at joints with or without accompanying electromyography (Murray 1999, Quintern 1999).
Safety: the incidence of adverse or serious adverse events.
Secondary
Efficacy: change in activity limitation (disability) ratings or in quality of life scores. Duration of treatment efficacy.
Search methods for identification of studies
1) Electronic Searches of i) Cochrane Multiple Sclerosis Group trials Register, ii) The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 1, 2004), iii) MEDLINE (1966‐ to 2004), iv) EMBASE (1966‐to 2004) using the term: (ataxia OR tremor) AND multiple sclerosis.
2) Reference lists from published reviews on symptom control in multiple sclerosis and identified RCTs.
3) Personal communication with first authors of relevant trials or reviews and other multiple sclerosis experts.
4) Drug manufacturers for drugs identified in relevant RCTs.
5) National Health Service National Research Register (NRR) including the Medical Research Council Clinical Trials Directory.
Unpublished trials will be identified using strategies 3, 4 and 5.
Data collection and analysis
Study selection and data extraction
Titles and abstracts of papers identified using the above strategies will be assessed by three independent reviewers (RJM, CAY and TF); full text versions will be viewed if necessary. Agreement on which studies meet the inclusion criteria will be reached by consensus.
Assessment of methodological quality
The methodological quality of the studies will be assessed as per the guidelines in the Cochrane Reviewers' Handbook (Clarke 2003) for: selection bias, performance bias, attrition bias and detection bias. A summary rating of A (low bias), B (moderate bias) or C (high bias) will be given to each study. Studies with high risk of bias will be discarded. Patient and study characteristics and outcome data will be abstracted by the three reviewers.
Analysis
Data will be entered into an electronic database (Review Manager). Weighted treatment effects will be calculated across trials using inverse variance weights and a random effects model (DerSimonian 1986). For dichotomous outcomes the results will be expressed as odds ratios (OR with 95% confidence intervals (CI)). Some results will also be presented as risk differences (RD with 95% CI). For continuous data, mean differences (with 95% CI) will be given. Heterogeneity among the studies will be explored. Sensitivity analyses will be performed in order to investigate the influence of subgroups (e.g. cross‐over trials, treatment duration or studies with low methodological quality). If two or more trials are investigating the effects of the same intervention with similar participants and outcome measures, then results will be pooled for further analysis.
