Demyelinating disorders are immune-mediated conditions characterized by preferential destruction of central nervous system (CNS) myelin. The peripheral nervous system (PNS) is spared, and most patients have no evidence of an associated systemic illness. Multiple sclerosis (MS), the most common disease in this category, is second only to trauma as a cause of neurologic disability beginning in early to middle adulthood.
Multiple sclerosis (MS) is a chronic disease characterized by inflammation, demyelination, gliosis (scarring), and neuronal loss; the course can be relapsing-remitting or progressive. Lesions of MS typically occur at different times and in different CNS locations (i.e., disseminated in time and space). MS affects ˜350,000 individuals in the United States and 2.5 million individuals worldwide. Manifestations of MS vary from a benign illness to a rapidly evolving and incapacitating disease requiring profound lifestyle adjustments.
New MS lesions begin with perivenular cuffing by inflammatory mononuclear cells, predominantly T cells and macrophages, which also infiltrate the surrounding white matter. At sites of inflammation, the blood-brain barrier (BBB) is disrupted, but unlike vasculitis, the vessel wall is preserved. Involvement of the humoral immune system is also evident; small numbers of B lymphocytes also infiltrate the nervous system, and myelin-specific autoantibodies are present on degenerating myelin sheaths. As lesions evolve, there is prominent astrocytic proliferation (gliosis). Surviving oligodendrocytes or those that differentiate from precursor cells can partially remyelinate the surviving naked axons, producing so-called shadow plaques. In many lesions, oligodendrocyte precursor cells are present in large numbers but fail to differentiate and remyelinate. Over time, ectopic lymphocyte follicles appear in perivascular and perimeningeal regions, consisting of aggregates of T and B cells and resembling secondary lymphoid structures. Although relative sparing of axons is typical of MS, partial or total axonal destruction can also occur, especially within highly inflammatory lesions. Thus, MS is not solely a disease of myelin, and neuronal pathology is increasingly recognized as a major contributor to irreversible neurologic disability. Inflammation and plaque formation are present in the cerebral cortex, and significant axon loss indicating death of neurons is widespread, specially in advanced cases (see “Neurodegeneration,” below).
Nerve conduction in myelinated axons occurs in a saltatory manner, with the nerve impulse jumping from one node of Ranvier to the next without depolarization of the axonal membrane underlying the myelin sheath between nodes (Fig. 380-1). This produces considerably faster conduction velocities (˜70 m/s) than the slow velocities (˜1 m/s) produced by continuous propagation in unmyelinated nerves. Conduction block occurs when the nerve impulse is unable to traverse the demyelinated segment. This can happen when the resting axon membrane becomes hyperpolarized due to the exposure of voltage-dependent potassium channels that are normally buried underneath the myelin sheath. A temporary conduction block often follows a demyelinating event before sodium channels (originally concentrated at the nodes) redistribute along the naked axon (Fig. 380-1). ...