Description of the condition
Multiple sclerosis (MS) is an autoimmune, inflammatory, demyelinating disease of the central nervous system (CNS), which mainly affects individuals between 20 and 50 years of age (Miller 2012). The lesions of MS can occur in many parts of the CNS and result in a wide range of symptoms including sensory impairment, fatigue, walking or balance problems, visual impairment, vertigo and cognitive disabilities (National MS Society 2012). The clinical course of MS has four different patterns (Lublin 1996):
- relapsing-remitting MS (RRMS), characterised by unpredictable exacerbations of existing symptoms or appearance of new symptoms;
- secondary progressive MS (SPMS), a progressive form after an initial relapsing-remitting course;
- primary progressive MS (PPMS), which is progressive from onset without relapses; and
- progressive-relapsing MS (PRMS), which is progressive from onset but is then punctuated by relapses.
A relapsing-remitting course occurs in approximately 85% of patients, while 10% to 15% present with a primary progressive or progressive relapsing form (Miller 2012).
The worldwide incidence rate of MS is 3.6 cases per 100,000 person-years in women and 2.0 in men (Alonso 2008), while the prevalence is between 20 to 144 people per 100,000 (Simpson 2011). It is estimated that the disease affects about 400,000 people in the United States, with 200 more people diagnosed every week and more than 2.1 million people worldwide affected (National MS Society 2012). Recent studies show an almost universal increase in the prevalence of MS (Al-Hashel 2008; Etemadifar 2011; Marrie 2010). Due to longer survival and its increasing incidence over time, the prevalence of MS is expected to increase in the future.
MS takes a significant physical, psychological and economic toll on patients' families and caregivers, and this burden rises as the disease progresses. A cross-sectional study found that 20% of caregivers spent more than 3.5 hours per day aiding patients with MS. Care-giving time was influenced by the cognitive and ADL (activities of daily living) status of the person with MS and the number of care-giving activities performed (Finlayson 2008). Another survey carried out in the United States indicated that the total annual per patient cost of MS was USD 47,215 with 53% attributed to direct medical and non medical costs, 37% to production losses and 10% to informal care (Kobelt 2006).
At present, the most commonly used MS treatments are immunomodulating agents, such as beta interferon and glatiramer acetate. Although these agents have all been shown to reduce relapse frequency, they have little effect on the disability that characterises the progressive forms of the disease (Goodin 2002; Miller 2012). Stopping or reversing disease progression remains an important unmet need in patients with MS. Accumulating studies indicate that the degree of disability is predominantly related to the extent of axonal injury (Bjartmar 2001; Hyland 2011; Kapoor 2006). Immunomodulating agents only have a limited neuroprotective effect, probably because immune attack is only one of several potential mechanisms of axonal injury. So far there are no clearly effective agents which prevent the accumulation of deficits that lead to the progression from an inflammatory phase to a neurodegenerative phase (Tselis 2010). Hence, in addition to immunomodulating agents, novel therapeutic strategies are required to reduce axonal degeneration to prevent disability progression in MS.
Description of the intervention
Research on the potential neuroprotective effect of sodium channel blockers has increased since the important role of increased sodium (Na
How the intervention might work
In clinical practice, sodium channel blockers, such as carbamazepine, topiramate, lamotrigine and riluzole, are widely used for treating epileptic seizures, and it is becoming increasingly evident that these antiepileptic sodium channel blockers might also be effective in several neurological disorders, including migraine, neurodegeneration and neuropathic pain (Ettinger 2007; Mantegazza 2010; Rogawski 2004). In MS, carbamazepine, a type of sodium channel blocker, is used to treat tonic flexion spasms, Lhermitte's sign and neuropathic pain (Thompson 2010). Phenytoin, lidocaine and its orally absorbed derivative mexiletine have also been used for these applications in patients with MS with some degree of success (Waxman 2008).
In a clinical trial, which aimed to assess whether the sodium channel blocker lamotrigine is also neuroprotective in patients with SPMS, 120 patients with SPMS were treated with lamotrigine (target dose 400 mg/day) or placebo for two years. The primary outcome was rate of reduction in partial (central) cerebral volume over two years. Unfortunately, treatment with lamotrigine neither altered cerebral volume loss nor had a beneficial effect on other secondary outcomes, except that the rate of deterioration of the timed 25-foot walk was markedly lower in the lamotrigine group (Kapoor 2010).
From the perspective of clinical practice, if partial blockade of voltage-gated sodium channels could result in neuroprotection in patients with MS, this would be of benefit for preventing disability progression in these patients.
Why it is important to do this review
Neuroprotection is emerging as a potentially important strategy for preventing disability progression in MS and consequently the burden of the disease. The field is relatively new and gathering experience from clinical trials could contribute by translating the potential of individual strategies into clinical practice. No systematic review currently exists in the peer-reviewed literature that focuses on the effects of sodium channel blockers on disease progression.
We will undertake a systematic review to determine whether there is clear evidence of efficacy and safety of sodium channel blockers for neuroprotection in MS to prevent the occurrence of disability and the burden of the disease.
Criteria for considering studies for this review
Types of studies
We will include all relevant randomised controlled trials (RCTs), irrespective of blinding, publication status or language. We plan to use only data from the first period of any included cross-over trials.
Types of participants
We will include participants of any age and gender, with a diagnosis of definite MS according to the Poser (Poser 1983), McDonald (McDonald 2001) or revisions to the McDonald diagnostic criteria (Polman 2005; Polman 2011). Participants with any pattern of disease course (relapsing-remitting, secondary progressive, primary progressive and progressive-relapsing) will be included.
Types of interventions
All RCTs that examined sodium channel blockers used alone or as an add-on to any approved treatments for MS will be included.
- sodium channel blockers versus placebo only;
- sodium channel blockers plus approved treatments (such as beta interferon) versus placebo plus approved treatments.
Types of outcome measures
We will assess following outcomes at the end of the treatment period and scheduled follow-up period (at six months, one, two and three years, and at the end of the follow-up time).
- The number of participants who experienced disability progression. Disability progression will be defined as a one-point increase in the Expanded Disability Status Score (EDSS) score (or a half-point increase for patients with a baseline score ≥ 5.5) that was confirmed three or six months later, in the absence of relapse (Freedman 2011; Gold 2012; Jacobs 1996; Johnson 1995; PRISMS 1998; Polman 2006). In addition, other definitions of disability progression reported in the trials (such as the Multiple Sclerosis Functional Composite) will be accepted (Cohen 2012).
- The number of patients experiencing at least one relapse. Definitions of relapse given in the original studies will be accepted.
- Adverse events (AE) as reported in the trial:
- the number of patients experiencing at least one AE, irrespective of whether mild or severe (no period restriction);
- the number of patients experiencing treatment discontinuation caused by AE.
- MRI (magnetic resonance imaging) measurements of cerebral atrophy. Atrophy can be measured in several ways, such as whole brain volume, grey matter volume, white matter volume, mean cross-sectional cervical spinal cord area, and T1 and T2 lesion volumes; any measures of cerebral atrophy using MRI will be considered. We will calculate the change from baseline in these measures (such as whole brain volume, grey matter volume, white matter volume, T1 and T2 lesion volumes).
- The mean change in Expanded Disability Status Score (EDSS).
- The mean change in Multiple Sclerosis Functional Composite (MSFC).
- MRI parameters of disease activity: changes in the number of new gadolinium (Gd)-enhancing lesions or number of high signal intensity lesions on T2 weighted MRI or number of low signal intensity lesions on T1 weighted MRI.
- Annualised relapse rate (number of relapses per patient-year).
- Global measures of activities of daily living (ADL): the mean change in the Rankin scale or Barthel Index score (Cohen 2012).
Search methods for identification of studies
We will apply no language restrictions to the search.
The Trials Search Co-ordinator will search the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's Specialised Register, which is updated regularly and contains trials identified from the following databases.
- The Cochrane Central Register of Controlled Trials (CENTRAL) (latest issue)
- MEDLINE (PubMed) (1966 to date)
- EMBASE (Embase.com) (1974 to date)
- CINAHL (EBSCO host) (1981 to date)
- LILACS (Bireme) (1982 to date)
Information on the Group's Trials Register and details of search strategies used to identify trials can be found in the 'Specialised Register' section within the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's module in The Cochrane Library (Module 2011).
The keywords we will use in the search strategy are listed in Appendix 1.
In addition, we will search the following Chinese databases using the keyword 'sodium channel blockers'.
- The China Biological Medicine Database (CBM) (1978 to date) (http://sinomed.imicams.ac.cn/zh/)
- The Chinese National Knowledge Infrastructure (CNKI) (1979 to date) (http://epub.cnki.net/grid2008/index/ZKCALD.htm)
- Chinese Science and Technique Journals Database (VIP) (1989 to date) (http://vip.fjinfo.gov.cn/index.asp)
- Wanfang Data (1984 to date) (http://www.wanfangdata.com/)
We will also search the following ongoing trials register: U.S. National Institute of Health Ongoing Trials Register (ClinicalTrials.gov).
Searching other resources
To identify other relevant study data we will:
- check reference lists of published reviews and retrieved articles;
- contact authors of published studies if data reported are incomplete;
- search databases of conference abstracts: Conference Proceedings Citation Index - Science (CPCI-S) and China Medical Academic Conferences (CMAC 1995 to present) in CMCC (Chinese Medical Current Contents).
Data collection and analysis
Selection of studies
Two review authors (Yang, Zhang) will independently assess the abstracts of studies resulting from the electronic searches and exclude those that are obviously irrelevant. We will obtain the full text of all potentially relevant studies for further assessment to determine if the trial meets the inclusion/exclusion criteria. We will list publications that do not meet the inclusion criteria in the 'Characteristic of excluded studies' table with the reason for exclusion. Discrepancies will be resolved by discussion among the review authors or by consulting a third review author (Hao) if disagreement persists.
Data extraction and management
Two review authors (Yang, Zeng) will independently extract the data from the included studies using a data extraction form. We will summarise all studies that meet the inclusion criteria in the 'Characteristics of included studies' table provided in the Review Manager (RevMan) 5 software developed by The Cochrane Collaboration (Review Manager 2011) and include details on study design, participants, interventions and outcomes measures. If necessary, we will contact principal investigators of included studies to provide data and clarification. Discrepancies will be resolved by discussion among the review authors or by consulting with a third review author (Hao) if disagreement persists.
Assessment of risk of bias in included studies
Two review authors (Yang, Zeng) will independently assess the methodological quality of the included studies using the Cochrane 'Risk of bias' tool (Higgins 2011). We will rate the following domains separately for each of the included studies as 'low risk of bias', 'high risk of bias' and 'unclear' if the risk of bias was uncertain or unknown.
- Random sequence generation
- Allocation concealment
- Blinding of participants and personnel
- Blinding of outcome assessment
- Incomplete outcome data
- Selective reporting
- Other sources of bias
We will report these assessments in the 'Risk of bias' table for each individual study.
We will resolve any disagreements between authors arising at any stage through discussion or with a third author (Wen).
Measures of treatment effect
We will express results for dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CI), and express results for continuous outcomes as mean difference (MD) (if the same scale for each trial is available) or standardised mean difference (SMD) (if different scales are used). For counts of rare events we will use rate ratios, which compare the rate of events in the two groups by dividing one by the other, while for counts of common events we will use the mean difference to compare the difference in the mean number of events (possibly standardised to a unit time period) experienced by participants in the intervention group compared with participants in the control group.
Unit of analysis issues
In cases of studies with non-standard designs (e.g. cross-over trials, cluster-randomised trials), we will manage the data according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). For example, if we find any cross-over trials, we will only analyse the data from the first period.
Dealing with missing data
If data are missing, we will contact the investigators for additional information. If some data remain unavailable, we will undertake sensitivity analyses in which we will impute missing data and compare results for both best-case and worst-case scenarios.
Assessment of heterogeneity
We will determine statistical heterogeneity according to the I
Assessment of reporting biases
We will assess publication bias according to the recommendations on testing for funnel plot asymmetry (Egger 1997) as described in section 10.4.3.1 of the Cochrane Handbook for Systematic Reviews on Interventions (Higgins 2011).
We plan to perform statistical analysis using the Cochrane Review Manager software (Review Manager 2011) to synthesise the available data and perform all analyses in accordance with the intention-to-treat method. We will give a descriptive analysis of the results if the outcome data from different studies cannot be pooled.
Subgroup analysis and investigation of heterogeneity
We will perform the following subgroup analyses if a sufficient number of studies are included.
- Type of sodium channel blocker (e.g. lamotrigine, topiramate)
- Pattern of disease course (e.g. relapsing-remitting, secondary progressive)
- Co-interventions (e.g. beta interferon, glatiramer acetate)
- Different definition of outcome measurements (e.g. disability progression measured by EDSS or MSFC)
We plan to conduct a sensitivity analysis to assess the robustness of our results by repeating the analysis with the following adjustments, if it is necessary in relation to trials quality.
- Excluding studies with inadequate concealment of allocation
- Excluding studies in which outcome evaluation is not blinded
- Excluding studies in which loss to follow-up is greater than 10%
- Excluding studies with missing data
We gratefully thank Liliana Coco, Review Group Managing Editor and the editorial team of the Cochrane Multiple Sclerosis Group for advice and support in writing this protocol.
Appendix 1. Keywords
sodium channel blockers[MeSH Terms] OR "sodium channel blockers"[All Fields] OR sodium channel blockers[Text Word]
Contributions of authors
Drafting the protocol: Chunsong Yang, Lingli Zhang, Zilong Hao, Linan Zeng and Jin Wen
Searching for trials: Chunsong Yang and Linan Zeng
Obtaining copies of relevant references: Chunsong Yang and Jin Wen
Trial selection and evaluation: Chunsong Yang, Lingli Zhang, Zilong Hao and Jin Wen
Data extraction and data entry: Chunsong Yang, Lingli Zhang and Linan Zeng
Analysis, writing the final review and interpreting the results: Chunsong Yang, Lingli Zhang, Zilong Hao, Linan Zeng and Jin Wen
The review will be updated by Chunsong Yang and Lingli Zhang
Declarations of interest