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, 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 an autoimmune disease of the CNS characterized by chronic inflammation, demyelination, gliosis (scarring), and neuronal loss; the course can be relapsing-remitting or progressive. Lesions of MS typically develop at different times and in different CNS locations (i.e., MS is said to be disseminated in time and space). Approximately 350,000 individuals in the United States and 2.5 million individuals worldwide are affected. The clinical course can be extremely variable, ranging from a benign condition 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, myelin-specific autoantibodies are present on degenerating myelin sheaths, and complement is activated. Demyelination is the hallmark of the pathology, and evidence of myelin degeneration is found at the earliest time points of tissue injury. A remarkable feature of MS plaques is that oligodendrocyte precursor cells survive—and in many lesions are present in even greater numbers than in normal tissue—but these cells fail to differentiate into mature myelin-producing cells. In some lesions, surviving oligodendrocytes or those that differentiate from precursor cells partially remyelinate the surviving naked axons, producing so-called shadow plaques. As lesions evolve, there is prominent astrocytic proliferation (gliosis). Over time, ectopic lymphocyte follicle-like structures, consisting of aggregates of T and B cells resembling secondary lymphoid tissue, appear in the meninges and especially overlying deep cortical sulci and also in perivascular spaces. 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, demyelination, and plaque formation are also present in the cerebral cortex, and significant axon loss indicating death of neurons is widespread, especially 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. 45-1). This ...