What is Multiple Sclerosis (MS)
Multiple sclerosis (MS) is the most common non-traumatic disabling disease that typically affects young adults. It is a chronic, autoimmune (disease caused by antibodies or lymphocytes produced against substances naturally present in the body), inflammatory, neurodegenerative (causing destruction/degeneration of the nerves) disease of the central nervous system (CNS). MS presents with progressive demyelination (damage to the protective covering, called the myelin sheath, present around the nerve fibers; a nerve fiber and its myelin sheath are comparable to an electric wire and its outer protective covering, respectively) and subsequent axonal (the long threadlike part of a nerve cell along which impulses are conducted from the cell body to other cells) degeneration. This disease has a huge impact on the quality of life of the affected individuals, both functionally and financially.
The findings of the 3rd edition of the Atlas of MS (2020) that were derived from pooled incidence rates across 75 reporting countries, are as follows. The estimated number of people with MS worldwide increased from 2.3 million in 2013 to 2.8 million in 2020. The pooled incidence rate across 75 reporting countries was 2.1 per 100,000 persons/year. Recognition of pediatric-onset MS has increased substantially with ≥ 30,000 cases in individuals under the age of 18. Globally MS is twice more prevalent in females than males.
Triggers of MS development
Vitamin D deficiency, diet, obesity in early life, and cigarette smoking have been reported to trigger the development of MS; low Vitamin D levels and cigarette smoking have a strong association with MS. MS may also be triggered by certain infections, such as, Epstein-Barr virus (EBV) infection. Carriers of the HLA DRB1*15 allele (an allele constitutes one of two or more versions of a gene, placed on the same chromosome) are 3 times more susceptible to MS than non-carriers. Additionally, IL2RA, IL7RA, CD58, TYK2, STAT3, and TNFRSF1A have been linked with MS. Although a few studies suggest that vaccination against yellow fever might increase the relapse rate of MS, the existing evidence is non-confirmatory of this association.
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The pathophysiology of MS
The pathophysiology (the course of development of a disease) of MS remains poorly understood although several explanatory mechanisms have been proposed. The most popular theory, proposed by Osterman et al. in 1975, states that partially demyelinated axons favor the ectopic generation of spontaneous nerve impulses which transversely spread to other axons within the nerve fiber tracts, ultimately manifesting as symptoms or attacks. Alternatively, an inflammatory component in MS has been proposed based on the favorable response to steroids in many reported cases. Furthermore, a third mechanism – ion channel dysfunction in partially demyelinated axons, has been proposed, which is supported by the proven high efficiency of acetazolamide and anti-epileptics (anti-seizure medicines) in reducing the frequency of MS attacks. However, these theories remain purely speculative, and a combination of these factors cannot be excluded either. Additionally, the possibility of other unknown phenomena leading to the development of MS, exists. Essentially, MS is a chronic neurodegenerative disease that is autoimmune in nature and targets the CNS. It is mediated by autoreactive lymphocytes that cross the blood-brain-barrier (BBB) and enter the CNS where they cause nerve demyelination, axonal damage, and subsequent neurological dysfunction due to the formation of multiple plaques or gliotic scarring (areas of the nerve fiber where the myelin is stripped-off) in the gray and white matter of the brain and the spinal cord; these processes comprise the hallmarks of the pathophysiology in MS. The plaques in MS are found mainly in the white matter around the brain-ventricles, optic nerve and its tract, corpus callosum, cerebellar peduncles, long tracts and the subpial region of the spinal cord and the brainstem.
The spectrum of MS
The affected individuals, in most cases, present with an initial relapsing-remitting disease course that is followed by a progressive phase which lasts for several years. In pregnant women with MS, a transient improvement in MS relapse rate is seen in the 3rd trimester, which is followed by increased MS relapse rate, at around 3 months after delivery; studies have attributed this fluctuation to the natural immunomodulation brought about by sex hormones and the placental hormones in pregnant women. MS is divided into 4 subtypes based on the clinical disease pattern which appear to have dissimilar underlying pathophysiology – RRMS (Relapsing-Remitting MS), SPMS (Secondary Progressive MS), PPMS (Primary Progressive MS), and PRMS (Progressive Relapsing MS). This may be suggestive of MS being a heterogenous group of related diseases. MS is a spectrum of diseases ranging from less aggressive, treatable forms to highly aggressive fatal forms.
The diagnosis of MS is based on the presence of CNS lesions that are disseminated in time and space (i.e., occur in different regions of the CNS, at least 3 months apart), with no better explanation for the disease process. Clinical presentation remains the gold standard for diagnosing MS, which is supported by the findings of investigations comprising neuroimaging (mainly magnetic resonance imaging – MRI), sensory evoked potential testing, cerebrospinal fluid (CSF - clear fluid that surrounds the brain and spinal cord) analysis, and serologic tests (examination of blood serum). The symptoms of MS depend primarily on the anatomic location of the plaques along the neural axis and include paraparesis (partial inability to move one’s legs) or paraplegia (paralysis of the legs and/or lower body), tremor, ataxia, aphasia, dysarthria (difficult/unclear speech), dysphagia (difficulty/discomfort in swallowing, as a symptom of disease), bladder and bowel problems, visual defects, and cognitive decline. Unfortunately, there is no cure for MS. The available therapies aim at improving the health-related quality of life (HRQoL) in affected individuals. The management comprises disease-modifying medications, symptomatic cure, and rehabilitation. The focus of research in MS is to understand its immunopathology, to identify new targets, and develop precision therapies to treat MS.
Written by: Manasa Devi, M.D.S. & Lawrence D. Jones, Ph.D.