Pathophysiology
Summary
Multiple sclerosis (MS) is the most prevalent CNS demyelinating disorder, resulting from autoimmune destruction of oligodendrocytes—the glial cells that forge myelin sheaths in the CNS.
MS predominantly affects women in their early adulthood (ages 20s-30s). Genetic predisposition, particularly the HLA-DR2 genotype, and viral infections increase susceptibility. Notably, MS incidence rises further from the equator. At its core, the pathogenesis involves autoreactive helper T-cells reacting improperly to myelin antigens, leading to the release of inflammatory cytokines.
MS is typified by the creation of ‘active plaques’, which are localized inflammatory sites in the white matter of the brain or spinal cord. These plaques, rich in CD8+ cytotoxic T-cells and macrophages engulfing myelin debris, undergo ‘active gliosis’ due to the surrounding proliferating astrocytes responding to nerve tissue injury. Although most neuronal axons within these plaques remain unharmed, some are injured. Over time, these acute active plaques transition to a chronic inactive state, characterized by complete demyelination, macrophage disappearance, loss of axons and oligodendrocytes, an a glial scar filled in by astrocytes. Though these plaques can manifest anywhere in the CNS, their frequent appearance is near the ventricles.
Clinically, MS is marked by neurologic manifestations not attributable to a single lesion and commonly follows a relapsing-remitting trajectory. Common symptoms include fatigue, especially in hot environments,, and ocular disturbances such as optic neuritis. Optic neuritis presents with unilateral eye pain, vision loss (central scotoma), and a relative afferent pupillary defect. Another ocular manifestation is internuclear ophthalmoplegia, a disorder in which damage to the medial longitudinal fasciculus interrupts results in the inability of one eye to turn adduct while the other eye abducts during horizontal gaze.
MS also exhibits sensory symptoms such as hyperreflexia, muscle spasticity, Lhermitte sign, bowel & bladder dysfunction, cerebellar symptoms (e.g. intention tremors), and a unique ‘scanning speech’.
Diagnosis of MS involves MRI, which reveals areas of demyelinated plaques, particularly near the ventricles. Lumbar puncture is also used to collect CSF, which can show oligoclonal bands representing IgG antibodies, indicating autoimmunity.
Lesson Outline
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FAQs
Oligodendrocytes, a type of glial cell in the central nervous system (CNS), play a critical role in multiple sclerosis (MS). These cells have cellular projections that apply myelin sheaths around axons in the CNS. In MS, which is caused by autoimmune destruction of oligodendrocytes, demyelination occurs. This means the myelin sheaths that protect nerve cells are damaged, which interrupts the transmission of nerve impulses and can lead to a multitude of sensory and motor issues.
Individuals with the HLA-DR2 genotype appear to have an increased susceptibility to multiple sclerosis (MS). The HLA-DR2 genotype is associated with a particular immune response that is more likely to mistakenly target one's own body's cells. In MS, this immune response becomes directed at oligodendrocytes, contributing to the demyelination characteristic of the disease.
Multiple sclerosis (MS) can present in numerous ways, often displaying symptoms associated with the region of the brain or spinal cord affected by demyelination. Common presentations can include optic neuritis, internuclear ophthalmoplegia, sensory symptoms, muscle spasticity, Lhermitte sign, bowel & bladder dysfunction, tremors, and changes in speech known as ‘scanning speech’. MS also frequently presents with a fatigue that is particularly exacerbated by heat.
Diagnosis of multiple sclerosis (MS) typically involves a combination of clinical presentations, MRI findings, and lumbar puncture results. On MRI, areas of demyelination known as plaques are often visible, particularly near the ventricles. Lumbar puncture followed by protein electrophoresis of CSF can reveal oligoclonal bands representing IgG antibodies, indicating the immune activity against the body's own cells that is characteristic of MS.
Active and chronic inactive plaques in multiple sclerosis (MS) have distinct pathological characteristics. Active plaques contain abundant CD8+ cytotoxic T cells, and are surrounded by proliferating astrocytes, known as ‘active gliosis.’ In an active plaque, a small proportion of neuronal axons may be lost, although the majority remain uninjured. Acute active plaques eventually progress to a chronic inactive phase, where the acute inflammation has subsided axons. Chronic inactive plaques are completely demyelinated, no longer contain macrophages, and astrocytes have filled the lesion with a glial scar.
