Vascular pathology of multiple sclerosis

Multiple sclerosis (MS) is perceived to be an immune-mediated disease of the human central nervous system, characterized by a relapsing and progressive clinical course, which eventually leads to irreversible disability in many patients.1 The cause of and cure for MS remain elusive at this time. While the pathogenesis of MS includes a number of well-recognized mechanisms such as disruption of the blood–brain barrier (BBB), inflammatory demyelination, loss of oligodendrocytes and, ultimately, neuronal and axonal loss, there is no unifying hypothesis to lump all these components under one umbrella.2 Interaction among environmental factors and multiple genes can potentially cause the heterogeneity found in histopathological and clinical studies. The presences of HLA-DR*1501, vitamin D deficiency, immune responses to Epstein–Barr virus, and cigarette smoking are the most compelling risk factors associated with an increased risk of developing MS.2^–4 While the hypotheses of ‘MS as an immune-mediated disease’ or ‘MS as a viral disease’ or ‘MS as a genetic disease’ may explain certain neurobiological aspects of MS pathogenesis, there are other features such as endothelial activation and disintegration of the BBB which can be easily explained based solely on these concepts.5 In this special issue, Minagar et al.6 discuss recent findings and new advances in our knowledge regarding leukocyte migration through the endothelial frontier of the BBB and how this can be exploited to treat MS patients.

For more than a century, many scientists have paid attention to the concept of ‘a vascular component for MS’.7^–10 One of the main questions is whether MS disease originates from vascular abnormalities and, if so, how these abnormalities impact MS patients clinically.

The purpose of this issue of Neurological Research is to synthesize current concepts and most recent findings concerning the evaluation, pathogenesis, and clinical relevance of the vascular pathology of MS. The most convincing evidence towards a ‘vascular origin’ for MS comes from neuropathological observations showing that MS plaques are exclusively perivenular and dimensions of the veins determine the shape, course, and dimension of the lesions.7,9 In addition, recent imaging studies using high- and ultra-high-field magnetic resonance imaging (MRI) extend these findings by showing that a majority of MS lesions are associated with centrally coursing veins.11^–14 Whether occlusion of veins in the MS lesions may be related to blockage or reduced flow in the areas preceding visible lesions is unknown at this time. In this special issue, the article by Beggs et al.15 investigated the sensitivity and specificity of decreased venous vasculature visibility on susceptibility-weighted imaging venography in MS patients versus controls, and found that altered venous vasculature visibility indices on susceptibility-weighted imaging venography showed high sensitivity and specificity for MS. Future ultra-high-field MRI studies should explore this topic, at early disease stages and against patients with other neurological diseases.

Recently, the ‘venous obstruction’ hypothesis returned to the forefront of MS research with a report that chronic cerebrospinal venous insufficiency (CCSVI) is found in 100% of MS patients and not in non-MS controls.16 CCSVI was described as a vascular condition characterized by anomalies of the main extra-cranial cerebrospinal venous routes that interfere with normal blood outflow.16^–18 These anomalies were described in the internal jugular veins, the vertebral veins, and the azygos vein. It was hypothesized that these venous anomalies may cause alterations to blood flow that eventually result in iron deposition, degeneration of neurons, and the characteristic brain injury patterns found in MS patients.19,20 Nevertheless, an increasing number of recent reports suggest that CCSVI is not unique to MS, but can be detected in a substantial number of patients with other neurological diseases as well as in healthy subjects.21 Some recent studies have questioned the existence of CCSVI in patients with MS.21 In the current issue, Morovic and Zamboni22 discuss in a balanced way the arguments both for and against CCSVI as a medical entity, and its association with MS. The article by Utriainen et al.23 reviews the current state-of-the-art methods using MRI, as applied to imaging MS patients and CCSVI, including the role of high iron content that may indirectly indicate progression of existing vascular pathology. In addition, the article by Feng et al.24 discusses the role of quantitative flow imaging and its potential in assessing possible biomarkers for abnormal flow. Given the controversy CCSVI caused and the attention it received in the scientific community,25 and taking into consideration that many radiographic descriptions of anatomical structures related to the CCSVI hypothesis are yielding conflicting results, it is essential to establish CCSVI autopsy correlates through pathological and histological studies. The article by Diaconu et al.26 is the first to establish a detailed technical procedure for studying the anatomical correlates of CCSVI in cadavers of MS patients and control subjects, and to compare their findings of the normal anatomic venous structures, with reference to previous descriptions from the literature.

Mounting evidence suggests that MS patients are more susceptible to cardiovascular risk factors than healthy controls.27 In this special issue, a number of articles discuss the association of MS with an increased risk of cardiovascular diseases. Christiansen28 reviews eight relevant studies describing the occurrence or risk of one or more vascular diseases. He concludes that MS is associated with an increased risk for vascular disease within the first 5 years after MS onset compared with the general population. The risk declines thereafter, but remains elevated for stroke and venous thromboembolism. Karmon et al.29 review vascular risk factors with specific emphasis on lipid abnormalities reported to be associated with MS. They describe recent emerging evidence that there is an association between lipoproteins and cholesterol metabolism and MS disease progression. Further evidence of an association between ischemic types of events and the MS disease progression is provided in an article by Zivadinov et al.30 who prospectively investigated over 3 years the associations of baseline serum anti-phospholipid antibody (APLA) status on the evolution of clinical and MRI measures in an MS patient cohort treated with interferon-beta. The study suggested that APLA-positive MS patients treated with interferon-beta-1a develop more severe MRI and clinical deterioration, indicating that APLA-related macro- and microvascular damage may be an important component of the MS disease process as it advances.

While it has been convincingly shown that MS patients are more susceptible to arterial vascular risk factors than healthy controls, the possible ‘venous comorbidity’ has not yet been completely elucidated. This issue provides one of the first pieces of evidence that arterial and venous vascular risk factors may be similar. The article by Dolic et al.31 investigated the possible association of risk/protective factors with the presence of extra-cranial venous abnormalities in a large cohort of volunteers without known central nervous system pathology. The study found that there is a close association between extra-cranial, venous system pathology, and the presence of heart disease, overweight, and smoking, suggesting that the simultaneous occurrence of arterial and venous abnormalities together with the advance of MS disease may share the same origin.

The present issue of Neurological Research presents a compilation of different manuscripts on the vascular pathology of MS and we have attempted to present a fair and balanced discussion regarding various issues under this topic. We very much appreciate all the contributors to this issue who provided us with their exceptional articles. We hope that the contents of this issue will entice our readers to continue their research on this subject and eventually discover a cure for this incurable disease. We also would like to express our appreciation to Dr Ben Roitberg, Editor-in-Chief of Neurological Research, and to Ms Maggie Ford, as well as to other hardworking personnel of Maney Publishing for their invaluable assistance in putting this special issue together.

The authors wish to thank Eve Salczynski for technical assistance in the preparation of this manuscript.