Multiple sclerosis and chronic cerebrospinal venous insufficiency: a critical review

Abstract

Chronic cerebrospinal venous insufficiency (CCSVI) was recently proposed as a contributing factor in the pathology of multiple sclerosis. This concept has gained remarkable attention, partly because endovascular neurointervention has been suggested as a treatment strategy. This review summarizes available evidence and provides a critical analysis of the published data. Currently, there is inconclusive evidence to support CCSVI as an etiological factor in patients with multiple sclerosis. Endovascular procedures should not be undertaken outside of controlled clinical trials. Keywords: chronic cerebrospinal venous insufficiency, multiple sclerosisThe origin of the hypothesis Chronic cerebrospinal venous insufficiency (CCSVI) as a potential etiopathogenic entity in multiple sclerosis (MS) has recently been suggested and gained significant attention.Over the past few years, Zamboni and colleagues were the first to propose and explore this novel and controversial idea [Zamboni et al. 2009b,c,d]. The theory of CCSVI suggests that MS may be causally related to an inflammatory or immune reaction to iron that accumulates in the central nervous system (CNS) secondary to insufficiency of cervical and cerebral venous blood vessels [Zamboni, 2006]. The same investigators detected venous insufficiency by ultrasound and transcranial Doppler. These patterns of venous insufficiency in cranial and cervical blood vessels were seen in patients with MS and absent in control cohorts.In 2010, Zivadinov and colleagues studied 16 patients with relapsing remitting MS (RRMS) and eight matched, healthy controls by 3 T scanner using susceptibility-weighted imaging sequence [Zivadinov et al. 2010]. According to the authors, all 16 patients with MS fulfilled the diagnosis of CCSVI compared with none of the healthy controls. In patients with MS higher iron concentrations were found in the thalamus, globus pallidus, and hippocampus. Iron concentration measures were related to longer disease duration and increased disability, and increased MRI lesion burden and brain atrophy. Similar results were reported by Haacke and colleagues in the same year . Subsequent studiesAs mentioned above, the proposal of CCSVI as an etiological factor or disease modifier in MS is controversial. Subsequent to the initial observations, other investigators conducted their own studies to determine the existence and prevalence of CCSVI in patients with MS and control cohorts.One positive study by Al-Omari and Rousan showed that in 25 patients with MS there was evidence of CCSVI in 84%, whereas none of the 25 controls displayed evidence of cerebral or cervical venous abnormalities [Al-Omari and Rousan, 2010]. There was no blinding of the investigators in this study.All other published studies, however, could not reproduce the findings published by Zamboni and coworkers [Doepp et al. 2010;Krogias et al. 2010;Sundstrom et al. 2010;Wattjes et al. 2010;Yamout et al. 2010]. Doepp and colleagues found no evidence of CCSVI in patients with MS using Doppler criteria [...

No Evidence for Impairment of Venous Hemodynamics in Children or Young Adults with Pediatric-Onset Multiple Sclerosis

“…hronic cerebrospinal venous insufficiency (CCSVI), a sonography-defined pattern of cerebral venous drainage, has been reported in a variable proportion of adults with multiple sclerosis (reviewed in Awad et al 1 and Laupacis et al 2 ). A combination of findings of altered venous flow, venous stenoses with presumed secondary venous drainage patterns (termed "excision circles"), or reflux in extracranial draining veins led to the term CCSVI.…”

Iron in the brain: Heavy metal mismanagement

“…There has also been a problem with consistency. Studies conducted afterwards failed to reproduce the results found by Zamboni [6]. A potential explanation of this lack of consistency could be due to inadequate methods.…”

“…Zamboni's publications, detailing the findings of vascular anomalies in MS patients and purporting CCSVI as a cause of MS, however alluring, were treated with skepticism in the scientific community due to the lack of a double-blind randomized control normally required for clinical trials. In surveys, such as the one conducted by Zamboni, the Hill Criteria can be used to infer causality [6]. Criteria on the Hill checklist include temporality and consistency.…”

“…Criteria on the Hill checklist include temporality and consistency. As Awad et al deftly review, Zamboni's hypothesis as CCSVI being a cause of MS fails a number of the criteria [6]. In the case of temporality, it requires that if CCSVI is indeed a cause of MS, then it should always be present before the development of the disease [6].…”

“…As Awad et al deftly review, Zamboni's hypothesis as CCSVI being a cause of MS fails a number of the criteria [6]. In the case of temporality, it requires that if CCSVI is indeed a cause of MS, then it should always be present before the development of the disease [6]. It was observed that CCSVI is rare at clinical onset of MS, but its occurrence increases as the disease progresses [5,7].…”