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Abstract
Background It has been recently hypothesised that chronic cerebrospinal venous insufficiency (CCSVI) may be an important factor in the pathogenesis of multiple sclerosis (MS). The proposed treatment for CCSVI is percutaneous transluminal angioplasty, also known as the ‘liberation procedure’, which is claimed to improve the blood flow in the brain, thereby alleviating some of the symptoms of MS. Our objective was to determine the effects of percutaneous transluminal angioplasty used for the treatment of CCSVI in people with MS.
Methods We searched the following databases up to June 2012 for randomised controlled trials: The Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register, CENTRAL, in The Cochrane Library 2012, Issue 5, MEDLINE (from 1946), EMBASE (from 1974) and reference lists of articles. We also searched several online trials registries for ongoing trials.
Results Our searches retrieved 159 references, six of which were related to ongoing trials. No randomised controlled trials met our inclusion criteria.
Conclusions There is currently no high level evidence to support or refute the efficacy or safety of percutaneous transluminal angioplasty for treatment of CCSVI in people with MS. Clinical practice should be guided by evidence supported by well-designed randomised controlled trials: closure of some of the gaps in the evidence may be feasible at completion of the six ongoing clinical trials.
- Multiple Sclerosis
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Introduction
Multiple sclerosis (MS) is a chronic inflammatory disease of the nervous system and the most frequent cause of neurological disability in young adults. The disease is characterised by demyelination, axonal loss and inflammation.1 ,2 The most widely accepted hypothesis on the pathogenesis of MS is that it is an immune-mediated disease characterised by lymphocytic infiltration, leading to damage of myelin and axons.1 ,2 A more recent hypothesis suggests that chronic venous congestion may be an important factor in the pathogenesis of MS.3–6 Local erythrocyte extravasation due to increased pressure in the veins of the central nervous system (CNS) followed by degradation of erythrocytes, iron-driven phagocytosis and subsequent lymphocytic infiltration is hypothesised to be responsible for the mostly venotopic presence of MS lesions.7 This concept has been called ‘chronic cerebrospinal venous insufficiency’ (CCSVI) and is featured by stenoses of the internal jugular veins, azygos veins, or both, limiting the normal blood flow from the CNS, along with the development of small collateral veins that may have evolved to compensate for the restricted blood drainage.1 ,4 The conceptual association between CCSVI and MS implies that CCSVI may be a treatable cause of MS and hence it has formed the basis for the so-called ‘liberation procedure’, which consists of balloon angioplasty of the narrowed or blocked veins.1 ,8 Much of the research on this topic has, over recent years, generated a major interest and continuing debate in the scientific community on the definition of CCSVI as a pathological entity, the correlation between CCSVI and MS, the proposed aetiopathogenetic mechanisms, and as a consequence, on the utility of its treatment.1 The MS-CCSVI hypothesis has provoked both enthusiasm and scepticism among people with MS and the specialists who treat them. The ‘liberation procedure’ has attracted considerable attention among people with MS, the media and in discussion groups on the Internet.1 ,9 ,10 MS patients have been frequently exposed to media hyperbole with exaggerated claims that have led to unrealistic expectations. As a consequence, CCSVI treatment has been offered to MS patients in many countries, mostly not at conventional MS centres or within research trials, in spite of the lack of confirmation of early evidence from Zamboni's pivotal trials. Recognising the significant interest in this topic to people with MS and notwithstanding the lack of consensus in the scientific community about the relationship between MS and CCSVI, a systematic review was vital to examine the potential benefits and risks of this intervention.1
We performed a systematic review which attempted to identify possible methodological issues in existing and proposed clinical trials and which might ultimately enable a robust evaluation of the effect of treating CCSVI in people with MS.1 Its ultimate aim was to ensure that the expectations of people with MS and the claims of efficacy made by clinicians were realistic and stayed within the boundaries of the evidence-based medicine paradigm. This report is a summary of this Cochrane systematic review.
Methods
We conducted a systematic review of randomised controlled trials (RCTs) assessing the effects of percutaneous transluminal angioplasty in adults with MS who have been diagnosed to have CCSVI.1
We searched for RCTs in The Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register, CENTRAL, in The Cochrane Library 2012, Issue 5, MEDLINE (from 1946 until June 2012), EMBASE (from 1974 until June 2012) and reference lists of articles. We also searched several online trials registries for ongoing trials and tried to contact trial investigators to request missing data or to clarify study details. Three review authors independently assessed the titles and abstracts for eligible RCTs.
Our primary outcomes were (a) the number of participants with at least one adverse event at 12 months, 24 months and at the end of the study; (b) the number of participants who experienced progression on the Expanded Disability Status Scale (EDSS).11 Definitions of progression reported in the original studies were accepted. However, we sought to evaluate these outcomes using the definition of progression as a persistent worsening of at least 1 point in EDSS recorded outside a relapse and confirmed by a follow-up assessment at 6 months; a persistent half-point increase was to be adopted if baseline EDSS was 5.5 or worse; (c) patient reported outcomes (PROs) could include any of the following, if reported, such as change in quality of life (QoL) assessed using any validated disease-specific (eg, MSQOL-54,12 MSQLI,13 MusiQoL14) or generic instrument (eg, short form 36 (SF-36)15); mean change in well-being as measured with a visual analogue scale; mean change in Modified Fatigue Impact Scale (MFIS)16 or other recognised and validated MS-fatigue scale; or any other PRO.
Secondary outcomes were (i) restenosis of target vessel primary and secondary patency; (ii) mean change in cognitive functions assessment through a validated battery of tests for MS (ie, Brief Repeatable Battery of Neuropsychological Tests (BRBNT)17); (iii) in the relapsing remitting MS subgroup only, the number of participants experiencing at least one relapse. We accepted definitions of relapse as reported in the original studies.
No studies matched our inclusion criteria. For future updates of our Cochrane review, details of eligible trials will be extracted and summarised using structured data extraction forms by two review authors. They will, as well, independently assess the risk of bias using The Cochrane Collaboration tool for assessing risk of bias as described in Chapter 8, Section 8.5, in the Cochrane Handbook for Systematic Reviews of Interventions.18
Statistical methods
No statistical analyses were carried out as no study met our inclusion criteria. Although no data were included, for future updates the following methods and statistical analysis will be used: Binary outcomes will be analysed calculating risk ratios and we will present continuous outcomes where possible on the original scale as reported in each individual study. If similar outcomes are reported using different scales, these will be standardised by dividing the estimated coefficient by its SD, thereby allowing comparisons to be made between scales. All outcomes data will be reported with their associated 95% CIs and will be analysed in Review Manager (Revman).19
We will assess clinical heterogeneity by examining the characteristics of the studies, the similarity between the types of participants, the interventions and the outcomes as specified in the criteria for included studies. Statistical heterogeneity will be assessed using a χ2 test and the I2 statistic. We will report heterogeneity as important if it was at least moderate to substantial with an I2 statistic >50%. The outcomes sought in this review will require studies of long duration with repeated observations on participants for several time periods of follow-up, and are therefore likely to present unit of analysis issues. With respect to their analysis and reporting, we will follow the recommendations provided in Section 9.3.4 of the Cochrane Handbook for Systematic Reviews of Interventions.20
Results
Our searches retrieved 159 references, six of which were related to ongoing trials. After examination of the titles and abstracts, four duplicate references were discarded and a further 148 references were also subsequently excluded from the review. A full-text copy of the one remaining study21 was obtained, assessed independently for eligibility by three authors and only excluded after consensus was reached (see figure 1). The study, although stated to be a RCT, utilised a sequence generation which was not truly random but based on the availability of passports by those participants recruited in Buffalo, and in Italy the participants were randomly assigned in alphabetical order. It was also not designed to compare percutaneous transluminal angioplasty versus no treatment, sham treatment or other MS treatment. No RCTs were found that fulfilled our inclusion criteria.
Flow diagram illustrating study selection.
Discussion
Unfortunately, at present no RCTs could be included in our Cochrane review (see table 1).
Summary of findings
Several ongoing studies were identified that may eventually help to fill in some of the gaps in the evidence for the efficacy and safety of percutaneous transluminal angioplasty for CCSVI.1 In view of the lack of evidence, there is a pressing need for well-designed RCTs which can help inform and guide clinical practice. As MS is a chronic and distressing disease accompanied by increasing disability and with a huge impact on QoL, the importance of assessing the efficacy and safety of this intervention should not be underestimated.
We made every attempt to limit bias in the review process by ensuring a comprehensive search for potentially eligible studies. Our independent assessments of eligibility of studies for inclusion in this review minimised the potential for additional bias.
Taking into account the lack of studies included in this review, we are in broad agreement with the relevant National Institute for Health and Care Excellence guidance, that ‘current evidence on the efficacy of percutaneous venoplasty for CCSVI for MS is inadequate in quality and quantity’.22
Concurrent with our implications for research, the guidance also recommends further RCTs but that these studies should ‘clearly define selection criteria and patient characteristics’ as well as ‘technical success which may include measurement of pressure gradients across treated vein segments before and after venoplasty. Outcomes should include clinical and quality of life measures’.1 ,22
The findings of another systematic review and meta-analysis reported a positive association between CCSVI and MS, but also concluded that poor reporting of the success of blinding and marked heterogeneity among the included studies precluded any definitive conclusions.1 ,23 Although this meta-analysis did not specifically address the effect of percutaneous transluminal angioplasty on CCSVI, it does nevertheless help improve understanding of a possible association if not causal relationship between CCSVI and MS.
The objectives of a further review were to ‘critically analyse the scientific basis of CCSVI and the current literature on the relationship between CCSVI and MS, as well as the methodology of the ultrasound that has been claimed to provide evidence of impaired cerebral venous drainage’.24 This was a classical literature review which, although it did not provide any evidence that a systematic and complete search of the relevant research had been conducted, did nevertheless provide a valuable and comprehensive background to the theory surrounding CCSVI, the related diagnostic criteria and the proposed therapy. However, in concluding that ‘no piece of the CCSVI puzzle has a solid supportive scientific evidence’, the authors failed to provide any indication of how studies, on which their conclusions appear to have been based, were selected, critically evaluated and could be designated as reliable sources of evidence either for, or in their opinion against, the efficacy of the ‘liberation’ procedure or indeed were capable of rejecting the CCSVI hypothesis. The conclusions of their literature review on the CCSVI hypothesis would also appear to be at some divergence with the systematic review which reported evidence of a ‘strong association’ between CCSVI and MS.23 Furthermore, their caution against any further ‘controlled liberation trials until solid scientific evidence of a causal relationship between CCSVI and MS has been clearly demonstrated’ would appear to countermand the recommendations of the systematic review as indeed the recommendations of our review.1
Following the publication of this series of reviews, a more recent observational study failed to illustrate a correlation between CCSVI and MS, which would appear to question the necessity of further RCTs.25 ,26
However, and while making no specific recommendations, if any future RCTs are undertaken these must be well-designed, well-conducted and adequately delivered with subsequent reporting, including high-quality descriptions of all aspects of methodology. Reporting should conform to the Consolidated Standards of Reporting Trials (CONSORT) statement which will enable appraisal and interpretation of results, and accurate judgement has to be made about the risk of bias and the overall quality of the evidence.27 For further research recommendations based on the EPICOT (evidence, population, intervention, comparison, outcomes and time) format, see table 2.28
Research recommendations based on a gap in the evidence of the effects of percutaneous transluminal angioplasty for treatment of chronic cerebrospinal venous insufficiency in multiple sclerosis patients
Further small and methodologically unsound studies should be discouraged as they can be considered unethical and only add further to the existing confusion about the pros and cons of CCSVI and the effects of ‘liberation therapy’ in MS.
Our review considered the necessity of RCTs evaluating the effects of this intervention, such that they might ultimately provide reliable evidence to help inform clinical decision-making.1
References
Footnotes
Footnote: This paper is based on a Cochrane review published in Issue 12, December 2012, of The Cochrane Library 2012 (see http://www.CochraneLibrary.net for further information). 1
Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms. The Cochrane Library should be consulted for the most recent version of this review.
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Contributors The study protocol was designed by EvZ, ZF, EP, VJ and ER. Study selection was performed by EvZ, ZF and VJ. All authors contributed to the drafting of the article and revising it critically for important intellectual content.
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Competing interests In the last 3 years, EP has received honoraria and travel grants for scientific and educational activities supported from Sanofi Aventis, Novartis, Biogen Idec, Merck Serono and Teva. EP has received funds from a non-profit association, the ‘Associazione Marchigiana sclerosi multipla e altre malattie neurologiche’; in the last 3 years, this association has received donations from Biogen Dompé, Merck-Serono and Teva. The other review authors have no financial conflicts of interest and they do not have any associations with any parties who may have vested interests in the results of this review. One of the authors (ER) has undergone the procedure under consideration in this review.
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Provenance and peer review Not commissioned; externally peer reviewed.
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