Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy Multiple sclerosis is a systemic venous vasculopathy: A single unifying mechanism Anish Kapadia ⁎ , Adam A. Dmytriw Sunnybrook Health Sciences Centre, Department of Medical Imaging, University of Toronto, Toronto, ON, Canada ABSTRACT Multiple sclerosis (MS) is a potentially debilitating disease affecting the central nervous system (CNS) clinically characterized by progressive neurological dete- rioration. It is the most common condition under the umbrella of demyelinating disease, thought to occur as a result of a primary autoimmune insult. Various genetic and environmental risk factors have been implicated as potential triggers and/or predisposing factors; however, the exact mechanism of disease remains elusive. Diagnosis and management are based on clinical presentation, with adjunct imaging and biochemical assessment. Since the 19th century anatomical distribution of lesions in MS have been observed to demonstrate a characteristic periventricular, perivenular distribution; spinal cord and cortical lesions also demonstrate this perivenous preponderance. Venous abnormalities have long been observed on pathology characterized by irregular narrowing and dilatation with associated venous wall and perivenous infiltrates. Active CNS lesions are characterized by perivenular inflammatory infiltrates. There is accompanying global dysfunction of the blood- brain barrier, even within normal appearing tissue, with low levels of inflammatory change and tissue injury seen at pathology. Although several CNS antigens have been identified as potential candidates, including myelin related antigens, a specific pathogenic antigen remains elusive. Evaluation of the cerebrospinal fluid reveals characteristic oligoclonal bands, indicating a broad inflammatory response against a variety of CNS antigens. Antibodies have been identified against endothelial elements in sera of patients with MS, their role is not yet clearly elucidated. Emerging evidence suggests there may be a more systemic inflammatory process, heralded by a systemic preclinical prodrome. In light of such seemingly-discrepant clinical, anatomic, immunologic and pathologic findings we propose a unifying theory; specifically we propose that MS is a primary autoimmune vasculopathy, with a predilection of CNS venous structures. Characteristic CNS lesions are a secondary manifestation resulting from an inflammatory response to the uncovering of usually privileged CNS antigens. Introduction Multiple sclerosis (MS) is understood to be an autoimmune, in- flammatory disease of the central nervous system, affecting the brain and spine. It is a potentially debilitating disease that is initially char- acterized by relapsing-remitting course, with accumulation of deficits over time results in progressive neurological deterioration in the long term [1]. Regarding its natural history, the course is variable and highly unpredictable, with diagnosis made clinically with supporting evidence from imaging and laboratory studies [2]. The disease arises as a result of genetic susceptibility and potential environmental triggers resulting in repeated episodes of neurological damage. This neurological damage is characterized by demyelinating lesions primarily of white matter. On imaging, this corresponds to a presentation of predominantly periven- tricular brain and peripheral spinal cord lesions. Although involvement of the grey matter was demonstrated in the early 20th Century, only recently is it being recognized as an important feature of the disease process. In addition to the widely accepted theory of autoimmune de- myelination, chronic cerebrospinal venous insufficiency (CCSVI) has been proposed as a possible mechanism which was received with re- sounding scepticism. Multiple environmental factors have been proposed as contributory to the development of MS including EBV ex- posure, infection, lack of sunlight exposure, smoking and vitamin D deficiency. More recently, obesity and stress have also been linked with increased risk of developing MS [3,4]. However, the exact mechanism of the disease remains elusive. Here we attempt to synthesize the see- mingly-discrepant anatomic, genetic, immunologic and pathologic findings of the disease in order to put forward a unifying hypothesis. Specifically, we propose that multiple sclerosis is in fact an autoimmune vasculopathy which affects the venous system resulting in secondary central nervous system (CNS) lesions. Anatomy of MS lesions Early descriptions of MS note perivascular distribution of lesions. This was first identified by Swiss pathologist Georg Eduard Rindfleisch [5], even before it was proposed as a distinct entity by Jean-Martin Charcot [6]. Subsequently James Dawson expanded on this by de- scribing the “growth” of periventricular cone-like lesion progression towards the cortex [7]. Modern imaging with MRI corroborates this with observation of predominantly periventricular abnormalities pro- gressing over time with coalescence and progressive involvement https://doi.org/10.1016/j.mehy.2020.109645 Received 2 February 2020; Received in revised form 22 February 2020; Accepted 25 February 2020 ⁎ Corresponding author at: Department of Medical Imaging, University of Toronto, 263 McCaul St, Toronto M5T 1W7, ON, Canada. E-mail address: anish.kapadia@mail.utoronto.ca (A. Kapadia). Medical Hypotheses 140 (2020) 109645 0306-9877/ © 2020 Elsevier Ltd. All rights reserved. T