Multiple sclerosis is a systemic venous vasculopathy: A single unifying mechanism

Multiple sclerosis (MS) is a potentially debilitating disease affecting the central nervous system (CNS) clinically characterized by progressive neurological deterioration. 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.