Multiple Sclerosis

Introduction and Facts

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) that causes damage to myelin. It is estimated that there were around 2.2 million cases of MS worldwide in 2016, an increase of 10.4% higher than in 1990. The prevalence of MS is increasing in areas further away from the equator, while Asia has low MS frequency, about 30 cases per 100,000 population.

Pathophysiology

Based on the pathophysiology of MS, it is known that the pathological characteristics of MS are the presence of plaques resulting from demyelination, neuronal and axonal degradation, and astrocyte scarring. In someone with a genetic susceptibility to MS, there will be a cross-reaction between environmental antigens and myelin and/or oligodendrocyte components or myelin proteins such as S-100 protein, phosphodiesterase, etc. This triggers the sensitization of T lymphocytes so that they are autoreactive to myelin and oligodendrocytes that have undergone cross-reaction. If an antigen (which cross-reacts with myelin) enters the body, macrophages will phagocytose that antigen. Antigen-presenting cells (APCs) such as dendritic cells present these antigens or antigen proteins by forming a complex between the antigen and the major histocompatibility complex (MHC) on the cell surface. Receptors will recognize the antigen complex with MHC on the surface of CD4 T-lymphocytes. As a result, these cells will be activated and differentiated into T helper-1 (Th-1) cells. Th-1 will trigger proinflammatory cytokines, which will activate receptors for endothelial adhesion molecules in blood vessels of the blood-brain barrier. As a result, the blood-brain barrier becomes more easily traversed by T . cells

After crossing the blood-brain barrier, Th-1 will undergo reactivation by APC, while the antigen brought by APC this time is myelin protein. Reactivation will trigger proinflammatory cytokines, nitric oxide, antibodies, complement, as well as molecules that mediate apoptosis. Proinflammatory cytokines will also stimulate microglia and astrocytes so that the permeability of the blood-brain barrier increases. Chemotactic molecules that facilitate the entry of T cells, antibodies, and macrophages are also stimulated. The immune cascade will result in edema, demyelination, and the death of axons.

In chronic demyelination, microglia will be activated, which results in the formation of oxidative stress. This will trigger axon mitochondrial and oligodendrocyte damage. In addition, microglia activation will also affect glutamate transport in astrocytes, resulting in neuronal and oligodendrocyte excitotoxicity. The accumulation of lesions in progressive MS is associated with retrograde and anterograde degeneration of demyelinated axons. This occurs due to abnormal axon excitability and amplification of microglia activation.

The most relevant characteristic of progressive phase immunopathology is the presence of unusual demyelination characterized by slowly expanding plaques and foamy macrophages containing fat, particularly in areas of white matter.

Clinical Symptoms and Complications

Clinical symptoms of MS patients are generally noted by doctors only when the patient is on treatment, and sometimes patients do not routinely check with the doctor. The progress of the patient's symptoms can depend on the doctor's assessment using the calculation of the disability score. Initiating a change in MS treatment early in the progression of events can be one of the factors that influence the patient's prognosis.

MS patients will experience periods of relapse-remission early in the course of the disease. Still, some will progress to a progressively worse stage, commonly referred to as secondary progressive multiple sclerosis (SPMS).

Patients with relapsing-remitting multiple sclerosis (RRMS) will develop SPMS within ten years in 25% of patients, 20 years in 50% of patients, and 30 years in more than 75% of patients. The majority of patients will experience conversion to SPMS by the age of 40 years.

Diagnosis

Based on the consensus established by the international expert association, SPMS is defined as a disease that initially takes the form of RRMS followed by progression with or without relapse, minor remission, and plateau. SPMS was also defined as the occurrence of disability progression with an increase in the EDSS value of 1 in patients with EDSS 5.5 or an increase of 0.5 in patients with EDSS 6 without any relapse, a minimum EDSS value of 4 and a functional score (FS) in the pyramidal section of 2, and confirmed progress within 3 months. The accuracy of this definition is 87% compared to the consensus-based diagnosis of SPMS.

The features of head MRI imaging in SPMS show more hyperintense lesions on T2 than in patients with RRMS, and focal spinal cord lesions are seen more in SPMS. However, from several studies that have been conducted, this does not always correlate with patient disability. The number of contrast-enhanced lesions tends to decrease in patients with RRMS who enter the progressive phase because contrast-enhanced lesions exhibit the inflammatory activity of this disease. The number of high-contrast lesions at baseline was a significant predictor of lesion activity on subsequent MRI but only predicted clinical evolution at the initial two years.

Management and Treatment

Treatment options for SPMS are limited, but unlike primary progressive multiple sclerosis (PPMS), there is still an opportunity to provide therapy in the relapse phase with ongoing inflammation. In several studies regarding the administration of interferon beta 1b (IFNB) that has been carried out, it has been proven that IFNB can reduce the number of relapse rates and the number of T2 lesions. Still, IFNB administration is not recommended in SPMS patients. When it has entered the progressive phase, the anti-inflammatory effect of IFNB cannot slow down the rate of progress.

According to a review from Cochrane, glatiramer acetate can be administered to patients with RRMS who progress to SPMS early on. However, the supporting evidence is still lacking. Mitoxantrone is the only drug approved by the U.S. Food and Drug Administration (FDA) for worsening SPMS, PRMS, and RRMS. Methotrexate (MTX) is an immunosuppressive agent used in various rheumatological diseases with limited side effects and low cost. Cyclophosphamide (CPP) showed more effective results in stabilizing disease activity than intravenous methylprednisolone in treating SPMS, but with a standard drug tolerance profile. While azathioprine (AZA), which is quite widely used in RRMS patients in Indonesia, has limited evidence for use in patients with SPMS. CD20 monoclonal antibody is said to be used as a therapy for progressive MS because of its ability to reduce peripheral B cells, which indirectly affects the B cell population in the central nervous system.

References: 

Devianca N, Maharani K, Imran D, Estiasari R. Secondary progressive multiple sclerosis, clinical diagnosis and management. Neurona 2020;37(3):202-8.