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). This redistribution ultimately allows continuous propagation of nerve action potentials through the demyelinated segment. Conduction block may be incomplete, affecting high- but not low-frequency volleys of impulses. Variable conduction block can occur with raised body temperature or metabolic alterations and may explain clinical fluctuations that vary from hour to hour or appear with fever or exercise. Conduction slowing occurs when the demyelinated segments of the axonal membrane is reorganized to support continuous (slow) nerve impulse propagation.
Nerve conduction in myelinated and demyelinated axons. A. Saltatory nerve conduction in myelinated axons occurs with the nerve impulse jumping from one node of Ranvier to the next. Sodium channels (shown as breaks in the solid black line) are concentrated at the nodes where axonal depolarization occurs. B. Following demyelination, additional sodium channels are redistributed along the axon itself, thereby allowing continuous propagation of the nerve action potential despite the absence of myelin.
MS is approximately threefold more common in women than men. The age of onset is typically between 20 and 40 years (slightly later in men than in women), but the disease can present across the life span. In ˜10% of cases it begins before age 18 years and a in a small percentage it begins before the age of 10 years.
Geographic gradients have been repeatedly observed in MS, with the highest known prevalence for MS (250 per 100,000) in the Orkney Islands, located north of Scotland. In other temperate zone areas (e.g., northern North America, northern Europe, southern Australia, and south New Zealand), the prevalence of MS is 0.1–0.2%. By contrast, in the tropics (e.g., Asia, equatorial Africa, and the Middle East), the prevalence is often ten- to twentyfold less.
One proposed explanation for the latitude effect on MS is that there is a protective effect of sun exposure. Exposure of the skin to ultraviolet-B (UVB) radiation from the sun is essential for the biosynthesis of vitamin D, and this endogenous production is the most important source of vitamin D in most individuals. At high latitudes, the amount of UVB radiation reaching the earth's surface is often insufficient, particularly during winter months, and, consequently, low serum levels of vitamin D are common in temperate zones. Prospective studies have confirmed that vitamin D deficiency is associated with an increase in MS risk and preliminary data also suggest that ongoing deficiency may increase the relapse rate in established MS. Immunoregulatory effects of vitamin D could explain this apparent relationship.
At least three sequential (population-wide) environmental events are implicated in the causal pathway leading to MS. The first factor seems to occur either in utero or in the early postnatal period and is supported, in part, by the almost twofold increase in MS risk for dizygotic ...