Description of the condition

Multiple sclerosis (MS) is a leading cause of neurological disability in young adults. The disease is characterised by focal white matter lesions, characterised by inflammation and demyelination that are associated with axonal damage (Kuhlmann 2017). Four clinical forms of MS can be distinguished: relapsing‐remitting (RRMS); secondary progressive (SPMS); primary progressive (PPMS); and progressive relapsing (PRMS) (Lublin 1996). RRMS and SPMS are the clinical forms of MS that account for approximately 80% to 85% of sufferers, and SPMS evolves from the RRMS form. MS is heterogeneous, both histopathologically and clinically (Lucchinetti 2000), and the natural history can be difficult to predict. In most cases it begins as RRMS with episodic, largely reversible neurological dysfunction. Natural history studies, which followed cohorts of MS patients not treated with any disease‐modifying drugs, have shown that, after a period of approximately 10 years, almost 50% of people with MS gradually develop permanent disability which may also include acute relapses. After a median of 15 to 28 years from disease onset, a disability milestone equivalent to the use of an assistive walking device is reached (Weinshenker 1989). Clinical features include all of the symptoms caused by the impairment of the central nervous system (e.g. loss of vision, double vision, muscle weakness, sensory disturbances, bladder dysfunction, impotence, constipation, ataxia, vertigo, tremor, spasticity, pain, cognitive impairment and dysarthria). Fatigue, anxiety and depression are also frequent occurrences. Magnetic resonance imaging (MRI) can support the clinical diagnosis, and it is integrated with clinical and other para‐clinical diagnostic methods (e.g. examining cerebrospinal fluid and evoked potentials) to facilitate the diagnosis of MS (Thompson 2018). MRI parameters are also used as surrogate markers of disease activity and progression. The disease has an adverse impact on the health‐related quality of life (HRQoL) of people with MS and their families and may also pose a financial burden, even when the disease is not physically disabling.

The age of onset of MS is usually between 20 and 40 years. Incidence is low in childhood and is rarer at the age of 50 years or older. Female‐to‐male ratios vary between 1.5:1 and 2.5:1 in most populations (Sellner 2011). The incidence and prevalence of MS varies geographically (Simpson 2011): high‐frequency areas (prevalence in excess of 60 per 100,000 people) include all of Europe in addition to southern Canada, northern USA, New Zealand, and south‐east Australia. In many of these areas the prevalence is more than 100 per 100,000 people. This geographic variance may be explained in part by racial differences: white populations, especially those from northern Europe, appear to be most susceptible.

The most widely accepted hypothesis on the pathogenesis of MS is that it is an immune‐mediated disease characterised by infiltration of blood‐derived monocytes, microglia, and lymphocytes leading to damage of myelin and axons. Although the aetiology is largely indeterminate, a large proportion of the scientific community considers that MS develops in genetically predisposed subjects and that environmental factors play a central role in its pathogenesis, based on immune‐mediated mechanisms. It is thought that aberrant immune responses to self or foreign antigens cause and perpetuate inflammation (Wu 2011). The inflammation leads to demyelination and subsequent axonal damage. The role of inflammation is considered to be complex, however, and may include both beneficial and detrimental effects (Martino 2002).

The hypothesis suggesting that chronic venous congestion may be a factor in the pathogenesis of MS became a focus in multiple sclerosis research when public participation emphasised interest in the procedure to correct it. (Zamboni 2006;Zamboni 2011) The predominantly venotopic location of MS lesions in the CNS is postulated to be a consequence of local erythrocyte extravasation owing to elevated transmural venous pressure, followed by erythrocyte degradation and iron‐driven phagocytosis and subsequent lymphocytic infiltration (Singh 2009). This condition has been named 'chronic cerebrospinal venous insufficiency' (CCSVI) and is characterised by stenoses of the internal jugular veins or azygos veins, or both, which restrict the normal blood flow from the brain, along with the appearance of small collateral veins that may have developed to reduce the impact of the stenoses. In his initial study, Zamboni found CCSVI in all subjects in the study group that were diagnosed with MS, and none in the healthy controls (Zamboni 2011). CCSVI, as defined by Zamboni and colleagues, is diagnosed with combined extracranial and transcranial echo colour Doppler (ECD) radiography when two or more of five established parameters are present (Zamboni 2009b).

There has been some criticism of several of the limitations in the ultrasound‐based investigation used to measure the rather complex and dynamic (i.e. postural dependent) cerebrospinal venous outflow. These include the wide individual variability, operator dependence and intra‐ and inter‐rater bias, the difficulty of standardising values for diagnostic criteria and the necessity of venography as a gold standard (Doepp 2010; Hojnacki 2010; Zivadinov 2011b). A high degree of correlation between CCSVI and MS was found in a number of studies (Al‐Omari 2010; Bavera 2011; Hojnacki 2010; Simka 2010); but this has been contested by other studies (Baracchini 2011; Centonze 2011; Comi 2013; Doepp 2010; Krogias 2010; Marder 2011; Sundström 2010; Tsivgoulis 2011; Wattjes 2011; Yamout 2010). Several reviews have reported that the incidence of CCSVI varies in people with MS, ranging from 0% to 100% and from 0% to 23% in healthy controls (Ghezzi 2011; Zivadinov 2011b). One study of 499 people with MS found an increased prevalence of CCSVI but with a modest sensitivity and specificity, and suggestive of a less likely primary causative role for CCSVI in the development of MS (Zivadinov 2011a). A further study found no relationship between CCSVI and HLA DRB1*1501, a genetic variation that has been consistently linked to MS (Weinstock‐Guttman 2011). Attempts have been made to correlate CCSVI with specific symptoms of MS: in particular, an association with fatigue (which often severely affects people with MS) (Malagoni 2010).

The hypothesised association between CCSVI and MS implicates CCSVI as a treatable cause of MS and hence it has formed the basis for the so‐called 'liberation procedure' which is based on the technique of venous balloon angioplasty (Zamboni 2009a; Zamboni 2012). Venous stent placement has also been used to treat CCSVI in people with MS but this treatment has been associated with a small number of serious adverse events (Anon 2010; Burton 2011). Much of the research on this topic has generated 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 etiopathogenetic mechanisms; and, as a consequence, on the utility of its treatment (Bagert 2011; D'haeseleer 2011; Dorne 2010; Ghezzi 2011; Khan 2010; Lazzaro 2011; Reekers 2011; van Rensburg 2010; Waschbisch 2011; Zivadinov 2011b).

The narrative of scientific research underwent a revolutionary change as the participation of the MS community and social media became the mobilizing factors for conduct of research in this field to help the scientific community to provide evidence for or against this 'liberation procedure' (Benjaminy 2018; Driedger 2017).

Description of the intervention

Percutaneous transluminal angioplasty (PTA) involves the insertion of a small catheter with a balloon attachment via percutaneous access to the left femoral vein. Initially a venogram is performed so that images can be obtained to identify the narrowed sections of the veins. The catheter is then inserted and advanced into the azygos and internal jugular veins. The balloon is inflated at the narrowed section of the vein, thereby increasing its diameter and improving the flow of blood. The procedure is performed with venographic control. These procedures are performed generally as day surgery — overnight hospital stay is not required. Patients receive prophylactic low‐molecular‐weight heparin during subsequent weeks, to lower the thrombotic risk.

How the intervention might work

Were the CCSVI hypothesis tenable, repairing venous stenosis and re‐establishing correct venous flow from the brain toward the heart could have therapeutic effects.

Why it is important to do this review

The original review published in 2012 did not find studies meeting inclusion criteria (van Zuuren 2012). There have been several studies done over the last six years which have looked at the benefit and safety of PTA intervention in people with MS. CCSVI is characterized by restricted venous outflow from the brain and spinal cord. Whether this condition is associated with MS and whether venous PTA is beneficial in persons with MS and CCSVI is controversial. We felt it was important to update the 2012 review to provide up‐to‐date evidence on the effects of PTA in in people with MS.

The MS‐CCSVI hypothesis has generated both enthusiasm and skepticism among people with MS and the specialists who treat them (Paul 2014). The 'liberation procedure' has attracted considerable attention among people with MS as well as the media and on the Internet (Driedger 2017; Piga 2014). Consumers 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 participants in many countries, mostly not at conventional MS centres, in spite of the lack of confirmation of early results from Zamboni's pivotal trials (Zamboni 2009a; Zamboni 2012). This review update attempts to highlight possible methodological issues in available clinical trials in order to provide an evidence‐based review of the effect of treating CCSVI in people with MS. Our aim in this update is to contribute so that the expectations of people with MS stay within the boundaries of the evidence‐based medicine paradigm.